Charles G. Moertel

Effective Surgical Adjuvant Therapy for High-Risk Rectal Carcinoma

BACKGROUND Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study, combined radiation and chemotherapy improved survival significantly as compared with surgery alone, but not as compared with adjuvant radiation, which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy, decrease recurrence, and improve survival as compared with adjuvant radiation alone. METHODS Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil, which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU). RESULTS After a median follow-up of more than seven years, the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0.0016; 95 percent confidence interval, 12 to 50 percent). Initial local recurrence was reduced by 46 percent (P = 0.036; 95 percent confidence interval, 2 to 70 percent), and distant metastasis by 37 percent (P = 0.011; 95 percent confidence interval, 9 to 57 percent). In addition, combined therapy reduced the rate of cancer-related deaths by 36 percent (P = 0.0071; 95 percent confidence interval, 14 to 53 percent) and the overall death rate by 29 percent (P = 0.025; 95 percent confidence interval, 7 to 45 percent). Its acute toxic effects included nausea, vomiting, diarrhea, leukopenia, and thrombocytopenia. These effects were seldom severe. Severe, delayed treatment-related reactions, usually small-bowel obstruction requiring surgery, occurred in 6.7 percent of all patients receiving radiation, and the frequencies of these complications were comparable in both treatment groups. CONCLUSIONS The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis, as compared with postoperative radiation alone.

Prognostic effect of weight loss prior tochemotherapy in cancer patients

The prognostic effect of weight loss prior to chemotherapy was analyzedusing data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkins lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.

Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group.

One‐hundred‐ninety‐four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with high‐dose (6000 rads) radiation therapy alone, to moderate‐dose (4000 rads) radiation + 5‐fluorouracil (5‐FU), and to high‐dose radiation plus 5‐FU. Median survival with radiation alone was only 51/2 months from date of diagnosis. Both 5‐FU‐containing treatment regimens produced a highly significant survival improvement when compared with radiation alone. Forty percent of patients treated with the combined regimens were still living at one year compared with 10% of patients treated with radiation only. Survival differences between 4000 rads plus 5‐FU and 6000 rads plus 5‐FU were not significant with an overall median survival of ten months. Significant prognostic variables, in addition to treatment, were pretreatment performance status and pretreatment CEA level.

Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.

The purpose of this study was to evaluate the effectiveness of several new approaches designed to enhance the activity of fluorouracil (5-FU) in the management of advanced colorectal cancer. A total of 429 patients were randomized to one of the following regimens: single-agent 5-FU, given by standard 5-day, intensive-course intravenous bolus technique; 5-FU plus high-dose folinic acid (leucovorin) or 5-FU plus low-dose leucovorin; 5-FU plus high-dose methotrexate (MTX) with oral leucovorin rescue; 5-FU plus low-dose MTX; and 5-FU plus cisplatin (CDDP). The median survival for patients receiving 5-FU alone was 7.7 months. The high- and low-dose leucovorin plus 5-FU regimens had median survivals of 12.2 and 12.0 months, respectively, and offered a significant survival advantage over 5-FU alone with one-sided P values of .037 and .050, respectively (P = .051 for each treatment after correction for prognostic variables). The only other regimen possibly associated with improved survival was high-dose MTX plus 5-FU, with a median survival of 10.5 months (P = .21, P = .076 corrected). In addition, both high- and low-dose leucovorin plus 5-FU regimens were associated with significantly improved tumor response rates (P = .04 and .001) and significantly improved interval-to-tumor-progression rates (P = .015 and .007) when compared with 5-FU alone. Only the low-dose leucovorin plus 5-FU regimen was associated with significant (P less than .05) superiority in each of the following parameters of quality of life: performance status, weight gain, and symptomatic relief. The overall most therapeutically favorable regimen in this trial was 5-FU given with low-dose leucovorin; fortuitously, this regimen is associated with very low drug cost. Whereas this is the first study to demonstrate both improved palliation and survival for any regimen compared with 5-FU given by rapid intravenous (IV) injection for 5 consecutive days at a dose of 500 mg/m2/d in patients with advanced colorectal cancer, the magnitude of the gain is still relatively small. Our low-dose leucovorin plus 5-FU regimen is currently being studied in a national trial with the hope that this increased advanced disease activity may produce more substantive gains in the surgical adjuvant setting.

Fluorouracil plus Levamisole as Effective Adjuvant Therapy after Resection of Stage III Colon Carcinoma: A Final Report

Carcinoma of the colon is one of the most common malignant diseases afflicting Western civilization. Most patients with this condition present with disease that is grossly completely resectable and in which any residual cancer is microscopic in nature. This is an ideal setting for reducing cancer mortality by adding adjuvant therapy to potentially curative surgery; pursuing the hope of such a reduction, clinical efforts at adjuvant therapy after surgery for colon cancer began more than 35 years ago and have involved numerous randomized trials enrolling several thousand patients treated with cytotoxic drugs, nonspecific immune stimulants, or various combinations thereof. Despite these efforts, no convincing evidence for the effectiveness of any regimen has been shown. Indeed, in a meta-analysis of all patients with colon cancer who were entered into trials of adjuvant therapy, Buyse and colleagues [1] found that the odds for dying were 8% higher for treated than for untreated patients. In 1989, a study by the North Central Cancer Treatment Group suggested that levamisole, a drug long used as an anthelmintic and presumed to have immunostimulatory activity [2], may be valuable. In this relatively small trial, levamisoleparticularly when used in combination with fluorouracilwas found to significantly reduce recurrence rates (P = 0.04) in patients with surgically treated stage II and stage III colorectal cancer. However, such therapy did not confer a statistically significant survival advantage, although the subset analysis suggested possible benefit for those patients with stage III disease. These results, although not convincing, were sufficiently intriguing to stimulate two large national intergroup trials. The first, which examined stage III disease, compared both postoperative levamisole alone and the postoperative combination of fluorouracil plus levamisole with surgery alone. The second trial, which examined stage II disease, compared only the postsurgical combination therapy with surgery alone. In 1990, we reported the early results of the stage III trial, which showed that patients treated with fluorouracil plus levamisole had a striking 41% reduction in the recurrence rate (P < 0.0001) and a 33% reduction in the mortality rate (P = 0.006) when compared with untreated controls [3]. On the basis of these results, a Consensus Panel convened by the National Institutes of Health recommended fluorouracil plus levamisole as standard therapy for patients with surgically treated stage III colon cancer [4]. Marketing of levamisole for this purpose was approved by the Food and Drug Administration. Our results, however, had been reported relatively early; the median follow-up time was only 3 years, and only a few patients had been followed for more than 5 years. Although the evidence for therapeutic benefit was strong, it was possible that we were only prolonging the interval to cancer recurrence and death rather than actually improving cure rates. In this report, we document our mature study with all patients able to be followed for more than 5 years. Methods Our methods have been described previously [3]. Within each of the three participating cooperative groups, patients with stage III (Dukes stage C) colon cancer who were fully recovered from surgery were grouped according to interval since surgery, depth of invasion of the primary tumor, and number of lymph nodes with metastasis. They were then randomly assigned to no further therapy, to treatment with levamisole alone, or to treatment with fluorouracil plus levamisole. Treatments could not be blinded, so no placebos were used. Levamisole was initiated 7 to 35 days after surgery at a dose of 50 mg administered orally three times/d for 3 days, repeated every 2 weeks for 1 year. Patients assigned to the combination therapy received the same regimen of levamisole plus fluorouracil at a dose of 450 mg/m2 body surface area, given by rapid intravenous injection daily for 5 days. Fluorouracil and levamisole were initiated simultaneously, 21 to 35 days after surgery. Twenty-eight days after the start of chemotherapy, weekly treatment with fluorouracil was begun at an intravenous dose of 450 mg/m2 body surface area and was continued for 48 additional weeks. Appropriate adjustments in dosage were made according to toxicity. Patients were followed with periodic medical examinations, which included blood counts, blood chemistries, chest radiographs, and imaging of the bowel using colonoscopy or proctoscopy plus radiography of the colon. Carcinoembryonic antigen assays were optional. Statistical analyses were done according to the procedures of the Statistical Analysis System [5]. Progression and survival curves were generated using the Kaplan-Meier method [6]; the log-rank statistic [7] was used to compare the distributions of survival times. The proportional hazards model [8] was used to determine the ratios of relapse and survival rates and to do all multivariate analyses. Backward regression was used to find the significant prognostic factors; variables were progressively eliminated on the basis of the maximum partial-likelihood statistics. To adjust for covariates when evaluating treatments, we kept the variable of treatment in the model and used backward regression for other covariates, keeping those whose maximum partial-likelihood statistics satisfied the criterion of P < 0.01. All P values reported are two-sided. The protocol was approved by the respective review boards of the participating institutions, and all patients gave written informed consent. Results A total of 971 patients were randomized in our stage III study. Forty-two (4.3%) of these were ineligible, in most cases because they had disease at a more advanced stage than that allowed by the protocol; these patients were excluded from the analysis. Fourteen patients refused to accept their treatment assignment. Because this withdrawal could be, and undoubtedly was, biased by treatment assignment, these patients were included in all analyses according to treatment assigned. At present, all patients entered into the study can potentially be followed for more than 5 years after surgery; the actual median follow-up time is 6.5 years. Ten patients have been lost to follow-up before 5 years but after a median time of 53 months (range, 9 to 59 months). As described in our earlier report [3], the clinical and pathologic characteristics of our patients were balanced among the study arms, except that more women were treated with fluorouracil plus levamisole, fewer patients receiving levamisole had tumors of the sigmoid colon and the rectosigmoid, and fewer patients receiving fluorouracil plus levamisole were 60 years of age or younger or had lesions invading adjacent organs. Cancer Recurrence Among the 315 patients assigned to no additional treatment, 177 have had proven recurrence. Among the 310 assigned to levamisole alone, 172 have had recurrence. In contrast, however, only 119 of the 304 patients assigned to fluorouracil plus levamisole have had recurrence. Figure 1 shows recurrence-free intervals according to treatment arm. Clearly, therapy with levamisole alone produced no benefit, whereas patients treated with fluorouracil plus levamisole have a highly significant advantage (P < 0.0001). These curves have no tendency to converge during long-term follow-up. Figure 1. Recurrence-free interval according to treatment arm. Figure 2 shows patterns of initial sites of recurrence according to treatment arm. It can be seen that recurrence in all common sites of metastasis was reduced in patients receiving fluorouracil plus levamisole when compared with untreated controls and with those receiving levamisole alone. It is noteworthy, however, that therapy had only a minimal effect on local or regional recurrence. Figure 2. Patterns of recurrence sites according to treatment arm. Table 1 shows the influence of patient and pathologic characteristics on recurrence. Depth of primary tumor invasion, number of metastatic lymph nodes, adhesion to or invasion of adjacent structures, regional implants, histologic differentiation, and preoperative carcinoembryonic antigen levels were all found to be determinants of recurrence (P < 0.01). After adjustment for the minor imbalances in prognostic variables among treatment arms, therapy with fluorouracil plus levamisole was again found to have an advantage over observation (40% reduction in recurrence rate; P < 0.0001). Levamisole alone had no detectable advantage (2% reduction in recurrence rate; P = 0.86). Table 1. Prognostic Factors for Recurrence Survival Four hundred forty-seven patients have died: 168 of the 315 patients assigned to observation only, 158 of the 310 receiving levamisole alone, and 121 of the 304 receiving fluorouracil plus levamisole. The survival curves shown in Figure 3 are similar to the recurrence curves. The survival pattern for patients receiving levamisole alone overlaps with that of the untreated control patients. Again, fluorouracil plus levamisole shows statistically and clinically significant advantages. The curves have no tendency to converge, which provides considerable evidence that cancer-related deaths have been prevented rather than simply delayed. These survival patterns were seen in each of the three cooperative groups. Figure 3. Survival according to treatment arm. The relations between patient or tumor characteristics and survival are shown in Table 1. Depth of primary tumor invasion, invasion of adjacent structures, regional implants, number of metastatic lymph nodes, histologic differentiation, and preoperative carcinoembryonic antigen level were each found to have prognostic significance (P < 0.01). After correction for the influence of prognostic factors through the use of a proportional hazards model, patients receiving fluorouracil plus levamisole were again found to have a significant survival advantage when compared with patients assi

Streptozocin–Doxorubicin, Streptozocin–Fluorouracil, or Chlorozotocin in the Treatment of Advanced Islet-Cell Carcinoma

BACKGROUND The combination of streptozocin and fluorouracil has become the standard therapy for advanced islet-cell carcinoma. However, doxorubicin has also been shown to be active against this type of tumor, as has chlorozotocin, a drug that is structurally similar to streptozocin but less frequently causes vomiting. METHODS In this multicenter trial, we randomly assigned 105 patients with advanced islet-cell carcinoma to receive one of three treatment regimens: streptozocin plus fluorouracil, streptozocin plus doxorubicin, or chlorozotocin alone. The 31 patients in whom the disease did not respond to treatment were crossed over to chlorozotocin alone or to one of the combination regimens. RESULTS Streptozocin plus doxorubicin was superior to streptozocin plus fluorouracil in terms of the rate of tumor regression, measured objectively (69 percent vs. 45 percent, P = 0.05), and the length of time to tumor progression (median, 20 vs. 6.9 months; P = 0.001). Streptozocin plus doxorubicin also had a significant advantage in terms of survival (median, 2.2 vs. 1.4 years; P = 0.004) that was accentuated when we considered long-term survival (greater than 2 years). Chlorozotocin alone produced a 30 percent regression rate, with the length of time to tumor progression and the survival time equivalent to those observed with streptozocin plus fluorouracil. Crossover therapy after the failure of either chlorozotocin alone or one of the combination regimens produced an overall response rate of only 17 percent, and the responses were transient. Toxic reactions to all regimens included vomiting, which was least severe with chlorozotocin; hematologic depression; and, with long-term therapy, renal insufficiency. CONCLUSIONS The combination of streptozocin and doxorubicin is superior to the current standard regimen of streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. Chlorozotocin alone is similar in efficacy to streptozocin plus fluorouracil, but it produces fewer gastrointestinal side effects than the regimens containing streptozocin. It therefore merits study as a constituent of combination drug regimens.

TREATMENT OF THE MALIGNANT CARCINOID SYNDROME: EVALUATION OF A LONG-ACTING SOMATOSTATIN ANALOGUE

We studied the effects of a long-acting analogue of somatostatin (SMS 201-995, Sandoz) in 25 patients with histologically proved metastatic carcinoid tumors and the carcinoid syndrome. This drug was self-administered by subcutaneous injection at a dose of 150 micrograms three times daily. Flushing and diarrhea associated with the syndrome were promptly relieved in 22 patients. All 25 patients had an elevated 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) (mean, 265 mg per 24 hours; range, 14 to 1079), which served as an objective indicator of disease activity. Eighteen of the 25 patients (72 percent) had a decrease of 50 percent or more in their urinary 5-HIAA levels, as compared with the pretreatment values. The median duration of this biochemical response was more than 12 months (range, 1 to greater than 18). Since no serious toxicity was observed, we conclude that SMS 201-995 may be appropriate for use as early therapy in patients with symptoms due to the carcinoid syndrome who have not responded to simpler measures.

Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms

Forty‐five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well‐differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, an overall regression rate of 67%. For anaplastic disease, the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity, which was severe for most patients, consisted primarily of vomiting, leukopenia, thrombocytopenia, anemia, alopecia, and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas, originating in typical neuroendocrine tumor sites (small and large bowel, pancreas, and stomach) or of unknown origin, who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.

Streptozocin Alone Compared with Streptozocin plus Fluorouracil in the Treatment of Advanced Islet-Cell Carcinoma

To evaluate the treatment of advanced islet-cell carcinoma, we randomly assigned 84 patients to streptozocin alone or streptozocin plus fluorouracil. Each regimen was given in five-day courses. The most frequent toxic effects were nausea and vomiting, mild and reversible renal toxicity, and bone-marrow depression with the combination regimen. The combination had advantages over streptozocin alone in overall rate of response (63 vs. 36 per cent) and in rates of complete response (33 vs. 12 per cent). There was no evidence of a preferential response among types of functional tumors. Objective responses were generally of long duration (median, 17 months) and of substantive clinical benefit. Treatment with the combination also yielded a survival advantage over treatment with streptozocin alone (medians, 26 and 16 1/2 months), but this difference is not statistically significant. In spite of gastrointestinal side effects, streptozocin combined with fluorouracil appears to be a valuable treatment for advanced islet-cell carcinoma.

Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic.

A total of 401 eligible patients with resected stages B and C colorectal carcinoma were randomly assigned to no-further therapy or to adjuvant treatment with either levamisole alone, 150 mg/d for 3 days every 2 weeks for 1 year, or levamisole plus fluorouracil (5-FU), 450 mg/m2/d intravenously (IV) for 5 days and beginning at 28 days, 450 mg/m2 weekly for 1 year. Levamisole plus 5-FU, and to a lesser extent levamisole alone, reduced cancer recurrence in comparison with no adjuvant therapy. These differences, after correction for imbalances in prognostic variables, were only suggestive for levamisole alone (P = .05) but quite significant for levamisole plus 5-FU (P = .003). Whereas both treatment regimens were associated with overall improvements in survival, these improvements reached borderline significance only for stage C patients treated with levamisole plus 5-FU (P = .03). Therapy was clinically tolerable with either regimen and severe toxicity was uncommon. These promising results have led to a large national intergroup confirmatory trial currently in progress.