Phase II study of intensive chemotherapy with carboplatin, ifosfamide and etoposide plus recombinant human granulocyte colony-stimulating factor and sequential radiotherapy in locally advanced, unresectable non-small-cell lung cancer.

From June 1991 to August 1994, 61 patients with stage III unresectable non-small-cell lung cancer (NSCLC; 16 cases of stage IIIA with N2 bulky disease and 45 cases of stage IIIB) were treated with ifosfamide given i.v. at 3 g/m2 on day 1, carboplatin given i.v. at 200 mg/m2 on days 1 and 2, etoposide given i.v. at 120 mg/m2 on days 1-3 (ICE) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) given s.c. at 5 micrograms/kg on days 4-13. Chemotherapy was given every 3 weeks for up to three cycles and, unless the disease progressed, was followed by thoracic radiotherapy on the tumor volume (total dose 60 Gy) and mediastinum (40 Gy). All patients had measurable or evaluable unresectable disease and a performance status (Eastern Cooperative Oncology Group) of 0-1. Only 61% of the enrolled patients received the full program of chemoradiotherapy according to the study design. At the end of sequential chemo-radiotherapeutic treatment, 41% of the patients had an objective response (24 partial responses and 1 complete response), 31% showed no change and 28% had progressive disease. The response rate noted for patients in stage IIIA with N2 bulky disease and that recorded for patients in stage IIIB did not differ significantly. The median time to progression was 5.4 months and the median survival was 8.2 months, with the 1-year survival rate being 31%. Sites of progression were mostly intrathoracic. Haematological toxicity was the main side effect, with grade III-IV thrombocytopenia being reported in 24% of the 165 courses of intensive ICE chemotherapy given. Febrile neutropenia was described in six courses (three patients). Non-haematological toxicities and radiotherapy-related side effects were generally mild and easily manageable. In conclusion, in unresectable stage III NSCLC a short program of moderately intensified ICE chemotherapy with rhG-CSF protection followed by sequential radiotherapy failed to increase the percentage of objective responses and reached a median survival comparable with that previously achieved with standard doses.

Surgical and adjuvant radiation therapy of resectable retroperitoneal soft tissue sarcomas in adults.

Primary soft tissue sarcoma of the retroperitoneum is a rare disease. A series of 11 evaluable adult patients with retroperitoneal soft tissue sarcomas is reported. These patients were treated with complete surgery and adjuvant radiation therapy (total dose from 50 to 64 Gy) using an 18 MeV linear accelerator. After a median follow-up of 48 months (range, 6-84), 4 patients had a local-regional recurrence, 3 had distant metastases, and 4 died of progressive disease. Four-year estimated disease-free survival was 54.5% and overall survival was 70%. Treatment was well tolerated by most patients: 7 patients experienced moderate gastrointestinal toxicity, mainly nausea and diarrhea, during radiotherapy; 2 cases had weight loss > 15% at the end of the therapy; and chronic ileitis was observed in 2 cases. We conclude that adjuvant radiotherapy seems to reduce the incidence of local-regional recurrences in these patients. No radiation-induced irreversible injury was observed, but one young woman had amenorrhea after radiotherapy. Controlled clinical trials are warranted to define the role and effectiveness of adjuvant radiotherapy and/or chemotherapy in retroperitoneal soft tissue sarcomas.

Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer.

Between January 1987 and June 1991, 173 patients with inoperable non-small cell lung cancer, Stage III, were entered into a randomized trial comparing radiotherapy only (RT) (45 Gy/15 fractions/3 weeks) (arm A) versus RT and a daily low dose of cDDP (6 mg/m2) (arm B). An overall response rate of 58.9% was observed in arm A and 50.6% in arm B, respectively. No differences in the pattern of relapse were noted between the two treatment groups. Median time to progression was 10.6 months for arm A and 14.2 months for arm B. Median survivals were 10.3 months and 9.97 months, respectively. Toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant advantage of the combined treatment over radiation therapy only was found. The encouraging results achieved in some trials together with the intractability of the disease suggest that further efforts should be made to optimize clinical trial protocols, perhaps by reviewing the radiobiological and pharmacological basis of the combined treatment.

Locally advanced breast-carcinoma - results of a multimodal therapy including alternating neoadjuvant chemotherapy, surgery and radiotherapy.

Thirty women with locally advanced breast cancer (LABC), but no evidence of distant metastases, were prospectively treated with four fixed cycles of neoadjuvant chemotherapy (CT). This regimen consisted of epidoxorubicin (Epi) alternated every 21 days with cyclophosphamide, methotrexate and 5-fluorouracil (CMF). After this induction CT, subsequent therapy was planned according to the response obtained as follows: (a) modified mastectomy with axillary dissection was performed in patients who had major objective response (complete or partial), followed by four doses of adjuvant CT and radiotherapy (RT); (b) debulking rescue surgery followed by RT and 2nd line CT with mitomycin C were given in patients with stable disease or minor response. The response rate to induction CT was 63% (19 of 30 patients) (95% confidence limits 46-80%). Overall, 43% of patients had no persistance of tumor at the end of the planned therapy. After a median follow-up time of 36 months, disease-free survival (DFS) and overall survival (OS) were 35% and 47%, respectively. The median duration of DFS was 16 + months (4-52+ months). A significantly better OS was observed in complete responders compared to the others (77% versus 23.5%; p=0.01). Compliance to treatment was high, gastrointestinal and hematological toxicities were the most common side-effects. Thus, this multimodal approach is effective in reducing primary tumor size with acceptable morbidity. Five of the 11 (45%) patients non responsive to induction CT obtained a transient local control of disease after debulking surgery, RT and mitomycin C. To assess the role of alternating non cross resistant regimens as induction therapy in LABC vs conventional schedules, phase III comparative studies are warrented.

Multivariate-analysis of prognostic factors in 232 patients with clinical stage-I endometrial adenocarcinoma using the new figo surgical staging system.

A retrospective analysis is reported in 232 patients with clinical Stage I endometrial adenocarcinoma diagnosed between 1980 and 1988, treated with combined surgery and adjuvant irradiation. Tumors were restaged according to the FIGO (1988) surgical staging system (SSS) in order to assess the prognostic value of this revised classification and of the conventional clinico-pathological features (age, performance status, grade and depth of myometrial invasion). The 5-year relapse-free survival (RFS) and overall survival (OS) of the series was 85% and 90.8%, respectively. Both 5-year RFS and OS were not significantly different adopting the FIGO (1971) clinical Stage (Stage IA 93% and 88% vs Stage IB 88.5 and 82%. respectively) whereas they were significant by FIGO SSS (Stage IA 96% and 93% vs Stage IB 94% and 88.5% vs Stage IC 74% and 63%, respectively) (p=0.001 and p=0.0005, respectively). Other factors that significantly affected 5-year RFS or OS at univariate analysis were age (p=0.01 and p<0.0001, respectively), performance status (p=0.035 and p=0.001, respectively), grade (p=0.015 and p<0.0001, respectively) and myometrial invasion (p=0.0017 and p=0.0003, respectively). A multivariate analysis of these prognostic variables showed that FIGO SSS was the only significant and independent (p=0.01) indicator for recurrence. However, when therapy was added to the model, FIGO SSS failed to retain significance (p=0.11). Concerning OS age (p<0.0001), performance status (p=0.04) and FIGO SSS (p=0.05) were significant and independent prognosticators, also when therapy was included in the analysis. In conclusion, this study shows that the new FIGO SSS is a useful prognosticator as well as is age and performance status, in early Stage endometrial adenocarcinoma.

[Advanced stages of rectosigmoid cancer. The role of postoperative radiotherapy]. / Stadi avanzati del cancro del sigma-retto. Ruolo della radioterapia postoperatoria.

In patients with advanced rectosigmoid adenocarcinoma treated with radical surgery alone, loco-regional relapse rate is quite high (29%-60%). When postoperative radiotherapy is performed, loco-regional relapse rate sharply falls to 7%-15%. A series of 42 patients, stage B2, C1 and C2, is presented. All patients were treated with radical surgery and postoperative radiotherapy. Only two loco-regional relapses were found (5%). Overall actuarial survival at 5 years is 76% for B2, and 46% for C1 and C2. The authors conclude that adjuvant postoperative radiotherapy is useful in reducing loco-regional relapses, whereas survival seems to be improved only for stage B2 patients.

The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcemia of malignancy.

54 patients with malignant hypercalcemia were treated with either dichloromethylene bisphosphonate (Cl2MBP) or aminobutane bisphosphonate (AHButBP). Both compounds infused intravenously (i.v.) were rapidly effective in lowering serum calcium to normal range and a potency ratio between Cl2MBP and AHButBP could be roughly estimated as 1:100-250. 600 mg of Cl2MBP infused in one day over 9 h in nine patients were only slightly less effective (serum calcium from 12.3 +/- 1.7 to 10.1 +/- 1.1 SE, mg/dl) than 3300 mg infused in 11 consecutive days (13.4 +/- 1.9 to 9.3 +/- 1.2 SE, mg/dl). Thus the effectiveness of treatment with Cl2MBP was related better to the overall time of infusion than to the cumulative dose administered. This could not be demonstrated in a similar trial using AHButBP. 1600 mg Cl2MBP daily p.o. was unable to prevent the relapse of hypercalcemia in four patients after a treatment course with i.v. bisphosphonates. 100 mg of Cl2MBP intramuscularly maintained serum calcium within the normal range in two out of eight patients; however, weekly infusions of either Cl2MBP or AHButBP prevented the relapse of hypercalcemia in eight similarly treated patients for several weeks. Providing that adequate dosages are adopted, parenteral Cl2MBP and AHButBP may be a useful measure for controlling hypercalcemia in patients with carcinoma.