This document summarizes the major complications of modern oncology treatments, integrating information from chemotherapy, radiotherapy, immunotherapy (ICI), and targeted therapies (TKI). Each complication is presented with symptoms, therapeutic options, and prophylactic measures based on current clinical evidence (as of July 2025).

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We have corrected the text in the z.docx file , in terms of grammar, spelling and medical terminology, preserving the structure and clinical meaning of the material. Note: we have corrected the formulations and terms of evidence; for strict validation of therapeutic doses/protocols, verification according to local oncology guidelines is necessary.

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I. HEMATOLOGICAL COMPLICATIONS

1. Neutropenia/leukopenia

Symptoms
Fever ≥ 38°C, chills, recurrent infections, asthenia; in severe neutropenia — ANC < 500/mm³ — there is a risk of potentially fatal sepsis.

Mechanisms
Chemotherapy: direct myelosuppression; immunotherapy: lower risk; radiotherapy: bone marrow damage at high doses.

Treatment grade 1–2
Clinical observation; nutritional support; granulocyte-clotting factors — G-CSF — as needed.

Grade 3–4 treatment
G-CSF: filgrastim 5 µg/kg/day subcutaneously or pegfilgrastim 6 mg subcutaneously, once per cycle. Broad-spectrum intravenous antibiotics in febrile neutropenia: piperacillin-tazobactam 4.5 g IV every 4–6 hours or carbapenem, e.g. meropenem 1 g IV every 8 hours. Antifungals — fluconazole or amphotericin B — if fever persists > 72–96 hours. Strict protective isolation.

prophylaxis
in high-risk cycles, for example in intensive chemotherapy. Prophylactic oral fluoroquinolones — ciprofloxacin 500 mg twice daily — in high-risk cycles. Prophylactic antifungals — fluconazole 400 mg/day — in very high-risk patients. Rigorous hygiene; pneumococcal, influenza and COVID-19 vaccination; avoidance of contact with sick people; avoidance of raw fruits and vegetables, as well as foods with high infectious risk.

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2. Thrombocytopenia

Symptoms
Petechiae, purpura, ecchymoses, epistaxis, microscopic or macroscopic hematuria, rectal bleeding, gingival bleeding, hemoptysis. Platelets < 10,000/mm³ → major bleeding risk, potentially fatal.

Mechanisms
Chemotherapy: myelosuppression, dependent on the dose and the agent used. Radiotherapy: less common, especially at high bone marrow doses.

Risk stratification
Grade 1: 75,000–150,000/mm³. Grade 2: 50,000–75,000/mm³. Grade 3: 10,000–50,000/mm³. Grade 4: < 10,000/mm³.

Treatment grade 1–2
Monitoring; avoiding mechanical trauma; avoiding NSAIDs and antiplatelet agents.

Treatment grade 3
Platelet transfusions: 1 unit of platelet concentrate per 10 kg body weight or 6 units if an adequate increase has not been previously achieved. Prophylactic transfusion at a threshold < 10,000/mm³, in the presence of symptoms or before invasive procedures. Therapeutic transfusion in case of active bleeding.

Treatment grade 4
Frequent transfusions, sometimes daily in the context of bone marrow transplantation; in case of alloimmunization, HLA-compatible platelet concentrates can be used. Thrombopoietin receptor agonists — romiplostim, eltrombopag — in chronic thrombocytopenia. Corticosteroids, e.g. methylprednisolone in pulses. In refractory cases: intravenous immunoglobulins — IVIG 1 g/kg — or anti-D in Rh-positive patients.

Prophylaxis
Monitoring of the blood count at each cycle; avoiding antiplatelet drugs — NSAIDs, aspirin; educating the patient to recognize signs of bleeding; limiting transfusions to the strictest necessary, due to the risk of sensitization.

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3. Anemia

Symptoms
Pallor, marked asthenia, dyspnea on exertion, tachycardia, palpitations, vertigo, lipothymia. Hb < 7 g/dL → severe anemia, with life-threatening risk. Hb < 6.5 g/dL → increased cardio-cerebral risk.

Etiology
Chemotherapy: myelosuppression. Blood loss, including from hemorrhagic tumors. Hemolysis induced by chemotherapeutic agents. Ifosfamide: hematuria.
Mitomycin C: microangiopathy.
Iron, vitamin B12 or folic acid deficiency.

Treatment grade 1–2
Nutritional support; iron supplements — ferrous sulfate 325 mg/day — and folic acid 5 mg/day, if deficiency exists; clinical observation.

Treatment grade 3–4
Packed red blood cell transfusions: 1 unit, approximately 275 mL, increases Hb by approximately 1 g/dL. Restrictive transfusion target: Hb 7–8 g/dL. Erythropoiesis-stimulating agents: epoetin alfa/beta 40,000 IU subcutaneously weekly or darbepoetin alfa 200–300 µg subcutaneously every 2–3 weeks. Indication: Hb 8–10 g/dL in patients undergoing chemotherapy; not routinely recommended in immunotherapy due to risk of tumor progression. Intravenous iron supplementation in case of deficiency: ferric carboxymaltose 750 mg IV.

Prophylaxis
Periodic monitoring of Hb at each cycle; prophylactic iron supplementation in patients at risk — chronic bleeding, reduced absorption; limiting myelosuppressive doses when possible. Priority is to identify and treat the cause of anemia, not just symptomatic treatment. Restrictive transfusion to avoid iron overload.

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4. Febrile neutropenia

Symptoms
Temperature > 38°C once or ≥ 38.5°C for one hour, associated with ANC < 500/mm³. Chills, hypotension, tachycardia, tachypnea. Signs of infectious focus: cough and pulmonary rales/crepitations in pneumonia, dysuria in urinary tract infection, pharyngeal pain in pharyngitis, cellulitis, diarrhea in colitis.

Risk
5–10% if untreated. Sepsis in 10–25% of cases. Bacteremia documented in 20–30% of cases.

Mechanisms
Chemotherapy — most common cause; immunotherapy — rare; massive radiotherapy.

Emergency evaluation
Blood cultures × 2 before administering antibiotics. Blood cultures from the central venous catheter, if present. Chest radiography. Urine collection and urine culture. If there are abdominal symptoms: abdominal CT with contrast medium. In case of suspected CNS involvement: CSF examination, culture and viral PCR.

Emergency treatment
Immediate hospitalization. Broad-spectrum intravenous antibiotics within the first hour, without waiting for culture results: piperacillin-tazobactam 4.5 g IV every 4–6 hours or carbapenem, e.g. meropenem 1 g IV every 8 hours. Fluoroquinolone monotherapy is not recommended.
In case of allergy to beta-lactams: fluoroquinolone — ciprofloxacin 400 mg IV every 8–12 hours — plus vancomycin, according to clinical assessment.
Antifungals, e.g. fluconazole 400 mg/day IV, if fever persists > 72–96 hours without response. Hemodynamic support: administration of IV fluids, crystalloids/colloids, vasopressors in case of shock. G-CSF — e.g. pegfilgrastim 6 mg SC — to accelerate neutrophil recovery. Oxygen therapy and continuous monitoring.

Continued therapy
After clinical stabilization and obtaining culture results, oral therapy, for example with fluoroquinolones, can be initiated at home if the patient is stable and has rapid access to medical services.

prophylaxis
: pegfilgrastim 6 mg SC on day 2–3 post-chemotherapy or filgrastim 5 µg/kg/day SC for 5–7 days, in cycles with ≥ 20% risk. Prophylactic oral fluoroquinolones: levofloxacin 500 mg/day or ciprofloxacin 500 mg twice daily, in high-risk regimens — acute leukemias, lymphoma, allogeneic bone marrow transplantation. Prophylactic antifungals — fluconazole 400 mg/day — in patients with bone marrow transplantation, GVHD, MDS or severe immunosuppression. Vaccination: antipneumococcal — preferably PCV20 — annual influenza, anti-COVID-19 and anti-hepatitis B, ideally before starting treatment. Rigorous oral and skin hygiene; avoidance of foods with infectious risk — raw foods, soft cheeses; avoidance of unnecessary exposures; avoiding central venous catheters when possible.

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II. CUTANEOUS COMPLICATIONS

1. Chemotherapy-induced alopecia

Symptoms
Hair loss usually occurs 1–2 weeks after chemotherapy. The frequency varies depending on the agent: 80–90% for anthracyclines and taxanes; 20–30% for 5-FU. Initially, it may be partial, with hairs seen on the pillow, but may become progressively total. It affects the scalp, eyebrows, eyelashes, nasal, axillary, pubic, and body hair.

Mechanisms
Chemotherapy destroys follicular matrix cells in the anagen phase. Immunotherapy rarely causes alopecia. Radiotherapy causes alopecia only in the irradiated area.

Duration
Alopecia is usually reversible within 3–6 months after completion of treatment. Permanent alopecia may occur in 5–10% of patients, more commonly after high cumulative doses of taxanes, especially docetaxel.

Psychological impact
Approximately 50–60% of patients report major psychological impact. In some patients, alopecia may be an important reason for hesitation or withdrawal from treatment.

Grade 1–2 treatment
Psychological counseling; emotional support; wigs, turbans, headscarves, hats, scarves and other accessories.

Grade 3–4 Treatment
Topical minoxidil 5%, applied to dry scalp, 1 mL twice daily; may stimulate hair regrowth, with variable effect. Topical JAK inhibitors—e.g., baricitinib 2% foam—with ongoing data for chemotherapy-induced alopecia. PRP—platelet-rich plasma—possibly associated with exosomes, with promising preliminary results. Low-level laser photobiomodulation—LLLT, 650–670 nm—2–3 times/week. Intralesional corticosteroids—triamcinolone 10 mg/mL—rarely used in chemotherapy-induced alopecia. Hair transplant or hair restoration procedures after hair regrowth. Dermal micrografts with autologous follicles—experimental method. Patient education regarding impact on quality of life is essential.

Prophylaxis — scalp cooling / cold cap
Mechanism: Scalp vasoconstriction reduces blood flow and follicle exposure to chemotherapeutics; lowering scalp temperature to 15–20°C reduces cellular metabolism. May reduce the incidence of alopecia from approximately 90% to 40–50%, depending on agent and protocol.

Technique
An ice cap or refrigerated system, such as DigniCap or Paxman, is used. It is applied 15 minutes before the infusion, maintained during the infusion, and continued for 15–30 minutes after administration. Tolerance is limited by discomfort, scalp irritation, and headache.

Agents with better efficacy for cold cap
Taxanes — paclitaxel, docetaxel — 50–70% efficacy. Doxorubicin — moderate efficacy. 5-FU — low efficacy. Not routinely recommended in hematological malignancies, due to theoretical risk of scalp involvement/metastasis; decision should be individualized.

Adverse effects
Discomfort, nausea, vertigo; rarely, post-cold headache.

Alternative prophylaxis
For onycholysis and nail fragility: avoidance of aggressive pedicures; topical antifungal treatment if fungal infection is suspected; biotin 2.5 mg/day in patients with nail fragility.

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2. Hand-foot syndrome

Palmar-plantar erythrodysaesthesia — PPE

Clinical symptoms
Grade 1: erythema, distal edema of the palms and soles, paresthesias, subtle burning sensation, sensitivity to touch. Grade 2: pronounced erythema, more pronounced edema, incipient blisters, moderate pain, difficulty walking or grasping. Grade 3–4: erosions, desquamation, ulcerations, subepidermal hemorrhage, fissures, functional inability.

Distribution
Palms, soles, lateral edges of fingers, plantar surface. Rare: nasal, oral or genital areas.

Mechanisms
Chemotherapy: cutaneous accumulation and direct toxicity. Agents frequently involved: capecitabine, 5-FU, liposomal doxorubicin, taxanes, paclitaxel. TKI: sorafenib, sunitinib — by inhibiting VEGFR. Radiotherapy may amplify toxicity in the irradiated area.

Timeline
Onset: 2–3 weeks after administration. Peak: 4–6 weeks. Resolution: 2–4 weeks after stopping treatment for grades 1–2; grades 3–4 may last 1–3 months.

CTCAE v5.0 stratification
Grade 1: erythema, edema, paresthesia, no functional impact. Grade 2: erythema with blisters, edema, moderate pain, mild functional impact. Grade 3: ulcerations, severe edema, severe pain, major impact on daily activities. Grade 4: necrosis, extensive ulcerations, total functional inability.

Grade 1 treatment
Protective emollients — CeraVe, Eucerin, Cetaphil — applied every 12 hours. Cream with 10–20% urea, with moisturizing and keratolytic effect. Avoidance of mechanical trauma: comfortable footwear, avoidance of intense exercise. Avoidance of hot water and sun exposure.

Grade 2 treatment
Clobetasol 0.05% cream or ointment, applied to lesions, possibly under occlusion 4–6 hours/day. Celecoxib 200 mg twice daily, if there are no contraindications. Reduction of chemotherapy dose by 20–25% or postponement/extension of the interval between cycles. Antihistamine — loratadine 10 mg/day — if there is pruritus. Gabapentin 300–900 mg three times daily for painful paresthesias.

Treatment grade 3–4
Discontinue chemotherapy in current cycle; resume at reduced dose after resolution. Pain management: paracetamol 1 g four times daily, tramadol 50–100 mg two–three times daily, or opioids for severe pain. Antibiotics—e.g., cephalexin 500 mg four times daily—if secondary infection is suspected. Advanced dressings: hydrocolloids, foam, alginate. Partial immobilization, limb elevation, orthopedic footwear. Avoidance of traumatic pedicures. Nutritional support, especially adequate protein intake, if malnutrition is present. Psychological counseling for pain adaptation and functional limitation. In refractory cases: off-label thalidomide, with close monitoring.

Prophylaxis
Emollients with 20–40% urea applied daily from the first cycle of chemotherapy — the most important primary prophylaxis. Avoidance of mechanical trauma: suitable shoes, cotton socks, avoidance of running and jumping. Reduction of physical activity on chemotherapy days and the following days. Local cooling during 5-FU infusion: immersion in cold water at 4–15°C before, during and after infusion. Celecoxib 200 mg twice daily prophylactically in very high-risk patients, if there are no contraindications. Avoidance of hot water and SPF 50+ sunscreen.

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3. Chemotherapy-induced hyperpigmentation

Clinical symptoms
Diffuse hyperpigmentation, more common in patients with dark skin. Localized hyperpigmentation on Blaschko lines or in folds. “Flagellate” pigmentation, characteristic of bleomycin, with pigmented lines on the trunk. Melanonychia: longitudinal black bands on the nails, associated with bleomycin or busulfan. Mucosal hyperpigmentation on the gums or tongue. Pigmentation on scars, possibly associated with cyclophosphamide.

Onset and course
Onset 1–3 months after treatment. May persist indefinitely; in some cases resolves slowly over months or years.

Agents involved
Bleomycin, busulfan, doxorubicin, paclitaxel, 5-FU, cyclophosphamide, procarbazine, ifosfamide. Tyrosine kinase inhibitors may be involved rarely.

Mechanism
Stimulation of melanocytes by inflammatory mediators, including TNF-α and IL-6; melanin deposition; cytotoxicity with stimulation of melanogenesis; possible involvement of a cytokine cascade, including TGF-β and IL-1.

treatment
: SPF 50+ with UVA/UVB protection, applied 15 minutes before exposure and reapplied every 2 hours; avoiding exposure between 10 am and 4 pm. Hydroquinone 4% cream + tretinoin 0.025% + weak corticosteroid — hydrocortisone 1% or desonide 0.05% — Kligman-type formula, daily for 4–12 weeks. Oral tranexamic acid 500 mg twice daily, 3–6 months, with limited evidence in chemotherapy-induced hyperpigmentation. Topical tranexamic acid 3–5%. Cysteamine 5% cream — preliminary data. Q-switched Nd:YAG 1064 nm laser or alexandrite laser, with risk of post-inflammatory hypopigmentation. Chemical peeling with glycolic acid or salicylic acid, with risk of irritation. Depigmentation with monobenzone 20% only as a last resort in diffuse cases, due to risk of vitiligo.

Prophylaxis
Rigorous photoprotection SPF 50+ during treatment and for 6–12 months after treatment. Oral tranexamic acid 500 mg twice daily prophylactically in bleomycin or busulfan regimens, if indicated. Niacinamide 5% + N-acetylcysteine 5% topical — preliminary data. Avoidance of intense sun exposure and skin trauma. Avoidance, as much as possible, of sun exposure in the days immediately following infusion.

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4. Radiation dermatitis

Clinical symptoms
Grade 1: subtle erythema, mild edema, mild pruritus, no functional impact. Grade 2: moderate erythema, obvious edema, dry scaling, moderate pruritus, possible local pain. Grade 3: wet scaling, erosions, ulcerations, intense pain, severe pruritus, major psychosocial impact. Grade 4: necrosis, deep ulcerations that do not heal, complete functional impairment, need for intensive medical care.

Chronology
Onset 1–2 weeks after initiation of treatment. Gradual progression until the end of radiotherapy. Peak 1–2 weeks post-radiotherapy. Resolution grade 1–2: 2–4 weeks. Grade 3–4: healing in months or permanent sequelae.

Risk factors
Dose/fraction > 2 Gy, cumulative dose > 60–70 Gy, large irradiated volume. Individual factors: dark skin, obesity with moist skin folds, diabetes, immunosuppression, advanced age, smoking. Thoracic location may increase the risk through sweating and friction.

Treatment grade 1–2
Skin care with gentle washing; avoid rubbing. Warm water, below 37°C. Moisturize immediately after washing. Emollients — CeraVe, Eucerin, Aquaphor — applied 2–3 times/day; avoid highly occlusive ointments if they cause maceration. Weak or moderate topical corticosteroids — hydrocortisone 1%, triamcinolone 0.1% — with avoidance of prolonged use of potent steroids. Oral antihistamines — loratadine 10 mg/day or cetirizine 10 mg/day — for pruritus. Avoid hot water, aggressive washing, friction, perfumes, alcohol, topical NSAIDs, and irritating products.

Optimal prophylaxis grade 1–2
Proactive application of silicone films, e.g. Mepitel Film, from the first radiotherapy session. Mometasone furoate 0.1% topical prophylactic, applied daily. Olive oil twice daily on irradiated areas, if tolerated. Avoidance of direct sun exposure. Loose, cotton clothing; avoidance of synthetic materials that promote moisture and friction. Low-level laser photobiomodulation — LLLT — 2–3 times/week, where available. Washing with lukewarm water, maximum 5 minutes. Avoidance of standard cosmetics with potential irritation. Anti-friction protection in fold areas — axilla, inguinal folds. Adequate oral hydration.

Grade 3 treatment — wet desquamation, erosions
Hydrocolloid dressings — Duoderm, Aquacel — to maintain a moist environment and absorb exudate. Foam dressings — Mepilex, Allevyn — for increased absorption and comfort. Alginate dressings for heavy exudate. Silicone dressings — Mepitel, Tegaderm — to reduce friction. Silver sulfadiazine 1% ointment, applied 1–2 times/day, to prevent infection and facilitate epithelialization. Systemic antibiotics — cephalexin 500 mg four times a day or doxycycline 100 mg twice a day — if secondary infection is suspected. Gabapentin 300–600 mg three times a day for neuropathic pain. Potent topical corticosteroids — clobetasol 0.05% — maximum 2–4 weeks, with caution due to the risk of skin atrophy. Postponement radiotherapy 3–7 days, if clinically possible. Elevation of the affected area, if it is a limb. If there is pus, secretions or a fetid odor: culture collection and appropriate antibiotic therapy. Nutritional support: increased intake of protein, vitamin C and zinc to support healing.

Grade 4 treatment — necrosis, deep ulceration
Surgical debridement of necrotic tissue. Autologous skin grafts, if necessary for extensive ulceration. Hyperbaric oxygen therapy — 2.0–2.5 atm, 90–120 minutes/session, 20–40 sessions — in selected cases of cutaneous radionecrosis. IV antibiotics, cultures, and drainage if collections are present. Hemodynamic support, albumin, transfusions if bleeding is present. Opioid analgesia, if necessary. Reconstructive surgery consultation.

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5. Rash/dermatitis induced by radiotherapy, chemotherapy or immunotherapy

Symptoms
Macular or papular rashes, initially isolated, then confluent and possibly generalized. Erythema, desquamation, moderate–severe pruritus. In severe forms: exfoliative dermatitis, generalized desquamation, ulcerative dermatitis with ulcerations on an erythematous base.

Chemotherapeutic agents involved
Taxanes — paclitaxel, docetaxel — where premedication is essential. EGFR inhibitors — erlotinib, gefitinib, cetuximab. Bleomycin, 5-FU. Immunotherapy — anti-PD-1, anti-CTLA-4 — can rarely cause severe skin reactions.

Immunotherapy agents
Anti-PD-1: pembrolizumab, nivolumab — rash 10–15%. Anti-CTLA-4: ipilimumab — rash 20–25%. Combination nivolumab + ipilimumab — rash 25–30%.

Chronology
Chemotherapy: onset 1–3 days after administration; taxanes: 1–5 days. Immunotherapy: onset variable, between 1 and 8 weeks. Evolution: progression within 24–48 hours if untreated.

Mechanisms
Chemotherapy: direct toxicity on keratinocytes, inflammation and hypersensitivity reactions. Immune checkpoint inhibitors — ICI: infiltration of T lymphocytes into the epidermis, immune activation and involvement of NK cells. Taxanes: hypersensitivity reactions, partially prevented by premedication.

CTCAE v5.0 stratification
Grade 1: localized rash, without symptoms. Grade 2: generalized rash, mild-moderate pruritus, without affecting daily activities. Grade 3: generalized rash, severe pruritus, functional impact, possible temporary interruption of treatment. Grade 4: severe generalized rash, ulcerations, pseudo-septic picture, possible hemolytic anemia — medical emergency.

Grade 1 treatment
Oral antihistamine: diphenhydramine 25–50 mg every 6 hours or loratadine 10 mg/day. Weak topical corticosteroid: hydrocortisone 1% or desonide 0.05%, applied twice daily. Emollients — CeraVe, Eucerin.
Avoidance of irritating soaps and hot water.
Patient education.

Grade 2 treatment
Oral antihistamine: diphenhydramine 25–50 mg every 6 hours or cetirizine 10 mg/day. Moderate–strong topical corticosteroid: triamcinolone 0.1%, applied 2–3 times/day. In severe pruritus: doxepin, if indicated and tolerated. Emollients and avoidance of irritants. Monitoring of progression.

Grade 3 treatment
Systemic corticosteroid: prednisone or prednisolone 0.5–1 mg/kg/day for 7–14 days, with progressive dose reduction. Oral antihistamine: diphenhydramine 25–50 mg four times a day. Gabapentin 300–900 mg three times a day for neuropathic pruritus. In severe cases: IV methylprednisolone in pulses, according to clinical assessment. Antibiotics if there is secondary infection — cephalexin 500 mg four times a day. In suspected DRESS — Drug Reaction with Eosinophilia and Systemic Symptoms — evaluate for systemic involvement, lymphadenopathy, hepatitis, and viral reactivations; treatment may include IV corticosteroids and, in selected cases, IVIG. Temporary interruption of oncological treatment until stabilization.

Grade 4 treatment — emergency
Hospitalization. IV corticosteroid: methylprednisolone 1–2 mg/kg/day. IV antihistamine. Broad-spectrum IV antibiotics, e.g. ceftriaxone and vancomycin, if infection or sepsis is suspected. Fluid and electrolyte support. Transfusions if hemolytic anemia is present. Dermatological and infectious disease consultation. Permanent discontinuation of the causative agent, especially in case of DRESS, Stevens-Johnson syndrome or toxic epidermal necrolysis — TEN.

Taxane
prophylaxis Mandatory premedication: dexamethasone, according to protocol — e.g. 8 mg IV before infusion, at the time of infusion and after infusion or oral regimen the previous day. Diphenhydramine 25–50 mg IV 30 minutes before. H2 antagonist or proton pump inhibitor, according to local protocol — e.g. famotidine/ranitidine or omeprazole. Monitor patient for the first 15 minutes for hypersensitivity reactions: chest pain, flushing, dyspnea. In case of reaction: immediate stop of infusion and administration of emergency medication.

Prophylaxis in immunotherapy
Careful clinical monitoring for rash in the first 2–3 cycles. Patient education for immediate reporting of any skin rash: location, distribution, type — macule, papule, pustule, vesicle — pruritus, pain, duration and triggers. Dermatological consultation for grade ≥ 2 rash or if systemic complications are suspected — DRESS, Stevens-Johnson syndrome. In combined ICI regimens — anti-PD-1 + anti-CTLA-4 — the risk of rash is higher. Avoidance of introduction of new topical agents with irritating potential during radiotherapy, chemotherapy or immunotherapy.

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III. NEUROLOGICAL COMPLICATIONS

1. Chemotherapy-induced peripheral neuropathy (CIPN)

Clinical symptoms

Paresthesias — tingling, numbness, sensation “as if the foot is asleep”, with “glove and stocking” distribution in the fingers and soles; loss of osteotendinous reflexes — Achilles, patellar; distal muscle weakness — inability to lift the toes off the ground, ankle instability; neuropathic pain — burning in the soles, sensations of electric shocks in the fingers, sensation of “hot water”; allodynia — pain on light touch; hyperesthesia — increased sensitivity; balance disorders → ataxia → falls, with a risk of 27–30%; risk of fractures in elderly patients.

Agents involved

Chemotherapy: taxanes — paclitaxel, docetaxel, with an incidence of 60–70%, dependent on the cumulative dose; platinum compounds — cisplatin, with an incidence of 60–90%, dependent on the cumulative dose; vinca alkaloids — vincristine, vinblastine; bleomycin; etoposide; bortezomib — proteasome inhibitor; thalidomide; lenalidomide; ixazomib.

Stratification according to CTCAE v5.0 — NCI

Grade 1: paresthetic sensations without functional impact.

Grade 2: paresthesias with mild functional impact — difficulty putting on boots, slightly difficult typing.

Grade 3: paresthesias with severe functional impact — inability to perform daily activities, recurrent falls, gait disturbances; constitutes a reason for discontinuation of chemotherapy.

Grade 4: paralysis, inability to walk — medical emergency.

Mechanism

Taxanes stabilize microtubules, disrupt neuronal cytoskeletal dynamics, damage mitochondria, and induce axonal apoptosis. Platinum compounds cause neuronal DNA damage and apoptosis. Vinca alkaloids inhibit microtubules. All of these agents can accumulate in peripheral nerves, producing chronic toxicity that is dependent on cumulative dose.

Risk factors

Cumulative dose — the main risk factor; advanced age, over 65 years; pre-existing neuropathy — diabetes, alcoholism, HIV infection; renal dysfunction — reduced elimination; poor nutritional status; hereditary neuropathy — Charcot-Marie-Tooth disease, with increased risk; genetic factors — CEP72, ABCB1, SLCO1B1 polymorphisms, which determine the metabolism of chemotherapeutics.

Initial and serial monitoring

Initial assessment: specific questions regarding paresthesias; sensory testing—10 g monofilament on the soles, loss of sensation predicting persistent neuropathy; reflexes—Achilles reflex as a landmark; muscle strength—antigravity muscles.

Validated scale: EORTC QLQ-CIPN20 — 20 questions, score 0–100, international standard.

Quantitative sensory testing — vibration/temperature, if available.

Pharmacogenetic testing — optional but useful

CEP72 — associated with the metabolism of platinum compounds and taxanes; polymorphisms are associated with increased risk of neuropathy.

ABCB1 — MDR1 transporter; variations may influence neuronal accumulation of chemotherapeutics.

Studies show limited utility in current practice, but testing may guide dose reduction in patients at high genetic risk.

Recommendation: may be considered in patients with pre-existing neuropathy or suggestive family history.

Treatment for grades 1–2 — prevention of progression

Duloxetine — SNRI, serotonin and norepinephrine reuptake inhibitor — first line.

Initial dose: 30 mg/day for one week, then 60 mg/day.

Efficacy: 50–60% of patients show significant reduction in paresthesia after 4–8 weeks.

Mechanism: inhibits monoamine reuptake in nociceptive pathways, reducing pain.

Contraindications: narrow-angle glaucoma, recent administration of MAOIs, severe liver failure.

Adverse effects: dry mouth — approximately 20%; initial nausea — 10–20%; drowsiness — approximately 10%; rarely, orthostatic hypotension.

Treatment for grades 3–4 — reducing symptoms and functional risk

Chemotherapy dose reduction: usually 20–25% dose reduction in the next cycle; may improve neuropathy if treatment is continued.

Extending the interval between cycles: an additional 1–2 week interval allows for partial nerve recovery.

Cessation of chemotherapy: in grade 4, chemotherapy is usually not resumed in the same regimen; switching to an alternative agent or monitoring during the recovery period is recommended.

More rarely, in irreversible cases, it may be necessary to stop oncological treatment.

Prophylaxis

Initial assessment: EORTC QLQ-CIPN20, sensory and motor neurological examination, recording of any pre-existing neuropathy.

2. Chemotherapy and immunotherapy-induced encephalopathy

Clinical forms

Acute — onset ≤7 days: confusion, disorientation, agitation, drowsiness, insomnia, headache; risk of seizures; in severe forms: coma, decerebrate posture.

Subacute — 1–4 weeks: cognitive disorders — memory, attention, concentration, processing speed; altered behavior, depressive state, anxiety.

Chronic — over 4 weeks: progressive cognitive decline, working memory impairment, slow speech.

Agents involved

Chemotherapy: ifosfamide — most common, with an incidence of 10–30%, especially at high doses; methotrexate — intrathecal or systemic in high doses; cisplatin in high doses; fludarabine; cyclophosphamide in high doses; 5-FU.

Immunotherapy: anti-PD-1 — rare, 0.1–0.5%; anti-CTLA-4 — rare; CAR-T — ICANS, immune effector cell-associated neurotoxicity syndrome, with an incidence of 40–50%, especially in pediatric patients.

Mechanism of ifosfamide-induced encephalopathy

Ifosfamide produces neurotoxic metabolites, such as chloroacetaldehyde and chloroethylamine, which affect the blood-brain barrier, cause direct neuronal toxicity, accumulate in the cerebrospinal fluid, and disrupt neurotransmission—low GABA, high glutamate.

The risk is increased in renal dysfunction — reduced elimination, dehydration, age over 50 years, and doses above 10–12 g/m².

Timeline of ifosfamide-induced encephalopathy

Onset: 24–72 hours post-infusion.

Peak: 48–72 hours.

Resolution: 3–7 days after stopping treatment, if intervention is initiated promptly.

Severity stratification

Grade 1: mild confusion, drowsiness.

Grade 2: moderate confusion, abnormal behavior.

Grade 3: severe confusion, hallucinations, seizures.

Grade 4: coma, decerebrate posture.

Grade 5: death.

ICANS diagnosis — CAR-T associated neurotoxicity

CARTOX score — CAR-T-associated Toxicity, 0–4: from grade 1 — attention deficit, anorexia — to grade 4 — coma, status epilepticus.

Imaging: Brain MRI, which may show diffuse or focal cerebral edema, FLAIR hyperintensity.

EEG: abnormalities such as slowing of brain activity or epileptiform activity.

CSF: lymphocytic pleocytosis, increased proteinuria; useful for ruling out infection.

Treatment of acute ifosfamide-induced encephalopathy — emergency

Immediate discontinuation of ifosfamide — do not administer the next dose; current cycle is stopped.

Medical support: frequent neurological monitoring — Glasgow Coma Scale, level of consciousness, seizures; telemetry, if available.

Anticonvulsants: lorazepam 2–4 mg IV bolus at first signs of seizure; do not wait for confirmation of seizures. Thereafter, continue with levetiracetam 500–1000 mg twice daily or valproate 15–20 mg/kg/day, with therapeutic level 50–100 µg/mL.

Correction of electrolytes: K+, Na+, Mg2+, Ca2+ and blood sugar; hypokalemia and hyponatremia amplify neurotoxicity.

Hydration: IV crystalloids 1–2 L/day, to restore intravascular volume and facilitate the elimination of metabolites.

Dexamethasone: 4–8 mg IV or orally every 6 hours if cerebral edema is suspected. Edema is rare in ifosfamide-induced encephalopathy but more common in ICI/CAR-T toxicity. Not routinely given.

Specific treatment for ifosfamide-induced encephalopathy

Methylene blue — specific antidote for ifosfamide-induced encephalopathy.

Dose: 50 mg IV every 4–6 hours.

Mechanism: inhibits MAO, restores neurotransmitter balance — increases GABA — and reduces glutamatergic excitotoxicity.

Effectiveness: 70–80% of patients respond within 24–48 hours.

Protocol: 50 mg IV bolus, then 50 mg every 6 hours for 24–72 hours after stopping ifosfamide or until mental status clears.

Monitoring: blue discoloration of urine and sometimes skin, risk of hemolysis in patients with G6PD deficiency, risk of serotonin syndrome in patients treated with serotonergic drugs.

Contraindications: MAOIs, G6PD deficiency, severe renal failure.

Other agents, if encephalopathy is refractory

Methylphenidate — Ritalin — 5–10 mg twice daily; stimulant, increases attention and alertness; effect in 1–2 hours; rarely used in persistent encephalopathy.

Physostigmine — acetylcholinesterase inhibitor; rarely used, with old data.

ICANS treatment — CAR-T-associated neurotoxicity

Grade 1–2: close observation; dexamethasone 10–20 mg IV every 6 hours — reduces cerebral edema and inflammation.

Tocilizumab — an IL-6 inhibitor — is not routinely administered for pure ICANS; it is indicated in CRS, cytokine release syndrome, and less commonly in isolated ICANS.

Support: prophylactic levetiracetam.

Prophylaxis of ifosfamide-induced encephalopathy

Aggressive hydration: 2–3 L pre-infusion and 1 L post-infusion; minimum urine output 300 mL/h, to dilute ifosfamide metabolites and reduce neurotoxicity.

Mesna: useful for preventing cyclophosphamide/ifosfamide-induced hemorrhagic cystitis, but does not prevent ifosfamide neurotoxicity.

Avoidance of risk factors: in patients over 50 years of age, a reduced initial dose is recommended; in renal dysfunction — creatinine >1.5 × upper limit of normal — avoidance or drastic reduction of doses is recommended; prevention of dehydration by monitoring electrolytes and volume repletion; avoidance of alcohol, which enhances neurotoxicity; avoidance of CNS depressants, such as benzodiazepines, if possible; premedication with diazepam is not recommended.

CAR-T prophylaxis — ICANS

Dexamethasone: 10 mg IV × 4 doses around CAR-T infusion — pre- and post-infusion — as per current practice.

Tocilizumab: available in the hospital, at the point of administration, with the possibility of administering 4 IV doses every 12 hours, if necessary during treatment; especially indicated for concomitant CRS or ICANS.

Intensive neurological monitoring: Glasgow Coma Scale daily, brain MRI if symptoms occur, EEG if seizures are suspected.

Anticonvulsant prophylaxis — optional: levetiracetam 500 mg twice daily in high-risk patients — previous neurological symptoms, CNS involvement, neurological comorbidities.

3. Radiation Optic Neuropathy — RION — and Hearing Loss

symptom

Painless, progressive, mono- or binocular visual loss; visual field deficits — central scotoma, hemianopsia; pallor of the optic disc on ophthalmoscopy; ischemic variant: sudden onset, immediate severity.

Mechanism

Radiotherapy by direct irradiation of the optic nerve/optic chiasm causes vascular ischemia, fibrosis and axonal degeneration.

The risk is increased at doses >54–60 Gy, at SRS with a single dose >8 Gy, and in the case of tumors located near the optic pathways — pituitary, paracavernous.

Timeline

Onset: 6 months–2 years post-radiotherapy; rare, early, at 3–6 months.

Dose–risk curve: <54 Gy — risk 1–3%; >60 Gy — risk 25–50%.

Progression: 6–36 months if untreated, with possible progression to blindness.

Diagnostic

Ophthalmology: visual acuity, visual field — automated perimetry, fundus photographs.

Imaging: T2 MRI — optic nerve edema, “trail of tears” sign — suggestive of RION.

MRI also helps rule out other causes — tumor compression, recurrence, inflammation.

Treatment

There is no consistently proven effective treatment for RION. Results are mixed.

Options to consider:

IV/oral corticosteroids: dexamethasone 4–8 mg daily for 10–14 days or prednisone 1 mg/kg/day for 14 days, tapered; uncertain effect.

Immunosuppressants — off-label: azathioprine 1–2 mg/kg/day, methotrexate; anecdotal data.

Bevacizumab — anti-VEGF: intravitreal injection 1.25 mg/0.05 mL monthly for 3–4 months; studies show stabilization or slight improvement in 30–40% of patients.

Hyperbaric oxygen therapy — HBO: 20–40 sessions, 2.0–2.5 atm; limited data in RION, better in radiation retinopathy/optic neuritis.

Plasmapheresis: rarely used, preliminary data, not a therapeutic standard.

Prophylaxis

Prevention is essential: the dose to the optic nerve/optic chiasm should be kept <54 Gy in conventional fractionation — 1.8–2 Gy/day.

Single-dose SRS: <8 Gy per voxel.

IMRT/FSRS with strict constraints on optical pathways — maximum/average dose, V54 and V60 = 0 for optic nerve/chiasma volume.

Advanced technologies: proton therapy — Bragg peak, with posterior dose reduction; dynamic IMRT with photons.

Optimal protection of the optical pathways in tumor contouring: 2–3 mm margin from the optical pathways to minimize risk.

HEARING LOSS DUE TO RADIOTHERAPY — SNHL, sensorineural hearing loss

symptom

Progressive bilateral hearing loss, initially at high frequencies — 4–8 kHz — with progression to low frequencies; tinnitus; difficulty understanding speech in noisy environments; rare vertigo; very rare ataxia.

Concomitant chemotherapeutic agents

Cisplatin — severe chronic ototoxicity; carboplatin — rare; bleomycin — rare; doxorubicin — low incidence.

The combination of chemotherapy + thoracic/head-neck radiotherapy synergistically increases the risk.

Mechanism

Irradiation with doses to the cochlea >45–50 Gy causes destruction of cochlear hair cells — outer hair cells are more sensitive — fibrosis of the stria vascularis and atrophy of the organ of Corti.

Concomitant platinum compounds produce synergistic toxicity.

Cumulative risk

Mean dose to the cochlea — MHD, calculated based on DVH, Dose-Volume Histogram:

<35 Gy: risk of SNHL <5%.

35–45 Gy: 10–20% risk.

>45 Gy: 30–50% risk.

Concomitant administration of platinum compounds increases the risk to 20–40%, even below 45 Gy.

Timeline

Onset: 6 months–5 years post-radiotherapy.

Slow progression, over the years.

With concomitant platinum treatment: accelerated progression, within a few months.

Diagnostic

Pure tone audiometry — initially, at each chemotherapy cycle, and at 1, 3, 6, and 12 months post-radiotherapy; measures hearing acuity in dB at frequencies of 250–8000 Hz.

Speech audiometry — speech discrimination.

Acoustic impedance — evaluates the tympanic membrane and excludes the conductive component.

Imaging: Craniocerebral MRI/CAI to exclude other causes — vestibular schwannoma, malformations.

Treatment

Hearing aids: for mild-moderate hearing loss, with loss >20 dB; audiological evaluation for prosthetics; frequency-selective amplification.

Cochlear implant: severe–profound bilateral deafness, loss >90 dB, speech discrimination <30%; otological intervention, electronic implant. Results: 80–90% of patients regain useful communication.

Sodium Thiosulfate — Sodium Thiosulfate, STS: FDA approved in 2022 for the prevention of cisplatin-induced sensorineural hearing loss in children. Dose: 9 g/m² IV bolus immediately after cisplatin, ideally <6 hours post-infusion. Mechanism: platinum chelation, reduction of nephrotoxicity and ototoxicity. Efficacy: 50–70% reduction in severe SNHL in children. In adults: limited data, not standard.

Transtympanic drainage — ventilation tube insertion: for conductive component, if present — fluid in the middle ear, rarely post-radiotherapy.

Prophylaxis

Cochlear dose limitation: average dose to the cochlea <35–45 Gy, ideally <35 Gy, preferably if platinum compounds are administered concomitantly; assessment on DVH. V40 and V50 = 0 for cochlear volume.

Cochlear protection in radiotherapy techniques: IMRT/VMAT/proton therapy, with strict constraints on the cochlea; unilateral versus bilateral irradiation, depending on location.

Avoiding concomitant cisplatin: if possible, administering cisplatin in separate cycles from radiotherapy or replacing with a less ototoxic platinum compound, such as carboplatin.

Initial and serial audiometry: before treatment, at each chemotherapy cycle if platinum is administered, and at 1, 3, and 6 months post-radiotherapy.

Patients with loss >20 dB at frequencies of 4–6 kHz have a prognosis of progressive deafness; early audiological counseling and prompt prosthetics are recommended.

4. Cerebellar syndrome and myelopathy

CEREBELLOS SYNDROME

symptom

Ataxia — incoordination when walking, wide-based, unsteady gait; limb incoordination on Romberg/Tandem testing.

Dysarthria — scanning speech, slow speech.

Intentional tremor — tremor that increases as you approach the target.

Nystagmus — rhythmic movement of the eyes, horizontal, vertical, or rotational.

Nausea, vomiting, vertigo.

Evolution: rapidly progressive, over days-weeks.

Agents involved

Chemotherapy: cytarabine — Ara-C — in high doses, >3 g/m²/day, with an incidence of 10–30%, direct cerebellar toxicity; 5-FU — rare, more common at high intra-arterial doses; thalidomide, lenalidomide — rare.

Radiotherapy: Direct irradiation of the cerebellum—eg, total cranial irradiation, posterior fossa gliomas—rare in the IMRT era.

Mechanism of high-dose cytarabine

Cytarabine produces the metabolite ara-CTP, which inhibits neuronal DNA/RNA synthesis, accumulates in the cerebellum — high concentration in CSF — and causes apoptosis of Purkinje cells, specific to the cerebellum, as well as glutamatergic excitotoxicity.

Cumulative risk

Cumulative dose of cytarabine:

<10 g/m²: 1–2% risk.

10–20 g/m²: 5–10% risk.

>30 g/m²: 20–50% risk.

The relationship is not linear; there is an approximate threshold of 10–15 g/m², after which the risk increases exponentially.

Timeline

Onset: 3–7 days after high-dose cytarabine cycle, during treatment or on days 1–3 post-infusion.

Rarely, delayed onset up to 4–6 weeks.

Progression: rapid, in days–weeks, followed by stabilization and slow recovery, in months–years.

Recovery is frequently partial; 30–40% of patients remain with residual deficit.

ASSESSMENT

Urgent neurological consultation: cerebellar tests — Romberg, Tandem walking, diadochokinesia, index-nose test, heel-knee test; evaluation of nystagmus, speech, and gait.

Imaging: Brain MRI — cerebellar edema, T2/FLAIR hyperintensities, cerebellar atrophy in chronic cases.

EEG: standard, to exclude concomitant seizure activity.

CSF: lymphocytic pleocytosis, increased proteinuria — nonspecific.

Electrolytes: hyponatremia may exacerbate ataxia.

Urinary toxicology.

Emergency treatment

Immediate discontinuation of cytarabine — no further doses are administered within the cycle.

Intensive neurological support: hourly neurological monitoring for progression — Glasgow Coma Scale, level of consciousness, seizures; telemetry, if available.

Anticonvulsant prophylaxis: levetiracetam 500 mg twice daily; seizures are not expected, especially if the patient is symptomatic. Cytarabine-induced cerebellar toxicity may be associated with a risk of concomitant seizures.

Dexamethasone: 4–8 mg IV/po q6h if there is significant cerebellar edema on MRI; reduces inflammation and edema. Benefit is uncertain, without strong support from randomized trials, but is used in clinical practice.

Antiemetics: ondansetron 8 mg IV every 8 hours; vomiting in the context of cerebellar ataxia is severe and increases the risk of aspiration.

Emergency physical therapy: Specialized PT/OT, for fall prevention, safe positioning, and progressive mobilization; ideally in a center with ATI experience.

There is no specific established pharmacological treatment for cerebellar ataxia.

Pentoxifylline — Trental: no convincing evidence.

L-serine: preliminary studies, mixed data.

Ginkgo biloba: anecdotal evidence.

Nicotinamide: no evidence.

Prophylaxis

Avoid high-dose cytarabine in patients at risk: patients over 50 years of age — reduced initial dose, 1.5–3 g/m², or avoidance.

Strict cerebellar monitoring: initial cerebellar testing and during treatment; if symptoms such as incipient nystagmus or mild dysarthria occur, cytarabine is stopped immediately.

Cumulative dose management: calculate cumulative dose before each cycle; if threshold exceeds 10 g/m² in patients at risk, reconsider regimen change.

Electrolytes: management of hyponatremia—including cytarabine-induced SIADH; monitor Na+ at each cycle and correct if Na+ <130 mEq/L.

MYELOPATHY — intrathecal chemotherapy and spinal radiotherapy

Early symptoms

Lhermitte’s sign — electrical sensation that radiates down the neck upon cervical flexion; characteristic of spinal cord irritation.

Back discomfort when flexing.

Late symptoms

Progressive weakness of the limbs — paraparesis in the lower limbs or tetraparesis in the upper and lower limbs.

Sensory level — loss of sensation below a specific spinal level, for example, loss of sensation below D6 suggests injury at the D6 level.

Bladder dysfunction — urinary retention, incontinence, refractory constipation.

Severe back pain.

Evolution: progressive, over weeks-months, with possible progression to incomplete or complete paralysis.

Intrathecal chemotherapeutic agents

Intrathecal methotrexate — standard dose 12.5 mg, high dose 24–30 mg; acute toxicity — leukoencephalopathy; chronic toxicity — myelopathy.

Intrathecal cytarabine — standard dose 50–75 mg, high dose 100–150 mg; may cause myelopathy and progressive ataxia.

Intrathecal thiotepa — rarely used.

Hydrocortisone — coadministered intrathecally for arachnoiditis prophylaxis, 12.5–25 mg; mild neurotoxicity.

Radiation therapy agents to the bone marrow

Direct irradiation: doses >45–50 Gy in conventional fractionation — 1.8–2 Gy/day; the risk of myelopathy increases exponentially above 50 Gy.

SRS: single dose >8–10 Gy per voxel — increased risk.

Concomitant chemotherapy — platinum compounds, bleomycin — increases the synergistic risk.

Mechanism

Intrathecal chemotherapy: uneven distribution in CSF, local accumulation, direct toxicity on neurons, axons and myelin.

Radiotherapy: direct irradiation of myelin fibers — demyelination; vascular damage — vasculitis, fibrosis; progressive edema → ischemia → medullary necrosis. The process develops progressively.

Timeline

Intrathecal chemotherapy: 1–3 months post-administration; rarely, delayed onset at 6–12 months.

Radiotherapy: 6–36 months post-radiotherapy; rarely, early at 3–6 months.

ASSESSMENT

Urgent neurological consultation: motor evaluation — antigravity muscles, reflexes, Babinski sign; sensory evaluation — sensory level, vibration, proprioception; abdominal/cremasteric cutaneous reflexes; vesico-rectal evaluation — anal tone, rectal sensitivity; catheterization testing for post-micturition residue.

Imaging: Spinal cord MRI with IV gadolinium-based contrast — T2 hyperintense edema, atrophy, syringomyelia, i.e. a cavity in the cord; no contrast uptake in chronic cicatricial lesions versus contrast uptake in acute inflammation.

Electrophysiology: EMG/VCN — confirms spinal cord injury and its degree, including atrophy and fibrillations.

Urodynamics, if there is vesicorectal involvement.

Treatment

Chronic myelopathy induced by intrathecal chemotherapy — there is no curative treatment.

Immediate discontinuation of intrathecal treatment — no further doses are administered.

IV pulse methylprednisolone: 500–1000 mg/day IV for 3 days; attempt to reduce acute inflammation, with limited utility in chronic forms.

Gabapentin: 300–1200 mg three times a day — for paresthesia and pain.

Amitriptyline: 10–75 mg in the evening — for neuropathic pain and secondary depression.

Tramadol: 50–100 mg three times a day — for moderate pain.

Opioids: morphine 5–20 mg four times daily, titrated according to response and tolerance — for severe pain.

Vesicorectal management: clean intermittent catheterization 4–6 times/day to prevent retention and recurrent urinary tract infections; patient/caregiver education.

Laxatives and stool softeners: docusate 100 mg twice daily, bisacodyl in the evening — for frequent refractory constipation.

Antispasmodics: baclofen 5–20 mg three times a day; tizanidine 2–8 mg three times a day.

Intensive physiotherapy: early mobilization to prevent contractures and thrombosis; physiotherapy sessions 5 times/week, if possible; psychology sessions for adaptive support and depression. Chronic myelopathy produces major disability and substantial psychological impact.

Functional rehabilitation: gait training, if paraparesis is incomplete — orthoses, cane; transfer training; adaptation of daily activities.

Medical-surgical support: spinal surgery consultation to evaluate options; rare cordotomy, for intractable refractory pain.

Occupational therapy: home adaptations, assistive equipment — cane, frame, wheelchair.

Intrathecal chemotherapy prophylaxis

Precise doses and correct dilution: intrathecal methotrexate — check before administration; do not administer concentrate; dilute in 10 mL CSF.

Intrathecal cytarabine — dilution in 5–10 mL of CSF, with hydrocortisone 12.5–25 mg for prophylaxis of arachnoiditis.

Neurological monitoring after intrathecal administration: clinical neurological assessment 1–2 hours after administration, as Lhermitte’s sign may be a precursor; weekly monitoring during weeks 1–4.

Avoiding arachnoiditis: diazepam is not administered as premedication because it may enhance intrathecal neurotoxicity.

Mobilization of the patient after intrathecal administration; strict rest according to old protocols is not recommended.

Intrathecal administration rate: slow injection, over 5 minutes, to minimize peak local concentration.

Prophylaxis of spinal cord radiotherapy

Dose to the spinal cord: maximum dose <45–50 Gy in conventional fractionation.

SRS constraints: single dose <8–10 Gy per voxel.

BED — biological effective dose — <100 Gy2 for multifractionation.

Spinal cord protection in planning: precise contouring on CT/MRI, clinical expansion margin of 3–5 mm, conformal doses — IMRT, VMAT, proton therapy — to avoid “hot spots” >110% of the prescribed dose.

Avoid concomitant neurotoxic chemotherapy: platinum compounds, bleomycin; if necessary, consider post-radiotherapy postponement, separation of radiotherapy/chemotherapy doses or dose reduction .

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IV. PULMONARY COMPLICATIONS

1. Chemotherapy and immunotherapy-induced pneumonitis

Drug-Induced Interstitial Lung Disease / DI-ILD

Clinical symptoms

Chemotherapy- or immunotherapy-induced pneumonitis may manifest as a persistent dry cough, present in approximately 80% of patients, progressive dyspnea, initially on exertion and later at rest in severe forms, subfebrile or fever between 37 and 38.5°C, sensation of chest pressure, hypoxemia with SpO₂ below 92% in ambient air, and fine bibasal crackles on auscultation, “Velcro” type. In severe forms, cyanosis and respiratory failure may occur.

Indicted agents

Agents implicated include bleomycin, with an estimated incidence of 5–10% and increased risk at cumulative doses above 300–400 units, busulfan, docetaxel, paclitaxel, methotrexate, gemcitabine, and pemetrexed.

Among the immune checkpoint inhibitors, nivolumab, pembrolizumab, and ipilimumab may be involved. The combination of nivolumab + ipilimumab is associated with a higher risk of pulmonary toxicity, including grade ≥2 forms. Also, the combination of pembrolizumab + chemotherapy may increase the risk of pneumonitis.

Mechanism

Chemotherapy can produce direct toxicity on the lung epithelium, particularly on type I and II pneumocytes, capillary endothelial inflammation, and progressive fibrosis through collagen deposition.

Immune checkpoint inhibitors can cause T-lymphocyte infiltrate in the lung, predominantly with CD8+ T lymphocytes, release of proinflammatory cytokines, such as IL-2 and IFN-γ, and the development of interstitial pneumonitis.

Thoracic radiotherapy can cause direct damage to the lung parenchyma, with the development of radiation pneumonitis and, subsequently, post-radiotherapy pulmonary fibrosis.

Cumulative risk associated with bleomycin

At a cumulative dose below 300 units, the risk is estimated at 3–5%. At doses between 300 and 400 units, the risk increases to 5–15%, and at doses above 400 units it can reach 20–50%, with an exponential increase.

Factors that may modify risk include administration of increased perioperative FiO₂, renal dysfunction, and advanced age.

Severity stratification according to CTCAE v5.0

Grade 1 corresponds to asymptomatic forms, detected by imaging or pulmonary function tests.

Grade 2 includes mild symptoms, such as cough and mild dyspnea, with DLCO between 75 and 89% of baseline.

Grade 3 involves moderate symptoms, with dyspnea on exertion and DLCO between 50 and 74%.

Grade 4 includes severe symptoms, dyspnea at rest, DLCO below 50%, SpO₂ below 90% in ambient air, and respiratory failure.

Grade 5 corresponds to death.

Diagnostic

Diagnosis is clinical and imaging. An initial chest HRCT is recommended before chemotherapy in patients at risk of bleomycin pulmonary toxicity. The investigation is repeated when pulmonary toxicity is suspected.

HRCT appearance may include interstitial pneumonitis, with predominantly basal ground-glass opacities. In late stages, fibrosis, reticular lines, architectural distortions, and traction bronchiectasis may occur.

Pulmonary function tests are performed initially and periodically, for example every 3 months in the case of bleomycin treatment or every cycle if symptoms occur. DLCO, i.e. the diffusing capacity for carbon monoxide, is often the first parameter to change, and may decrease by 10–15% before lung volumes change.

A DLCO value below 75% of the initial value or a decrease of more than 10% in 3 months is an alarm signal and requires reevaluation of chemotherapy.

Treatment — grade 1

Close observation is recommended. Systemic corticosteroids are not routinely given. HRCT and pulmonary function tests are repeated after approximately 4 weeks. Symptoms, especially dyspnea and cough, are closely monitored. Consider stopping chemotherapy if DLCO falls by more than 10–15%.

Treatment — grade 2

Prednisone or prednisolone can be administered at a dose of 0.5–1 mg/kg/day for 7–14 days, followed by gradual reduction over a total duration of 4–6 weeks, for example by 10 mg per week.

Empirical antibiotics, such as levofloxacin 500 mg twice daily or moxifloxacin 400 mg once daily for 10–14 days, may be administered to exclude or treat a concomitant bacterial infection, including atypical pathogens such as Mycoplasma or Chlamydia.

Monitoring includes repeat HRCT every 2–4 weeks, serial pulmonary function tests, dyspnea assessment, and SpO₂ monitoring. Chemotherapy is discontinued during the current cycle and reconsidered after pulmonary toxicity resolves. The risk of relapse is approximately 20–30% if the same agent is reintroduced, so changing the therapeutic regimen is preferable.

Treatment — grade 3

Intravenous methylprednisolone is recommended at a dose of 1–2 mg/kg/day for 3–5 days, usually 500–1000 mg/day, followed by oral prednisone 0.5–1 mg/kg/day, with gradual reduction over 4–8 weeks.

Intravenous antibiotics may be administered, for example ceftriaxone 1 g twice daily associated with azithromycin 500 mg daily, to cover community-acquired pneumonia, or intravenous levofloxacin.

Supplemental oxygen is administered, with a target SpO₂ above 92%, by progressively adjusting FiO₂. The patient requires hospitalization, and intensive care management may be necessary in severe cases.

Bronchoscopy with bronchoalveolar lavage — BAL — is indicated if the diagnosis is uncertain, to exclude infection or malignancy, and to collect secretions for bacterial, fungal, viral, and Pneumocystis jirovecii cultures. A BAL with >50% lymphocytes is suggestive of drug-induced pulmonary toxicity.

Treatment — grade 4, medical emergency

Pulse methylprednisolone, 500–1000 mg/day intravenously for 3 days, is administered, followed by oral prednisone with gradual reduction.

The patient requires admission to intensive care. Mechanical ventilation is indicated in cases of refractory progressive dyspnea, SpO₂ below 88% at FiO₂ 100%, or respiratory failure with CO₂ retention.

Hemodynamic support may include intravenous fluids and vasopressors, such as noradrenaline, in case of hypotension.

In case of corticosteroid refractoriness, after 72–96 hours of maximal corticosteroid therapy without improvement or with clinical deterioration, second-line agents may be considered: infliximab 5 mg/kg intravenously, mycophenolate mofetil 1–1.5 g twice daily orally, tocilizumab 8 mg/kg intravenously, intravenous immunoglobulins in a total dose of 2 g/kg administered for 3–5 days or, rarely, cyclophosphamide as a last therapeutic option.

Bleomycin toxicity prophylaxis

It is recommended to perform pulmonary function tests and DLCO before treatment with bleomycin, to establish the reference value.

Initial HRCT is recommended in patients at high risk: age over 50 years, renal dysfunction, pulmonary comorbidity, or smoking history. The goal is to rule out pre-existing pneumonitis.

Serial monitoring is done with pulmonary function tests, including DLCO, after each bleomycin cycle or every 1–3 months if treatment is prolonged. HRCT is repeated at cycle 3–4 or if symptoms occur. A decrease in DLCO of more than 10% or imaging deterioration requires stopping bleomycin and recalculating the risk/benefit ratio.

Prophylaxis of immune checkpoint inhibitor-induced pneumonitis

Close clinical monitoring is necessary. The patient should be educated to report cough, dyspnea, and fever early. Vigilance is greatest during the first 1–3 cycles of treatment.

Preventive bronchoscopy is optional. Some centers perform BAL at the first cycle of immunotherapy in patients with pulmonary comorbidities, such as COPD or pulmonary fibrosis, to assess underlying inflammation and rule out a concomitant infection.

Supplemental oxygen should be administered sparingly, avoiding increased FiO₂ without a clear indication.

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2. Post-treatment pulmonary fibrosis

symptom

Post-treatment pulmonary fibrosis manifests as progressive chronic dyspnea, initially on exertion and later at rest, progressing over months or years. Chronic dry, nonproductive cough, reduced exercise tolerance, hypoxemia with decreased SpO₂ on exertion, and fine basal, “Velcro”-like crackles on auscultation may occur.

Timeline

Onset may occur 3–12 months after chemotherapy, especially bleomycin, or later, 1–5 years after thoracic radiotherapy. Progression is slow, over years. Fibrosis is generally permanent and not reversible.

Agents involved

Agents implicated include bleomycin, busulfan, and thoracic radiotherapy. Post-radiotherapy pneumonitis may progress to pulmonary fibrosis.

Mechanism

Pulmonary fibrosis involves progressive collagen deposition, epithelial remodeling, and loss of lung elasticity. Fibroblasts transform into myofibroblasts, which produce collagen. The chronic mechanism is not fully elucidated, but hypotheses include persistent inflammation and angiogenesis, with scar tissue formation.

Risk factors include cumulative bleomycin dose above 300 units and radiotherapy dose above 60 Gy.

Imaging diagnosis

Thoracic HRCT may reveal reticular opacities, fine lines, traction bronchiectasis, architectural distortions, and, rarely, a “honeycombing” appearance in advanced fibrosis.

There may be a pattern similar to UIP — usual interstitial pneumonia — or NSIP — non-specific interstitial pneumonia. The UIP pattern usually has a more progressive course.

Pulmonary function tests

Pulmonary function tests reveal a restrictive pattern, with decreased FVC, normal or increased FEV₁/FVC ratio, DLCO decreased by 10–40% compared to baseline, and reduced TLC, i.e. total lung capacity.

Treatment

Treatment may include antifibrotic drugs, such as nintedanib 150 mg twice daily or pirfenidone. These drugs inhibit fibrotic processes through pathways such as TGF-β, PDGF, and FGF. They may slow the decline in FVC but do not reverse fibrosis. Treatment is usually long-term.

Prophylaxis

Prophylaxis consists of limiting cumulative doses, especially bleomycin below 300–400 units. For busulfan, therapeutic drug monitoring (TDM) is recommended for dose optimization.

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3. Radiation pneumonitis

Radiation-Induced Lung Injury — RILD

Acute phase — early RILD, 1–6 months after radiotherapy

The acute phase is manifested by persistent non-productive cough, progressive dyspnea, from exertion to rest, low-grade fever or moderate fever, pleuritic pain due to irritation of the irradiated pleura, and fatigue.

Symptoms may overlap with those of infectious pneumonia, but bacterial and viral cultures are negative. Therefore, differential diagnosis is essential.

Chronic phase — late RILD, more than 6 months after radiotherapy

The chronic phase is manifested by progressive chronic dyspnea, evolving over months or years, and pulmonary fibrosis, as described in the section on post-treatment pulmonary fibrosis.

Mechanism

Direct irradiation of the lung produces pneumocyte damage, especially type I pneumocytes, capillary endothelial inflammation, and macrophage recruitment, which release TNF-α, IL-1, and IL-6. The progression can range from acute inflammation to progressive fibrosis with collagen deposition.

The lung is an organ with intermediate radiosensitivity.

Dose-volume and RILD risk models

A mean lung dose — MLD — of less than 15 Gy is associated with a risk of less than 5%. At 15–20 Gy, the risk is approximately 5–10%, and at more than 20 Gy it can reach 15–25%.

V20 represents the lung volume that receives at least 20 Gy. A V20 below 30% is considered low risk, 30–40% moderate risk, and above 40% high risk of RILD.

V25 and V30 have a similar significance, with the risk increasing exponentially with the lung volume exposed to high doses.

BED — biologically effective dose — takes into account the fractionation and biological effect of the dose on tissues.

Diagnostic

Diagnosis is clinical and imaging. Thoracic HRCT may reveal, in the acute phase, focal alveolar consolidations in the irradiated area or diffuse pneumonitis. In the late phase, localized fibrosis is observed in the irradiated volume, according to the radiotherapy field.

Pulmonary function tests may show decreased DLCO and a restrictive pattern.

Infection should be excluded by sputum or BAL culture, as well as tumor recurrence or progression. PET-CT may be useful, as RILD tends to have a lower SUV compared to active malignancy. Comparison of current imaging with planned radiotherapy volume is important.

Treatment of acute RILD

Prednisone or prednisolone can be administered at a dose of 1 mg/kg/day, e.g. 60–80 mg/day, for 7–14 days, followed by gradual reduction over a total duration of 4–6 weeks.

Empirical antibiotics, such as levofloxacin 500 mg twice daily for 10–14 days, may be administered to exclude or treat a secondary bacterial infection, including atypical organisms.

Supplemental oxygen is administered with a target SpO₂ above 92%. Monitoring includes HRCT every 2–4 weeks, pulmonary function tests, and clinical assessment of dyspnea.

Treatment of chronic RILD

Treatment is similar to that for post-treatment pulmonary fibrosis and may include antifibrotic drugs, such as nintedanib or pirfenidone, oxygen therapy, pulmonary rehabilitation, and, rarely, lung transplantation.

RILD prophylaxis

Prophylaxis is based on conformational planning of radiotherapy, using techniques such as IMRT, VMAT or proton therapy, to minimize the irradiated lung volume.

Lung dosimetric constraints are essential. Ideally, MLD below 20 Gy and V20 below 30% are recommended. V5 and V10 are less predictive of RILD but may be relevant in some contexts.

In patients who smoke or have pre-existing COPD, the risk may be increased, and dosimetric constraints should be applied more strictly. In patients with stage III non-small cell lung cancer treated with radiochemotherapy, the risk of RILD may be significant, requiring careful optimization of the treatment plan.

Advanced technologies, such as proton therapy, dynamic IMRT, VMAT, and FLASH radiotherapy, can reduce exposure to healthy tissue, but some of these technologies are still in clinical evaluation.

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V. CARDIAC COMPLICATIONS

1. Anthracycline-induced cardiomyopathy

Anthracycline-Induced Cardiomyopathy — AIC

symptom

Initially, anthracycline-induced cardiomyopathy may be asymptomatic, being detected only by decreased ejection fraction on echocardiography.

As it progresses, exertional dyspnea may occur, followed by rest dyspnea, orthopnea, paroxysmal nocturnal dyspnea, marked fatigue, peripheral edema in the lower limbs, palpitations, and syncope caused by ventricular arrhythmias.

In the advanced form, the classic picture of congestive heart failure appears, with orthopnea, peripheral edema, ascites, and severe exercise intolerance.

Agents involved

The agents involved include doxorubicin, daunorubicin, idarubicin, epirubicin, liposomal doxorubicin, which has a lower risk than the conventional form, and mitoxantrone, which is associated with moderate cardiotoxic risk.

Mechanism

Anthracyclines generate reactive oxygen species, induce oxidative stress, cardiomyocyte apoptosis, and progressive myocardial fibrosis. Lost cardiomyocytes do not regenerate efficiently.

Toxicity is dependent on cumulative dose. For doxorubicin, the risk increases significantly above a threshold of approximately 450 mg/m².

An important mechanism involves inhibition of topoisomerase II beta — TOP2β — in cardiomyocytes, which causes DNA damage, mitochondrial dysfunction, and apoptosis.

Cumulative risk for doxorubicin

At doses below 250 mg/m², the risk of congestive heart failure is less than 1%. Between 250 and 300 mg/m², the risk is approximately 1–2%. Between 300 and 400 mg/m², the risk increases to 3–5%, and between 400 and 450 mg/m² to 5–8%. Above 450 mg/m², the risk can reach 15–20%, with an exponential increase.

Liposomal doxorubicin has a lower cardiotoxic risk, and maximum cumulative doses may be higher than for the conventional form, depending on the clinical context.

Additional risk factors

Risk factors include age over 60 years, pediatric age under 5 years, female gender, hypertension, diabetes mellitus, obesity, smoking, previous thoracic radiotherapy, and concomitant administration of other cardiotoxic drugs, such as 5-fluorouracil, cyclophosphamide, or taxanes.

Pretreatment screening

Initial echocardiography is recommended to assess ejection fraction, valvular morphology, and cardiac chamber volumes. An ejection fraction above 55% is usually considered favorable for initiating anthracycline therapy.

Global Longitudinal Strain — GLS — by speckle-tracking is more sensitive than ejection fraction for early detection of myocardial dysfunction. Normal values are approximately between -18% and -22%. A relative reduction in GLS of more than 11–15% from baseline may suggest incipient cardiotoxicity.

Monitoring during treatment

Echocardiography is repeated at a cumulative dose of approximately 250 mg/m², then at 400 mg/m², and then more frequently after the threshold of 450 mg/m² is exceeded. In centers with intensive monitoring, the assessment may be repeated every 50–100 mg/m² cumulative dose.

Treatment — grade 1–2, ejection fraction above 40%, asymptomatic patient

Careful monitoring is recommended, with echocardiography every 3–6 months, troponin and BNP or NT-proBNP dosing at each cycle, and patient education for early reporting of dyspnea, palpitations, and edema.

Dexrazoxane may be used as a cardioprotective agent in certain situations. It is usually given in a 10:1 ratio to the dose of doxorubicin. It acts by chelating iron and reducing oxidative stress induced by anthracyclines. Its use is not routine in all adults, but may be considered in high-risk patients or those in whom high cumulative doses are anticipated.

Treatment — grade 3–4, ejection fraction below 40% or symptoms of heart failure

Standard treatment for heart failure is recommended, according to guidelines, including, as appropriate, angiotensin-converting enzyme inhibitor or ARNI, beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor. Treatment should be individualized by the cardiologist, in collaboration with the oncologist.

In severe forms, permanent discontinuation of the anthracycline, hospitalization, diuretic treatment, rhythm monitoring and, in advanced cases, circulatory support may be necessary.

Prophylaxis

Prophylaxis involves limiting the cumulative dose of doxorubicin to a maximum of 450 mg/m², when possible. If continued treatment beyond this threshold is necessary, switching to liposomal doxorubicin or the use of dexrazoxane may be considered, depending on the oncological indication and cardiovascular risk.

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2. Myocarditis induced by immune checkpoint inhibitors

symptom

Immunotherapy-induced myocarditis may manifest as retrosternal chest pain, pressure-like or sharp, dyspnea, orthopnea, palpitations, and fever.

In severe forms, cardiogenic shock, hypotension, dizziness, syncope, ventricular tachycardia, ventricular fibrillation or complete atrioventricular block may occur, with severe bradycardia and pulse below 40 beats/minute.

Agents involved

Agents involved include PD-1 inhibitors, such as pembrolizumab, nivolumab, and cemiplimab, CTLA-4 inhibitors, such as ipilimumab and tremelimumab, and immunotherapy combinations, especially nivolumab + ipilimumab. Immunotherapy + chemotherapy combinations may also require close monitoring.

Incidence and severity

Immune checkpoint inhibitor-induced myocarditis is rare but potentially fatal. The incidence is estimated to be approximately 0.1–1% for overt clinical forms, and severe forms can have high mortality, especially when progressing to cardiogenic shock.

Timeline

Onset is variable, most frequently in the first few cycles of treatment, especially between cycles 1 and 8, with a median around cycles 2–3. Early-onset myocarditis occurs within the first 6 months of immunotherapy initiation, and late-onset forms are rarer. The course may be rapidly progressive, over hours or days.

Mechanism

Immune checkpoint inhibitors block the physiological mechanisms that inhibit the immune response, increasing the activation of T lymphocytes. This phenomenon can cause lymphocyte infiltrate at the myocardial level, release of proinflammatory cytokines, such as IL-2, TNF-α and IFN-γ, edema, inflammation and myocardial necrosis.

One proposed mechanism is cross-reactivity between tumor antigens and cardiac antigens.

Overlap syndromes

Immunotherapy-induced myocarditis may coexist with myasthenia gravis, myositis, or rhabdomyolysis. Myasthenia gravis may present with eyelid ptosis, diplopia, and proximal muscle weakness. Anti-acetylcholine receptor or anti-MuSK antibodies may be present.

The association of myocarditis with myasthenia gravis is particularly dangerous, as it can simultaneously produce respiratory failure and severe cardiac arrhythmias.

Diagnostic

Diagnosis is urgent and is based on the clinical picture, ECG, cardiac biomarkers and imaging.

ECG may reveal PR interval prolongation, atrioventricular block, ST segment elevation, T wave changes, or arrhythmias.

Ultrasensitive cardiac troponin is an essential marker. An increase above the upper limit of normal suggests myocardial necrosis. An increase of 5–10 times the normal limit is suggestive of moderate myocarditis, and values above 10 times the normal limit may indicate severe myocarditis.

Echocardiography may show normal or reduced ejection fraction. Cardiac MRI may confirm myocardial inflammation, and endomyocardial biopsy is reserved for unclear or severe cases.

Severity stratification

Mild or moderate forms may have slightly elevated troponin, normal or slightly reduced ejection fraction, above 45%, without hemodynamic instability and without severe arrhythmias.

Severe or fulminant forms manifest as markedly elevated troponin, reduced ejection fraction, ventricular arrhythmias, advanced atrioventricular block, acute heart failure, or cardiogenic shock.

Treatment — mild or moderate forms

Immunotherapy is discontinued immediately. Resumption of treatment is discussed individually, in a multidisciplinary team, but is not standard, especially if there is a risk of cardiac progression.

Systemic corticosteroids are administered as early as possible, usually intravenous methylprednisolone or high-dose prednisone, depending on severity. The patient requires cardiological monitoring, serial troponin, repeat ECG, and echocardiography.

Treatment — severe or fulminant forms

Immunotherapy is permanently stopped. The patient requires admission to cardiological intensive care or general intensive care.

Intravenous methylprednisolone is administered in high doses, e.g. 500–1000 mg/day for 3–5 days, followed by gradual tapering. In refractory forms, second-line immunosuppressive agents such as mycophenolate mofetil, abatacept, intravenous immunoglobulins, tocilizumab, or antithymocyte globulin may be considered, depending on the center’s protocol.

Heart failure, arrhythmias, and conduction disorders are treated. Temporary cardiac pacing, vasopressor support, inotropic support, or mechanical circulatory support may be required.

Prophylaxis

ECG, ultrasensitive troponin and, if appropriate, BNP or NT-proBNP are recommended before initiating immunotherapy. Initial echocardiography is useful to exclude pre-existing cardiomyopathy and to establish baseline ejection fraction.

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3. Radiation-induced pericarditis

Radiation-Induced Pericarditis

Symptoms in the acute form

Acute pericarditis manifests itself as sharp, pleuritic chest pain, aggravated by breathing and relieved in a sitting position, with the trunk bent forward.

A pericardial friction rub may be present on auscultation. ECG may reveal diffuse ST segment elevation and PR segment depression.

Symptoms in chronic forms

Chronic forms may progress to cardiac tamponade or constrictive pericarditis. Tamponade may manifest as peripheral edema, ascites, jugular turgor, paradoxical pulse, and hypotension.

Chronic constrictive pericarditis manifests itself through dyspnea, fatigue, and exercise intolerance.

Timeline

Acute pericarditis can occur 6–12 months after thoracic radiotherapy, sometimes earlier, at 3–6 months. Late constrictive pericarditis can occur 5–20 years after radiotherapy. The chronic risk is estimated at 2–6% in patients who have received thoracic radiotherapy.

Radiation-related risk factors

The mean heart dose — MHD — is an important factor. At values below 2.5 Gy, the risk is low. Between 2.5 and 5 Gy, the risk increases, and above 10 Gy it can become significant.

The volume of the heart irradiated is also important. V25, that is, the volume of the heart that receives at least 25 Gy, should be kept as low as possible, ideally below 10% of the total heart volume.

Diagnostic

Diagnosis is clinical and electrocardiographic. ECG may show diffuse ST segment elevation, PR depression and progressive ST-T segment changes.

Echocardiography is essential for the evaluation of pericardial effusion, signs of tamponade, and cardiac function. Cardiac CT or MRI may be useful in chronic or constrictive forms.

Treatment of mild or moderate acute pericarditis

Treatment includes nonsteroidal anti-inflammatory drugs, such as ibuprofen 600–800 mg three times a day for 2–4 weeks or indomethacin 25–50 mg three times a day, if there are no contraindications.

Colchicine can be administered at a dose of 0.5 mg twice daily for 3 months, reducing the risk of relapse. The data come mainly from viral or idiopathic pericarditis, but are extrapolated to other forms of pericarditis.

Treatment of severe, recurrent or refractory acute pericarditis

Corticosteroids, such as prednisone 0.5–1 mg/kg/day for 7–14 days, followed by a gradual taper, may be used if NSAIDs are ineffective or contraindicated or if there is severe pericardial effusion. They are usually not the first choice because they may increase the risk of relapse.

Treatment of chronic constrictive pericarditis

Surgical pericardiectomy is the definitive treatment for severe constrictive pericarditis. Medications cannot reverse the chronic constriction caused by fibrotic scar tissue.

The procedure involves pericardial decortication and can improve ventricular compliance and hemodynamics. A significant proportion of patients experience symptom improvement, but the procedure carries significant surgical risk.

Cardiac tamponade — emergency

Cardiac tamponade requires emergency echocardiographically guided pericardiocentesis. A needle or catheter is inserted into the pericardial space to drain the fluid, which can rapidly relieve hypotension and hemodynamic instability.

“Blind” pericardiocentesis, without imaging guidance, is rarely indicated and has an increased risk of complications.

Prophylaxis

Prophylaxis consists of conformational planning of radiotherapy, using techniques such as IMRT, VMAT or proton therapy, to minimize cardiac dose, especially at the pericardium level.

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4. Hypertension induced by tyrosine kinase inhibitors and anti-VEGF agents

symptom

Hypertension induced by these agents is frequently asymptomatic and is detected by blood pressure screening.

Headaches may occur, especially at systolic values above 160 mmHg, dizziness or vertigo. In severe forms, hypertensive crisis may occur, with hypertensive encephalopathy, confusion, seizures, coma, chest pain, dyspnea or palpitations.

Agents involved

Agents involved include VEGFR inhibitors, such as sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, regorafenib, and lenvatinib. Bevacizumab, although not a tyrosine kinase inhibitor, is an anti-VEGF monoclonal antibody and can also induce hypertension.

Mechanism

Inhibition of VEGF signaling at the vascular endothelium reduces endothelium-dependent vasodilation and promotes vasoconstriction, which causes an increase in blood pressure.

Proposed mechanisms include decreased nitric oxide, increased endothelin-1, and vascular oxidative stress.

Timeline

Onset usually occurs 1–4 weeks after initiation of treatment, with a median of around 4–6 weeks. Blood pressure may increase progressively over months or may increase rapidly to very high values.

Severity stratification

Grade 1 corresponds to systolic blood pressure between 140 and 150 mmHg or diastolic between 90 and 99 mmHg.

Grade 2 corresponds to systolic blood pressure between 150 and 160 mmHg or diastolic blood pressure between 100 and 109 mmHg and requires antihypertensive treatment.

Grade 3 corresponds to systolic blood pressure above 160 mmHg or diastolic blood pressure above 110 mmHg and requires prompt management.

Grade 4 corresponds to hypertensive crisis with target organ damage, such as hypertensive encephalopathy, myocardial infarction, or stroke, and represents a medical emergency.

Diagnostic

Blood pressure should be measured at each clinic visit. Home blood pressure monitoring is recommended for at least 3 consecutive days, morning and evening.

24-hour ambulatory monitoring is the gold standard for confirming the diagnosis and ruling out white coat hypertension.

Treatment of mild or moderate hypertension

Non-pharmacological measures include reducing sodium intake to below 2000 mg/day, moderate physical exercise 30 minutes a day, 5 days a week, weight loss in overweight patients, limiting alcohol consumption, and relaxation techniques.

If blood pressure values persist, antihypertensive treatment is initiated, usually with dihydropyridine calcium channel blockers, such as amlodipine, or with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, depending on the patient’s profile and drug interactions.

Treatment of severe hypertension

For values above 160 mmHg systolic or above 110 mmHg diastolic, prompt initiation of antihypertensive treatment, frequently with 2–3 agents, is recommended. Temporary discontinuation of the oncology inhibitor may be necessary until blood pressure is controlled.

Hypertensive crisis

Hypertensive crisis with target organ damage requires emergency hospitalization, preferably in intensive care, and administration of intravenous antihypertensives, such as nicardipine, labetalol, or nitroprusside, depending on the clinical context and comorbidities.

Prophylaxis

Baseline blood pressure should be measured before initiating treatment with TKIs or anti-VEGF agents. Thereafter, weekly monitoring is recommended for the first 6 weeks, the period of highest risk. If systolic blood pressure exceeds 140 mmHg in the first weeks, early initiation of antihypertensive treatment is recommended.

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5. QT prolongation and arrhythmias induced by chemotherapy, TKI and immunotherapy

symptom

QT prolongation may be asymptomatic or may present with palpitations, dizziness, presyncope, or syncope. In severe cases, polymorphic ventricular tachycardia, including torsades de pointes, ventricular fibrillation, cardiac arrest, and sudden cardiac death may occur.

Agents involved

Agents involved include anthracyclines, methotrexate, 5-fluorouracil, docetaxel, paclitaxel, etoposide, ifosfamide, and cisplatin.

Among immunotherapies, pembrolizumab and nivolumab may be rarely implicated, mainly through indirect mechanisms or through myocarditis.

Among the tyrosine kinase inhibitors, sunitinib, sorafenib, and pazopanib may be involved.

Concomitant medication may increase the risk, especially fluoroquinolones, such as levofloxacin and moxifloxacin, macrolides, such as azithromycin, antipsychotics, such as haloperidol, and antiemetics, such as ondansetron in high doses.

Mechanism

QT prolongation occurs through blockade of cardiac potassium channels, particularly the hERG channel, which prolongs ventricular repolarization. This electrical dysfunction predisposes to polymorphic ventricular arrhythmias, including torsades de pointes, with a risk of sudden death.

Risk factors

Risk factors include hypokalemia, with K⁺ below 3.5 mEq/L, hypomagnesemia, with Mg²⁺ below 2.0 mg/dL, hypocalcemia, bradycardia below 50 beats/minute, female gender, anemia, heart failure, ventricular remodeling, and hepatic or renal dysfunction, which may alter drug metabolism.

Diagnostic

Initial ECG is recommended before treatment to assess QTc. QT correction for heart rate can be done using the Bazett formula: QTc = QT/√RR.

Normal values are generally below 440 ms in men and below 460 ms in women. The ECG is repeated after the first cycle, at 24–48 hours, then at each cycle for drugs with a risk of QT prolongation.

Treatment of asymptomatic QT prolongation

Reversible factors are identified and corrected. If potassium is below 4.0 mEq/L, supplement with oral or intravenous KCl until values are above 4.0 mEq/L.

If magnesium is below 2.0 mg/dL, administer intravenous magnesium sulfate, e.g. 1–2 g initially. If hypocalcemia is present, intravenous calcium gluconate may be administered.

Discontinue, if possible, concomitant medications that prolong the QT interval.

Treatment of severe QT prolongation or arrhythmias

If QTc exceeds 500 ms or torsade de pointes occurs, the offending drug is stopped immediately.

In torsades de pointes, intravenous magnesium sulfate is administered, even if serum magnesium is normal. If the patient is hemodynamically unstable, cardioversion or defibrillation is performed according to the resuscitation protocol. In recurrent cases, temporary pacing or isoproterenol may be necessary, depending on the context.

Readministration of chemotherapy or TKI after an arrhythmic episode

Resumption of treatment is decided individually, in the oncologist-cardiologist team. If oncological treatment is vital, rechallenge can be considered with utmost caution, but as a rule, the same agent is not resumed after a severe arrhythmia.

In case of resumption, electrolytes should be maintained in optimal ranges, e.g. K⁺ 4.5–5.0 mEq/L and Mg²⁺ 2.5–3.0 mg/dL. A low dose can be started, with slow titration, continuous ECG monitoring and hospitalization with telemetry. In some cases, beta-blocker prophylaxis can be considered, as recommended by the cardiologist.

Prophylaxis

ECG and electrolyte evaluation are recommended before treatment with drugs that may prolong QT. Correct hypokalemia, hypomagnesemia, and hypocalcemia before initiating treatment. Avoid combining multiple drugs with a risk of QT prolongation whenever possible.

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Below is the text corrected for grammar, spelling, and terminology, without preserving the table structure.

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VI. ENDOCRINE COMPLICATIONS

BMT and cranial radiotherapy

Hypothalamic-pituitary dysfunction

Clinical symptoms

GH deficiency — Growth Hormone
In children, it causes growth retardation and progressive short stature. In adults, it can cause decreased muscle mass, abdominal obesity, reduced cardiorespiratory capacity, and decreased quality of life.

Hypogonadism
can cause amenorrhea in women, infertility and erectile dysfunction in men.

Secondary adrenal insufficiency
is manifested by severe asthenia, hypotension, recurrent hypoglycemia and risk of potentially lethal adrenal crisis in situations of intercurrent stress, such as infections, surgery or trauma.

Central hypothyroidism
can cause lethargy, slowed metabolism, constipation, and bradycardia.

Central diabetes insipidus
is manifested by polyuria, with increased urinary volume and dilute urine, polydipsia and chronic dehydration.

Timeline

Onset usually occurs 6 months–5 years after cranial radiotherapy or after BMT. Rarely, it can occur early, at 3–6 months. The evolution is progressive, over several years.

GH deficiency is the most common, occurring in 70–100% of patients who have received radiotherapy with doses >18–30 Gy to the hypothalamic-pituitary level. ACTH deficiency, with secondary adrenal insufficiency, occurs in approximately 40–50% of patients. TSH deficiency, with central hypothyroidism, occurs in 30–40% of patients, and gonadotropin deficiency in 20–30%.

Risk factors

The risk depends on the dose administered to the hypothalamic-pituitary axis. Doses <18 Gy are associated with low risk, doses between 18 and 30 Gy with moderate risk, and doses >30 Gy with high risk.

Allogeneic BMT, especially in combination with busulfan, may have a synergistic effect on endocrine risk. Children <5 years of age are more sensitive. Hormonal deficiencies occur progressively, usually at a distance from treatment.

Diagnostic

Annual endocrine screening, with a complete hormonal panel, is recommended for all patients who have received >18–30 Gy of radiotherapy to the hypothalamic-pituitary level or who have undergone BMT.

The recommended panel includes: IGF-1, morning cortisol, TSH, fT4, LH, FSH, testosterone or estradiol, serum osmolality, and urine osmolality.

Long-term hormone replacement therapy

Glucocorticoid replacement in ACTH deficiency is the therapeutic priority and should not be delayed. Hydrocortisone 15–25 mg/day can be administered in divided doses, e.g. 10 mg in the morning, 5 mg at noon, and, if necessary, 5 mg in the afternoon. Alternatively, prednisone 5–7.5 mg/day can be administered.

It is essential that levothyroxine not be initiated before corticosteroid therapy in patients with suspected secondary adrenal insufficiency. Initiating levothyroxine before glucocorticoid replacement may increase cortisol metabolism and requirements, precipitating a potentially fatal adrenal crisis.

Complication: hypothalamic obesity

GH deficiency and hypothyroidism may contribute to central abdominal obesity, dyslipidemia, insulin resistance, and progressive metabolic syndrome.

GLP-1 receptor agonists, such as semaglutide or liraglutide, can be used as adjunctive therapy, according to approved indications, and can contribute to weight loss of approximately 10–15% in eligible patients.

Prophylaxis

Annual endocrine screening is recommended for all patients who have received >18–30 Gy of radiotherapy to the hypothalamic-pituitary level or who have undergone BMT. Evaluation should include IGF-1, morning cortisol, TSH, fT4, LH, FSH, testosterone or estradiol, serum and urine osmolality.

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VII. GASTROINTESTINAL COMPLICATIONS

1. Mucositis / stomatitis

Chemotherapy, BMT, and radiotherapy

Clinical symptoms

Mucositis is manifested by mucosal erythema, edema, and painful ulcerations in the oral cavity, including the palate, gums, tongue, buccal mucosa, and pharynx.

Dysphagia may occur, initially as pain on swallowing, later with the impossibility of oral feeding. In severe forms, the patient can no longer swallow saliva, with a risk of aspiration, aspiration pneumonia, dehydration and the need for enteral or parenteral nutrition.

Timeline

Onset usually occurs 3–5 days after chemotherapy, with peak severity on days 7–14. Recovery generally occurs within 3–4 weeks, if no complications arise.

In the context of BMT, mucositis frequently lasts at least 2–3 weeks, and recovery depends on hematological reconstitution.

Agents involved

Chemotherapeutic agents commonly associated with mucositis include methotrexate, 5-fluorouracil — 5-FU, docetaxel, paclitaxel, bleomycin, doxorubicin, etoposide, and ifosfamide.

Radiotherapy to the head and neck, palate, or oral cavity increases the risk of mucositis. In BMT, the risk is increased by intensive conditioning regimens, including those containing busulfan or other cytostatics with mucosal toxicity.

Severity stratification — CTCAE v5.0

Grade 1: erythema, no ulceration and no significant impact on nutrition.
Grade 2: focal ulceration, with slight reduction in oral nutrition.
Grade 3: diffuse ulceration, severe pain, inability to eat orally and need for enteral or parenteral nutrition.
Grade 4: extensive ulceration, bleeding, inability to swallow saliva and risk of aspiration; represents a medical emergency.

Treatment — grade 1

Daily oral rinses with 0.9% saline or sodium bicarbonate solution, for example one teaspoon in a glass of water, are recommended. These keep the mucosa moist, reduce the accumulation of secretions and remove local debris.

For pain, viscous lidocaine 2%, e.g. 15 mL before meals, may be used as directed by a physician. Avoidance of acidic, hot, spicy, or irritating foods, as well as alcohol and smoking, is recommended. Patient education is important for early recognition of worsening symptoms.

Treatment — grade 2

Oral rinses with bicarbonate and saline 4–6 times a day are recommended. Viscous lidocaine 2% can be administered before meals, usually 15 minutes before, to reduce pain when eating.

For systemic analgesia, paracetamol or ibuprofen can be administered, if there are no contraindications. Aspirin should be avoided in patients at risk of bleeding, thrombocytopenia, or extensive mucosal lesions.

A soft diet is recommended, with foods such as purees, yogurt, creams, pureed soups and high-calorie nutritional supplements. Hard, rough-edged, acidic, spicy or very hot foods should be avoided. Toothpastes without sodium lauryl sulfate — SLS are recommended, as it can be irritating to the mucosa. Ozonated water or other irritating solutions should be avoided.

Treatment — grades 3–4

In severe cases, systemic analgesia is required. Tramadol 50–100 mg up to 4 times daily or opioids such as morphine, titrated to pain intensity, may be used. In severe mucositis, opioid use should not be unduly restricted, as pain control is essential for hydration, nutrition, and quality of life.

Patients with severe mucositis may require intravenous hydration, enteral or parenteral nutrition, monitoring for infections, and antimicrobial treatment if superinfection is suspected.

Mucositis prophylaxis

Oral cryotherapy may be useful in certain protocols, especially when the cytostatic has a short exposure time. This consists of keeping ice in the oral cavity for 7–15 minutes before infusion and continuing throughout administration, for example in the case of 5-FU administered as a bolus.

The mechanism consists of local vasoconstriction, with reduced exposure of the oral mucosa to the chemotherapeutic agent. Cryotherapy can reduce the incidence of severe mucositis, but may cause discomfort through cold or dental pain, which is why the patient must be properly educated.

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2. Nausea and vomiting

symptom

Nausea is a persistent feeling of stomach discomfort, without immediate vomiting. Vomiting can be moderate, with 1–5 episodes in 24 hours, or severe, with more than 6 episodes in 24 hours.

Clinical impact includes reduced food intake, malnutrition, dehydration, electrolyte imbalances, especially hypokalemia with risk of arrhythmias, as well as reduced absorption of orally administered medication if vomiting occurs after administration.

Agents involved

Highly emetogenic chemotherapy includes cisplatin, dacarbazine, streptozocin, and mechlorethamine, with a risk of nausea and vomiting in over 90% of patients in the absence of antiemetic prophylaxis.

Moderately emetogenic chemotherapy includes docetaxel, paclitaxel, doxorubicin, carboplatin, and 5-FU, with a risk of 30–90%. Low-emetogenic chemotherapy includes bleomycin and low-dose taxanes, with a risk of less than 30%.

Mechanism

Cytostatics can activate the chemoreceptor trigger zone (CTZ) located in the area postrema, a region with a permeable blood-brain barrier. This transmits signals to the vomiting center in the brainstem, particularly the dorsal vagal complex, causing motor responses such as reverse peristalsis, relaxation of the pyloric sphincter, and vomiting.

Stratification of emetogenic potential

Chemotherapy with very high emetogenic potential, such as cisplatin, dacarbazine, and mechlorethamine, requires aggressive antiemetic prophylaxis, usually with combination regimens.

Antiemetics available

5-HT3 receptor antagonists, such as ondansetron and granisetron, block serotonergic 5-HT3 receptors. They have good efficacy in chemotherapy with moderate or high emetogenic potential.

Ondansetron can be administered, for example, at a dose of 8 mg intravenously before infusion, repeated every 8 hours, depending on the protocol. Granisetron can be administered intravenously or orally, according to the recommended regimen.

MASCC/ESMO 2024 antiemetic regimen

For chemotherapy with very high emetogenic potential, such as cisplatin or dacarbazine, the original text mentions the need for an antiemetic regimen according to MASCC/ESMO recommendations, but the therapeutic regimen is not completed in the document provided.

Management of refractory nausea and vomiting

If nausea persists despite standard prophylaxis, treatment escalation is necessary. The addition of olanzapine may be considered, as well as complementary measures such as acupuncture, psychological interventions, and management of anxiety, which may exacerbate nausea.

Alternative causes, such as ulcers, gastritis, intestinal obstruction, severe constipation, metabolic disorders, or disease progression, should also be evaluated. Imaging is indicated if obstruction or other acute abdominal cause is suspected.

Anticipatory nausea prophylaxis

Psychological measures may include music, distraction techniques, guided relaxation, and mental imagery. A calm environment in the clinic, with a reduction in unpleasant odors and noises, is helpful.

The patient should be educated to understand that nausea is usually temporary, passing, and controllable with medication, not permanent or inevitable. Reassurance and appropriate training can reduce anxiety and anticipatory nausea.

Nutritional management in severe nausea

Small, frequent meals, 6–8 times a day, are recommended instead of three large meals. Liquid or semi-liquid foods, such as soups, purees, and smoothies, are often better tolerated.

Fatty, high-fiber, or difficult-to-digest foods should be avoided because they slow gastric motility. Lean proteins, such as chicken, fish, or eggs, are often better tolerated than red meat. Cold, slightly carbonated, or ginger-flavored drinks may relieve discomfort in some patients. Intravenous hydration is necessary in cases of severe dehydration.

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3. Diarrhea

Chemotherapy — irinotecan, 5-FU; radiotherapy — enteritis

symptom

Diarrhea is characterized by increased stool frequency. Moderate forms may include 2–3 additional stools per day, and severe forms may include more than 7 stools per day or incontinence.

The stools are usually watery. Abdominal cramps may occur, including at night, which disrupt sleep. Severe diarrhea can cause dehydration, weakness, electrolyte imbalances, and urgency to defecate, with major impairment of quality of life.

Agents involved

Irinotecan is frequently associated with diarrhea, which may occur acutely or late. Irinotecan-induced diarrhea may occur in a high percentage of patients, and severe forms may be seen in approximately 20%.

Other agents implicated include 5-FU, capecitabine, docetaxel, and methotrexate. Abdominal or pelvic radiotherapy can produce post-radiotherapy enteritis, with diarrhea that may persist for months or years after treatment.

Mechanism of irinotecan-induced diarrhea

Irinotecan is a topoisomerase I inhibitor. It is metabolized to SN-38, a much more potent active metabolite, which can produce toxicity to the intestinal mucosa.

SN-38 can be excreted biliarily and reabsorbed via the enterohepatic circuit, increasing intestinal exposure. Late diarrhea commonly occurs 4–5 days after administration and is caused by mucosal damage, increased water and electrolyte secretion, and osmotic/secretory diarrhea.

Severity stratification — CTCAE v5.0

Grade 1: 1–2 additional stools per day, with minimal impact.
Grade 2: 3–6 additional stools per day, with moderate impact on daily activities.
Grade 3: 7 or more additional stools per day, incontinence, dehydration, and need for intravenous repletion.
Grade 4: Diarrhea with severe complications, such as colitis, perforation, or hemodynamic instability; represents a medical or surgical emergency.

Treatment — grades 1–2 in chemotherapy-induced diarrhea

Loperamide is the first-line antidiarrheal agent. An initial dose of 4 mg orally can be administered, followed by 2 mg after each loose stool, without exceeding the maximum recommended dose, according to local protocol.

Loperamide reduces intestinal motility and can significantly improve diarrhea. It is relatively contraindicated if diarrhea is bloody, if the patient has fever, or if there is suspicion of invasive bacterial infection or severe colitis, due to the risk of toxic megacolon.

Treatment — grades 3–4

In severe diarrhea, intravenous hydration with lactated Ringer’s solution or 0.9% saline is required, for example 1–2 L/day or more, depending on volume status, blood pressure, diuresis, and electrolytes.

Monitoring of potassium, sodium, creatinine, urea and acid-base status is recommended. The patient may require hospitalization, antimicrobial treatment if infection is suspected, and temporary or permanent discontinuation of the causative chemotherapy.

Treatment — grades 1–2 in post-radiotherapy enteritis

Loperamide can be administered in a dose of 2–4 mg after each unformed stool, without exceeding the maximum daily dose. Continuous administration should be avoided if constipation or alternating diarrhea-constipation occurs.

Treatment — grades 3–4 in chronic refractory enteritis

Octreotide extended-release can be used in chronic refractory forms, e.g. 20–30 mg intramuscularly monthly, as medically indicated. It may reduce chronic diarrhea and improve quality of life.

The mechanism consists of inhibition of intestinal secretion, reduction of motility and effects on splanchnic circulation.

Prophylaxis of irinotecan-induced diarrhea

Routine prophylaxis with loperamide is not standard for all patients. Loperamide is usually reserved for the onset of diarrhea. However, it may be considered prophylactically in patients who have experienced severe diarrhea in previous cycles of irinotecan, according to oncology protocol.

Post-radiotherapy enteritis prophylaxis

Positioning the patient in the prone position and irradiating with a full bladder can reduce exposure of the small intestine to the radiotherapy volume. These measures may decrease the risk of post-radiotherapy enteropathy.

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VIII. LIVER COMPLICATIONS

Hepatotoxicity and veno-occlusive disease — VOD — in BMT

Hepatotoxicity induced by chemotherapy or radiotherapy

symptom

Hepatotoxicity can manifest as skin and scleral jaundice, right hypochondrium pain, fatigue, nausea, asthenia, and anorexia.

In severe forms, hepatic encephalopathy may occur, with confusion and asterixis, coagulopathy with bleeding, and, rarely, fulminant liver failure.

Grading — CTCAE v5.0

Grade 1: mild elevations in transaminases or bilirubin above the upper limit of normal.
Grade 2: moderate elevations in AST, ALT or bilirubin.
Grade 3: significant elevations in transaminases or bilirubin, usually requiring interruption or adjustment of treatment.
Grade 4: severe liver injury, with functional liver failure, coagulopathy, increased INR, ascites or hepatic encephalopathy.

Agents involved

Chemotherapeutic agents associated with hepatotoxicity include methotrexate, 5-FU, azathioprine, 6-mercaptopurine, thalidomide, and lenalidomide. Thalidomide and lenalidomide are more commonly associated with thrombotic risk, but can rarely cause liver damage.

Radiotherapy to the upper abdomen, with irradiation of the liver parenchyma, especially at high doses, may increase the risk of radiation-induced liver disease.

Mechanism

Chemotherapy can cause direct toxicity to hepatocytes, oxidative stress, apoptosis, and cholestasis. Radiotherapy can cause vascular endothelial damage, inflammation, and fibrosis, leading to radiation-induced liver disease (RILD).

Treatment — grades 1–2

Clinical observation, monitoring of transaminases, bilirubin and INR, as well as reduction of chemotherapy dose if necessary, is recommended.

Concomitant hepatotoxic drugs and substances, such as alcohol and high doses of paracetamol, should be avoided. Corticosteroids are not routinely administered unless there is a specific indication, for example immune-mediated hepatitis.

Treatment — grades 3–4

Immediate discontinuation of the causative agent and avoidance of subsequent doses is recommended until the cause is clarified and liver function has recovered.

Treatment is mainly supportive: maintaining hydration, avoiding hepatotoxins, monitoring liver function by TGO/AST, TGP/ALT, bilirubin, INR and albumin, as well as hepatological evaluation. In severe forms, hospitalization, monitoring of coagulopathy and specific treatment depending on the etiology may be necessary.

Prophylaxis

Monitoring of AST, ALT and bilirubin is recommended before each chemotherapy cycle, especially in patients treated with methotrexate or 5-FU.

Hepatological evaluation is indicated if transaminases increase significantly, for example above 3 times the upper limit of normal, or if jaundice, coagulopathy, or suggestive symptoms occur.

It is recommended to avoid concomitant hepatotoxins, adjust methotrexate doses in patients with liver failure, and vaccinate against hepatitis B when indicated, especially before immunosuppressive therapies with a risk of viral reactivation.

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Hepatic veno-occlusive disease — VOD / SOS

Severe post-BMT complication

symptom

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome, SOS, has an acute onset, usually between day 0 and day 30 after BMT.

It manifests itself through rapid weight gain of 2–10% in 1–2 days, jaundice, severe pain in the right hypochondrium, progressive ascites, peripheral edema, palpable hepatomegaly and, in late stages, hepatic encephalopathy.

Mechanism

Myeloablative conditioning regimens, particularly those with busulfan, cyclophosphamide, etoposide, and/or total body irradiation, can produce damage to hepatic sinusoidal endothelial cells.

These lesions cause endothelial activation, microthrombosis, blood stasis, portal congestion, and progressive liver damage. Severe forms of VOD/SOS are associated with high mortality.

Cumulative risk

The risk is increased in conditioning regimens that include high cumulative dose busulfan, e.g. >16 mg/kg orally or >9.6 mg/kg intravenously, cyclophosphamide >120 mg/kg, the combination of busulfan + cyclophosphamide, and total body irradiation.

The combination of busulfan + cyclophosphamide has synergistic risk and may significantly increase the risk of severe VOD.

Diagnostic

Early diagnosis is essential. Clinically, VOD/SOS should be suspected in a post-BMT patient who develops acute ascites, weight gain >5%, painful hepatomegaly, and jaundice, especially in the first 10–30 days after transplantation.

Abdominal Doppler ultrasound may reveal hepatomegaly, ascites, and changes in portal flow, including reduced or reversed portal flow, suggestive of severe disease.

Laboratory tests may show moderate elevations in transaminases, elevated bilirubin, usually >2 mg/dL, prolonged INR, and other signs of coagulopathy.

Treatment

Severe VOD/SOS is a medical emergency.

Defibrotide is the approved specific therapy for severe VOD/SOS. The usual dose is 6.25 mg/kg intravenously every 6 hours, i.e. 25 mg/kg/day, usually administered for a minimum of 21 days or until clinical signs resolve.

Defibrotide has endothelial protective, antithrombotic and profibrinolytic effects at the microvascular level. It can reduce mortality and promote the reversal of severe VOD/SOS, although the prognosis remains reserved in forms with multiorgan dysfunction.

Supportive treatment includes fluid restriction and close monitoring, diuretics if indicated, monitoring of renal and hepatic function, correction of coagulopathy when necessary, and intensive care care in severe cases.

VOD/SOS prophylaxis

Prophylaxis is essential in high-risk patients post-BMT. Prophylactic defibrotide may be considered in very high-risk patients, for example those with high cumulative doses of busulfan, high-dose cyclophosphamide, and concomitant total body irradiation.

The commonly used prophylactic regimen is defibrotide 6.25 mg/kg intravenously every 6 hours, starting before BMT, for example on day -6, and continuing for approximately 21 days, according to the transplant center protocol.

Preemptive anticoagulation with low-dose heparin, e.g., continuous infusion, has been used in some centers to reduce microthrombosis, but the evidence is inconsistent. Its use should be individualized according to thrombotic and hemorrhagic risk.

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IX. RENAL AND GENITURINARY COMPLICATIONS

1. Chemotherapy-induced nephrotoxicity — cisplatin

symptom

Nephrotoxicity can manifest as oliguria, defined as diuresis below 500 mL/24 hours, generalized edema, including facial and peripheral edema, hypertension, asthenia, and nausea secondary to uremia. In severe forms, acute renal failure may occur, with an increase in creatinine to more than three times the upper limit of normal and an increase in blood urea nitrogen — BUN — above 60 mg/dL, a potentially fatal situation.

Indicted agents

Cisplatin is an agent with significant toxicity, being ototoxic, neurotoxic, and nephrotoxic. Nephrotoxicity is dose-dependent, and at cumulative doses of cisplatin above 350–400 mg/m², increases in creatinine and BUN may occur in a significant percentage of patients.

Carboplatin is less nephrotoxic than cisplatin. Mitomycin C can rarely cause hemolytic uremic syndrome — HUS.

Mechanism of cisplatin-induced nephrotoxicity

Cisplatin is glomerularly filtered and taken up in the proximal renal tubule, where it accumulates intracellularly. This accumulation causes mitochondrial toxicity, oxidative stress, and tubular necrosis, leading to acute tubular necrosis (ATN) and oliguria.

The risk is increased in patients with pre-existing renal dysfunction, creatinine above 1.5 times the upper limit of normal, dehydration, concomitant administration of diuretics, nonsteroidal anti-inflammatory drugs — NSAIDs — or other nephrotoxic drugs.

Severity stratification — CTCAE v5.0

Grade 1: creatinine 1–1.5 times the upper limit of normal.

Grade 2: creatinine 1.5–3 times the upper limit of normal.

Grade 3: creatinine above 3 times the upper limit of normal or oliguria.

Grade 4: acute kidney failure requiring dialysis.

Treatment of acute renal failure — emergency

Treatment consists of aggressive intravenous hydration with 0.9% saline, administered 1–2 L/hour before cisplatin infusion, followed by continued hydration with 2–4 L/24 hours after the infusion. The goal is to dilute the urine and reduce the tubular concentration of cisplatin.

Diuresis is strictly monitored, with a minimum target of 200–300 mL/hour during cisplatin administration.

Cisplatin dose adjustment

In patients with normal baseline creatinine, approximately 1.0–1.2 mg/dL, the standard dose of cisplatin can be administered, usually 75–100 mg/m², depending on the oncological protocol used.

Prophylaxis of cisplatin-induced nephrotoxicity

Prophylaxis is essential and is based on preemptive hydration, considered the main preventive measure. It is recommended to administer 1 L of 0.9% saline by infusion, for 4–6 hours before cisplatin. This expands the intravascular volume, dilutes the urine and reduces the concentration of cisplatin at the tubular level, significantly decreasing the incidence of nephrotoxicity.

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2. Cyclophosphamide and ifosfamide-induced hemorrhagic cystitis

symptom

Hemorrhagic cystitis manifests itself through macroscopic hematuria, with red or pink urine, dysuria, pain during urination, pollakiuria, urinary urgency, and suprapubic pain.

In severe forms, urinary retention may occur due to obstruction with clots, recurrent urinary tract infections, and, rarely, fistulas in chronic forms.

Mechanism

Cyclophosphamide and ifosfamide are metabolized to form acrolein, a toxic metabolite that is excreted renally and concentrated in the urine. Acrolein causes direct toxicity to the bladder epithelium, with ulceration, vascular hemorrhage, and edema.

Inflammatory mechanisms may include T-lymphocyte infiltrate and local inflammation, contributing to the occurrence of hemorrhage.

Risk factors

The risk increases with high cumulative doses of cyclophosphamide, above 500 mg/m², and ifosfamide, above 10 g/m². Dehydration favors urine concentration and increases local toxicity. Infrequent micturition prolongs acrolein contact with the bladder epithelium and increases the risk of hemorrhagic cystitis.

Treatment of acute hemorrhagic cystitis grade 1–2

In mild and moderate forms, aggressive hydration is recommended, with 2–3 L of water daily. If dysuria is severe and limits urination, hydration can be achieved intravenously with 0.9% saline or lactated Ringer’s solution.

The goal is to dilute the urine and reduce bladder irritation.

Treatment of severe hemorrhagic cystitis — grade 3–4

In severe cases with massive bleeding, continuous bladder irrigation via a three-way Foley catheter is recommended. 0.9% saline is usually used for continuous irrigation, with an adapted flow rate, for example 1–3 L/hour, to evacuate clots, maintain catheter patency, and ensure mechanical hemostasis.

Preventing catheter obstruction by clots is essential.

Chronic complications

Chronic complications are rare and occur mainly after severe or untreated episodes of hemorrhagic cystitis. These include bladder fibrosis, with a shrunken and contracted bladder, reduced bladder capacity, and persistent urinary symptoms. Rectovesical or vesicovaginal fistulas may rarely occur, especially after prolonged untreated bleeding.

Prophylaxis

Prophylaxis is critical and is based on the administration of MESNA — 2-mercaptoethanesulfonate — in the case of treatments with cyclophosphamide or ifosfamide, according to the oncological protocol.

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X. METABOLIC COMPLICATIONS

1. Tumor Lysis Syndrome, TLS

symptom

Tumor lysis syndrome is manifested by severe metabolic disorders.

Hyperkalemia, with serum potassium above 5.5 mEq/L, can cause cardiac arrhythmias, bradycardia, atrioventricular block, and cardiac arrest.

Hyperuricemia, with uric acid above 8–10 mg/dL, can cause acute gout, urate nephropathy, and renal obstruction.

Hypocalcemia, with serum calcium below 7 mg/dL, can produce tetany, cramps in the hands and feet, perioral paresthesias, seizures, and laryngospasm.

Mechanism

Cytotoxic chemotherapy causes massive destruction of tumor cells, with the release of intracellular contents: potassium, phosphates, and uric acid resulting from purine catabolism.

Increased serum concentrations of these metabolites may exceed renal elimination capacity, especially in the context of renal failure, oliguria, or volume overload, leading to cardiac, neurological, and renal complications.

Risk factors

The risk is increased in hematological tumors, such as acute leukemias and lymphomas, especially those that are bulky or rapidly growing. Solid tumors rarely cause TLS, but it can occur in neuroblastoma or small cell lung cancer.

Major risk factors include large tumor volume, rapid proliferation, increased sensitivity to chemotherapy, and acute lymphoblastic leukemia with a leukocyte count above 50,000/µL.

Timeline

Onset usually occurs 6–72 hours after initiation of chemotherapy, with a median of 12–24 hours. Spontaneous TLS is rare, and the occurrence of metabolic disturbances before treatment should be interpreted with caution.

Risk Stratification — MASCC/ASCO

High risk is associated with acute lymphoblastic or myeloid leukemia with leukocytes over 50,000/µL, bulky lymphoma with tumor mass over 10 cm, elevated basal uric acid over 7.5 mg/dL, creatinine over 1.5 times the upper limit of normal, and pre-existing renal dysfunction.

Diagnostic

Laboratory diagnosis of TLS requires the presence of at least two of the following changes within 12 hours before or after treatment: potassium ≥6 mEq/L, uric acid ≥8 mg/dL or increase of at least 25% from baseline, phosphate ≥4.5 mg/dL, and calcium ≤7 mg/dL.

Treatment of acute TLS — emergency

Treatment consists of aggressive intravenous hyperhydration with 0.9% saline, at a dose of 2–3 L/24 hours. Potassium solutions are not administered, as they may worsen hyperkalemia.

The aim is to dilute the urine, force diuresis, and reduce the urinary concentration of metabolites. The target is a diuresis of 200–300 mL/m²/hour, closely monitored, preferably by Foley catheter.

TLS prophylaxis in high-risk patients

In high-risk patients, prophylaxis should be initiated 24–48 hours before chemotherapy. Intravenous hydration and electrolyte monitoring should be continued after chemotherapy. Dialysis should be readily available, and the nephrology team should be notified in very high-risk cases. Urinary catheterization allows accurate monitoring of urine output.

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2. Hyperglycemia and ketoacidosis induced by corticosteroids or immunotherapy

symptom

Hyperglycemia can manifest as polyuria, with frequent urination and increased urine volume, polydipsia, marked asthenia, and nausea.

Ketoacidosis is manifested by Kussmaul breathing, deep and labored, confusion, and, in severe forms, coma.

Indicted agents

Corticosteroids, such as dexamethasone and prednisone, can cause hyperglycemia, especially at doses greater than 20 mg/day prednisone equivalent.

Immunotherapy with immune checkpoint inhibitors, such as anti-PD-1 or anti-CTLA-4, can rarely induce type 1 diabetes. Taxanes can cause moderate hyperglycemia.

Mechanism of corticosteroid-induced hyperglycemia

Corticosteroids increase hepatic gluconeogenesis and induce peripheral insulin resistance by antagonizing insulin action. The risk is greater in patients with pre-existing diabetes, obesity, advanced age, a family history of diabetes, or membership in high-risk ethnic groups.

Diagnostic

Hyperglycemia is defined as fasting plasma glucose above 126 mg/dL or random blood glucose above 200 mg/dL.

Ketoacidosis is characterized by arterial pH below 7.35, bicarbonate below 15 mEq/L, anion gap above 12, and variable potassium, which may be low in case of severe osmotic diuresis.

Treatment of mild-moderate hyperglycemia

For blood glucose levels below 300 mg/dL, insulin therapy is initiated according to local protocol. Basal insulin can be used, for example insulin glargine 10–20 IU in the evening, titrated according to morning blood glucose and with a glycemic target of approximately 100–150 mg/dL.

Alternatively, a basal-bolus regimen can be used, with rapid-acting prandial insulin, adjusted according to postprandial blood glucose levels.

Treatment of diabetic ketoacidosis — emergency

Diabetic ketoacidosis requires hospitalization, usually in intensive care, continuous monitoring, intravenous insulin infusion, and correction of electrolyte imbalances.

Prophylaxis of corticosteroid-induced hyperglycemia

Before initiating corticosteroids, it is recommended to determine fasting blood glucose and glycosylated hemoglobin — HbA1c — to identify pre-existing diabetes or increased metabolic risk.

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XI. COMPLICATIONS OF COAGULATION

1. Disseminated intravascular coagulopathy — DIC — and venous thromboembolism — VTE

Disseminated intravascular coagulopathy — DIC

symptom

DIC can manifest as spontaneous multilocal bleeding, in the mucous membranes and skin, petechiae, ecchymoses, deep hematomas, and bleeding at intravenous or intramuscular puncture sites.

Hematuria, hematochezia, or hemoptysis may occur. Microthrombosis may cause acrocyanosis, with a blue-blackish discoloration of the fingers, nose, or ears, peripheral necrosis, and gangrene.

In severe forms, shock may occur, with hypotension, tachycardia, and confusion.

Mechanism

Cytotoxic chemotherapy can cause massive tumor destruction, with the release of tissue factor derived from cancer cells. This activates the coagulation cascade, leading to progressive consumption of coagulation factors, platelets, and fibrinogen.

The result is a paradoxical situation, with bleeding concomitant with consumptive vascular microthrombosis.

Incriminated agents and situations

Acute promyelocytic leukemia — APL/AML-M3 — has a very high risk of DIC in the absence of treatment. Other acute leukemias, such as AML and ALL, can be associated with DIC, especially when there are a large number of malignant blasts.

DIC can also occur in some solid cancers, such as mucinous adenocarcinomas and prostate cancer.

Diagnosis — ISTH score

Diagnosis is based on prolonged prothrombin time, with INR above 1.2, thrombocytopenia, elevated D-dimers, and low fibrinogen, below 100 mg/dL. An ISTH score of at least 5 is suggestive of overt DIC.

Treatment of acute DIC — emergency

The main treatment consists of treating the underlying cause. In acute promyelocytic leukemia, specific treatment is urgently initiated, such as ATRA — all-trans retinoic acid — associated with arsenic trioxide, according to the protocol. Differentiation of leukemic cells leads to progressive remission of the coagulopathy.

In acute leukemias, specific oncological treatment is a priority.

Supportive treatment includes intravenous hydration, red blood cell transfusions in case of severe anemia, and vasopressors in case of shock.

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Venous thromboembolism — VTE: deep vein thrombosis and pulmonary embolism

Symptoms of deep vein thrombosis

Deep vein thrombosis is manifested by unilateral edema of the lower limb, sudden onset, rapid progression, erythema, calf pain, local warmth, and limitation of mobility. Differential diagnosis includes cellulitis.

Mechanism of cancer-associated VTE

The tumor may release tissue factor, activating coagulation. Interaction between cancer cells and platelets, prolonged immobilization, and the presence of a central venous catheter further increase the risk.

This entity is known as cancer-associated thrombosis (CAT) and has a significantly higher risk than in the general population.

Incriminated agents and situations

Thalidomide, lenalidomide, and pomalidomide increase the risk of VTE, especially in combination with corticosteroids or doxorubicin.

Anti-CTLA-4 immunotherapy, such as ipilimumab, may rarely be associated with VTE.

Central venous catheters, including PICC lines, can promote mechanical thrombosis. Immobilization, brain metastases, paralysis, and bedridden status increase the risk of thrombosis.

Diagnostic

Diagnosis of deep vein thrombosis is made by compression Doppler vascular ultrasound. Venography is considered the reference standard, but is less commonly used. D-dimers may be elevated, but have high sensitivity and low specificity, especially in oncological patients.

Treatment of cancer-associated VTE

Direct oral anticoagulants — DOACs — represent a modern first-line option in eligible patients, according to bleeding risk, tumor location, and drug interactions.

VTE prophylaxis in patients treated with thalidomide or lenalidomide

Thromboprophylaxis is mandatory in patients treated with thalidomide or lenalidomide in regimens with high thrombotic risk. Anticoagulation should not be considered optional when the risk of VTE is high.

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XII. COMPLICATIONS IN WOMEN: INFERTILITY AND EARLY MENOPAUSE

Chemotherapy-induced infertility

Indicted agents

Gonadotoxic chemotherapy includes alkylating agents, such as cyclophosphamide and ifosfamide, which are associated with an increased risk of infertility. Other agents involved are platinum compounds, such as cisplatin and carboplatin, taxanes, vinblastine, and etoposide.

Radiation therapy to the gonads can produce permanent azoospermia or amenorrhea.

Mechanism

Chemotherapy causes direct toxicity to the germinal epithelium, affecting spermatocytes and oocytes. Radiotherapy produces direct irradiation of the testicular or ovarian germinal tissue, with apoptosis of reproductive cells.

Busulfan can cause permanent azoospermia, especially at high cumulative doses.

Fertility in women

The ovary contains a finite reserve of germ cells, which do not regenerate. Chemotherapy causes a dose-dependent decrease in fertility.

The risk is influenced by the cumulative dose of chemotherapy and age at the time of treatment. Patients under 20 years of age have a better reproductive prognosis, while patients over 40 years of age have a significantly reduced viable ovarian reserve.

Amenorrhea occurs in a significant percentage of women treated with moderately or highly gonadotoxic chemotherapy. Menstrual recovery may occur within 1–2 years after chemotherapy in some premenopausal women, but permanent ovarian failure is possible.

Male fertility

Spermatogenesis has a long cycle, approximately 72–74 days. Post-chemotherapy azoospermia can last 6–12 months and is often reversible.

Permanent azoospermia is rarer, but can occur after busulfan or high-dose scrotal radiotherapy, over 6 Gy at the testicular level.

Gamete preservation before treatment

Fertility preservation should be discussed before initiating chemotherapy.

In women, oocyte cryopreservation involves hormonal stimulation for approximately 10–14 days, oocyte retrieval under transvaginal ultrasound guidance, and rapid freezing via vitrification. The procedure can increase the chances of future fertility.

In men, sperm cryopreservation is recommended before intensive chemotherapy.

Treatment of post-chemotherapy infertility

Assisted reproductive technology (ART) can be used in women, including in vitro fertilization with previously cryopreserved oocytes or donated oocytes. The success rate depends on the age of the oocyte, ovarian reserve, embryo quality, and medical background.

In the case of early menopause, hormone replacement therapy with estrogen and progesterone may be recommended until the physiological age of menopause, in the absence of contraindications.

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Early menopause — premature ovarian failure, POI

Definition

Premature menopause is defined as the onset of menopause before the age of 40. Chemotherapy significantly increases the risk of premature ovarian failure.

symptom

Symptoms include amenorrhea, defined as the absence of menstruation for more than 3 consecutive months, hot flashes, night sweats, vaginal dryness, dyspareunia, mood disorders, anxiety, depression, fatigue, and increased risk of osteoporosis due to decreased estrogen levels.

Diagnostic

The diagnosis is based on elevated FSH, above 40 mIU/mL, low estradiol, low antral follicle count on ovarian ultrasound, and low AMH — anti-Müllerian hormone — usually below 1 ng/mL.

Treatment

Treatment consists of hormone replacement therapy, in the absence of contraindications. Conjugated estrogens 0.625–1.25 mg daily orally or transdermal estradiol 0.05–0.1 mg, associated with progesterone, for example medroxyprogesterone 5–10 mg daily, cyclically or continuously, can be used.

The goal is to correct the hormonal deficiency, improve symptoms, and prevent osteoporosis.

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XIII. DEVELOPMENT OF A SECONDARY MALIGNANCE

Secondary malignancy associated with oncological treatment

Definition

Secondary malignancy is a new malignant tumor arising in a cancer survivor, with possible etiology related to chemotherapy, radiotherapy or immunotherapy. It must be differentiated from recurrence of the primary tumor.

Types of secondary malignancies

Secondary leukemias and secondary myelodysplastic syndromes — sAML/sMDS — can occur after chemotherapy with alkylating agents, such as cyclophosphamide and busulfan, usually 5–10 years after treatment.

Topoisomerase II inhibitors, such as etoposide, may be associated with earlier-onset secondary leukemias, usually 2–5 years after treatment.

Secondary solid cancers can include skin cancers, such as squamous cell carcinoma, basal cell carcinoma, and melanoma, especially after radiotherapy.

Secondary lung cancer, especially non-small cell lung cancer, can occur in patients with a history of smoking and previous exposure to chemotherapy or radiotherapy.

Bone or soft tissue sarcomas can occur in irradiated fields, including radiation-induced osteosarcoma and fibrosarcoma.

Cumulative risk

The risk increases with the cumulative dose of chemotherapy, especially for alkylating agents. In the case of radiotherapy, the risk is proportional to the cumulative dose and the volume irradiated. The latency period is usually 5–10 years.

Prophylaxis and screening

Preventive screening adapted to the type of treatment received, cumulative doses, location of radiotherapy and individual risk is recommended.

Basic screening after chemotherapy or radiotherapy

The patient must receive medical education and a “survivorship care plan”, which should include the oncological treatments received, the types and cumulative doses of chemotherapy, the locations and doses of radiotherapy, as well as a long-term follow-up plan.

It is recommended to follow periodic screening protocols and report new symptoms early, such as the appearance of a mass, unexplained bleeding, or dyspnea.

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XIV. GENERAL PRINCIPLES OF PREVENTION AND MULTIDISCIPLINARY APPROACH

Pretherapeutic evaluation

Cardiac assessment

Echocardiography with evaluation of ejection fraction and global longitudinal strain — GLS, global longitudinal strain — ultrasensitive troponin, BNP or NT-proBNP dosing and ECG are recommended.

Pulmonary assessment

Pulmonary function tests, including FVC, FEV1, and DLCO, are recommended. Thoracic HRCT is indicated in high-risk patients, especially those undergoing bleomycin or thoracic radiotherapy. Baseline pulmonary function tests are mandatory before bleomycin treatment.

Neurological evaluation

Initial neurological examination is recommended, with assessment of reflexes, muscle strength, and proprioception. Screening for neuropathy may include 10-g monofilament sensitivity testing and the EORTC QLQ-CIPN20 questionnaire in patients receiving taxanes or platinum compounds.

Renal evaluation

It is recommended to determine creatinine, BUN, electrolytes — sodium, potassium, magnesium — and estimate creatinine clearance using the Cockcroft-Gault formula or eGFR.

Liver evaluation

Determination of TGO, TGP, bilirubin and albumin is recommended. HBsAg testing is indicated to assess the risk of hepatitis B reactivation, especially in the context of immunosuppressive treatments.

Audiological evaluation

Initial audiometry is recommended in patients undergoing treatment with cisplatin or other ototoxic agents. Audiometry should include frequencies between 250 and 8000 Hz.

Ophthalmological evaluation

Visual evoked potentials — VEPs — may be performed in patients receiving agents with potential for optical toxicity, such as intrathecal methotrexate.

Endocrine evaluation

It is recommended to determine IGF-1, TSH, fT4, LH, FSH, testosterone or estradiol, morning cortisol and serum osmolality, especially before hypothalamic-pituitary radiotherapy with doses above 18 Gy.

Fertility assessment

Fertility preservation counseling is recommended before intensive chemotherapy, especially in adolescents and young adults. Options include cryopreservation of oocytes or sperm, with the involvement of a reproductive endocrinologist.

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Standardized serial monitoring

At each chemotherapy cycle

, electrolyte determination, ultrasensitive troponin in patients treated with anthracyclines or immune checkpoint inhibitors, and blood pressure monitoring in patients treated with tyrosine kinase inhibitors are recommended .

Every 2–4 cycles

Pulmonary function tests are recommended in patients treated with bleomycin, audiometry in those treated with cisplatin, and screening for neuropathy by EORTC QLQ-CIPN20 in patients treated with taxanes or platinum compounds.

Every 4–6 cycles

Echocardiography is recommended in patients treated with anthracyclines, especially when the cumulative dose exceeds 250 mg/m² of doxorubicin or equivalent. GLS assessment is also recommended.

After completing chemotherapy

Echocardiography is recommended 1–3 months after completion of chemotherapy, with evaluation of ejection fraction and GLS, pulmonary function tests with DLCO, troponin, and audiometry.

Repeat echocardiography and pulmonary function tests are recommended every 6 months.

Complete cardiac, pulmonary and neurological reassessment is recommended at 1 year, then annually for 5 years or according to individual protocol.

After thoracic radiotherapy

1 year after thoracic radiotherapy, thoracic HRCT is recommended to assess fibrosis and pulmonary function tests.

At 5 years, echocardiography is recommended to screen for cardiac complications, including pericarditis, followed by annual monitoring.

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Multidisciplinary approach — cardio-oncology and integrated care team

The cardiologist specializing in cardio-oncology monitors cardiac toxicity, optimizes treatment according to guidelines — including ARNI, beta-blockers, and SGLT2 inhibitors — and evaluates the indication for ICD or CRT.

The pulmonologist interprets pulmonary function tests, evaluates HRCT, prescribes oxygen therapy, and manages treatment-induced pneumonitis or pulmonary fibrosis.

The oncologist adjusts chemotherapy doses, reduces or stops treatment in case of severe toxicity, and reschedules cycles based on the patient’s recovery.

The neurologist screens for chemotherapy-induced peripheral neuropathy, manages encephalopathy, and evaluates myelopathy.

The dermatologist manages alopecia, rashes, and severe dermatitis.

The nephrologist treats nephrotoxicity, determines the indication for hemodialysis, and optimizes electrolyte disorders.

The hepatologist manages hepatotoxicity, veno-occlusive disease, and evaluation for transplantation, when necessary.

The audiologist performs audiometry, recommends hearing aids, and evaluates the indication for a cochlear implant.

The ophthalmologist performs retinopathy screening and optic neuropathy evaluation.

The reproductive endocrinology specialist provides counseling for fertility preservation and management of premature ovarian failure.

The psychiatrist and psychologist provide support for anxiety, depression, and psychological adjustment after treatment.

The nutritionist manages malnutrition and adapts the diet based on complications such as mucositis or diarrhea.

Specialists in medical rehabilitation, physiotherapy and occupational therapy contribute to the rehabilitation of patients with peripheral neuropathy, functional recovery and fall prevention.

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CONCLUSION

Oncological complications (chemotherapy, radiotherapy, immunotherapy) are multidimensional complexes, requiring early detection , active monitoring , and prompt intervention to optimize outcome. Comprehensive pre-therapeutic evaluation and a multidisciplinary approach are cornerstones for the management of complications. Patient education on symptoms and adherence to monitoring are essential for the success of long-term oncological treatment with optimized quality of life.

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Dr. Onisim Florin Senior Medical Oncologist Founder of OncoExpertAI