Complications Of Cancer Treatment

Complications of Cancer Treatment

A 40 year old premenopausic female was referred for adjuvant chemotherapy of Stage II B (T2 N1Mo) Estrogen Receptor negative her-2-neu 2+ (FISH) Invasive Ductal Carcinoma of the left breast. She had a left sided Modified Radical Mastectomy three weeks ago.

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What information should be disclosed during the oncologic consultation? What are the adverse reactions to cancer treatment?

Case The physician recommended the following regimen for adjuvant chemotherapy: 4 cycles of Doxorubicin + Cyclophosphamide followed by 4 cycles of Paclitaxel with Trastuzumab for one year and radiation to the chest wall and

Case 

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What are the most likely acute adverse reactions this patient will have during chemotherapy? What is the known acute and long term adverse reactions to doxorubicin? What other reactions are observed with other agents? What are the long term adverse reactions to chemotherapy What are the adverse reactions to radiation?

Acute Reactions(1)     

Hair loss Nausea and vomiting Fatigue Mucositis Change in skin pigmentation

Acute Reactions (2)     

Myelosuppression Hypersensitivity Hepatotoxicity Neurotoxicity Vascular toxicity

Disclosure for Patients with Cancer  Diagnosis  Stage of disease  Options for treatment  Complications of treatment  

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Acute Long term

Prognosis

Adverse Reactions to Cancer Treatment

Non-hematologic toxicities

•Nausea & vomiting •Oral •Gastrointestinal •Pulmonary •Cardiac •Hair loss •Gonadal dysfunction •Second cancers •Miscellaneous Adverse reactions

Hematologic toxicities •Anemia •Leukopenia Neutropenia •Thrombocytopenia

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Hair loss 

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immense burden psychologically and physically occurs within 2 to 3 weeks of chemotherapy treatment normally resolves within 2 to 3 months after completion or cessation of chemotherapy Adverse reactions

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Therapeutic Interventions in Alopecia

Decrease local delivery  

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Protection of the hair bulb  

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Scalp tourniquet Scalp hypothermia Topical minoxidil AS101

Inhibitors of cyclin-dependent kinase         

Thiol solution Inactivate chemotherapy locally ImuVert Epidermal growth factor and fibroblast growth factor Topical cyclosporine Interleukin-1 Topical calcitriol Liposome-entrapped monoclonal antibody Pulsed electrostatic field

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Emetic syndromes related to chemotherapy

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Acute 

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occurring within the first 24 hours after administration of CT (usually within 1 to 2 hours) generally most severe during the initial 4 to 6 hours.

Delayed 

occurring 24 or more hours after CT  

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range of 16 to 24 hours maximal risk at 48 hours

most commonly associated with cisplatin, carboplatin, cyclophosphamide, and doxorubicin

Anticipatory 

learned or conditioned response that typically occurs before, during, or after the administration of CT

Adverse reactions Nausea & vomiting

Mechanisms 

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activation of the chemoreceptor trigger zone (CTZ) either directly or indirectly peripheral stimulation of the gastrointestinal (GI) tract vestibular mechanisms cortical mechanisms alterations of taste and smell.

Adverse reactions Nausea & vomiting

Risk factors •prior exposure to chemotherapy •Chronic and heavy alcohol usage •heightened level of anxiety during the chemotherapy infusion •being prone to motion sickness •severe emesis during pregnancy Adverse reactions Nausea & vomiting

Pharmacologic agents    

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Selective 5-HT3 antagonists Metoclopramide Corticosteroids Others: phenothiazines, butyrophenones, and cannabinoids Adjuvants: Antianxiety agents

Adverse reactions Nausea & vomiting

Guidelines for Antiemetic Dosing Antiemetic

Dose: Acute Emesis

Dose: Delayed Emesis

5-Hydroxytryptamine type 3 receptor antagonists: administer once prechemotherapy Ondansetron

0.15 mg/kg IV or 8 mg IV 12–16 mg PO

Granisetron

0.01 mg/kg IV or 1 mg IV 1 mg PO

Dolasetron

1.8 mg/kg IV or 100 mg IV 100–200 mg PO

Palonosetron

0.25 mg IV

Corticosteroid Dexamethasone

10–20 mg IV

8 mg b.i.d. x 2–3 d

High risk: 8 mg PO b.i.d. d 2–4 Moderate risk: 4–8 mg PO b.i.d. d 2–3

Guidelines for Antiemetic Dosing Antiemetic

Dose: Acute Emesis

Dose: Delayed Emesis

Dopamine antagonists Metoclopramide

2–3 mg IV prechemotherapy Repeat 2 h postchemotherapy

Prochlorperazine

10 mg IV or PO every 3–4 h p.r.n

Adverse reactions Nausea & vomiting

0.5 mg/kg or 20–40 mg PO q.i.d d 2–5

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Oral Complications 

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chemotherapy- and radiation therapy–related stomatitis and associated oropharyngeal pain xerostomia oral infection oral chronic graft-versus-host disease (cGVHD)

Adverse reactions Oral complications

Patient Risk Factors for Stomatitis            

Age older than 65 y or younger than 20 y Gender Poor oral health and hygiene Periodontal diseases Microbial flora Chronic low-grade mouth infections Salivary gland secretory dysfunction Herpes simplex virus infection Inability to metabolize chemotherapeutic agent effectively Poor nutritional status Exposure to oral stressors such as alcohol and smoking Ill-fitting dental prostheses Adapted from

Barasch A, Peterson DE 1999 Dodd MJ, Miaskowski C, Shiba GH, et al, 2003

Treatment-Related Risk Factors for Stomatitis         

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Radiation: dose, schedule Chemotherapy: drug, dose, schedule Myelosuppression Neutropenia Immunosuppression Reduced secretory immunoglobulin A Oral care during treatment Infections: bacterial, viral, fungal Use of antidepressants, opiates, antihypertensives, antihistamines, diuretics, and sedatives Impairment of renal and/or hepatic function Protein or calorie malnutrition, and dehydration Adapted from Barasch A, Peterson DE Xerostomia

1999 Dodd MJ, Miaskowski C, Shiba GH, et al, 2003

Chemotherapy induced stomatitis 

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40% of chemotherapy patients develop stomatitis approximately 50% of these patients develop severe painful lesions requiring treatment modification or parenteral analgesia patients undergoing BMT have high incidence rates of stomatitis of more than 60%

Adverse reactions Oral complications

Chemotherapy induced stomatitis  

asymptomatic erythema progresses from solitary, white, elevated desquamative patches that are slightly painful to large, contiguous, pseudomembranous, painful lesions

Adverse reactions Oral complications

Graft versus Host Disease 

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an alloimmune condition derived from an immune attack mediated by donor T cells recognizing antigens expressed on normal tissues 80% of patients who have extensive cGVHD have some sort of oral involvement

Adverse reactions Oral complications

Oral cGVHD 

presents with  

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tissue atrophy and erythema lichenoid changes (hyperkeratotic striae, patches, plaques, and papules) pseudomembranous ulcerations occurring typically on buccal and labial mucosa and the lateral tongue, angular stomatitis xerostomia

Adverse reactions Oral complications

Prevention & Treatment 

Pretreatment oral/dental stabilization 

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to eliminate sites of oral infection and trauma provide adequate cleaning encourage appropriate oral hygiene

Frequent oral cavity assessment is necessary to capture clinical signs before, during, and after the treatment time course Pain management Adverse reactions Oral complications

Prevention & Treatment 

Sialogogues 

Pilocarpine 

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Amifostine (Ethyol) 

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side effects of glaucoma, cardiac problems, and sweating

200 mg/m2 as a 3-minute IV infusion 15 to 30 minutes before each fraction of radiation

Oral hygiene regimens

reduce colonization and proliferation of oral pathogens  water or saline  daily fluoride application with brushing teeth at least Adverse reactions three times daily. 

Oral complications

Prevention & Treatment

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Direct Cytoprotectants:Sucralfate 

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Not efficacious in 5FU induced or radiation induced stomatis but patients reported less pain

Benzydamine 

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nonsteroidal agent with analgesic, anesthetic, antiinflammatory, and antimicrobial properties efficacious for both stomatitis and radiation therapy–induced stomatitis

Steroid mouthwashes  Allopurinol Adverse reactions 

Oral complicatons

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Acute Anthracycline induced cardiotoxicity  

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rare, but reversible presents as a myocarditis, with or without pericarditis may result in transient congestive heart failure (CHF)/arrhythmias

Adverse reactions Cardiac

Delayed Anthracycline induced cardiotoxicity  

irreversible, dilated cardiomyopathy presents clinically as       

fatigue dyspnea on exertion orthopnea sinus tachycardia S3 gallop rhythm pedal edema/pleural effusions elevated jugular venous distention

Adverse reactions Cardiac

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Risk factors for Cardiomyopathy

Cumulative dose 

5% risk is seen    

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450 900 935 223

mg/m2 mg/m2 mg/m2 mg/m2

for for for for

doxorubicin daunorubicin epirubicin idarubicin

Cofactors  

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mediastinal irradiation older (particularly older than 70 years) or younger (younger than 15 years) age coronary artery disease (CAD), other valvular or myocardial conditions hypertension

Adverse reactions Cardiac

Cardiotoxicity

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Mediastinal radiation Drugs 

Anthracyclines 

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Doxorubicin

Mitoxantrone Cyclophosphamide Ifosfamide Paclitaxel Docetaxel 5-fluorouracil

Monoclonal antibodies: trastuzumab

Adverse reactions

Diagnosis 

compare baseline with serial left ventricular function studies using radionuclide imaging or echocardiography, or both

Adverse reactions Cardiac

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Causes of anemia in patients with cancer

• cytotoxic chemotherapy • malignancy: anemia of chronic disease bone marrow involvement • bleeding • nutritional: iron, vitamin B12, folic acid

Management of anemia in patients with cancer

•Determine the cause! •Blood transfusions: packed RBC •Recombinant human erythropoietin Anemia secondary to chemotherapy

•Therapy with iron, and vitamins if deficien

Febrile neutropenia

Fever: one temperature > 38.5’C

or three readings > 38’C but < 38.5’C + Neutropenia: ANC < 500 cells/uL

Management of patients with febrile neutropenia Careful history and physical examination Diagnostics Chest Xray Gram stain & culture of blood, urine & sputum, if any In this patient, one blood specimen should be drawn from intravenous catheter Treatment Empiric antibiotic coverage: broad spectrum with anti-Pseudomonas activity Modifications based on individual patient presentations

Management of febrile neutropenia Transfusion of granulocytes: as initial treatment, no role •reserved for patients unresponsive to antibiotics Colony stimulating factors • enhance neutrophil recovery after chemotherapy, thereby shorten the period of maximal vulnerability to fatal infection •adverse effects: fever, hypoxemia, pleural effusion, Serositis •expensive

Factors that favor low risk for severe infection ANC > 100 cells/mm3 Absolute monocyte count > 100 cells/mm3 Normal findings on chest radiograph Duration of neutropenia < 7 days Resolution of neutropenia expected in < 10 days No intravenous catheter site infection

Factors that favor low risk for severe infection Early evidence of bone marrow recovery Malignancy in remission Peak temperature < 39’C No appearance of illness No abdominal pain No neurological or mental changes No comorbidity complications

Thrombocytopenia 

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Risk of bleeding depends on the platelet count among other factors, like infection, mucosal breaks Follow guidelines for platelet transfusion Back

Chemotherapeutic agents associated with pulmonary toxicity Chemotherapeutic agent Bleomycin

Incidence

Mitomycin

3–14%

Carmustine (BCNU)

20–30%

Methotrexate

2–8%

Paclitaxel

3–10% (acute hypersensitivity)

up to 10%

•Rare: Busulfan,Cyclophosphamide,Chlorambucil,Melphalan,Docetaxel

Adverse reactions Pulmonary

Mechanisms 

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direct toxic effect on alveolar epithelial cells induction of an inflammatory immunologic response endothelial cell injury or activation causing capillary leak syndrome

Adverse reactions Pulmonary

Neurotoxicity       

Vinca alkaloids Cisplatin , Oxaliplatin Thalidomide Cytarabine Ifosfamide Methotrexate Paclitaxel , docetaxel

Adverse reactions

Vincristine Neurotoxicity 

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Axonal injury with relative preservation of the myelin sheath Peripheral, central or autonomic nervous system most common and initial manifestations

depression of the deep tendon reflexes Adversereactions paresthesias of the distal extremities 

Neurotoxicity

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Vincristine Neurotoxicity

Motor dysfunction and gait disorders are initially manifested as lower extremity weakness Cranial nerves may be affected and cause ophthalmoplegia and facial palsy Toxicity to the parasympathetic nervous system is manifested by constipation and difficult micturition Autonomic neuropathy can also produce orthostatic hypotension (which can be symptomatic or clinically silent) and erectile and ejaculatory dysfunction Adverse reactions

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Hypersensitivity Reactions

Hypersensitivity to Taxanes clinical manifestations of type I hypersensitivity reaction  bronchospasm and wheezing, agitation, chest and back pain, rash, angioedema, and hypotension  onset is usually within minutes of starting a drug infusion  even very small drug doses are capable of initiating a reaction  apparent hypersensitivity that may be delayed in onset is pulmonary infiltrates typical of a hypersensitivity pneumonitis that may either resolve spontaneously or after corticosteroid therapy Adverse reactions 

Hypersensitivity reactions 

Paclitaxel  

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Frequency : 5% Cremophor EL excipient used to maintain solubility of paclitaxel most often (more than 70% of the time) occur with the first drug dose suggests a nonimmunologic mechanism

Docetaxel

Adverse reactions

Prophylaxis vs. Hypersensitivity  

Infusion over 1 to 3 hours Premedication with corticosteroids and antihistamines

Adverse reactions

Hypersensitivity reactions 

l-Asparaginase produces hypersensitivity reactions in 10% to 20% of patients 

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polypeptide of bacterial origin, displaying multiple antigenic sites that can stimulate production of immunoglobulin E (IgE) or other immunoglobulins acute onset of wheezing, pruritus, rash, angioedema, extremity pain, agitation, and hypotension Back

Adverse reactions

Hepatotoxicity 

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direct effect of either the parent drug or a metabolite acute event serum hepatic enzymes rise as cellular damage occurs fatty infiltration & cholestasis may occur as the toxic effect progresses.

Adverse reactions

Antitumor Agents That Cause Hepatotoxicity High potential for hepatotoxicity      

L-Asparaginase Cytarabine Gemtuzumab ozogamicin Interferons (in high doses) Methotrexate (long-term therapy) Streptozocin

High potential for hepatotoxicity with high doses       

Busulfan Carmustine (BCNU) Cyclophosphamide Cytarabine Dactinomycin Methotrexate Mitomycin

Antitumor Agents That Cause Hepatotoxicity

Occasional irreversible hepatotoxicity       

Busulfan (in high doses) Carmustine (in high doses) Cytarabine Dacarbazine Gemcitabine Methotrexate Mitomycin

Isolated instances of hepatotoxicity       

Dacarbazine Hydroxyurea Interferons (in low doses) 6-Mercaptopurine Pentostatin 6-Thioguanine Vincristine

Causes of Enzymatic Abnormalities   

hepatic metastases viral hepatitis drugs administered for other therapeutic purposes (e.g., antiemetics) Back Adverse reactions

Drugs most likely to cause enzyme abnormalities          

l-asparaginase carmustine in high doses cytarabine dactinomycin etoposide levamisole in combination with 5-FU 6-mercaptopurine methotrexate in high doses streptozocin vincristine.

Adverse reactions

Vascular toxicity  

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Veno-occlusive Disease thrombotic microangiopathy with hemolytic uremic syndrome venous or arterial thrombosis vascular ischemia (involving cerebral, myocardial, or extremity arterial vessels) Back

Adverse reactions

Nephrotoxicity 

Manifestations range from rise in creatinine level or mild proteinuria to ARF requiring dialysis

Adverse reactions

Antitumor Agents That Cause Nephrotoxicity High potential for nephrotoxicity        

Aldesleukin (interleukin-2) Azacitidine Cisplatin Gallium nitrate Ifosfamide Methotrexate (in high doses) Mitomycin Streptozocin

Antitumor Agents That Cause Nephrotoxicity Azotemia without nephrotoxicity  

L-Asparaginase Dacarbazine

Occasional irreversible nephrotoxicity        

Cisplatin Fludarabine Ifosfamide Interferons Lomustine (CCNU) Mitomycin Pentostatin Streptozocin

Cisplatin renal toxicity   

dose related cumulative manifested primarily by a decrease in the glomerular filtration rate 

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clinically approximated by increases in the serum creatinine level and decreases in creatinine clearance

electrolyte abnormalities such as hyponatremia and hypomagnesemia

Adverse reactions

Prophylaxis for cisplatin nephrotoxicity 

Hydration with normal saline 

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high chloride level inhibits cisplatin hydrolysis in the tubules which adds to the nephrotoxicity protection effect of diuresis

Mannitol is also used to enhance diuresis Monitor renal function & electrolytes

Adverse reactions

Pulmonary Toxicity: Clinical Presentation

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dyspnea nonproductive cough or a cough productive of small amounts of pinkish sputum fever is unusual signs of pulmonary involvement are minimal occasionally, moist rales, a pleural friction rub, or evidence of pleural fluid may be heard over the area of irradiation

Adverse reactions

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Impact of Cancer and Cancer Therapy on the Reproductive System Tumor

Direct gonadal involvement Reproductive tract involvement Hypothalamic and pituitary involvement Concern about heritability of cancer susceptibility

Surgery

Removal of gonad Genital mutilation Failure of emission and retrograde ejaculation Impotence and loss of orgasm

Impact of Cancer and Cancer Therapy on the Reproductive System Radiotherapy or chemotherapy

Germ cell depletion Loss of gonadal hormones Mutagenic changes in germ cells Teratogenic effects on fetus

Chemotherapy

Seminal transmission of drug

Radiotherapy (cranial)

Loss of gonadotropic hormones

Gonadal dysfunction in men 

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After cytotoxic treatment, sperm count diminishes with a time course that depends on the sensitivities of the different spermatogenic cells and their kinetics of maturation to sperm loss of germ cells has secondary effects on the hypothalamic-pituitary-gonadal axis

Adverse reactions

Gonadal dysfunction in women 

temporary amenorrhea  

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may occasionally last several years often a result of direct ovarian damage, which causes loss of maturing follicles or failure of follicular recruitment alternative causes: stress, malnutrition, or weight loss alter hypothalamic activity and estrogen metabolism age independent

Adverse reactions

Gonadal dysfunction in women 

permanent amenorrhea 

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may begin during chemotherapy or subsequently, after several years of oligomenorrhea dramatically and continuously increases with age at treatment

Adverse reactions

Second cancers 

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Not all second cancers are due to therapy Other causes: 

host influences  

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genetic susceptibility immunodeficiency

common carcinogenic influences clustering of risk factors diagnostic surveillance chance event

Adverse reactions

Second cancers 

Radiation induced   

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Leukemia Breast cancer Lung cancer

Chemotherapy related 

AML  

Alkylating agents Topoisomerase II inhibitors Back

Adverse reactions

Radiation-Induced Nausea and Vomiting 

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related to the size of the radiation field, the dose per fraction, and the site of irradiation exact mechanism of radiationinduced emesis remains unclear  

Central peripheral

Adverse reactions Nausea & vomiting

Radiation Therapy–Induced Stomatitis 

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universal when radiation therapy includes the oropharyngeal area severity dependent on     

type of ionizing radiation volume of irradiated tissue dose per day cumulative dose duration of radiotherapy

Adverse reactions Oral complications

Radiation Pneumonitis 

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5% to 15% of patients receiving highdose external-beam radiation for treatment of lung cancer Factors that can add to the development of radiation pneumonitis   

concomitant chemotherapy previous irradiation withdrawal of steroids

Adverse reactions Pulmonary