Effect of split-course radiotherapy on survival and local control in advanced localized prostatic carcinoma.

PURPOSE: to analyze the effect of overall treatment time of radiotherapy on survival and local control in locally advanced prostatic cancer in a split-course treatment setting. METHODS AND MATERIALS: 168 patients with Stage C prostatic cancer treated during 1979-1989 by the split-course method where the overall treatment time is protracted. Treatment consisted of whole pelvis irradiation of 40 Gy in 4 weeks, followed by a planned 3-week interruption and an additional 26 Gy by the reduced field technique to a total dose of 66 Gy in 9 weeks and 30-33 fractions. The overall treatment time varied from 55 to 100 days. Thirty-eight percent (63) of the patients were treated primarily with radiotherapy, while the rest (105) had received androgen ablative therapy during 2 to 4.5 years before radiotherapy. To examine the effect of treatment time on local control, the patients were divided into three groups ( < or = 63 days, 64-70 days, and > 70 days) by treatment time. RESULTS: the 5-year actuarial survival rates, calculated from the date of diagnosis, were 91% for the hormonally manipulated patients and 69% for the patients treated with radiotherapy alone. The 5-year actuarial local control rates, counted from the start of radiotherapy, were 84% for radiotherapy and 80% for the hormonally manipulated group. Overall, no significant effect of treatment time could be seen, either for radiotherapy alone or for the hormonally manipulated group. The results were similar when the material was further divided by T category and histologic grade. CONCLUSIONS: no significant effect of overall treatment time (55 to 100 days) on survival or local control was found in either group. The survival time from diagnosis was longer in the hormonally pretreated group. Apparently, with adequate doses ( > or = 65 Gy) the overall treatment time becomes less important for local control of advanced prostatic cancer, even in a split-course treatment setting.

Natural interferon alfa as maintenance therapy for small cell lung cancer.

We performed a 3-armed phase III study between 1982 and 1990 to evaluate low dose natural interferon alfa (nIFN-alpha) as a maintenance therapy in small cell lung cancer (SCLC) following induction chemotherapy (CT) and consolidation radiotherapy (RT). All patients received four cycles of CT (cyclophosphamide, vincristine, etoposide), followed by split-course RT (55 Gy in 20 fractions over 7 weeks). 410 patients entered the study. 237 patients who completed induction CT + RT and were classified as responders (complete response + partial response) were randomly assigned to arm 1: low dose nIFN-alpha (91 patients); arm 2: maintenance CT, six cycles of CAP (cyclophosphamide, doxorubicin, cisplatin) (59 patients); or arm 3: control arm (no maintenance treatment) (87 patients). Halfway through the study the CAP arm was discontinued. There was no difference in median survival between the groups (IFN: 11 months, CAP: 11 months, control: 10 months), but a clear difference in long-term survival and in survival in the limited disease group, favouring nIFN-alpha maintenance therapy. Proportional hazards regression analysis also showed a significant effect of IFN treatment on survival. Our results suggest a role for nIFN-alpha in maintaining a clinically disease-free status achieved with other treatment modalities.

Radical surgery and postoperative split-course radiotherapy in squamous cell carcinoma of the mobile tongue: factors influencing local control and the time to recurrence.

During 1981-1988 63 patients with squamous cell carcinoma of the oral tongue (27 females and 36 males) were treated with radical surgery and postoperative split-course radiotherapy. The 3-week rest period was compensated with a 10% increase in the total radiation dose to 66 Gy. The local control rate was 76% in stage I, 71% in stage II, 45% in stage III and 0% in stage IV. Failures were observed in 25 (40%) patients, and 8 patients died of intercurrent diseases. For further analysis the material was stratified in three groups according to the time interval between surgery and postoperative radiotherapy: less than 6 weeks, 6-8 weeks and greater than 8 weeks. The local control rate in the three strata were 75, 57 and 44%, and the 5-year actuarial survival 61, 46 and 30%, respectively. In the logistic regression analysis and the proportional hazard's regression analysis the histologic grade of the primary tumour and the time interval between surgery and the start of radiotherapy were the most important factors influencing respectively local control and time to recurrence. However, it appeared that the lengthening of the time interval was often caused by factors or events which directly can influence the prognosis, such as surgical complications, infections and poor general condition. When cases with such special causes for lengthening of the interval were excluded, the effect of the time interval nearly completely disappeared. It would seem that a final evaluation of the effect of the time interval requires a prospective randomized trial. The same may well hold true for reliable evaluation of the influence of overall treatment time.

A comparison of cis-platinum-vindesine and cis-platinum-etoposide combined with radiotherapy for previously untreated localized inoperable non-small cell lung cancer.

Seventy-two previously untreated patients with localized inoperable non-small cell lung cancer were randomized to a study comparing the efficacy of cis-platinum-vindesine (P-VDS) and of cis-platinum-VP16 (P-VP16), both combined with split-course radiotherapy. Fifty-nine patients were evaluable for response after the minimum requirement of two chemotherapy cycles. Both arms were further randomized to two split intervals, 3 or 5 weeks. The response rate to chemotherapy only (three cycles) was 66% for P-VDS and 50% for P-VP16. Radiotherapy increased the response rates to 83 and 67%, respectively. A Karnofsky score of 80% or more and the 3-week split interval were significant positive prognostic factors. Of all patients, 66% had local or combined recurrences and 17% relapsed at a distant site only. Since the 2-year survival rates are not strikingly better than those obtained by radiotherapy alone, we feel that these regimens should be restricted to further investigations of the role of chemotherapy in the treatment of different clinical presentations of NSCLC.

Treatment of small cell lung cancer. Two-drug versus four-drug chemotherapy and loco-regional irradiation with or without prophylactic cranial irradiation.

Fifty-five patients with untreated small cell lung cancer were allocated randomly to receive either a standard 2-drug or a 4-drug chemotherapy regimen. The patients were further randomized to receive or not to receive prophylactic cranial irradiation (PCI) 40 Gy/20 fractions/4 weeks. Each patient also received split-course irradiation against the primary tumour (55 Gy/25 fractions/8 weeks), the mediastinum, and the supraclavicular areas. The standard 2-drug regimen consisted of cyclophosphamide 10 mg/kg i.v. days 1-4 and vincristine 1 mg i.v. days 1 + 4; every 4 weeks. The 4-drug regimen comprised cyclophosphamide 10 mg/kg i.v. days 1-3, vincristine 2 mg i.v. day 1 and 1 mg i.v. day 5, methotrexate 30 mg i.v. days 3 and 5, CCNU 80 mg/m2 i.v. day 2; every 7 weeks. The total treatment time for both protocols was 9 to 12 months. Objective response after 2 cycles of chemotherapy was seen in 46% of patients with the 2-drug regimen and in 56% with the 4-drug regimen. Local radiotherapy increased the response rates to 58% and 90% respectively. The median survival time was 12 months with the 2-drug regimen and 14 months with the 4-drug regimen. The 2-year and 3-year survival rates were 11% and 0% in the 2-drug group and 19% and 15% in the 4-drug group respectively. Toxicity was more severe in the 4-drug group with 4 deaths due to myelosuppression. Altogether, 25 patients received PCI. This did not in any subgroup increase median survival significantly but a reduction of relapses in the central nervous system was seen. Median survival was 13 months with versus 10 months without PCI; 2-year survival rates were 15% and 6% respectively. Morbidity due to PCI did not occur. Although no statistically significant survival advantage could be documented, there was obviously a higher rate of complete responses with multidrug therapy, and longer median duration of remission, median survival and maximal survival.

Inoperable non-small cell lung cancer: radiation with or without chemotherapy.

We report a randomized multicentre study of split-course radiotherapy (RT), with or without combination chemotherapy (CT), in 238 patients with inoperable non-small cell lung cancer (NSCLC), previously untreated, confined to one hemithorax and the mediastinal nodes. In both treatment groups RT consisted of 55 Gy in 20 F given over 7 weeks with a 3-week rest interval. CT consisted of the 3-drug regimen CAP: C = cyclophosphamide 400 mg/m2, A = adriamycin 40 mg/m2, P = cisplatin 40 mg/m2; 2 cycles of CAP given before RT, one during the rest interval and six after RT. Seventy per cent in the RT arm and 67% in the RT-CT arm had epidermoid carcinoma. No significant difference was apparent between the RT and the RT-CT arms with respect to objective response rates (CR + PR) (44 and 49%, respectively), median duration of response (278 and 320 days), local failure (31 and 20%), distant progression (23 and 20%) or median survival (311 and 322 days). The survival figures showed an almost significant (P = 0.05) therapeutic advantage of the combined regimen with stage IIIM0 disease. Progressive disease was the cause of death in 92% and 88%. We conclude that chemotherapy did not contribute significantly to either local control or survival as compared to radiotherapy alone.

Vincristine-cyclophosphamide, the classical two-drug regimen for small-cell lung cancer, evaluated in a randomized study with vindesine.

We performed a randomized study from February 1979 to August 1981 in patients with small-cell lung cancer (SCLC) with the aim of defining the potential advantages of replacing vincristine (VCR) with vindesine (VDS), at that time a new semisynthetic vinca alcaloid, in the classical two-drug combination cyclophosphamide (CTX)-VCR. A total of 116 previously untreated patients were admitted to the study. Of 104 patients evaluable for response, 49 had limited disease and 55 extensive disease. Patients received 10 mg/kg CTX i.v. on days 1-4 and either 1 mg VCR i.v. or 2 mg/m2 VDS i.v. on days 1 and 4, and repeatedly every 4 weeks for 12 courses. In addition, the patients with limited disease received split-course radiotherapy (30 Gy/10 F, 3 or 5 weeks rest, 25 Gy/10 F, total treatment time 7 or 9 weeks) to the primary tumor, the mediastinum, and the supraclavicular areas between the second and third cycles of chemotherapy. The response rate to the first two chemotherapy cycles was 47% (4 complete response [CR] and 22 partial response [PR]) to CTX-VCR and 47% (4 CR and 19 PR) to CTX-VDS. Subsequent to radiotherapy the response rate increased to 93% for CTX-VCR and 100% to CTX-VDS, respectively, in the patients with limited disease. Local recurrence and/or progression occurred in 49% of limited disease responders and in 96% of extensive disease responders. In responders with limited disease, the first site of relapse was loco-regional in 25% for the VDS group as opposed to 15% in VCR group. In the patients with extensive disease, the corresponding figures were 62% for the VDS and 50% for the VCR group. Median duration of remission in all patients treated with CTX-VCR was 132 days compared to 203 days in the CTX-VDS group (not significant, NS). Median survival was 338 days for CTX-VCR vs. 342 for CTX-VDS in patients with limited disease, and 214 days for CTX-VCR vs. 312 days for CTX-VDS in extensive disease (NS). One-year survival figures were 47% for CTX-VDS and 35% for CTX-VCR patients. Two-year survivals were 4 and 9%, respectively. Neurotoxicity was the main toxic manifestation in both treatment groups. Severe peripheral neuropathy (grade 4, World Health Organization [WHO]) did not occur with either drug regimen. Treatment was discontinued because of grade 2-3 neuropathy in one patient after 6 cycles of CTX-VCR and in five patients after 1-6 cycles of CTX-VDS.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvant postoperative radiotherapy, chemotherapy, and immunotherapy in stage III breast cancer. II. 5-year results and influence of levamisole.

One hundred twenty pathologically confirmed operable Stage III breast cancer patients were randomized to receive either postoperative radiotherapy or chemotherapy, or a combination of these, with or without levamisole immunotherapy. Radiotherapy was given to regional lymph nodes and chest wall. Chemotherapy consisted of six cycles of vincristine, doxorubicin, and cyclophosphamide. Radiotherapy provided local and chemotherapy systemic control over the tumor, but the best patient-saving results were achieved with a combination of radiotherapy and chemotherapy. This clinical trial was commenced in 1976, and the first 60 of 120 patients also received oral levamisole, 150 mg/day, on 2 consecutive days weekly as immunotherapy. All patients were followed for at least 5 years. At this stage levamisole seems to increase disease-free and overall survival in all three treatment arms (radiotherapy, chemotherapy, combined treatment). Significance is reached in disease-free survival (P = 0.035) and overall survival, adjusted for all other treatment modalities (P = 0.019).

Effects of roentgen irradiation on human melanoma metastases in the skin.

Skin metastases of malignant melanomas in 17 patients were irradiated with three different levels of total dose (40 Gy, 60 Gy and 80 Gy), using a constant fraction size of 5 Gy five times a week. The tumors were removed 10 to 14 days after the last irradiation. The morphologic alterations of the tumor tissue correlated with the total dose. More extensive destruction was seen only after 80 Gy, but even at this level and with this fraction size viable appearing tumor cells remained in all cases. The tumors of one patient exhibited exceptional radiosensitivity. No completely resistant tumor was seen.

Prognostic factors in neuroblastoma.

Between 1951 and 1978 88 patients under 15 years of age were admitted with the diagnosis of neuroblastoma or ganglioneuroblastoma to the Helsinki University Central Hospital for treatment. The relative importance of various prognostic factors for survival was investigated by the use of the Cox regression analysis and by comparison of adjusted survival curves. In regression analysis prior to classification of the patient sample, stage emerged as the overwhelmingly most significant prognostic variable, while histology and age showed a weaker effect and chemotherapy did not display any effect in this setting. Adjusted comparison of survival curves showed significantly improved survival for patients under one year of age in combined stages III and IV, and for stage III patients treated with combination chemotherapy following non-radical surgery. Thus, while stage is the strongest overall prognostic factor, the effect of age is seen especially in the more advanced cases and the beneficial effect of chemotherapy in the cases where radical operation has not been possible.

Levamisole in the treatment of stage II breast cancer. Five-year follow-up of a randomized double-blind study.

The effect of levamisole combined with postoperative radiotherapy in Stage II breast cancer was investigated in a double-blind randomized study comprising 72 patients. All patients were followed for at least 5 years. Disease-free survival was slightly prolonged in the levamisole group as a whole. Among postmenopausal patients, levamisole significantly increased both disease-free and total survival (P = 0.003) and P = 0.008, respectively). The levamisole group also showed fewer distant metastases as the first sign of recurrence. Levamisole treatment was associated with a risk of granulocytopenia and agranulocytosis (10%), but, as in the authors' previous studies, this seemed to be totally reversible and did not worsen the prognosis.

Prognosis of cryptogenic fibrosing alveolitis.

We have analysed retrospectively 100 consecutive patients with cryptogenic fibrosing alveolitis, who were treated with corticosteroids and followed for at least three years. At the time of diagnosis biopsy specimens were available in 64 cases. The clinical, radiographic, physiological, and histological features and the response to steroid treatment have been correlated with the prognosis. An early objective functional improvement was observed in 30%. Analysis of the survival data (life table and log rank test) showed a longer survival in younger patients and in patients with a shorter duration of symptoms before presentation, less radiographic abnormality, and less impairment of diffusing capacity, but not clearly in patients with more cellular histological appearances. The most favourable prognostic sign seemed to be an early response to steroid treatment.