Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12.

Unresectable cancer of the pancreas was treated with the combination of weekly paclitaxel and external beam irradiation in an effort to improve palliation and extend life expectancy. One hundred twenty-two patients were entered in a multicentered protocol. Thirteen patients were either ineligible, cancelled, or had delinquent data, thus providing 109 for analysis. Unresectable cancer was based on imaging studies (computed tomography or magnetic resonance imaging), all had histologic proof of adenocarcinoma, and none had evidence of metastatic disease or peritoneal seeding. Image-guided radiotherapy treatment consisted of 50.4 Gy in 28 fractions over 5.5 weeks with coplanar anterior/posterior and lateral ports. An initial dose of 45 Gy was given to fields covering the primary tumor plus the regional peripancreatic, celiac, and porta hepatis lymph nodes. A cone down field was used for the last three fractions to encompass the gross tumor volume with a 1- to 1.5-cm margin. Paclitaxel was administered weekly with irradiation in a dosage of 50 mg/m2 as a 3-hour infusion. The median age was 63 and 53% were female. The Karnofsky performance status was greater than or equal to 80 in 81%. Eighty percent were classified T3 or 4; 20% had N1 disease. The primary tumor was located in the pancreatic head in 65%. Eighty-five percent received all six cycles of paclitaxel per protocol, whereas 93% received irradiation with acceptable protocol variation. Field placement, total dose, fractionation, and overall treatment time were given per protocol in greater than or equal to 90%. Acute toxicity (worst per patient) occurred in 39% with grade III (35% of these were asymptomatic neutropenia), 5% with grade IV, and one patient died of infection during the fourth cycle of chemotherapy (grade V). The median follow-up time for alive patients is 20.6 months (range 5-30). The median survival is 11.2 months (95% CI 10.1, 12.3) with estimated 1- and 2-year survivals of 43% and 13%, respectively. External irradiation plus concurrent weekly paclitaxel is well tolerated when given with large-field radiotherapy. The median survival is better than historical results achieved with irradiation and fluoropyrimidines. These data provide the basis for a new Radiation Therapy Oncology Group trial using paclitaxel and irradiation combined with a second radiation sensitizer, gemcitabine, now under way.

'Neo-FAC' (5-fluorouracil, doxorubicin, and cyclophosphamide) for poor-prognosis stage IV breast cancer: a Southwest Oncology Group Phase II Study.

The authors report a phase II pilot investigation in the Southwest Oncology Group examining a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) incorporating modulated 5-FU in patients with poor-prognosis stage IV breast cancer. Patients with poor-prognosis stage IV breast cancer were treated with this "neo-FAC" as front-line therapy. The regimen consisted of 5-fluorouracil by continuous ambulatory infusion pump at 200 mg/m2/day for 42 days, repeated at 56-day intervals; doxorubicin at 20 mg/m2/week intravenously to a maximum cumulative total dose (including adjuvant therapy, if any) of 500 mg/m2; cyclophosphamide 60 mg/m2/day taken orally; methotrexate 15 mg/m2/week intravenously beginning 1 week after termination of doxorubicin; and oral prednisone decreasing from 60 mg/day on a tapering schedule for a total of 7 weeks of treatment. Treatment was continued until progression, unacceptable toxicity, or patient refusal. Twenty-four patients were accrued to this study. Of these, two were ineligible, and the remaining 22 were evaluable for response. Ten patients experienced grade 3 toxicity, and six had grade 4. There were no treatment-associated deaths. Best responses were a complete response in one patient (5%) and partial responses in 6, for an overall response rate of 32% (7/22 evaluable patients). Overall survival in five pilot studies in the Southwest Oncology Group in this poor-prognosis population are relatively superimposable. The present regimen, with its relatively poor outcome and the expense and inconvenience of administering chemotherapy by ambulatory infusion pump, will not be pursued further.

Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study.

PURPOSE: To compare failure-free survival (FFS) and overall survival (OS) for patients with metastatic breast cancer treated with the gonadotropin-releasing hormone (GN-RH) agonist, goserelin versus surgical ovariectomy. PATIENTS AND METHODS: Between August 1, 1987 and July 15, 1995 138 (136 eligible) premenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive metastatic breast cancer were entered by the Southwest Oncology Group (SWOG), North Central Cancer Treatment Group (NCCTG), and Eastern Cooperative Oncology Group (ECOG). Prior chemotherapy or hormone therapy for metastatic disease was not allowed. Patients were randomly assigned to goserelin (3.6 mg subcutaneously every 4 weeks; (n = 69) versus surgical ovariectomy (n = 67). The study was initially designed as an equivalence trial with 80% power to rule out a 50% improvement in survival due to ovariectomy. However, accrual was slow and the study was terminated early, which resulted in a final power of 60% for the alternative hypothesis of equal survival distributions. RESULTS: FFS and OS were similar for goserelin and ovariectomy. The goserelin/ovariectomy death hazards ratio was .80 and the associated 95% confidence interval (CI) was .53 to 1.20. The test of 50% improvement in survival due to ovariectomy was rejected at P = .006. Goserelin lowered serum estradiol to postmenopausal levels. Hot flashes (75% v 46%) and tumor flare (16% v 3%) were more common with goserelin. CONCLUSION: Goserelin and ovariectomy resulted in similar FFS and OS. We can rule out a moderate advantage for ovariectomy. Goserelin was safe and well tolerated.

A study of reproductive function in patients with seminoma treated with radiotherapy and orchidectomy: (SWOG-8711). Southwest Oncology Group.

PURPOSE: The results of Southwest Oncology Group Study 8711 (Group 2B) are presented. The objective was to evaluate the natural history of sperm concentration and selected hormonal parameters in patients with testicular cancer treated with orchiectomy and radiotherapy. METHODS AND MATERIALS: Of a total of 207 patients enrolled on SWOG 8711, 53 pure seminoma patients were identified who were treated with orchiectomy and radiotherapy only. Sperm concentration, follicle-stimulating hormone (FSH) levels, and sexual satisfaction scores were the main parameters followed. RESULTS: A fraction of the patients were infertile prior to receiving radiotherapy. Our analysis indicates that incidental radiation dose to the remaining testicle affects time to recovery of fertility, and at an aggregate level, changes in FSH mirror changes in sperm concentration over time. This phenomenon is the same as that described in patients free from testicular cancer. These men evaluated their sexual activity as good after orchidectomy. CONCLUSION: Our data support the use of clamshell-type testicular shields as a means of providing maximum protection to the remaining testicle.

Treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: a phase III intergroup study.

PURPOSE: Our study was designed to compare the effects of preoperative irradiation and cystectomy to surgery alone in patients with transitional cell carcinoma of the bladder. MATERIALS AND METHODS: A total of 140 patients with documented invasive bladder cancer or rapidly recurring superficial high grade tumors was randomized to receive 2,000 rad of pelvic irradiation followed by cystectomy within 1 week or surgery alone. RESULTS: The 5-year survival rate was 53% (95 confidence intervals 41 to 65%) in the surgery only group and 43% (95% confidence intervals 30 to 56%) in the irradiation plus surgery group. The p value for the log rank statistic comparing the survival distributions was 0.23. CONCLUSIONS: Although this trial showed no benefit for preoperative irradiation and cystectomy, the confidence intervals were wide. This finding does not exclude the possibility of a favorable effect of radiation in a subset of patients with high stage tumors. Overall, however, the dominant effect of distant disease as a cause of treatment failure diminishes any potential impact of radiation on results.

Endobronchial irradiation with 192Ir in the treatment of malignant endobronchial obstruction.

From Jan 1, 1983 to April 30, 1989, 32 patients underwent 38 endobronchial treatments with 192Ir, bronchoscopically inserted for treatment of endobronchial obstructions secondary to bronchogenic carcinoma. Thirty-four of the 38 treatments were far enough apart to allow separate response analysis. Thirty of the 34 patients were symptomatically improved or stable; 22 of 24 patients who could be evaluated roentgenographically showed improved or stable chest roentgenograms, and ten of 12 patients evaluated bronchoscopically demonstrated improved patency of bronchial lumen.

Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group.

Beginning in February 1984, 187 evaluable patients with adenocarcinoma or large cell carcinoma of the lung clinically confined to the chest were randomized to receive either conventionally fractionated thoracic irradiation alone or thoracic irradiation with concurrent, prophylactic cranial irradiation. The study population included 161 patients treated for medically or surgically inoperable primary cancers, and 26 patients undergoing adjuvant postoperative mediastinal irradiation following attempted curative resection of primary cancers found to have metastasized to hilar or mediastinal lymph nodes. Elective brain irradiation was not effective in preventing the clinical appearance of brain metastases, although the time to develop brain metastases appears to have been delayed. Eighteen of 94 patients (19%) randomized to chest irradiation alone have developed brain metastases as opposed to 8/93 patients (9%) randomized to receive prophylactic cranial irradiation (p = .10). No survival difference was observed between the treatment arms. Among the 26 patients undergoing prior resection of all gross intrathoracic disease, brain metastases were observed in 3/12 patients (25%) receiving adjuvant chest irradiation alone, compared to none of 14 receiving prophylactic cranial irradiation (p = .06). In the absence of fully reliable therapy for the primary disease, and without effective systemic therapy preventing dissemination to other, extrathoracic sites, prophylactic cranial irradiation for inoperable non-small cell lung cancer cannot be justified in routine clinical practice. Further investigation in the adjuvant, postoperative setting may be warranted.

Patterns of failure after curative resection of pancreatic carcinoma.

Thirty-six patients underwent curative resection of a primary pancreatic carcinoma from January 1977 to September 1987; 26 had Whipple resections, seven had total pancreatectomies, and three had distal pancreatectomies. Twenty-six patients manifested recurrent disease, four died of intercurrent disease, and six were apparently cured. Median survival was 11.5 months with actuarial survival at 2 and 5 years of 32% and 17%, respectively. Of the eventual recurrences, 19% were local only (pancreatic bed, regional nodes, adjacent organs, and immediately adjacent peritoneum) and 73% had a component of local failure. All patients failing did so with a component in the intraabdominal cavity. Peritoneal (42%) and hepatic failures (62%) were common. Extraabdominal metastases were documented in only 27%, but never as a sole site. Fourteen patient and tumor characteristics were evaluated for any relationships with failure or survival. No single variable independently predicted for local failure. However, a group of three (age greater than 60 years, T2 or T3 stage, and location of tumor in the body or tail) was associated with a substantial local failure risk (85% of all patients with local failure). Multivariate analysis showed that low tumor grade (P = 0.002), female sex (P = 0.002), and adjuvant radiation (P = 0.02) were all independent predictors of prolonged survival. Ten patients were treated in an adjacent setting. Those given 55 Gy or greater had improved local control (50% versus 25%) and cure (33% versus none) when compared with patients treated to lower doses. The authors conclude that local failure after curative resection remains a significant problem and further efforts to improve local control are warranted. However, peritoneal and hepatic relapses occur frequently. Thus, adjuvant treatment strategies using wide-field radiation techniques or intraperitoneal therapy, in combination with local tumor bed irradiation and chemotherapy, should be explored.

Combined therapy of osteosarcoma: preoperative irradiation, surgery, and chemotherapy.

The rationale for prebiopsy and preoperative irradiation in a multimodal approach to treatment of osteosarcoma is presented. Six patients with osteosarcoma underwent preoperative irradiation, amputation, and elective chemotherapy. Five of these also received prebiopsy irradiation: three survive without metastases at 29, 36, and 56 months, with no therapy for 10, 16, and 37 months, respectively; two patients died at 6 and 19 months of pulmonary metastases which appeared at 2 and 10 months, respectively. The latter two did not receive prebiopsy irradiation. Another patient, whose pulmonary metastasis regressed at 6 months with adriamycin and was later resected, died of cardiac failure at 59 months without evident metastasis. Immunologic aspects of the disease are also discussed.