7.1 Treatment late effects and sequelae

7.1.1 Treatment toxic deaths
The major toxicities of combination chemotherapy are due to side-effects of the specific agents used. Treatment-associated death rates from all causes are 0% to 4% in limited-stage and 2% to 8% in extensive stage SCLC patients.

7.1.2 Radiotherapy sequelae
Following radiation therapy, the most frequently reported sequelae noted were pneumonitis (approximately 10% grade 2 and 4.6% grade 3), pulmonary fibrosis (approximately 20% grade 2 and 8% grade 3 or greater), esophagitis (about 12% grade 2 and 3% grade 3) and esophageal stricture (about 1%). Thoracic spinal cord myelopathy was observed in four out of 1380 patients (0.3%). Radiation treatment fractionation (>2.67 Gy) is critical for the increased risk of radiation pneumonitis (7.IX). Pulmonary impairment is moderate in long-term survivors, but is not strikingly worse than what expected in a heavy smokers population.

7.1.3 Prophylactic brain irradiation sequelae
Prophylactic brain irradiation may induce clinical and radiological signs of various types and degrees of brain injury, including neurological deficit, memory loss, and dementia. These sequelae were associated with concomitant administration of chemotherapy and doses of about 30 Gy in 10 fractions of 3 Gy. Symptoms appeared between a few months to several years after cranial irradiation. The most effective suggested management is to limit total radiation doses to 30 Gy with doses per fraction not greater than 2.0 Gy. Some degree of neurological impairment preexist to brain irradiation and they are probably disease-related so that prophylactic cranial irradiation seems not responsible for additional neurotoxicity. More recent studies are in favour of this observation (7.IV, 7.V).

7.2 Related and secondary tumors

7.2.1 Related tumors
The incidence of NSCLC is markedly increased in long term survivors from SCLC with an incidence of about 4-5% per year, which is 10 times higher than in the large cohort of smokers over 45. These secondary tumors, as SCLC itself, are most likely induced by smoking. The latter is supported by the finding that patients with NSCLC in early stages have a similar high risk for secondary NSCLC after surgery alone. The risk of secondary aerodigestive cancer increases to more than 10% after more than 10 years from treatment. Cigarette smoking cessation is associated with a reduction in risk for a second smoking-related primary tumor (7.VIII).

7.2.2 Secondary tumors
Alkylating agents, such as nitrosoureas or procarbazine, especially when given protracted, and etoposide can increase the risk of therapy-related acute myeloblastic leukemias. The risk of an acute leukemia 2-3 years after therapy for SCLC ranged between 2-18% (7.II, 7.XI).


References

7.I
Chang AE, Steinberg SM, Culnane M, Lampert MH, Reggia AJ, Simpson CG, et al. Functional and psychosocial effects of multimodality limb-sparing therapy in patients with soft tissue sarcomas. J Clin Oncol 1989; 7: 1217-1228.

7.II
Johnson DH, Porter LL, List AF et al. Acute nonlymphocytic leukemia after treatment of small cell lung cancer. Am J Med 1986; 81:962-968.

7.III
Johnson BE, Grayson J, Makuch RW, Linnoila RI, Anderson MJ, Cohen MH et al. Ten-year survival of patients with small cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 1990; 8: 396-401.

7.IV
Komaki R, Meyers C, Shin Dm et al. Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation. Int J Radiat Oncol Biol Phys 1995; 33: 179-182.

7.V
Oosterhout van AG, Ganzevles PG, Wilmink JT et al. Sequelae in long term survivors of small cell lung cancer. Int J Radiat Oncol Biol Phys 1996; 34: 1037-1044.

7.VI
Østerlind K, Hansen HH, Hansen M, Dombernowsky P. Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small cell lung cancer. J Clin Oncol 1986; 4: 1044-1052.

7.VII
Perez CA, Azarnia N, Cox JD, Shapiro SJ. Sequelae of definitive irradiation in the treatment of carcinoma of the lung. In: Motta G. (ed). Lung Cancer: Advanced concepts and present status. Genova, Italy, 1989.

7.VIII
Richardson GE, Tucker MA, Venzon DJ et al. Smoking cessation after successful treatment of small-cell lung cancer is associated with fewer smoking related second primary cancer. Ann Intern Med 1993;119:383-390.

7.IX
Roach M, Gandara DR, Yuo HS et al. Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors. J Clin Oncol 1995;13:2606-2612.

7.X
Twijnstra A, Boon PJ, Lormans ACM et al. Neurotoxicity of prophylactic cranial irradiation in patients with small cell carcinoma of the lung. Eur J Cancer Clin Oncol 1987; 23: 983-986.

7.XI
Zulian GB, Jotterand Bellomo M, Cabrol C, Beris P, Mermillod B, Alberto P. Etoposide and secondary haematological malignancies: coincidence or causality? Ann Oncol 1993; 4: 559-566.

© European School of Oncology, 1996

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