Phase II study of high dose ifosfamide plus mesna in inoperable non small cell lung carcinoma.
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Biomedical subjects
Publications and source records attributed to R Arriagada.
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Eleven cases of epithelial tumours of the thymus or thymoma and two thymuses without tumour were studied, using immunohistochemistry with anti-keratin antibodies (KL-1) which recognise cyto-keratin with a high molecular weight. In the normal thymus, KL-1 positivity seems to be limited to medullary epithelial elements and in particular Hassal's corpuscles. All the epithelial thymic tumours studied showed a net positivity for KL-1 overall in the tumour cells. This result and the demonstration of more or less well differentiated Hassal's corpuscles in these tumours make one think that these epithelial thymic tumours express some characters in relation with a differentiation of medullary type.
One hundred nine patients with limited small cell lung carcinoma were entered in a phase II study of treatment consisting of alternating 6 cycles of combination chemotherapy and 3 courses of mediastinal radiotherapy. Chemotherapy consisted of 40 mg doxorubicin/m2 on day 1; 75 mg etoposide/m2 on days 1, 2, and 3; 300 mg cyclophosphamide/m2 on days 3, 4, 5, and 6; and 400 mg methotrexate/m2 on day 2 (plus folinic acid rescue) or 100 mg cisplatin/m2 on day 2. The total mediastinal radiation dose was 45 or 55 Gy. A 6- to 8-cycle maintenance chemotherapy followed this induction protocol. The complete remission rate at the end of the induction therapy was 79%. The local recurrence rate was 25%, and the distant metastases rate was 52%. Median survival is 17.2 +/- 1.2 months and survival rate at 3 years is 26%. Lethal toxicity occurred in 3% of the patients, and long-term survivors are being evaluated. Our results justify further investigations with this alternating schedule.
Progress achieved in the understanding of small cell lung cancer (SCLC) include: the establishment and characterization of cell lines with the identification of a variant type with poor prognosis; the use of non-specific biochemical markers such as neuron specific enolase (NSE) and calcitonin; the generation of monoclonal antibodies (MoAbs) directed against SCLC antigens; growth factors including GRP and IGF. GRP or human bombesin produced by the tumor cells favours their own growths; in cytogenetics, with the observation of a characteristic chromosomal abnormality: the deletion of the short arm of chromosome 3 (3p 14-23). The region deleted is currently under study to identify the genes potentially involved in the oncogenesis of SCLC. the activation of several oncogenes: C-myc, N-myc, L-myc, Myb, Raf-1. The amplification of C-myc favors the tumor cell progression and is related to a bad prognosis. This biological approach has confirmed the neuroendocrine origin of these tumor cells (as a result of protein studies of the cytoskeleton and of MoAbs); it has allowed the use of tumor markers in the diagnosis and work-up of SCLC and the consideration of new therapeutic approaches. Current studies concern the deletion of 3p- and the integration of the cytogenetic data, growth factors and oncogenes in a coherent model of the genesis of SCLC.
The results of 2 chemotherapeutic regimens used in 170 cases of inflammatory breast cancer were compared with those obtained in 60 historical controls treated with radiotherapy and hormonal therapy. Inflammatory breast cancers could be divided into evolutive phase 2 with limited signs of inflammation and evolutive phase 3 where inflammation involved the whole breast. The 60 controls had been treated between 1967 and 1974 with radiotherapy (45 Gy plus an extra dose of 20 or 30 Gy); premenopausal patients underwent ovarian irradiation. The 91 patients treated with regimen A between 1976 and 1980 received a DVM-type induction chemotherapy (doxorubicin 40 mg/m2 on day 1, vincristin 1 mg/m2 on day 2, and methotrexate 6 mg/m2 on days 3, 4, 5) every 3 or 4 weeks, and a VCF-type maintenance chemotherapy (vincristin 1 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2, 3, 4 and 5-fluorouracil 300 mg/m2 on days 2, 3, 4) every 4 weeks. Premenopausal patients had their ovaries irradiated; postmenopausal patients received tamoxifen. The therapeutic sequence was: 3 DVM - 45 Gy - DVM - 15 Gy - 4 DVM - 4-12 VCF. The 79 patients treated between 1980 and 1982 with regimen B received a DVCMF-type induction therapy (doxorubicin 50 mg/m2 on day 1, vincristin 0.6 mg/m2 on day 2, 5-fluorouracil 300 mg/m2 on days 3, 4, 5, cyclophosphamide 200 mg/m2 on days 3, 4, 5 and methotrexate 10 mg/m2 on days 3, 4, 5) every 4 weeks. Hormonal therapy was the same as with regimen A. The sequence was 3 DVCMF - 45 Gy - DVM - 20-25 Gy - 4 DVM - 4-12 VCF. The survival rate at 3 years was 42% in controls, 53% in regimen A patients and 74% in regimen B patients (P less than 0.05). The relapse-free survival rates in these three groups at 3 years were 15%, 32% and 54% respectively (P less than 0.0008). These results suggest that a multidisciplinary approach and initial chemotherapy are useful in this type of breast cancer. The value of prolonged maintenance treatment is discussed.
Between June 1970 and April 1982, 592 patients with unilateral T1 and small T2 breast cancers were managed conservatively at the Institut Gustave-Roussy. The treatment policy for the axilla was to perform a lower axillary dissection and to proceed to axillary clearance ( +/- radiotherapy) in patients with axillary invasion by tumor (N+). Some N+ patients had only lower axillary dissection and radiotherapy. Five hundred fifty-eight patients underwent axillary surgery which was a lower axillary dissection in 374 patients (67%) and axillary clearance in 184 patients (33%). There was axillary invasion in 198 cases (36%). Only five patients relapsed in the axilla and the probability of axillary relapse at 5 years was 1.2%. There were no axillary relapses in N+ patients who had had an axillary clearance whether irradiated or not. The incidence of upper limb complications was significantly greater in patients undergoing axillary surgery and radiotherapy compared with axillary surgery alone (p less than 0.0001). It is concluded that a lower axillary dissection accurately identifies N-patients and an axillary clearance in N+ patients ensures good local control and avoids the morbidity associated with axillary irradiation.
The fibroscopic examination of 180 patients treated for small cell lung carcinoma is studied. The fibroscopy permits a good diagnosis in at least 93.3% of cases. In the case of failure a mediastinoscopy or transparietal cytopuncture are indicated. The absence of a correlation between a radiological remission and endoscopic remission justifies an endoscopic control prior to each therapeutic step. After treatment, the endoscopy permits the evaluation of chemotherapeutic and mainly radiotherapeutic bronchial sequellae. Two out of 70 patients treated by both chemotherapy and radiotherapy presented normal bronchial endoscopy.
Radiotherapy plays a vital role in the treatment of small cell lung carcinoma. Nevertheless, it has recently become a subject of controversy. Local recurrences are frequently the cause of therapeutic failure in localized stages. The analysis of randomized trials has not clearly established the role of radiotherapy in the improvement of survival. The quality of radiotherapy, the dose, the volume, the fractionation as well as combined radiotherapeutic/chemotherapeutic regimens appear to be important factors.
One hundred and nine patients with limited small cell lung carcinoma were entered in a phase II study alternating six cycles of combination chemotherapy and three courses of mediastinal radiotherapy. Chemotherapy consisted of doxorubicin 40 mg/m2 day 1, etoposide 75 mg/m2 days 1, 2, 3, cyclophosphamide 300 mg/m2 days 3, 4, 5, 6, and methotrexate 400 mg/m2 day 2 (+folinic acid rescue) or cisplatin 100 mg/m2 day 2. The total mediastinal radiation dose was 45 or 55 Gy. A 6 to 8 cycle maintenance chemotherapy followed this induction protocol. The complete remission rate at the end of the induction therapy was 79%. The local recurrence rate was 25% and the distant metastases rate was 52%. Median survival is 17.2 +/- 1.2 months and survival rate at 3 years is 26%. Lethal toxicity occurred in 3% of patients during induction therapy, and long term survivors are being evaluated. Our results justify further investigations with this alternating schedule.
Prophylactic cerebral irradiation reduces significantly the occurrence of cerebral metastases, but its modalities need to be defined. Late neurological sequelae have been reported. Prospective trials are required in order to define its exact value.
The authors analyze the respiratory sequelae in 19 patients with limited small cell lung carcinoma who survived for more than 30 months following an alternating chemo-radiotherapeutic combined regimen. The clinical tolerance measured with respiratory functional test is acceptable. In two patients an effort dyspnea is increased by evolutive, chronic obstructive bronchopneumopathy. Radiologic sequellae are constant and correlated with the volume of irradiation and cumulative etoposide doses. The role of a combined chemo-radiotherapeutic in pulmonary toxicity is discussed.
Three to 15% of the whole population of patients with small cell lung carcinoma are long-term survivors. In a view of preventing iatrogenic sequellae and obtaining a better definition of therapeutic indications, the prognostic factors in this population will be defined.