George A. Higgins

Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: Report of 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/10 fractions/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 definite benefit to irradiated patients who undergo abdominoperineal resections, when compared with the controls. This advantage is reflected in improvement of 5‐year survival, and reductions 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 (to L2) to male patients who require abdominoperineal resections.

Adjuvant chemotherapy in the surgical treatment of large bowel cancer

In two large controlled cooperative trials, 1118 patients undergoing surgical resection for large bowel cancer were randomized to be treated by surgery alone or to receive 5‐fluorouracil during postoperative followup. The two studies differed slightly in the selection of patients for entry and in the dose regimens of 5‐fluorouracil. Following examination of the removed specimen, “curative” and palliative stratifications based on evidence of residual disease were made, so that the two trials actually consisted of five separate patient groups, two groups of patients who had “curative” resections and the other three smaller groups of patients who had palliative resections with residual disease or tumor at a margin of the resected specimen. In all five groups, survival was slightly better in patients receiving chemotherapy although no single difference is statistically significant. Any suggestion that these slight advantages represent a true therapeutic 5‐FU effect must be tempered by previous negative adjuvant studies by this group as well as others. Currently the group is conducting a trial using a combination of methyl‐CCNU and 5‐fluorouracil and has recently added a nonspecific immunostimulant, methanol extraction residue of BCG (MER), to one subgroup.

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.

Factors influencing survival after resection in cancer of the colon and rectum

Investigators from twenty-one Veterans Administration Hospitals (Table I) founded the VA Surgical Cancer Chemotherapy Study Group in 1957 to investigate the effect of cancer chemotherapy as an adjuvant to operation for resectable cancer of the lung, stomach, and large bowel. A preliminary report on the use of triethylenethiophosphoramide (TSPA) as an adjuvant to surgery in cancer of the colon and rectum was published in 1964 [I]. It was based on 1,171 resections, including 929 “curative” operations, with a two year follow-up study on 426 and a forty-four month follow-up study on eighty curative cases. The purpose of this paper is to give the five year results on the use of TSPA as an adjuvant, and also to examine characteristics of the patient, the disease, the operation, and the postoperative course for their influence on recurrence and survival in this group of patienk.

The glucagonoma syndrome: Surgically curable diabetes☆

Abstract The glucagonoma syndrome associated with alpha-2 cell tumors of the islets of Langerhans has emerged as a specific member of the apudoma tumor family. The first case was described in 1942, and the syndrome was well documented in 1966. There are now (including the 3 case reports presented herein) forty-seven cases in the literature, thirty appearing during the past three years. Major features of the syndrome are: (1) diabetes mellitus; (2) characteristic skin lesions (necrolytic migratory erythema); (3) glossitis; (4) normochromic, normocytic anemia; and (5) weight loss with associated elevation of the plasma level of immunoreactive glucagon. Of the patients, 59.6 per cent are female (28 of 47) aged twenty to seventy-three years. The tumors grow slowly, suggesting that early diagnosis and surgical excision can be curative; however 59.1 per cent (27 of 47) of the reported patients had extensive disease and/or hepatic metastases at the time of diagnosis. The primary tumor was located in the body or tail (30 patients) or head and neck (4), with the remaining being “extensive” (12) or not found (1). All patients on whom determinations were made (37) had elevated glucagon levels in the plasma or in the tumor, with plasma glucagon levels between 0.3 and 96 ng/ml (normal The three patients here reported are representative, one having a localized resectable tumor in the tail of the pancreas with complete reversal of symptoms and return of plasma glucagon to normal levels after operation, one having extensive metastases in the remote postresection period, and the third having an extensive nonresectable tumor. Increased awareness of the syndrome along with improved technics of diagnosis and localization have already produced a promising trend toward earlier diagnosis and treatment of this surgically curable type of diabetes.

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. Cancer 53:1–8 1984.

Randomized study of 5-FU and ccnu in pancreatic cancer: Report of the veterans administration surgical adjuvant cancer chemotherapy study group

Between the years 1973–1977, 152 male patients from 28 participating Veterans Hospitals with histologically proven nonresectable cancer of the pancreas were randomized in a two‐arm study. The treated group was to receive combination chemotherapy with 5‐FU and CCNU, and the controls were to receive no chemotherapy. Both groups were comparable with respect to age, amount of weight loss, extent of histologically proved metastases, and operation performed. In the treatment group, drug therapy was begun between 10 and 60 days postoperatively. Intravenous 5‐FU, 9 mg/kg, was administered on five consecutive days, and CCNU, 70 mg/m2, was given orally on the first day of each course. In the absence of toxicity, the course was repeated every six weeks for life; 146 drug courses were given. The incidence of toxicity was not great. One or more toxic reactions were reported for one‐third of the drug courses administered, but for the most part, these were mild. The most frequent toxic reaction was vomiting in 17% of the courses, and hematologic toxicity—primarily leukopenia—in 15% of the drug courses. There was no evidence of a beneficial effect on survival from drug treatment in the group as a whole or in any subgroup analyzed. The median survival of the control group was 3.9 months, and of the drug‐treated group, 3.0 months.

Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung

Eight hundred sixty‐five patients with a microscopically curative resection for carcinoma of the lung were accepted for study, none of whom were excluded from analysis. Adjuvant therapy was randomly assigned about the tenth to 14th postoperative day; 432 patients (treated) were to receive CCNU and hydroxyurea for one year, while 433 patients (controls) were to receive no adjuvant therapy. Toxic reactions to therapy were reported, but only 1% were severe enough to require stopping therapy. No evidence of improved survival or delayed recurrence of disease was seen in treated patients as a whole or when examined by cell type and by postsurgical TNM category. On the contrary, survival beyond the second year of follow‐up may have been impaired by the drugs when administered to patients without evidence of tumor spread to the lymph nodes. Cancer 50:1713‐1721, 1982.

Preoperative Irradiation of Operable Adenocarinoma of the Rectum and Rectosigmoid Colon

Preoperative irradiation in a moderate dose schedule (2,000–3,000 rads∕two weeks) followed promptly by surgery has had a favorable effect, when matched with controls, on the survival of male patients with operable and resectable adenocarcinoma of the rectum, particularly when the lesion is low-lying and requires an abdominoperineal resection. There is a significant reduction in the finding of positive lymph nodes in the treated group (27%) compared with the controls (40%). With 700 men already in the study, life table survivals at five years are documented at 40.4% for irradiated patients who undergo abdominoperineal resection vs. 27.5% for the control group. This favorable effect appears dose-related.

Use of chemotherapy as an adjuvant to surgery for bronchogenic carcinoma

The use of cytotoxic drugs in combination with surgical resection for lung cancer has been disappointing, for the most part, despite the numerous animal studies demonstrating marked effectiveness of adjuvant chemotherapy and surgery. None of the large controlled cooperative studies has shown any improvement in long‐term survival using Nitrogen Mustard or Cytoxan with standard surgical therapy. One exception to these generally negative findings has been a substantial increase in survival in patients with oat‐cell carcinoma having surgical resection followed by the administration of Cytoxan. This paucity of positive results in the large controlled trials emphasizes that effective systemic therapy must be found if survival rates in patients with lung cancer are to be improved.