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The authors conducted a randomized Phase III trial of three treatment regimens for patients with residual, nonmeasurable, intra-abdominal metastatic disease after undergoing resection for primary colorectal carcinoma.To be eligible for this study, patients had to be both free of other malignancies and capable of starting their therapy within 3-6 weeks after surgery. They were required to have an Eastern Cooperative Oncology Group performance status3; to be chemotherapy, radiation, and immunotherapy naïve; to have adequate bone marrow, renal, and hepatic function; and to provide written, informed consent. The patients were divided into two cohorts: patients with no demonstrable hepatic metastasis (Group A) and patients with hepatic metastasis (Group B).The 229 patients in Group A were randomized to receive either 5-fluorouracil (5-FU) (n = 116 patients) or 5-FU with levamisole (n = 113 patients). The median survival (15.4 months and 15.3 months, respectively, for Groups A and B) was virtually identical. The two groups also were similar in terms of time to treatment progression, which was 7.9 months for group that received 5-FU alone 7.7 months for the group that received levamisole with 5-FU. The 168 patients in Group B with hepatic metastasis underwent a three-way randomization: 5-FU alone (n = 60 patients), 5-FU with levamisole (n = 54 patients), and 5-FU with hepatic irradiation (n = 54 patients). The median overall survival for the three treatment arms were similar, with 17.3 months for the group that received 5-FU alone, 16 months for the group that received 5-FU with levamisole, and 14.4 months for the group that received hepatic irradiation in addition to 5-FU: The time to treatment failure was 6.7 months, 6.8 months, and 8.3 months, respectively, for the three groups. The toxicity experienced by patients was as expected with the regimens, and no differences were observed between any of the treatment groups. The primary toxicities were hematologic and gastrointestinal. There was one treatment-related death due to adult respiratory distress syndrome, which occurred on the first day of the fourth cycle of 5-FU and levamisole. Other Grade 4 toxicities included nine patients with Grade 4 leukopenia, one patient with Grade 4 sepsis, and one patient with Grade 4 gastrointestinal toxicity, including blood loss and diarrhea.This study showed no treatment advantage for any of the combined modalities over 5-FU alone in this group of patients with intra-abdominal, nonmeasurable disease.

The National Cancer Data Base (NCDB) represents a national electronic registry system now encompassing almost 60% of incident cancers in the United States. In combination with other programs of the American College of Surgeons Commission on Cancer, the NCDB offers a working example of voluntary, accurate, and cost-effective "outcomes management" on a both a local and a national scale.For the accession years 1985-1993, the NCDB has obtained information on demographics, patterns of care, disease stage, treatment, and outcome for a convenience sample of 57,407 gastric carcinoma cases (1.6% of total NCDB cases). In addition to describing trends, this report focuses on 5-year relative survival for a cohort of 1987-1988 cases staged according to the third edition of the American Joint Committee on Cancer's TNM classification, as well as patterns of care for a cohort of 1992-1993 cases.Stage-stratified 5-year relative survival for the 1987-1988 cohort was as follows: IA, 71%; IB, 56%; II, 37%; IIIA, 18%; IIIB, 11%; IV, 5%. Without noteworthy changes in stage distribution, demographics, or other factors, the proportion of patients treated by total gastrectomy is increasing slightly, but proximal gastrectomy for proximal cancers remains surprisingly popular. The proportion of cases receiving postoperative adjuvant treatment has declined slightly. Presumably because of advanced age and/or medical infirmity, a substantial proportion of U.S. patients with disease at every stage receive no treatment for cancer.This analysis of patterns of care has revealed unexplained variations in treatment and opportunities for improvement. Treatment of the elderly, infirm patient with gastric carcinoma appears problematic.

The role of clinical trials is becoming extremely important for our understanding of the effects of different therapeutic modalities of cancer treatment and the value of their interactions. Participation of patients in clinical trials remains disappointingly low, with less than 3% of the estimated 1.17 million patients with newly diagnosed cancers entering the studies. Several physician-based factors hinder accrual of patients--(1) lack of awareness of or access to clinical trials, (2) physician bias that the trial therapy is not as good as the "standard therapy" even though the standard therapy may provide a response rate of less than 20%, (3) physician's concern about losing patients to follow-up, (4) the complexity of the clinical trial(s), which requires excessive amount of time to discuss, implement, and follow-up the patient, (5) the lack of equitable compensation for the physician's time and effort, and (6) excessive costs of laboratory and radiologic tests that are not paid by the agency or group sponsoring the study, particularly in Phase I and II trials. These factors are confounded by the lack of institutional review boards in several community hospitals, associated with a complex and lengthy procedure to institute such a board. The article presents recent surveys dealing with attitudes and practices of health care providers toward clinical trials. The National Cancer Institute, the American Cancer Society, and other societies, groups, and agencies, including the health insurance industry, should continue to encourage and support clinical trials.

Tamoxifen and aminoglutethimide are two hormone therapies reported to be effective palliative approaches for patients with metastatic breast cancer. The current trial was designed to evaluate their relative therapeutic effectiveness.Two hundred forty-nine postmenopausal women with advanced breast cancer were randomized in an Eastern Cooperative Oncology Group (ECOG) Phase III study to treatment with adrenalectomy, aminoglutethimide, or tamoxifen with crossover to alternate therapy if disease progressed. Adrenalectomy was dropped as a treatment after 2 years because of low patient accrual.There were 216 evaluable patients entered in the study with 108 initially randomized to aminoglutethimide and 108 to receive tamoxifen therapy. The overall response rate for aminoglutethimide was 45%, and for tamoxifen it was 27%. One institution had a response rate of 60% with aminoglutethimide and only 4% with tamoxifen, whereas all of the other institutions combined had a response rate of 41% with aminoglutethimide and 34% with tamoxifen. Eighty-seven evaluable patients crossed over to the other drug (44 to aminoglutethimide and 43 to tamoxifen). There was a 36% response rate to aminoglutethimide and 19% to tamoxifen, with stable disease in 36% of both groups. The overall survival rates were identical. Toxicity was greater with aminoglutethimide (dermatitis) but was not life-threatening. Glucocorticoid support with either dexamethasone or hydrocortisone was acceptable.Both aminoglutethimide and tamoxifen produced responses in postmenopausal patients with breast cancer, and a significant number of crossover responses were observed. Of interest in this randomized study was the observation that one institution had a markedly different response rate on induction, reinforcing the need for multi-institution trials in Phase III studies.

The primary role of the neodymium yttrium aluminum garnet (Nd:YAG) laser has been to relieve obstruction and to control hemorrhage associated with malignant neoplasms throughout the gastrointestinal tract. In an initial series (IS), the authors demonstrated the efficacy of the Nd:YAG laser as initial preresectional therapy (PR) in 11 patients with obstructing and resectable left colonic or rectal tumors obviating initial operative diversion and allowing for primary resection and anastomosis. In addition, the authors have illustrated the benefit of the Nd:YAG laser in relieving obstruction and arresting bleeding in those patients with either widely metastatic or nonresectable (NR) locoregional disease. Their cumulative experience from 1985 to the present includes 53 patients (PR: 29 and NR: 24). In the PR group, 25 lesions were above the peritoneal reflection and 4 below. Twenty-five patients underwent low anterior resection and four abdominoperineal resection. In the NR group, 17 patients were treated for imminent obstruction and 7 for bleeding. Ten lesions were above and 14 below the peritoneal reflection. There was one laser-related complication in the series (1.8%). There was no significant morbidity or mortality in the PR group. The reduction in length of stay (LOS) and total hospital costs (THC), when compared to the IS has continued to be significant. Laser therapy for those patients in the NR groups is a safe and acceptable alternative to permanent colostomy with its accompanying morbidity and mortality.

An ancillary study (INT 0076) to the Intergroup clinical trial of node-negative breast cancer patients (INT 0011) was performed to retrospectively evaluate DNA flow cytometry measurements of ploidy (DNA content) and proliferative capacity (S-phase fraction) for their ability to predict time to recurrence. Of the 915 patients eligible for the clinical trial, 788 were registered for the ancillary flow cytometry study (INT 0076). Four hundred and three of these patients [estrogen receptor (ER)-positive, tumor size less than 3 cm] had been registered to the observation arm of the clinical trial and 385 (ER-negative and/or tumor size greater than or equal to 3 cm) had been randomly assigned to adjuvant chemotherapy (cyclophosphamide, methotrexate, fluorouracil, and prednisone for six cycles) or to observation. Paraffin blocks from 95% (748 of 788) of these patients were obtained, 712 of which had sufficient cancer tissue to be evaluable for the flow cytometric assay. DNA ploidy status (DNA diploid vs DNA aneuploid) was evaluable for 565 (79%) specimens, 64% of which were aneuploid. Proliferative capacity was estimated by the percentage of cells having an S-phase DNA content, using a trapezoidal modeling algorithm(s) as previously described. The median S-phase value for the entire group (both registered and randomly assigned patients) was 6.97%, which defined the cutoff for interpretation of high or low S-phase values. With a median follow-up time of 4.55 years, S-phase fraction, but not ploidy status, is a significant predictor for time to recurrence in both the randomly assigned and the untreated population (observed registered group and observed randomly assigned group).(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative women with breast cancer but without histopathological evidence of metastases to the axillary lymph nodes or clinical evidence of metastases were studied. Six hundred fifty-five "good-risk" patients who were estrogen receptor positive (ER+) with primary tumors less than 3 cm were registered for observation. Twenty-four of these patients were treated with chemotherapy. Five hundred thirty-six "poor-risk" patients who were either ER+ with primary tumors greater than or equal to 3 cm or estrogen receptor negative (ER-) with any primary tumor size were randomly assigned between chemotherapy and observation. Randomization was stratified by type of surgical procedure, number of lymph nodes examined, menopausal status, tumor size, and ER status. The chemotherapy (CMFP) consisted of six 4-week cycles of cyclophosphamide, 100 mg/m2 orally days 1-14; methotrexate, 40 mg/m2 intravenously (IV) days 1 and 8; fluorouracil, 600 mg/m2 IV days 1 and 8; and prednisone, 40 mg/m2 orally days 1-14. Treatment arms in the randomly assigned patients were balanced with respect to pretreatment characteristics. This analysis includes 445 eligible patients entered in the registration arm and 425 eligible patients entered into the randomized treatments. The median follow-up is 4.5 years in the randomly assigned cohort and 4.8 years in the registered cohort. The overall 5-year disease-free survival (DFS) among the randomly assigned patients was 83% with CMFP and 61% with observation (P less than .0001). A DFS treatment benefit was observed in premenopausal and postmenopausal patients as well as in patients with ER+ or ER- tumors. There were fewer local-regional and distant relapses among the CMFP-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Three hundred eleven patients with node-positive breast cancer were randomized to one of three adjuvant treatments: cyclophosphamide (Cytoxan), methotrexate, and 5-fluorouracil; all of the above with tamoxifen citrate; or all of the above with tamoxifen and bacillus Calmette-Guerin vaccination. Local therapy for all patients was a modified radical mastectomy. Estrogen receptors were measured on all primary tumors. Patients were stratified by the number of positive nodes (one to three nodes and more than three nodes) and estrogen-receptor value (less than 3 femtomole/mg and greater than or equal to 3 femtomole/mg). Follow-up is available, with a mean of 9.1 and maximum of 14.2 years. In this study the efficacy of short-term tamoxifen is apparent over that of chemoimmunotherapy alone and continues to be significant with prolonged follow-up. The addition of tamoxifen to chemoimmunotherapy significantly prolonged disease-free survival among patients with estrogen receptor-positive tumors who were postmenopausal, who had larger tumors (greater than 3 cm), or who had more extensive axillary node involvement (more than three nodes). Tamoxifen improved overall survival for patients with estrogen receptor-positive tumors larger than 3 cm. The addition of bacillus Calmette-Guerin Cytoxan, methotrexate, 5-fluorouracil, and tamoxifen did not significantly alter disease-free or overall survival.

Two hundred and fifty-eight patients with small cell carcinoma and 185 patients with adenocarcinoma were centrally randomized to receive either cyclophosphamide (1000 mg/m2 every 3 weeks) iv or cyclophosphamide (700 mg/m2 every 3 weeks) iv plus CCNU (70 mg/m2 every 6 weeks) orally. Those patients who were initially treated with the single agent were then treated with CCNU (130 mg/m2 every 6 weeks) at the time of cyclophosphamide failure. Objective tumor regression occurred more frequently with the combination regimen in patients with small cell carcinoma (43% vs 22%, P = 0.002), but no difference in response rates was apparent in patients with adenocarcinoma. In both cell types patients survived somewhat longer following treatment with the combination. The overall incidence of severe toxicity was equal for the two regimens in both cell types; however, the therapeutic index of the combination was superior to that of the single agent in small cell carcinoma. Severe drug toxicity was more frequent in small cell carcinoma patients with extensive disease, and survival was reduced in both cell types with extensive disease. Survival was better for ambulatory patients in both cell types and women survived longer than men. In women with small cell carcinoma, ambulatory status also was associated with a higher incidence of tumor regression. In patients with small cell carcinoma those who had prior lung surgery survived longer than those without prior surgery. Previous radiation therapy was associated with a reduced incidence of objective regression in men with small cell carcinoma. In both cell types patients with tumor regression lived longer than nonresponders; however, objective disease stability was associated with improved survival only in patients with adenocarcinoma. Stratification in future studies should consider extent of disease, performance status, sex, and prior therapy.

A prospective, randomized clinical trial of adjuvant treatment of 312 stage II breast cancer patients with use of chemotherapy, antiestrogen therapy, and immunotherapy is reported after 72 months of follow-up. The stratification of patients was based on nodal involvement and estrogen receptor (ER) assay of the primary tumors. Findings at 72 months indicate that antiestrogen therapy (tamoxifen, Nolvadex) added to chemotherapy with cyclophosphamide (Cytoxan), methotrexate, and fluorouracil (5-Fluorouracil) (CMF) resulted in significant delayed recurrence in ER-positive postmenopausal patients, ER-positive patients with four or more positive nodes, and ER-positive patients with tumors greater than 3 cm in diameter. The addition of nonspecific immunotherapy with bacillus Calmette-Guerin had no effect on disease-free survival. ER and progesterone receptor measurements in patients with primary breast cancer provide valuable prognostic information on subsequent recurrence and overall survival and should be documented in future clinical trials.

This study of 2382 breast, 182 rectal, 817 colon, and 351 lung cancer patients treated with combination chemotherapy on eight phase III Eastern Cooperative Oncology Group protocols indicates that 69% would receive a higher dose of at least one drug if surface area were calculated from actual weight rather than from the minimum of actual and ideal weight. Forty-eight percent of the patients would have at least a 10% increase in drug dose based on actual weight. Only on the premenopausal adjuvant breast cancer protocol and among women on the rectal adjuvant study do the differences in dose based on actual rather than ideal weight increase significantly with age. On the postmenopausal adjuvant breast study and on the lung cancer study, the differences in dose decrease significantly with age. For all age decades and both sexes within each protocol, the mean differences between dose based on actual and dose based on ideal weights were on the same order as the rounding factors for the 11 drugs studied. From the literature on the effect of doses of common chemotherapies on leukopenia, it appears that the percent of hematologic toxicity would not be raised to unacceptable levels by using actual weight to set doses.

A prospective study of plasma and tissue carcinoembryonic antigen (P-CEA and T-CEA) levels in 63 patients with early (Stage I and II) breast cancer was undertaken to determine if the presence of CEA in tissue and/or plasma at the time of primary surgery can be used as a prognostic factor. Thirty-two Stage I and 31 Stage II patients were evaluable with a median follow-up time of 26 months: 29/63 were T-CEA and/or P-CEA positive while 34/63 were T-CEA and P-CEA negative; 9/63 were both T-CEA and P-CEA positive; 13/63 were P-CEA positive alone, while 25/63 were T-CEA positive alone; 5/29 T-CEA and/or P-CEA positive showed disease progression with a mean DFI of 11.8 months, compared with 0/34 T-CEA and P-CEA negative patients (P less than 0.02); 2/9 T-CEA and P-CEA positive compared with 0/34 negative patients progressed (P less than 0.01). There was a significant difference (P less than 0.05) between P-CEA positive (3/13) patients with recurrence and P-CEA negative (2/50). When T-CEA positive patients (4/25) were compared with T-CEA negative (1/38), the difference approaches significance. When the recurrences were analyzed with respect to CEA, estrogen receptor (ER) and nodal status, only in the CEA + versus CEA - group was there a significant difference. The early data show that patients with positive T-CEA and/or P-CEA have a higher recurrence rate with probable poor prognosis. Prognosis correlates better with CEA status than with ER or nodal status.

The Nd:YAG laser has proved its efficacy for recanalizing obstructing lesions throughout the gastrointestinal tract. In a preliminary report using the Nd:YAG laser as a pre-resectional treatment for functionally obstructing colorectal carcinoma we showed that this modality accomplished good decompression, allowing for formal bowel preparation, a definitive one-stage operation with no increased mortality or morbidity, and that the use of the Nd:YAG laser was significantly cost-effective. Our cumulative experience from 1985 to 1988 includes 11 patients; nine underwent pre-resection laser therapy followed by primary resection and anastomosis, and two underwent abdominoperineal resection. Tumors were located above the peritoneal reflection in nine patients and below in two patients. All patients had orthograde bowel preparation with Golytley the day after laser therapy and underwent definitive surgery. There were no wound or intra-abdominal infections or postoperative fatalities. These 11 laser-treated patients were compared with age-matched controls who had undergone earlier colonic diversion. No significant differences were noted for age, sex, tumor location or differentiation, stage, or overall survival. Comparisons between laser-treated patients and controls for the preoperative length of stay and total length of stay were significantly different (p = 0.002 and p = 0.001, respectively). When comparing laser-treated patients and controls, preoperative and total hospital costs were significantly different (p = 0.003 and p = 0.01). We have found that pre-resectional laser recanalization has allowed for primary resection and anastomosis in patients who have obstructing left colon and rectal carcinomas without compromising patient safety.

A prospective, randomized clinical trial of adjuvant treatment of 318 stage II breast cancer patients, using chemotherapy, the antiestrogen tamoxifen, and immunotherapy is reported at 48 months follow-up. Women whose primary tumors have no estrogen receptors fall into a significantly poorer prognostic group than those whose tumors contain estrogen receptors. None of the adjuvant regimens appeared to offer any clear-cut advantage for the estrogen receptor negative patients. Those women whose primary tumor contains estrogen receptors appear to be in a prognostically favorable group, when their treatment regimen included the antiestrogen, tamoxifen. The adjuvant use of BCG immunotherapy does not appear to offer additional benefit, but the follow-up period of these treated patients is too brief to be conclusive. A longer period of observation is needed to determine whether this systemic treatment in estrogen receptor positive patients is preventing recurrence or merely delaying it.

We randomly assigned 536 women who had undergone either a modified radical mastectomy or a total mastectomy with low axillary-node dissection for potentially curable breast carcinoma to receive adjuvant chemotherapy or no-treatment observation. The patients were considered at high risk for recurrence because they had either an estrogen-receptor-negative tumor of any size or an estrogen-receptor-positive tumor at least 3 cm in diameter with no histopathological evidence of axillary-node involvement. The chemotherapy consisted of six four-week cycles of cyclophosphamide (100 mg per square meter of body-surface area orally on days 1 through 14), methotrexate (40 mg per square meter intravenously on days 1 and 8), fluorouracil (600 mg per square meter intravenously on days 1 and 8), and prednisone (40 mg per square meter orally on days 1 through 14). Treatments were balanced with respect to patients' characteristics. The analysis included 406 eligible patients who were entered in the study before October 1, 1987. The overall disease-free survival among patients treated with the four-drug regimen was 84 percent, as compared with 69 percent for the control group, at a median follow-up of three years (P = 0.0001). A treatment benefit was also observed in premenopausal and postmenopausal patients as well as in patients with estrogen-receptor-positive or with estrogen-receptor-negative tumors. Severe or life-threatening hematologic toxicity was encountered in 33 percent of the treated patients, with one death. Our results indicate that adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, fluorouracil, and prednisone is effective in improving three-year disease-free survival among high-risk patients with axillary-node-negative, operable breast cancer. An analysis of the effect of treatment on survival awaits a longer follow-up.

A prospective, randomized clinical trial of three treatment regimens: (1) Cytoxan, methotrexate, and 5-fluorouracil (CMF), (2) CMF plus the antiestrogen drug, tamoxifen (CMFT), and (3) CMFT plus bacillus Calmette-Guerin (BCG) vaccinations in women with stage 22 breast cancer is reported. All patients underwent mastectomy and estrogen receptor (ER) analysis was performed. The results of this study show that patients with ER- tumors have recurrences more rapidly and have a higher mortality rate than patients with ER+ tumors (P less than 0.0001). In ER+ patients CMFT treatment is more effective in delaying recurrence than CMF alone at 33 months (P = 0.0176). This effect appears to be occurring in both premenopausal and postmenopausal women. In ER- patients the recurrence rate is high, and there is no significant difference among the three treatment groups. In premenopausal patients treated with CMF alone, however, ER- patients recur more rapidly than ER+ patients (P = 0.0313) and suggests that the effect of CMF may be related to the suppression of ovarian function. These findings have demonstrated a significant role for the use of antiestrogen therapy in patients with state II, ER+ breast cancer.

Because zinc is an essential nutrient for tissue growth, cellular division, protein synthesis, and DNA and RNA replication, it also ought to play a critical role in the growth of tumors. To test this thesis, a series of experiments were performed to test the effect of zinc deficiency on the lethality of a variety of solid and ascites tumors in mice and rats. Specifically, the following models were tested: Walker 256 carcinosarcomas, solid and ascites forms in rats; three mouse leukemias (L5178yf, L1210, and P388) in CDF, male mice; and Lewis lung carcinoma in C57BI/6 male mice. Rats receiving a zinc-deficient diet showed marked reduction of tumor growth, both of solid or ascites models, and this was accompanied by striking increase in survival. Survival of mice with transplanted leukemia was also significantly prolonged by zinc deficiency. In addition, growth of the Lewis lung carcinoma was inhibited, but the survival through increased, was probably limited by the adverse effects of zinc deficiency. The results suggest that tumor inhibition is a general effect of zinc deficiency, irrespective of cell type, cell growth rate, species, or site of growth. There are numerous potential applications of zinc metabolism to the diagnosis, therapy, and understanding of cancer.

The results of adjuvant chemotherapy (CMF), endocrine therapy (t), and immunotherapy (BCG) in 318 women who had undergone mastectomy for Stage II breast cancer are reported after 45 months of life table analysis. CMFT therapy was found to be more effective than CMF alone in increasing recurrence-free survival. This beneficial effect appears to be limited to patients with estrogen receptor-positive tumors (ER+). Patients with estrogen receptor-negative tumors (ER-) (3 fmol/mg) have increased recurrence rates and higher mortality.