Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: reportof a National Veterans Administration randomized study.

In 1964 the Veterans Administration Surgical Adjuvant Group (VASAG) initiated a large-scale, controlled, randomized protocol to study the role of low-dose preoperative irradiation (2000-2500 rads/10fractions/12 days) in patients with operable adenocarcinoma of the sigmoid colon and rectum. This report analyzes the data in 700 patients, all at 5-year risk. There appears to be a definate benefit to irradiated patients who undergo abdominoperineal resections, when compared with the controls. This advantage is reflected in improvement of 5-year survival, and reduction in lymph node invasion, local recurrence, and distant metastases. A second protocol has been initiated in 30 VA hospitals employing a higher dose (3150 rads) to extended portals (toL2) to male patients who require abdominoperineal resections.     

Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group

Purpose: To determine the feasibility of using preoperative chemoradiotherapy to avert the need for more radical surgery for patients with T₃ primary tumors, or the need for pelvic exenteration for patients with T₄ primary tumors, not amenable to resection by standard radical vulvectomy.Methods and Materials: Seventy-three evaluable patients with clinical Stage III–IV squamous cell vulvar carcinoma were enrolled in this prospective, multi-institutional trial. Treatment consisted of a planned split course of concurrent cisplatin/5-fluorouracil and radiation therapy followed by surgical excision of the residual primary tumor plus bilateral inguinal–femoral lymph node dissection. Radiation therapy was delivered to the primary tumor volume via anterior-posterior–posterior-anterior (AP–PA) fields in 170-cGy fractions to a dose of 4760 cGy. Patients with inoperable groin nodes received chemoradiation to the primary vulvar tumor, inguinal–femoral and lower pelvic lymph nodes.Results: Seven patients did not undergo a post-treatment surgical procedure: deteriorating medical condition (2 patients); other medical condition (1 patient); unresectable residual tumor (2 patients); patient refusal (2 patients). Following chemoradiotherapy, 33/71 (46.5%) patients had no visible vulvar cancer at the time of planned surgery and 38/71 (53.5%) had gross residual cancer at the time of operation. Five of the latter 38 patients had positive resection margins and underwent: further radiation therapy to the vulva (3 patients); wide local excision and vaginectomy necessitating colostomy (1 patient); no further therapy (1 patient). Using this strategy of preoperative, split-course, twice-daily radiation combined with cisplatin plus 5-fluorouracil chemotherapy, only 2/71 (2.8%) had residual unresectable disease. In only three patients was it not possible to preserve urinary and/or gastrointestinal continence. Toxicity was acceptable, with acute cutaneous reactions to chemoradiotherapy and surgical wound complications being the most common adverse effects.Conclusion: Preoperative chemoradiotherapy in advanced squamous cell carcinoma of the vulva is feasible, and may reduce the need for more radical surgery including primary pelvic exenteration.     

Primary liver cancer. An Eastern Cooperative Oncology Group Trial

One hundred ninety-two patients with unresectable primary liver cancer studied by members of the Eastern Cooperative Oncology Group (ECOG) were evaluable in a prospectively randomized clinical trial. Patient discriminants such as performance status were carefully evaluated to assess their influence on prognosis and to evaluate the importance of patient status on response and survival. Patients who were totally bedridden or with signs of overt liver failure were not entered on study. The median survival time for all evaluable previously untreated patients was 17 weeks (19 weeks for North American and European, and 10 weeks for South African black patients). Among the South African patients, however, there was a significantly larger proportion with an initially poor performance status. Prognostic variables (performance status, jaundice, and reduced appetite) dominate any differences among the treatments studied. Among North American and European patients on intravenous (IV) 5-fluorouracil (5-FU) + Methyl-CCNU (MeCCNU) + Adriamycin (ADM, doxorubicin), the 19% response rate is offset by 63% with severe toxicity and a median survival time of only 17 weeks, making this treatment unacceptable clinically. The median survival time of North American and European patients treated with IV 5-FU +/- MeCCNU was 28 weeks in contrast to a median survival time of 12 weeks with ADM (P less than or equal to 0.01). EST 2273 was the ECOG study of patients with primary liver cancer. The results of the first part of the trial were published in 1978. This report updates those findings and reports the results of patients entered subsequently on the second part of that study after it was amended in 1979. With more than 300 evaluable patients in EST 2273, this duet of studies is the largest ever conducted in patients with primary liver cancer, and draws a new baseline from which to measure the disease and its response to treatment.     

Efficacy of prolonged intermittent therapy with combined 5-FU and methyl-CCNU following resection for gastric carcinoma. A Veterans Administration Surgical Oncology, Group report

This prospective evaluation of 5-fluorouracil (5-FU) and methyl-CCNU administered in combination to patients with surgery for histologically proved gastric adenocarcinoma is based upon 312 patients randomized between August 1974 and May 1980. Patients were stratified into three categories of resectability, (1) complete, (2) proven incomplete, and (3) nonresectable, prior to random treatment assignment to surgery alone or surgery followed by adjuvant chemotherapy. Drug therapy consisted of discrete 5-day courses administered at 7-week intervals. Toxic reactions were reported in association with 42% of the courses. Treatment was suspended or discontinued in 6% of the courses because of hematologic toxicity. Treated patients with curative resections experienced a more favorable survival than did controls, but the early advantage was lost by the end of the second follow-up year. However, no statistically significant improvements in survival or reductions in risks of recurrence were observed. Similar proportions of treated and control deaths were attributable to residual or recurrent disease.     

Efficacy of prolonged intermittent therapy with combined 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report

This prospective evaluation of 5-FU and methyl-CCNU administered in combination to patients with curative surgery for histologically proved colorectal adenocarcinoma is based upon 645 patients randomized between August 1973 and July 1979. Beyond the requirement that the resection be clinically and microscopically complete, patients were not stratified prior to random treatment assignment to surgery alone or surgery followed by adjuvant chemotherapy. Drug therapy consisted of discrete 5-day courses administered at 7-week intervals, start to start. Toxic reactions were reported in association with 40% of courses. In 10% of patients with hematologic toxicity, the reactions were sufficiently severe to require the suspension or discontinuation of treatment. Treated patients experienced a slightly more favorable survival than did controls. However, the advantage was seen only in the 216 patients (34% of total) with one to four positive lymph nodes in the resected specimen. Similar proportions of treated and control deaths were attributed to residual or recurrent disease.     

Surgical complications of intraoperative radiation therapy: the Radiation Therapy Oncology Group experience.

Intraoperative radiotherapy (IORT) is being used with increasing frequency in many institutions in the United States but little is known about the surgical complication rates. The Radiation Therapy Oncology Group initiated three prospective studies in IORT in 1986 and we report here the experience in advanced malignancies of the stomach, pancreas, and rectum. The incidence and nature of major surgical complications were reviewed and presented with their implications in regard to future IORT trials. Two hundred twenty-seven patients were entered on three studies by 20 participating institutions between 1985 and 1989. One hundred twenty-nine patients received IORT while 98 patients were found to have too advanced disease to be benefited by IORT and underwent palliative surgical procedures only. IORT doses ranged from 12-22 Gy and bowel anastomoses were not irradiated. Wound infection in the IORT group was 6% vs. 2% in the non-IORT patients but this was not significant at the P = 0.05 level. Other complications included anastomotic leak (n = 5), operative bleeding (n = 10), pancreatitis (n = 2), and were not statistically different in the IORT and non-IORT groups. The mortality rate for the IORT and non-IORT groups combined was 1.8%. This large multi-institutional experience in patients with advanced malignancy demonstrates that patients receiving IORT do not have a higher surgical complication rate than those not receiving IORT. Long-term survival data await the implementation of Phase III trials in advanced intra-abdominal malignancy.     

A Southwest Oncology Group phase II Trial of recombinant tumor necrosis factor in metastatic breast cancer

New approaches are needed in the treatment of advanced breast cancer. In vitro studies have shown that recombinant tumor necrosis factor (TNF) is a growth inhibitor for the MCF-7, ZR-75-1, and BT-20 human breast cancer cell lines. Based on these considerations, the Southwest Oncology Group performed a Phase II trial of recombinant TNF (Genentech) (150 micrograms/m2) given by 30-minute intravenous infusion on days 1 to 5 of every other week for 8 weeks. Patients with metastatic breast cancer who had received one prior chemotherapy regimen for advanced disease were eligible. Of the 22 patients who were entered, 3 were ineligible. Nineteen patients who had a performance status of 2 or less could be examined (median age, 53 years). One possible fatal toxic reaction has been seen in a patient who had intracranial bleeding caused by a previously undiagnosed brain metastasis; no other treatment-related deaths have occurred. Toxicity has included nausea, vomiting, fever, chills, myalgia, and fatigue. No Grade 4 toxicity has been observed. Grade 3 toxic reactions have included hypotension (two patients), diarrhea (one patient), transient leukopenia (two patients), and reversible elevations of liver function test values (two patients). No objective responses have been observed. Twelve of 19 patients have died (median survival time, 8.5 months). Recombinant TNF is inactive as a single agent in patients with previously treated metastatic breast cancer.     

Chemotherapy following surgery for head and neck cancer. A Radiation Therapy Oncology Group Study

The feasibility of chemotherapy of three courses of cis-platin and 120-h 5-fluorouracil (5-FU) infusion after definitive surgery, followed by standard radiotherapy, in patients with resectable locally advanced head and neck cancer was carried out in Radiation Therapy Oncology Group (RTOG). Seventy-nine percent of the patients had stage IV cancer, 65% of the tumors were moderately differentiated, and primary sites were 38% oropharynx and 28% larynx. Toxicity to chemotherapy was acceptable, with no life-threatening side effects. Nausea and vomiting were the most common side effects (78%) and were severe in 26%; 30% of patients experienced had leukopenia, 22% had anemia, 13% had thrombocytopenia, and 9% had renal impairment--all of which were mild and reversible. In six patients, chemotherapy was not given for medical conditions or because of patient refusal. Of 23 patients started on cis-platin and 5-FU postsurgery, 18 (78%) completed all three courses. Ninety-six percent of the patients finished adequate radiotherapy according to the protocol. With minimum follow-up of 24 months, 62% of the patients were alive. Of the expired patients, 5 died from other causes, without evidence of recurrence at the time of their death. It is our conclusion that chemotherapy with cis-platin and 5-FU infusion following definitive surgery is feasible on the group level, and a Phase III trial comparing this combined modality therapy to standard treatment of surgery and post-operative radiotherapy is underway by the Head and Neck Cancer Intergroup.     

Phase II trial of gemcitabine in refractory or relapsed small-cell lung cancer: Eastern Cooperative Oncology Group Trial 1597.

PURPOSE: Gemcitabine has shown a broad range of activity in solid tumors, including previously untreated small-cell lung cancer (SCLC). The objective of this phase II trial was to investigate the activity of gemcitabine in patients with relapsed SCLC. PATIENTS AND METHODS: SCLC patients with measurable disease who had experienced treatment failure with one prior chemotherapy regimen were considered eligible. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and adequate organ function; signed informed consent was also required. Treatment consisted of gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Patients were stratified according to their previous response to first-line chemotherapy (primary refractory v primary sensitive disease). RESULTS: Forty-six patients were enrolled onto this phase II trial (20 refractory and 26 sensitive patients). Forty-two of these patients were assessable for response and survival, and 44 were assessable for toxicity. Median patient age was 60 years, and median ECOG performance status was 1. Principal grade 3/4 hematologic toxicities included neutropenia (27%) and thrombocytopenia (27%). The main grade 3/4 nonhematologic toxicities were pulmonary (9%) and neurologic toxicity (14%). Objective responses occurred in 11.9% of patients overall, including one patient with refractory SCLC (5.6%) and four patients with sensitive SCLC (16.7%). Median survival for the overall group was 7.1 months. Survival was not significantly different for patients with refractory versus sensitive disease. CONCLUSION: Gemcitabine has modest activity in previously treated SCLC patients. The favorable toxicity profile warrants further investigation, either in combination chemotherapy regimens or with targeted biologic compounds.     

Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies

Between 1960 and 1975, the Veterans Administration Cooperative Urological Research Group conducted a consecutive series of 3 major randomized clinical trials comparing various endocrine treatments for newly diagnosed prostate cancer patients. Six major conclusions concerning hormonal treatment emerged from these studies: 1) increased hazard of cardiovascular death after therapy with 5 mg diethylstilbestrol (DES); 2) orchiectomy plus DES no better than orchiectomy or DES alone; 3) equivalent effect of 1.0 and 5.0 mg DES on cancer; 4) reduced cardiovascular hazard from therapy with 1.0 mg DES; 5) Premarin and Provera no better than 1.0 mg DES at doses studied; 6) decisions about hormone treatment at diagnosis dependent on patient characteristics, mainly age and Gleason grade. In this paper, these studies are reviewed briefly and data are presented to support these conclusions. Some tentative treatment recommendations are proposed.     

Preoperative irradiation for cancer of the rectum with extrarectal fixation

Tumor mobility of rectal cancer is well known to have prognostic significance for operative resection, local recurrence, and survival. Between 1976-1988, 220 patients have been consecutively treated with high dose preoperative radiotherapy at Thomas Jefferson University Hospital. During this time period, 134 patients were clinically determined by the surgeon and radiotherapist to have extrarectal tumor fixation as a primary indication for preoperative irradiation and are the subject of this review. The patient population can be further divided into two subgroups which include 49 patients with clinical tethering/partial fixation, and 85 patients with completely fixed tumors. Patients were treated with 4-field pelvic radiotherapy to 45 Gy in 25 fractions. Depending on location and degree of fixation, a localized boost dose was frequently delivered to the tumor for an additional 4.8-9.6 Gy using opposed high-energy lateral fields. Surgical resection was instituted 4-6 weeks post completion of radiotherapy. Significant tumor regression permitted sphincter preserving surgery in 105/134 (78%) of these patients. With a median follow-up of 37 months, the overall 5-year actuarial survival for our postradiation Stage A/B1 patients was 92% (n = 28), and 63% for Stage B2/C patients (n = 91). Local recurrence occurred in only 7% of the Stage A/B1 patients, and 18% in the Stage B2/C patients. Analyzed by pre-treatment clinical evaluation, the 5-year actuarial survival of these patients was 68% and 60% in the clinically tethered and fixed tumor subgroups, respectively (p = .51). Pelvic control was demonstrated in 86% of the patients in the tethered subgroup, and in 80% of the preoperative fixed patients. The combined treatment was well tolerated, with complications limited to 6% of the patient population. We conclude that preoperative radiotherapy for rectal carcinomas with clinical extrarectal fixation provides optimal presurgical cytoreduction and excellent survival. Furthermore, sphincter function can be maintained in a majority of patients with appropriate attention to patient selection.     

Preoperative radiation therapy for patients with T2-T3 carcinoma of the middle-to-lower rectum.

BACKGROUND: The aim of this study was to determine the effects of preoperative radiation therapy (RT) on the objective responses of patients with rectal carcinoma to their treatment. These effects were assessed with endorectal ultrasound (EUS) evaluation, histopathologic grading of postirradiation tumor mass reduction in the surgical specimen, and analysis of local and distant recurrences. METHODS: Fifty-nine consecutive patients with palpable adenocarcinoma of the rectum, classified by EUS examination as uT2-uT3 (which meant involvement of the muscular layer and the perirectal adipose tissue, respectively), received 45 grays (Gy) over 3 weeks (2 fractions per day of 1.5 Gy each) given as photons supplied through a high-energy linear accelerator (18 MeV) through 3 fields: 1 posterior and 2 opposed lateral. Surgery was scheduled 2-3 weeks after the end of RT and included a sphincter-saving resection (39 patients) and an abdominoperineal resection (20 patients). RESULTS: Greatest tumor dimension, which was evaluated with rectal endoscopy before RT and measurement of the lesion in the fresh specimen, showed a decrease among two-thirds of the patients; the decrease amounted to approximately one-third of the initial measurement. An echoendoscopic downstaging of the T component was observed among 24.5% of the patients. Complete tumor regression occurred in 8.5% of patients, whereas in 69% only the presence of rare residual cancer cells and prominent fibrosis were found at the pathologic examination of the specimen. Finally, the tumor regressed to pT0 and pT1 in 13.6% of the patients. The overall and disease free 2-year survival rates were 94.0% and 73.7%, respectively, for pT2 and pT3 patients, and 100% for those whose tumors regressed to pT0-pT1 after a median follow-up of 2 years. CONCLUSIONS: Hyperfractionated preoperative RT appears to be efficient in achieving tumor shrinkage and destroying the tumor. In this study, the subset of patients with a good response to RT therapy had an excellent clinical outcome at the time of a 2-year follow-up.     

The European Journal of Surgical Oncology and its contribution to cancer surgery

This article describes the European Journal of Surgical Oncology, the EJSO, its aims and objectives, and its conventional and electronic publishing strategy. It highlights the role of the journal in publishing original work and educational content in respect to the generality of the clinical and academic disciplines comprising modern surgical oncology. The journal is in a steady expansion phase with a growing impact factor, and the editorial team aims to consolidate its place in the premier league of specialist journals through the merit and quality of its content and publication standards.     

Phase II study of doxorubicin and paclitaxel as second-line chemotherapy of small-cell lung cancer: a Hoosier Oncology Group Trial

Forty-six evaluable patients with recurrent small-cell lung cancer were entered on a phase II Hoosier Oncology Group (HOG) protocol evaluating bolus doxorubicin 40 mg/m2 followed by paclitaxel 175 mg/m2 over 3 hours. Courses were repeated every 3 weeks for a maximum of 6 courses. Therapy was well-tolerated with grade III neurotoxicity in 5 patients (11%), grade III/IV emesis in 5 (11%), and grade III mucositis in 2 patients. One patient had grade IV myalgias and one patient had grade III cardiotoxicity. The main toxicity was myelosuppression. Twenty-nine patients (63%) had grade IV and 8 (17%) grade III granulocytopenia. Nine patients (20%) were hospitalized for granulocytopenic fever. There was no treatment-related mortality. Nineteen of 46 patients (41%) had an objective response, including 3 complete remissions. Two of 14 patients with refractory disease (progression less than 3 months after initial therapy) responded, compared to 17 of 32 (52%) with sensitive disease (progression beyond 3 months of initial chemotherapy regimen).