Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia.

Preliminary information has suggested that megestrol acetate leads to appetite stimulation and nonfluid weight gain in patients with breast cancer, other cancers, and AIDS. Pursuant to this, we developed a randomized, double-blind, placebo-controlled trial of megestrol acetate in patients with cancer-associated anorexia and cachexia. We randomly assigned 133 eligible patients to receive 800 mg of megestrol acetate per day or a placebo. Patients assigned to megestrol acetate more frequently reported improved appetite (P = .003) and food intake (P = .009) when compared with patients receiving the placebo. A weight gain of 15 lb or more over baseline was seen in 11 of 67 (16%) patients receiving megestrol acetate compared with one of 66 (2%) given the placebo (P = .003). Patients receiving megestrol acetate reported significantly less nausea (13% vs. 38%; P = .001) and emesis (8% vs. 25%, P = .009). No clinically or statistically significant toxic reactions were ascribed to megestrol acetate, with the exception of mild edema. This study convincingly demonstrated that megestrol acetate can stimulate appetite and food intake in patients with anorexia and cachexia associated with cancer, leading to significant weight gain in a proportion of such patients.

Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group.

PURPOSE: To compare the efficacy and safety of granisetron and ondansetron, serotonin (5-HT3) receptor antagonists shown to be effective in the prevention of chemotherapy-induced emesis. PATIENTS AND METHODS: In a double-blind, randomized, stratified, parallel-group study, the efficacy and safety of granisetron and ondansetron were compared in 987 chemotherapy-naive patients who received cisplatin in doses > or = 60 mg/m2. Granisetron was administered as a single dose of 10 or 40 micrograms/kg before the start of chemotherapy. Ondansetron was administered in doses of 0.15 mg/kg before and 4 and 8 hours after the start of chemotherapy. The three treatment groups were well-matched with respect to demographic characteristics and the dose of cisplatin administered. RESULTS: For all evaluations, single doses of granisetron 10 or 40 micrograms/kg were as effective as three 0.15-mg/kg doses of ondansetron. Total control (no vomiting, no retching, no nausea, and no use of rescue) was attained by 38%, 41%, and 39% of all patients who received granisetron 10 microgram/kg, granisetron 40 micrograms/kg, and ondansetron, respectively. No vomiting or retching and no use of rescue antiemetics were reported in 47%, 48%, and 51% of patients who received granisetron 10 micrograms/kg, granisetron 40 micrograms/kg, and ondansetron, respectively; no nausea and no use of rescue antiemetics were reported in 39%, 42%, and 40% of patients, respectively. CONCLUSION: All three treatment regimens were well-tolerated. The results of this study indicate that a single dose of granisetron 10 or 40 micrograms/kg is as effective as three doses of ondansetron 0.15 mg/kg in the prevention of nausea and vomiting induced by cisplatin chemotherapy.

The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin's lymphoma.

Non-Hodgkin's lymphoma (NHL) is a malignancy that occurs frequently in the elderly with a median age greater than 60 years. However, most chemotherapy trials have included predominantly patients less than 60 years of age. We treated 157 patients with diffuse aggressive NHL between September 1982 and May 1986 with cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), procarbazine, bleomycin, vincristine, and prednisone (CAP/BOP). There were no treatment exclusions for age. Patients in this study ranged in age from 15 to 91 years (median, 63) with 112 patients greater than or equal to 60 years of age. The overall complete remission (CR) rate was 65% with no significant difference for age less than 60 (76%) v age greater than or equal to 60 (61%) (P = .18). With a median 36-month follow-up (range, 22 to 65 months), the overall 5-year survival was 42%. The patients less than 60 years old had a 62% 5-year survival in contrast to a 34% 5-year survival in those patients greater than or equal to age 60 (P = .01). The deaths attributed to tumor or treatment-related toxicity were similar above and below age 60. The difference in survival was due to other causes of death not obviously related to the lymphoma or its therapy-occurring in 22% of patients greater than or equal to 60 years of age but only 2% of patients less than 60 years (P = .005). Our data supports the position that aggressive NHL in elderly patients is not significantly less responsive than in younger patients; however, the inclusion of older patients in clinical trials will decrease the overall survival secondary to deaths due to apparently unrelated causes.

Chemotherapy for diffuse large-cell lymphoma--rapidly responding patients have more durable remissions.

Fifty-one patients with diffuse large-cell lymphoma (DLCL) were treated with a six-drug combination chemotherapy regimen including cyclophosphamide, doxorubicin, procarbazine, bleomycin, vincristine, and prednisone. The patients were restaged after three cycles of therapy, and restaging was repeated at 2-month intervals in patients who had persistent disease. Responding patients received two cycles of therapy after documentation of complete remission (CR). With all patients considered evaluable, 73% of the patients achieved a CR. Twenty-six of the 37 CRs (70%) achieved remission in the first three treatment cycles. The durability of remission in the rapidly responding patients was significantly better than for patients who required five cycles to achieve CR (80% v 40% at 2 years, P = .02) despite the latter patients having received two more cycles of therapy. Rapidly responding patients with DLCL do not require prolonged therapy and have a better prognosis than patients achieving a CR more slowly.

Phase II studies of single-agent cimetidine and the combination N-phosphonacetyl-L-aspartate (NSC-224131) plus L-alanosine (NSC-153353) in advanced malignant melanoma.

We conducted parallel phase II trials of cimetidine as a single agent and the combination N-phosphonacetyl-L-aspartate (PALA) plus L-alanosine among 40 previously untreated patients with biopsy-proven, measurable disseminated malignant melanoma. We did not design the trial to be a comparative assessment of the two regimens. Among 19 patients treated with cimetidine, 300 mg orally four times daily, there was one complete response of extensive pleural and pulmonary metastases for 16+ months and two partial regressions of soft tissue lesions for 7 and 21+ months, respectively. Among 21 patients treated with the combination regimen, there was only one partial response in soft tissue for 1 month. The median times to progression and death were 1.4 and 6 months, respectively, for cimetidine, and 1.3 and 4 months, respectively, from the combination of PALA plus L-alanosine. Among patients who progressed on initial treatment, there were no responses in 12 who received crossover therapy with cimetidine and 11 with the combination regimen. Two patients treated with the combination program had severe stomatitis, two developed renal failure, and one had severe leukopenia and thrombocytopenia. Recognizing the limitations of small sample size, these early observations suggest that cimetidine may have intriguing implications in the management of disseminated malignant melanoma.

Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer.

In a previous study (J Clin Oncol 7:1407-1417, 1989), we identified two dosage administration schedules of fluorouracil (5FU) combined with leucovorin that were superior to single-agent 5FU for the treatment of advanced colorectal cancer. In this same study, a regimen of 5FU plus high-dose methotrexate (MTX) demonstrated a suggestive advantage over 5FU alone. To permit a more definitive comparison, we have extended our evaluation of these three regimens to involve an additional 259 patients. In all, 457 patients with advanced colorectal cancer were randomly assigned to one of the following regimens: 5FU plus low-dose leucovorin, 5FU plus high-dose leucovorin, or 5FU plus high-dose MTX with leucovorin rescue. We have found that each of the 5FU/leucovorin regimens demonstrates a significant (P less than or equal to .01) advantage over 5FU plus high-dose MTX for objective tumor response and interval to tumor progression. Moreover, 5FU plus low-dose leucovorin confers a significant survival benefit (P less than or equal to .01) compared with 5FU plus high-dose MTX. The 5FU plus high-dose leucovorin regimen shows a survival benefit only in unadjusted analyses (P = .04), but this difference is not significant when adjusted for imbalances in prognostic variables (P = .44). Evaluation of the two 5FU/leucovorin regimens rules out a 10% decrease in death rate for the high-dose leucovorin regimen compared with the low-dose leucovorin regimen (P less than .05). The regimen of 5FU plus low-dose leucovorin has now been shown to offer a statistically significant survival advantage versus 5FU alone and versus 5FU plus high-dose MTX, a regimen that had shown promise in earlier trials. These data confirm the efficacy of leucovorin combined with 5FU in patients with advanced colorectal cancer and establish that it is not necessary to use high doses of leucovorin to achieve these results.

Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer.

PURPOSE: The goal of this study was to determine the efficacy of intensive-course fluorouracil (5FU) plus low-dose leucovorin given for 6 months following potentially curative resection of colon cancer. PATIENTS AND METHODS: Three hundred seventeen patients with high-risk stage II or stage III colon cancer were randomly assigned 3 to 4 weeks following surgery to receive either (1) chemotherapy with six cycles of 5FU (425 mg/m2) plus leucovorin (20 mg/m2) by rapid intravenous injection daily for 5 consecutive days every 4 to 5 weeks, or (2) observation. RESULTS: The median follow-up duration is 72 months for patients still alive. Patients who received postoperative 5FU plus leucovorin experienced significant improvement in time to relapse (P < .01) and survival (P = .02) compared with control patients treated with surgery alone. Stomatitis, diarrhea, and leukopenia were the predominant chemotherapy toxicities. There were no treatment-related deaths. CONCLUSION: These results indicate that intensive-course 5FU plus low-dose leucovorin is effective in preventing tumor relapse and improving survival in patients with high-risk colon cancer. These benefits were seen with only six cycles of treatment, using low-dose leucovorin in combination with 5FU on a schedule convenient for outpatient administration.

Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. North Central Cancer Treatment Group.

PURPOSE: The purpose of this study was to evaluate the therapeutic effectiveness of fluorouracil (5-FU), doxorubicin, and methyl lomustine (CCNU) (FAMe), 5-FU, doxorubicin, and cisplatin (FAP), and FAMe alternating with triazinate (TZT) when compared with a standard therapy of 5-FU alone in patients with advanced gastric cancer. PATIENTS AND METHODS: Two hundred fifty-two eligible patients selected for study had proven locally unresectable and/or metastatic gastric adenocarcinoma. The majority had nonmeasureable disease. They were randomly assigned to receive one of the three drug combination regimens or to 5-FU alone administered by rapid injection in 5-day course. Survival was the primary study end point. RESULTS: None of the three drug combinations showed a significant advantage over 5-FU alone in improved performance score, weight gain, or patient survival. Each of the three combinations was more toxic than 5-FU alone. CONCLUSION: FAMe, FAP, or FAMe alternating with TZT cannot be recommended for the therapy of advanced gastric carcinoma. Therapy of this disease should remain an experimental endeavor. It would seem reasonable to prove the value of any new treatment approach by a randomized comparison to simple therapy with 5-FU alone.

Early evaluation of combined fluorouracil and leucovorin as a radiation enhancer for locally unresectable, residual, or recurrent gastrointestinal carcinoma. The North Central Cancer Treatment Group.

PURPOSE: To develop a tolerable regimen of fluorouracil (5-FU), low-dose leucovorin, and radiation, and to obtain an early estimate of therapeutic effectiveness. PATIENTS AND METHODS: Forty patients with locally unresectable or recurrent gastrointestinal carcinoma were studied (pancreas, n = 22; rectum and sigmoid, n = 10; gastric, n = 6; other, n = 2). Irradiation therapy was administered in 1.8-Gy fractions 5 days per week, with total doses ranging from 45 to 54 Gy. 5-FU 400 mg/m2/d plus leucovorin 20 mg/m2/d, both by rapid intravenous injection, were administered for 3 or 4 days during the first and fifth weeks of radiation. 5-FU 425 mg/m2/d plus leucovorin 20 mg/m2/d were administered for 4 days at 4 weeks following radiation and for 5 days at 9 weeks. RESULTS: Major toxicities with upper abdominal treatment were nausea, vomiting, weight loss, and leukopenia. A tolerable dosage regimen was radiation at 45 Gy with 4 days of 5-FU plus leucovorin during the first week and 3 days during the last week with postradiation chemotherapy. Major toxicities with pelvic radiation were diarrhea and leukopenia. A tolerable regimen was 54 Gy with 4 days of 5-FU plus leucovorin during the first and fifth week followed by the postradiation chemotherapy. Median survival durations for pancreatic and rectal/sigmoid carcinomas are 13 months and 31 months, respectively. Five patients have no evidence of disease from 38 to 50 months after the onset of therapy (rectal, n = 2; stomach, n = 2; pancreas, n = 1). CONCLUSION: We have developed patient-tolerable regimens for combined 5-FU plus leucovorin followed by radiation to the abdomen and to the pelvis. The favorable results observed in locally unresectable disease allow cautious optimism for possible effectiveness in the surgical adjuvant setting, a possibility currently being tested in national trials of rectal and gastric carcinoma.

Sucralfate in the prevention of treatment-induced diarrhea in patients receiving pelvic radiation therapy: A North Central Cancer Treatment Group phase III double-blind placebo-controlled trial.

PURPOSE: Randomized studies have suggested that sucralfate is effective in mitigating diarrhea during pelvic radiation therapy (RT). This North Central Cancer Treatment Group study was undertaken to confirm the antidiarrheal effect of sucralfate. Several other measures of bowel function were also assessed. PATIENTS AND METHODS: Patients receiving pelvic RT to a minimum of 45 Gy at 1.7 to 2.1 Gy/d were eligible for the study. Patients were assigned randomly, in double-blind fashion, to receive sucralfate (1.5 g orally every 6 hours) or an identical looking placebo during pelvic RT. RESULTS: One hundred twenty-three patients were randomly assigned and found assessable. Overall, there was no significant difference in patient characteristics between those receiving sucralfate and those receiving placebo. Moderate or worse diarrhea was observed in 53% of patients receiving sucralfate versus 41% of those receiving placebo. Compared with patients receiving placebo, more sucralfate-treated patients reported fecal incontinence (16% v 34%, respectively; P =. 04) and need for protective clothing (8% v 23%, respectively; P =. 04). The incidence and severity of nausea were worse among those taking sucralfate (P =.03). Analysis of patient-reported symptoms 10 to 12 months after RT showed a nonsignificant trend toward more problems in patients taking sucralfate than in those taking placebo (average, 2.3 v 1.9 problems, respectively; P =.34). CONCLUSION: Sucralfate did not decrease pelvic RT-related bowel toxicity by any of the end points measured and seems to have aggravated some gastrointestinal symptoms.

Evaluation of a somatostatin analog in the treatment of lymphoproliferative disorders: results of a phase II North Central Cancer Treatment Group trial.

PURPOSE: Malignant cells from non-Hodgkin's lymphomas (NHL) have been shown to express the somatostatin receptor on their cell surface and most NHL are visible on somatostatin radioscintigraphy scans. This provided the rationale to conduct a phase II trial of a somatostatin analog in patients with B- and T-cell lymphoproliferative disorders. PATIENTS AND METHODS: Sixty-one patients with measurable or assessable lymphoproliferative disorders (31 stage III or IV low-grade NHL; 21 chronic lymphocytic leukemia [CLL]; and nine cutaneous T-cell NHL [CTCL]) were enrolled. Patients were treated with somatostatin 150 micrograms subcutaneously (SQ) every 8 hours for 1 month. Patients with stable or responding disease received 2 additional months of therapy; those who responded after 3 months were treated for an additional > or = 3 months. RESULTS: Sixty patients were assessable for toxicity and 56 for response. There were no complete remissions. In the low-grade NHL group, 36% (10 of 28 patients; 95% confidence interval [CI], 19% to 56%) had a partial remission. Forty-four percent (four of nine; 95% CI, 14% to 79%) of patients with CTCL had a partial response. No patients with CLL had a partial remission. Among 45 patients with stable disease or a partial remission, the mean time to progression (TTP) was 10.9 months (median, 6.2; range, 1.6 to 48.5). The drug was well tolerated, with the most common side effects being diarrhea and hyperglycemia. CONCLUSION: Somatostatin at a dose of 150 micrograms every 8 hours is well tolerated and has activity in low-grade NHL.

Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia.

PURPOSE: Several placebo-controlled randomized clinical trials have demonstrated that megestrol acetate can result in appetite stimulation and nonfluid weight gain in patients with cancer anorexia/cachexia. The present trial was designed to compare megestrol acetate doses ranging from 160 to 1,280 mg/d. METHODS: This trial randomized 342 assessable patients with cancer anorexia/cachexia to receive oral megestrol acetate at doses of 160, 480, 800, or 1,280 mg/d. Patients were evaluated monthly by history, examination, patient-completed questionnaires, and serum albumin levels. RESULTS: The data demonstrate that there is a positive dose-response effect for megestrol acetate on appetite stimulation (P < or = .02). In concert, there was a trend for more nonfluid weight gain with higher drug doses. Megestrol acetate was well tolerated in this group of patients with advanced malignant disease. CONCLUSION: The positive dose-response effect that we observed for megestrol acetate on appetite stimulation supports both our prestudy hypothesis and other available literature. Nonetheless, based primarily on the cost and inconvenience associated with the use of higher doses of this drug, it is reasonable to use 160 mg/d for the initial treatment of cancer anorexia/cachexia in routine clinical practice.

Treatment of limited-stage small-cell lung cancer with cyclophosphamide, doxorubicin, and vincristine with or without etoposide: a randomized trial of the North Central Cancer Treatment Group.

In this randomized study involving patients with limited-stage small-cell lung cancer (LD-SCC), we compared treatment with either cyclophosphamide; doxorubicin, and vincristine (CAV) or CAV plus etoposide (CAVE). All patients received identical thoracic radiation consisting of 3,750 cGy in 15 fractions and prophylactic cranial radiation (3,000 cGy in 10 fractions). Among 231 evaluable patients, the two treatment arms were well matched with respect to sex, age, performance score, and presence or absence of heart disease. A major regression (REGR) was observed in 83% of all patients and a complete response (CR) in 60%. There was no difference in the response rate between the two treatment regimens. The median time to progression is 10.4 months (95% confidence interval [Cl], 8.9 to 12 months) for CAVE versus 8.9 months (95% Cl, 7.9 to 10.4 months) for CAV (P = .04). The median survival is 15.1 months (95% Cl, 11.7 to 17.8 months) for CAVE versus 12.4 months (95% Cl, 11 to 14.4 months) for CAV. This difference is not significantly different (P = .13). Toxicity was primarily myelosuppression and was significantly greater for the four-drug regimen. Fatal treatment-related toxicity was observed in two patients on the CAVE regimen and no treatment-related deaths were observed on the CAV treatment. In conclusion, the addition of etoposide to the CAV regimen resulted in increased toxicity but did not lead to a meaningful improvement in survival.

Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer.

A randomized clinical trial was performed to determine if combination hormonal therapy with tamoxifen (TAM) and fluoxymesterone (FLU) was more efficacious than TAM alone for the treatment of postmenopausal women with metastatic breast cancer. Patients failing TAM could subsequently receive FLU. The dose of both drugs was 10 mg orally twice daily. Objective responses were seen in 50 of 119 TAM patients (42%) and 63 of 119 TAM plus FLU patients (53%) (one-sided P = .05). Time to disease progression distributions were better for TAM plus FLU (median, 350 days v 199 days), but the log rank test only approached statistical significance (one-sided P = .07). Duration of response and survival distributions were similar between the two treatment arms. Toxicities, in terms of androgenic side effects, were greater on the TAM plus FLU regimen. Fifty-two patients are evaluable for response with FLU following TAM and 21 (40%) have achieved a response. We conclude that the advantages in terms of response rate and time to progression observed with TAM plus FLU probably represent a biological effect, but are not of sufficient magnitude to justify the routine clinical use of this combination given the lack of survival advantage and side effects encountered.

Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer.

PURPOSE: We evaluated the effect of recombinant interferon gamma (rIFN-gamma) on survival and toxicity in small-cell lung cancer (SCLC) patients in complete remission (CR). PATIENTS AND METHODS: One hundred patients in CR following treatment with six cycles of combination chemotherapy, thoracic radiotherapy (TRT), and prophylactic cranial irradiation (PCI) were studied. All patients had been enrolled onto a cooperative group trial (North Central Cancer Treatment Group [NCCTG] 86-20-51). Patients received observation only or rIFN-gamma at a dose of 4 x 10(6) U subcutaneously per day for 6 months. RESULTS: Six patients (12%) did not comply with rIFN-gamma treatment. Substantial nonhematologic toxicities consisting of chills, myalgia, lethargy, and alteration of mood-personality were observed. No patient experienced life-threatening or fatal toxicity. The median times to progression for rIFN-gamma treatment or observation were 6.9 and 8.1 months (P = .54). The median survival times were 13.3 and 18.8 months, respectively (P = .43). Approximately 70% of all patients relapsed within 2 years. CONCLUSION: Time to progression and survival were inferior in patients treated with rIFN-gamma compared with randomized control subjects, although this difference was not statistically significant. These data indicate that rIFN-gamma treatment is not associated with a 33% improvement in survival (P = .04). Because of the high rate of relapse, SCLC patients in CR are an ideal group in which to evaluate novel and minimally toxic agents.

Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer.

PURPOSE: To compare two commonly used schedules of fluorouracil (5FU) and leucovorin in the treatment of patients with advanced metastatic colorectal cancer. Each of these dosage administration schedules has been demonstrated to be superior to single-agent bolus 5FU in previous controlled trials. PATIENTS AND METHODS: Three hundred seventy-two ambulatory patients with metastatic colorectal cancer were stratified according to performance status, and presence and location of any measurable indicator lesion(s). They were then randomized to receive chemotherapy with one of the following regimens: (1) intensive-course 5FU plus low-dose leucovorin (5FU 425 mg/m2 plus leucovorin 20 mg/m2 intravenous [IV] push daily for 5 days with courses repeated at 4- to 5-week intervals); (2) weekly 5FU plus high-dose leucovorin (5FU 600 mg/m2 IV push plus leucovorin 500 mg/m2 as a 2-hour infusion weekly for 6 weeks with courses repeated every 8 weeks). RESULTS: Three hundred sixty-two of 372 patients randomized (97.3%) were eligible and included in the analysis. Three hundred forty-six patients (95.6%) have died. There were no significant differences in therapeutic efficacy between the two 5FU/leucovorin regimens tested with respect to the following parameters: objective tumor response (35% v 31%), survival (median, 9.3 v 10.7 months), and palliative effects (as assessed by relief of symptoms, improved performance status, and weight gain). There were significant (P < .05) differences in toxicity, with more leukopenia and stomatitis seen with the intensive-course regimen, and more diarrhea and requirement for hospitalization to manage toxicity with the weekly regimen. Financial cost was also higher with the weekly regimen. CONCLUSION: Intensive-course 5FU plus low-dose leucovorin appears to have a superior therapeutic index compared with weekly 5FU plus high-dose leucovorin using the dosage administration schedules applied in this study based on similar therapeutic effectiveness, but lower financial cost, and less need for hospitalization to manage chemotherapy toxicity.

A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma.

Three hundred thirty-five previously untreated patients with advanced colorectal carcinoma were randomly assigned to treatment with 5-fluorouracil (5-FU) alone, 5-FU plus N-(phosphonacetyl)-L-aspartic acid (PALA), 5-FU plus high-dose thymidine, 5-FU plus levamisole, or 5-FU plus methyl CCNU, vincristine, and streptozotocin (MOF-Strept). Dosages were designed to produce definite toxicity in the majority of patients, although the nature of dose-limiting reactions varied considerably among regimens. 5-FU alone and 5-FU plus levamisole produced mucocutaneous reactions, diarrhea, and leukopenia; 5-FU plus PALA produced primarily mucocutaneous reactions and diarrhea; 5-FU plus thymidine produced leukopenia with occasional neurotoxicity and hypotension; and MOF-Strept produced substantial nausea and vomiting with both thrombocytopenia and leukopenia. Objective response rates among patients with measurable disease varied from 12% (5-FU plus PALA) to 34% (MOF-Strept), but none of the regimens were significantly superior to 5-FU alone. Both interval to progression and survival were comparable among the five regimens with no reasonable chance that any combination regimen could produce as much as a 50% improvement when compared with 5-FU alone. Whereas we observed definite modulation of 5-FU dose--toxicity relationships, particularly with the thymidine and PALA combinations, this did not result in a detectable improvement in therapeutic effect. None of the combination regimens, administered in the dosages and schedules we used, can be recommended as standard therapy of advanced colorectal carcinoma.

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.

Inhibition of fluorouracil-induced stomatitis by oral cryotherapy.

Mucositis is a significant dose-limiting toxicity associated with fluorouracil (5FU), particularly when it is combined with leucovorin. We hypothesized that oral cryotherapy would cause local vasoconstriction and would temporarily decrease blood flow to the oral mucous membranes. If cryotherapy were used during the time of peak serum 5FU levels, then the oral mucous membranes would have less exposure to 5FU and thus develop less mucositis. To test this hypothesis, 95 patients scheduled to receive their first cycle of 5FU plus leucovorin were randomized to have oral cryotherapy at the time of chemotherapy administration or to serve as a control group. Subsequent mucositis was significantly reduced in the group assigned to receive cryotherapy as judged by the attending physicians (P = .0002) and by the patients themselves (P = .0001). We now routinely recommend this cryotherapy procedure for our patients receiving daily bolus 5FU plus leucovorin.

Phase II trial of irinotecan in patients with metastatic colorectal carcinoma.

PURPOSE: To evaluate the objective tumor response rate and toxicities of patients with metastatic colorectal carcinoma treated with irinotecan hydrochloride (CPT-11). PATIENTS AND METHODS: A total of 121 patients with advanced colorectal carcinoma--90 with prior fluorouracil (5-FU) exposure and 31 chemotherapeutically naive patients--were enrolled between May 1993 and June 1994. Patients were treated with CPT-11 at 125 mg/m2 intravenously weekly for 4 weeks followed by a 2-week rest. RESULTS: Among 90 patients with prior 5-FU chemotherapy, 12 partial responses were observed (response rate, 13.3%; 95% confidence interval [CI], 7.1% to 22.1%). Among 31 chemotherapy-naive patients, eight had partial responses (response rate, 25.8%; 95% CI, 11.9% to 44.6%). The median response duration as measured from time of initial treatment for the two groups was 7.7 months and 7.6 months, respectively. The major adverse reactions were gastrointestinal and hematologic. The incidence of grade 3 or 4 diarrhea was 36.4%, while the overall incidence of grade 3 or 4 leukopenia was 21.5% of patients. Only four of 121 patients (3.3%) developed neutropenic fever (grade 4 neutropenia with > or = grade 2 fever). The incidence of grade 4 leukopenia was higher in patients with prior pelvic radiotherapy (chi2 test P = .04), while the incidence of grade 3 or 4 diarrhea demonstrated no association with previous pelvic irradiation. CONCLUSION: According to the study design, CPT-11 showed promising activity in chemotherapy-naive patients with advanced colorectal carcinoma and modest activity in patients with prior 5-FU exposure. The toxicity with this schedule appears manageable with appropriate dose modification for individual patient tolerance and an intensive loperamide regimen for the management of diarrhea. Care should be taken when treating patients with prior pelvic radiotherapy because of the increased risk of neutropenia.