Age has no impact on acute and late toxicity of curative thoracic radiotherapy.

BACKGROUND AND PURPOSE: Radiotherapy is a treatment method frequently employed in the management of thoracic tumours. Although the highest incidence of these tumours is found in elderly people, tolerance to radiotherapy is not well documented in older age groups. Many physicians are tempted to alter the radiotherapy planning in a population with a supposed lower life expectancy in order to prevent acute reactions whereas late reactions are often ignored. The current study aimed to determine the influence of age on the frequency and severity of acute and late side-effects and also whether the prognosis of tumours sufficiently differed between ages to justify different attitudes towards their management. MATERIALS AND METHODS: Data from 1208 patients receiving chest irradiation and included in arms designed with RT of six EORTC randomized trials were evaluated. Data were extracted by a computer program elaborated for each study and were merged in a single database for analysis. Patients were split into six age ranges from 50 to 70 years and over. Survival and late toxicity were calculated with the Kaplan-Meier method and comparison between age groups was performed with the logrank test. The gamma-statistic test was used to test the impact of age on acute toxicity occurrence. RESULTS: Survival adjusted for the primary location of the tumour was comparable in each age group (P = 0.82). Data regarding age and acute toxicity were available for 1208 patients who experienced 640 grade > or =1 toxicities. The difference in distribution over age was not significant for acute nausea, dyspnea, oesophagitis, weakness and WHO performance status alteration. Weight loss was significantly different with regards to age with a trend toward increased weight loss in older age groups (P = 0.002). To minimize actuarial bias, only patients surviving more than 90 days were analyzed for late effect risks. Late toxicities were examined only if they occurred before an eventual tumour failure in order to avoid confusion between effects of first and second line treatments. In such conditions, 1082 grade > or =1 late toxicities were recorded in 935 patients of 1106 available for analysis. The mean time to complication was 13 months and was similar in all age groups. Forty percent of patients were free of complication at 4 years, the logrank test showing no significant difference between age groups (P = 0.57). For grade >2 side-effects, the calculation did not show any difference between each age group (P = 0.1). A detailed analysis of late dyspnea and late weakness studied with the same method did not demonstrate any difference between age groups. Only grade >2 late oesophagitis demonstrated a significant trend to be more frequent in older patients (P = 0.01), but this difference disappeared after adjustment on study (P = 0.32). CONCLUSION: The absence of toxicity observed in the current study regardless of age reinforces the conviction that age per se is not a sufficient reason to exclude patients in good general condition with thoracic tumour from curative radiotherapy when medically indicated.

The toxicity of radiotherapy following high-dose chemotherapy with peripheral blood stem cell support in high-risk breast cancer: a preliminary analysis.

High-dose chemotherapy with autologous bone marrow and/or peripheral blood stem cell (PBSC) support is increasingly employed in the adjuvant treatment of high-risk breast cancer. Subsequent radiotherapy has been reported to be associated with morbidity and mortality resulting from pulmonary toxicity. In addition, the course of radiation therapy may be hampered by excess myelosuppression. The aim of this study was to investigate the contribution to radiation-induced toxicity of a high-dose chemotherapy regimen (CTC) that incorporates cyclophosphamide, thiotepa and carboplatin, in patients with high-risk breast cancer. In two randomised single institution studies, 70 consecutive patients received anthracycline-containing adjuvant chemotherapy (FEC: 5-fluorouracil, epirubicin and cyclophosphamide) followed by radiotherapy to achieve maximal local control. Of these patients, 34 received high-dose CTC with autologous PBSC support. All patients tolerated the full radiation dose in the planned time schedule. Radiation pneumonitis was observed in 5 patients (7%), 4 of whom had undergone high-dose chemotherapy (P = 0.38). All 5 responded favourably to prednisone. Fatal toxicities were not observed. Myelosuppression did not require interruption or untimely discontinuation of the radiotherapy, although significant reductions in median nadir platelet counts and haemoglobin levels were observed in patients who had received high-dose chemotherapy (P = 0.0001). The median nadir of WBC counts was mildly but significantly decreased during radiotherapy (P = 0.01). Red blood cell or platelet transfusions were rarely indicated. Adequate radiotherapy for breast cancer can be safely administered after high-dose CTC with autologous PBSC support. Radiation-induced myelotoxicity is clearly enhanced following CTC, but this is of little clinical significance. Radiation pneumonitis after high-dose therapy may occur more often in patients with a history of lung disease or after a relatively high radiation dose to the chest wall. Other high-dose regimens, particularly those incorporating drugs with known pulmonary toxicity (such as BCNU), may predispose patients to radiation pneumonitis.

Feasibility of escalating daily doses of cisplatin in combination with accelerated radiotherapy in non-small cell lung cancer.

The aim of this study was to determine whether it is feasible to reduce the overall treatment time from 7 to 4 weeks in patients with non-small cell lung cancer (NSCLC) receiving radiotherapy with cisplatin. This follows an EORTC phase III randomised trial (08844) in which cisplatin given before each radiation dose resulted in improved local control and survival, but which had a relatively long treatment period of 7 weeks [Schaake-Koning et al., N Engl J Med 1992, 326, 524-530]. 38 patients with confirmed NSCLC (2 stage I, 1 stage II, 18 stage IIIA, 17 stage IIIB) received a total tumour dose of 55 Gy/20 fractions/26 days, from January 1992 to March 1994. Daily fractions of 2 Gy (5 times/week) were given to the macroscopic tumour and the non-involved adjacent lymph node areas. During the same session, a dose of 0.75 Gy was given to the macroscopic tumour (simultaneous boost). Cisplatin 6 mg/m2 was administered 1-2 h before each fraction, in an escalating total dose, during week 1 in 3 patients, during weeks 1 and 2 in 6 patients, during weeks 1, 2 and 3 in 5 patients and during the whole treatment in 24 patients. 38 patients were evaluable for acute side-effects (WHO). Maximal therapy-related toxicity (WHO) was grade 3 (nausea/vomiting in 2 patients, oesophagitis in 3 patients, dyspnoea in 3 patients, cough in 1 patient). Late side-effects were evaluated in 34 patients. There was grade 2 oesophagitis in 2 patients; grade 3 toxicity in 8 patients (tiredness in 3 patients, dyspnoea in 3 patients, oesophagitis in 2 patients); grade 4 toxicity in 4 patients (dyspnoea in 3 patients, cough in 1 patient). Pulmonary fibrosis grade 3 occurred in 4 and grade 4 in 6 patients. One patient developed a severe (grade 3) radiation pneumonitis. The low incidence of acute and late side-effects with this treatment, combining daily administration of 6 mg cisplatin with radical radiotherapy using a simultaneous boost technique, indicates that escalation of the radiation dose seems feasible.

Radiotherapy in non-small cell lung cancer: optimal doses and schedules.

The doses and schedules for radiation therapy as applied in Stages IIIB and IIIA non-small cell lung cancer patients show a great variety. Depending on its intent, several purely palliative schemes can be used. When a curative intent scheme is considered, patients can be treated with a more experimental approach as several options are tested to increase selectively the radiation dose in the tumour areas. If improvements in treatment schemes are proven, new standards can be set.

Radiosensitization by cytotoxic drugs. The EORTC experience by the Radiotherapy and Lung Cancer Cooperative Groups.

UNLABELLED: A three-arm randomized trial was performed to assess the acute and late toxicity and the impact on survival of the combination high-dose, split-course radiotherapy with 30 mg/m2 cisplatin (cDDP) weekly, with 6 mg/m2 cisplatin daily compared to radiotherapy alone in patients with non-small cell lung cancer (NSCLC). The study started in May 1984 and was closed in May 1989 after 331 patients were randomised. The analysis was performed after a minimum follow-up period of 22 months. Radiotherapy (RT) consisted of 30 Gy, 10 fractions, five fractions a week; then a 3-week split followed by 25 Gy in 10 fractions. Nausea and vomiting were increased for a majority of the patients in the combined treatment arms during treatment. There was no addition of bone marrow suppression, renal dysfunction or esophagitis. Increase of late radiation damage was not observed. Local control (= absence of local progression) was improved for patients treated according to the daily cisplatin arm. This has lead to an improvement in overall survival. There was no effect in time to distant metastasis due to the combined modality. The treatment influence was confirmed in the multivariate analysis. CONCLUSION: local control and survival can be improved by combining radiotherapy with daily low-dose cisplatin in patients with inoperable NSCLC.

Feasibility study of FEC-chemotherapy with dose-intensive epirubicin as initial treatment in high-risk breast cancer.

BACKGROUND: The prognosis of patients with stage III B breast carcinoma with metastasis to the apical axillary lymph nodes is poor despite adequate local control achieved by surgery and/or radiation therapy. This study evaluated the feasibility of a dose-intensive up-front chemotherapy regimen in this subgroup of patients. PATIENTS AND METHODS: A preoperative chemotherapy regimen consisting of 3 courses of fluorouracil 500 mg/m2, dose-intensive epidoxorubicin 120 mg/m2 and cyclophosphamide 500 mg/m2 (DIE-FEC), was administered at 21-day intervals without hematopoietic growth factors to 31 patients with apex-positive disease. All patients were below 60 years of age and none had had prior chemotherapy or radiotherapy. RESULTS: Seven patients achieved clinical complete responses (23%), and 21 achieved clinical partial responses (68%); three patients had stable disease (10%), one of whom had only ductal carcinoma in situ at histopathologic evaluation, which suggested an additional response to therapy. The major toxicity was moderate bone marrow suppression with a median WBC nadir of 1650/microliters (range 500-4600). Other toxic effects were mild. CONCLUSION: DIE-FEC is well-tolerated and highly effective as up-front chemotherapy in relatively young patients with high-risk breast cancer, with a 90% (CI 74%-98%) clinical objective response rate.

Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer.

BACKGROUND AND METHODS: Cisplatin (cis-diamminedichloroplatinum) has been reported to enhance the cell-killing effect of radiation, an effect whose intensity varies with the schedule of administration. We randomly assigned 331 patients with nonmetastatic inoperable non-small-cell lung cancer to one of three treatments: radiotherapy for two weeks (3 Gy given 10 times, in five fractions a week), followed by a three-week rest period and then radiotherapy for two more weeks (2.5 Gy given 10 times, five fractions a week); radiotherapy on the same schedule, combined with 30 mg of cisplatin per square meter of body-surface area, given on the first day of each treatment week; or radiotherapy on the same schedule, combined with 6 mg of cisplatin per square meter, given daily before radiotherapy. RESULTS: Survival was significantly improved in the radiotherapy-daily-cisplatin group as compared with the radiotherapy group (P = 0.009): survival in the radiotherapy-daily-cisplatin group was 54 percent at one year, 26 percent at two years, and 16 percent at three years, as compared with 46 percent, 13 percent, and 2 percent, respectively, in the radiotherapy group. Survival in the radiotherapy-weekly-cisplatin group was intermediate (44 percent, 19 percent, and 13 percent) and not significantly different from survival in either of the other two groups. The survival benefit of daily combined treatment was due to improved control of local disease (P = 0.003). Survival without local recurrence was 59 percent at one year and 31 percent at two years in the radiotherapy-daily-cisplatin group; 42 percent and 30 percent, respectively, in the radiotherapy-weekly-cisplatin group; and 41 percent and 19 percent, respectively, in the radiotherapy group. Cisplatin induced nausea and vomiting in 86 percent of the patients given it weekly and in 78 percent of those given it daily; these effects were severe in 26 percent and 28 percent, respectively. CONCLUSIONS: Cisplatin, given daily in combination with the radiotherapy described here to patients with nonmetastatic but inoperable non-small-cell lung cancer, improved rates of survival and control of local disease at the price of substantial side effects.

High dose rate brachytherapy in patients with local recurrences after radiotherapy of non-small cell lung cancer.

Thirty-one patients with recurrences of locally advanced Stage III lung cancer were treated with high dose rate brachytherapy. All patients had previously received a full course external beam irradiation. All treatments were performed under topical anaesthesia and took 6-14 min depending on the strength of the Iridium-192 source. The high dose rate brachytherapy was calculated as 10 Gy at one cm from the source axis for each session and this was repeated every 2 weeks to a maximum of three sessions. All treatments were well tolerated and no immediate treatment related complications were observed. Response evaluation 6 weeks after high dose rate brachytherapy showed that there was a partial response in 22 patients and nine patients were non-responders. Median survival was 7 and 3 months, respectively. All non-responders had initially presented with a T4N3 tumor. Ten patients died because of fatal pulmonary hemorrhages 2-24 weeks after brachytherapy and three others died because of a bronchial fistula. Endobronchial brachytherapy appears to be a valuable treatment alternative for local palliation. However, the relatively high number of complications at follow-up warrants further investigation to establish the optimal benefit to be derived from high dose rate brachytherapy treatment of locally advanced Stage III tumors.

The need for immediate monitoring of treatment parameters and uniform assessment of patient data in clinical trials. A quality control study of the EORTC Radiotherapy and Lung Cancer Cooperative Groups.

A quality control study was performed during the EORTC phase III study 08844: radiotherapy combined with low dose cisplatin (cDDP) in inoperable non-metastatic non-small cell lung cancer. Radiation alone (55 Gy, split course) was compared to radiotherapy with 30 mg/m2 cisplatin once a week and to radiotherapy with 6 mg/m2 cisplatin daily. The purpose of the control study was to check to which degree protocol guidelines were followed and to measure the extent of differences in assessment of tumour response, recurrence and toxicities between the individual institutes. A review team, consisting of a data manager, a diagnostic radiologist, a chest physician and two radiotherapists reviewed entry criteria, treatment data, tumour responses, recurrences and late toxicity of 177 patients (a total of 300 patients was required for the trial). Only departments which had entered more than 5% of this number of patients were visited. There was a 15% difference in T staging of the patients and a 17% discrepancy in N stage scoring between the review team and the local investigators. Radiotherapy field sizes were insufficient in 15% of the eligible patients during a period of the radiotherapy; in another 17% patients the tumour free margin was less than 1 cm. Radiation doses were incorrectly given to 7% of the patients. The given doses of cisplatin deviated in 10% of the patients treated with combined modalities. The interpretation of chest X-rays and computed tomography (CT) showed important differences in tumour response, tumour recurrence and late toxicity. From these data it is concluded that immediate checks can detect errors in treatments as planned at the local level and will make corrections possible at an early stage in multicentre studies. The quality of trial results will thus be improved. Uniform assessment of treatment outcome, tumour progression and forms of toxicity will lead to more sound trial conclusions.

Radiotherapy combined with low-dose cis-diammine dichloroplatinum (II) (CDDP) in inoperable nonmetastatic non-small cell lung cancer (NSCLC): a randomized three arm phase II study of the EORTC Lung Cancer and Radiotherapy Cooperative Groups.

UNLABELLED: A randomized Phase II study was carried out to assess the feasibility and tumor response of radiotherapy combined with low dose cis-diammine dichloroplatinum (II), (cDDP), in patients with inoperable non-small cell lung cancer (NSCLC). One hundred patients were treated with either radiotherapy alone (arm I), with radiotherapy plus cDDP given once a week (arm II), or daily (arm III). The endpoints were acute and late toxicity and tumor response. Esophagitis was observed more frequently in the cDDP arms, but was severe in only 4% of the patients. Nausea and vomiting were more frequent and more severe in patients treated with the combination therapy. In 37% they required medication or were intractable (WHO, grade 3-4). There were no deficits in renal function when hydration schemes were used. Lung fibrosis was similar in the three arms, with an average of 75% of which 50% was severe. Response (complete and partial remission) was observed in 21 out of 34 eligible patients in arm I, in 20 out of 30 patients in arm II, and 20 out of 30 patients in arm III. The 1- and 2-year survival data were 38% and 14% for radiotherapy alone, 49% and 17% for radiotherapy and cDDP given once a week, and 50% and 32% for radiotherapy combined with daily cDDP. IN CONCLUSION: a combination of concomitant cDDP and radiotherapy is tolerable. Based on these results, the study has been continued as a Phase III study with survival as most important end point.

Radiotherapy and cis-diammine dichloroplatinum (II) as a combined treatment modality for inoperable non-small cell lung cancer: a dose finding study.

A dose finding study was carried out to establish the dose of cis-diammine dichloroplatinum (II), cDDP, that can be combined with high dose radiotherapy routinely in patients with inoperable non-small cell lung cancer. The patients were irradiated over a period of 2 weeks, 5 fractions a week, followed by a rest period of 14 days. Thereafter a second course of 2 weeks was given; a total dose of 55 Gy was achieved. The weekly cDDP administration in a 3 hour infusion with pre- and posthydration preceded the first day irradiation. Twenty patients were evaluable for acute toxicity. The dose limiting factor appeared to be severe nausea and vomiting, which was not responsive to anti-emetic therapy at a cDDP level of 35 mg/m2. No renal or significant hematological side effects were observed. Complete response was seen in 10 patients, using X rays and CT scans; this was confirmed by bronchoscopy with biopsies in 9 patients. Partial remission was scored in 7 patients and no change in 4 patients. cDDP as a radiosensitizer will be further studied at a dose level of 30 mg/m2 a week or 6 mg/m2 a day in a prospective, randomized EORTC Phase II study.

Adjuvant chemo- and hormonal therapy in locally advanced breast cancer: a randomized clinical study.

UNLABELLED: Between 1977 and 1980, 118 breast cancer patients with locally advanced disease, T3B-4, any N, M0 or T1-3, tumor positive axillary apex biopsy, were randomized to one of three arms: I: radiotherapy (RT) to the breast and adjacent lymph node areas; II: RT followed by 12 cycles of cyclophosphamide, methotrexate, 5 fluorouracil (CMF) and tamoxifen during the chemotherapy period; III: 2 cycles of adriamycin and vincristine (AV), alternated with 2 cycles of CMF, then RT, followed by another 4 cycles of AV, alternated with 4 CMF; tamoxifen during the entire treatment period. The median follow-up period was 5 1/2 years. The adjuvant chemo- and hormonal therapy did not improve the overall survival; the 5-year survival was 37% for all three treatment arms. There was no statistically significant difference in RFS between the three modalities, nor when arm I was compared to arm II and III together, p = 0.11. Local recurrence (LR) was observed in 24 of the 86 patients (28%) who had reached complete remission (CR). LR was not statistically different over the three treatment arms. In 18 of the 24 patients with LR, distant metastases appeared within a few months from the local recurrence. In arm III, the CR rate after 4 cycles AV plus CMF and RT hardly changed after another 8 cycles of chemotherapy. The menopausal status did not influence the treatment results. Dose reduction in more than 4 cycles of chemotherapy was accompanied by better results, p = 0.04. IN CONCLUSION: adjuvant chemo- and hormonal therapy did not improve RFS and overall survival. These findings do not support the routine use of adjuvant chemo- and endocrine therapy for inoperable breast cancer.

Prognostic factors of inoperable localized lung cancer treated by high dose radiotherapy.

A retrospective study was made of the results of high dose radiotherapy (greater than or equal to 50 Gy) given to 171 patients with inoperable, intrathoracic non small cell lung cancer from January 1971-April 1973. Local control was dependent on the total tumor dose: after one year local control was 63% for patients treated with greater than 65 Gy, the two year local control was 35%. If treated with less than 65 Gy the one year local control was less than or equal to 40%. Tumor doses correlated with the size of the booster field. If the size of the booster field was less than 100 cm2, the one year local control was 72%; the two year local control was 44%. Local control was also influenced by the performance status, by the localization of the primary tumor in the left upper lobe and in the periphery of the lung. Local control for tumors in the left upper lobe and in the periphery of the lung was about 70% after one year, and about 40% after two years. The one and two years survival results were correlated with the factors influencing local control. The dose factor, the localization factors and the performance influenced local control independently. Tumors localized in the left upper lobe did metastasize less than tumors in the lower lobe, or in a combination of the two. This was not true for the right upper lobe. No correlation between the TNM system, pathology and the prognosis were found.