Recurrence and survival after surgical management of rectal cancer.

BACKGROUND: Reported local recurrence rates for rectal cancer are significantly reduced using a combination of superior surgical technique, in the form of total mesorectal excision, and routine radiotherapy. In an attempt to determine the effectiveness of current local management strategies, a review of Vancouver Island Cancer Centre patients with rectal cancer was performed and the overall local recurrence rate was identified. METHODS: We retrospectively reviewed the charts of 272 rectal cancer patients from 1988 to 1998. Two hundred and twenty-nine patients met inclusion criteria. Analysis of patient factors included age, gender, type of surgery, and adjuvant therapy. Tumors were assessed for level, stage, and grade. Local recurrence and distant metastases were also documented. Variables influencing local recurrence in this group were identified and disease-free and actuarial survival determined. RESULTS: Of 229 patients analyzed, 12.7% (29) had local recurrences. Variables influencing local recurrence were number of positive lymph nodes, vascular invasion, and neural invasion. There was no significant difference in local recurrence between patients having anterior resection and those having abdominoperineal resection. None of the patients who received preoperative radiotherapy had a local recurrence. Actuarial disease-free survival was 87% at 5 years. CONCLUSIONS: Limiting local recurrence is one of the most important goals in the treatment of rectal cancer. It is essential to identify those patients with "high risk" tumors as identified by endorectal ultrasound or pathologic features. These patients comprise the group most likely to benefit from a routine mesorectal excision combined with adjuvant radiotherapy.

Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors.

PURPOSE: Fluorouracil (5-FU) continuous infusion is superior to 5-FU bolus in patients with advanced colorectal cancer, but the survival difference between the two treatments is small and, therefore, the difference in toxicity profile is crucial in choosing a treatment for individual patients. MATERIALS AND METHODS: We conducted a meta-analysis of all randomized trials that compared 5-FU bolus with 5-FU CI, based on individual data from 1,219 patients, to compare the toxicity of the two schedules of 5-FU administration and to identify predictive factors for toxicity. The toxicities considered were World Health Organization (WHO) grade 3 to 4 anemia, thrombopenia, leukopenia, neutropenia, nausea/vomiting, diarrhea, mucositis, and hand-foot syndrome. RESULTS: Hematologic toxicity, mainly neutropenia, was more frequent with 5-FU bolus than with 5-FU CI (31% and 4%, respectively; P < .0001). Hand-foot syndrome was less frequent with 5-FU bolus than with 5-FU CI (13% and 34%, respectively; P < .0001). There was no difference between the two treatment groups in terms of other nonhematologic toxicities. Independent prognostic factors were age, sex, and performance status for nonhematologic toxicities, performance status, and treatment for hematologic toxicities, and age, sex, and treatment for hand-foot syndrome. CONCLUSION: Based on a large data set, this study confirmed and quantified the toxicity profile of the two schedules of administration of 5-FU and allowed the identification of clinical predictors of toxicity.

Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer.

PURPOSE: The administration of fluorouracil (5-FU) by continuous intravenous infusion (CI) is an alternative to the bolus administration of 5-FU in patients with advanced colorectal cancer. Although more than 1,200 patients have been enrolled onto randomized trials that compared these two treatment modalities, there is still no definitive evidence of an advantage of 5-FU CI, and the magnitude of this advantage, if any, is also controversial. A meta-analysis was performed to assess this benefit in terms of tumor response and survival, and to compare the toxicity profiles of these two modalities of administration of 5-FU. DESIGN: Individual data of 1,219 patients included in six randomized trials served as the basis for this meta-analysis, which was conducted by an independent secretariat in close collaboration with the investigators. RESULTS: Tumor response rate was significantly higher in patients assigned to 5-FU CI than in patients assigned to 5-FU bolus (22% v 14%; overall response odds ratio, 0.55; 95% confidence interval [95% CI], 0.41 to 0.75; P = .0002). Overall survival was also significantly higher in patients assigned to 5-FU CI (overall hazards ratio [HR], 0.88; 95% CI, 0.78 to 0.99; P = .04), although the median survival times were close. Multivariate analyses showed that randomized treatment and performance status were the only two significant predictors of tumor response, whereas the same plus primary tumor site were independent significant predictors of survival (patients with rectal cancer did somewhat better). Grade 3 or 4 hematologic toxicity was more frequent in patients assigned to 5-FU bolus (31% v 4%; P < 10(-16)), whereas hand-foot syndrome was more frequent in the 5-FU CI group (34% v 13%; P < 10(-7)). CONCLUSION: 5-FU CI is superior to 5-FU bolus in terms of tumor response and achieves a slight increase of overall survival. The hematologic toxicity is much less important in patients who receive 5-FU CI, but hand-foot syndrome is frequent in this group of patients.

Increased incidence of second malignancies associated with small bowel adenocarcinoma.

BACKGROUND: Some data suggest that there is an increased incidence of second malignancies associated with small bowel adenocarcinomas, but this has not been reviewed in the context of a tumour registry. OBJECTIVE: To review tumour registries based on population statistics to determine whether there is an increased incidence of second malignancies associated with small bowel adenocarcinomas. METHODS: The authors reviewed the tumour registries of two Canadian provinces (British Columbia and Manitoba) for small bowel adenocarcinoma to determine whether an increase in associated malignancies existed compared with those expected in the respective populations. RESULTS: A greater than eightfold increase in second malignancies was associated with small bowel carcinoma. The majority (73%) occurred before the diagnosis of the small bowel malignancy. Twenty-nine per cent were associated with cancers of the colon, rectum or both. CONCLUSIONS: There is an increased association of malignancy and the diagnosis of small bowel cancer. Generally, small bowel cancer is the second malignancy to be diagnosed, and the diagnosis is most often made in the elderly. Does this represent a syndrome related to an unstable gene (or genes) or a lack of repair, which makes individuals susceptible to this malignancy as they age?

A phase II survival comparison of patients with adenocarcinoma of the pancreas treated with 5-fluorouracil and calcium leucovorin versus a matched tumor registry control population.

Carcinoma of the pancreas is a virulent malignancy. We performed a Phase II survival study by treating 30 patients with pancreatic cancer with leucovorin, 200 mg/m2 x 5 days immediately followed by 5-fluorouracil, 370 mg/m2 every 4 weeks. We examined the survival of our 30 study patients with patients drawn from the Manitoba Tumor Registry, matched for important prognostic criteria. Classical response rates were also evaluated in those patients who had measurable tumors. The response rate was 13% with two complete remissions and one partial remission, with 40 patients (7.8%) demonstrating stable disease for 2 months, and 39% of patients demonstrating progressive disease while on treatment. The mean survival of the Phase II-treated group was 16 weeks, compared to 12 weeks in the matched controls, which indicated an increase in survival of 30%. This was significant at the p = .001 level. Toxicity was not as great as expected. This trial demonstrates that there may be marginal survival benefit with 5FU leucovorin in pancreatic cancer, but more profound prolongation needs to be seen with chemotherapy regimens before instituting randomized trials.

Late recurrence of testicular cancer.

Late recurrence of nonseminomatous germ cell tumours of the testis is rare. The authors report on a 35-year-old man treated initially for embryonal cell carcinoma of the testis with metastases, who presented 12 years later with an increasing serum alpha-fetoprotein level and a biopsy-proven embryonal cell cancer in the hilus of the left lung. Because the tumour was highly resistant to two separate courses of cis-platinum-based chemotherapy and one course of radiotherapy, surgical resection for salvage was carried out. The patient was free of disease 3.5 years after the second operation. The possible reasons for the occurrence of this highly resistant metastatic testicular cancer are discussed. They include a second primary tumour and malignant degeneration of the original tumour. In this patient the latter cause was the most plausible.

Escalated as compared with standard doses of doxorubicin in BACOP therapy for patients with non-Hodgkin's lymphoma.

BACKGROUND AND METHODS: In 1981 the Clinical Trials Group of the National Cancer Institute of Canada completed a pilot study in patients with advanced-stage non-Hodgkin's lymphoma with aggressive tumor histology. That study demonstrated the potential efficacy of escalating the dose of doxorubicin used in a regimen of bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP). In the present study, we compared standard BACOP (s-BACOP) with BACOP that included escalated doses of doxorubicin (esc-BACOP) in 238 patients 16 to 70 years old with previously untreated, advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma. During the first 28-day cycle all patients received doxorubicin in a dose of 25 mg per square meter of body-surface area on days 1 and 8. Patients randomly assigned to receive s-BACOP subsequently received five identical cycles, whereas those assigned to receive esc-BACOP received 40 mg of doxorubicin per square meter on days 1 and 8 of five subsequent cycles if granulocytopenia (< 1000 cells per cubic millimeter) had not developed during the first cycle. RESULTS: The 119 patients assigned to the esc-BACOP regimen received doxorubicin at a significantly higher mean weekly dose intensity (13.5 vs. 10.4 mg per square meter per week, P < 0.001) and mean total dose (296 vs. 231 mg per square meter, P < 0.001). Because of granulocytopenia during the first cycle of therapy, only 56 of these patients (47 percent) received the escalated doses of doxorubicin. During a median follow-up of 65 months, there were no differences between the s-BACOP and esc-BACOP groups in response rate, overall survival, or survival without disease progression. When the patients who actually received the escalated doses of doxorubicin were compared with the patients in the s-BACOP group in whom neutropenia did not develop during the first treatment cycle, no difference between their outcomes was observed. Toxicity was greater in the esc-BACOP group. CONCLUSIONS: In patients with advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma, escalating the dose of doxorubicin in the BACOP regimen increases toxicity but does not improve the rate of response or survival.

Systemic infusion versus bolus chemotherapy with 5-fluorouracil in measurable metastatic colorectal cancer.

From January 31, 1986 to January 31, 1989, 184 eligible patients were enrolled in a randomized study of either infusional or bolus 5-fluorouracil (5-FU) for the treatment of metastatic measurable colorectal cancer. Infusion was administered at an escalated dose schedule starting at 350 mg/m2 per day for 2 weeks with a 2-week rest period on a monthly basis, while bolus 5-FU was started at 400-450 mg/m2 for 5 days every 28 days. In these chemotherapy-naive patients with good performance status, the infusion arm produced a response in 11 of 88 patients versus 6 of 82 in the bolus arm (p = 0.384). Progression free survival was significantly longer (p = 0.0139) in the infusion group (3.8 versus 2.3 months), but no significant difference in survival was observed (p = 0.207). As expected, the toxicities of the regimens were different in character, but each had approximately a 20% incidence of significant toxicities. Neither of these methods of administering fluorouracil results in an exceptional response rate, nor does the infusion have an impact on survival as compared to the bolus route. If this type of complicated infusional approach is to continue, especially with increasing dosage (which could be accomplished on our schedule), randomized studies with survival as an endpoint must remain the gold standard.

The value of sputum cytology.

OBJECTIVE: To assess the value of cytologic examination of expectorated sputum in the diagnosis and management of patients with suspected lung cancer. DESIGN: Retrospective chart review. SETTING: Inpatient wards, tertiary care university hospital. MEASUREMENTS AND MAIN RESULTS: The charts of 357 patients were reviewed. Two hundred eighty-eight of the 357 patients had had initial sputum cytologic examination prior to other diagnostic procedures, of which 41 (15%) had positive cytologic results. Thirty-six of the 41 were confirmed histologically or shown to have metastatic spread by noninvasive tests. Of the 222 patients with negative or unsatisfactory sputum tests, 97 went on to bronchoscopy and 35 had needle-aspiration biopsies. In the population of patients whose chest x-rays were highly suggestive of primary or metastatic lung cancer, the positive rate for cytologic examination was 38/94 (40%). There was no false-positive test in this study. Of the 50 patients with positive cytologic results, five (10%) had diseases that were of a different cell type; two of these five (40%) had diseases that involved small-cell cancer. There was an unsatisfactory delay in obtaining these samples for analysis. CONCLUSIONS: Sputum cytology was found to be too insensitive and insufficiently accurate to be included in the routine workup of a patient suspected of having lung cancer. The results of the test did not influence further diagnostic procedures. This test should, therefore, be reserved for patients considered on initial assessment to be too sick for further investigations and treatment.

A phase II study of recombinant tumor necrosis factor in renal cell carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group.

The National Cancer Institute (NCI) Canada Clinical Trials Group conducted a phase II study of recombinant tumor necrosis factor (rTNF) given intravenously daily for 5 days every other week, in measurable metastatic renal cell carcinoma. Two of 26 patients responded with responses lasting greater than 200 days. Toxicity was severe including rigors, fever, headache, fatigue, hypotension, and localized pain. We conclude that rTNF, given as described, has only modest antitumor activity in renal cell carcinoma and produces considerable toxicity. We plan no further studies of rTNF in this disease.

A meta-analysis of stages I and II Hodgkin's disease.

To compare radiotherapy alone to chemotherapy plus radiotherapy in the treatment of early stage Hodgkin's disease, the English language medical literature was searched for reports on randomized clinical trials in Stages I and II Hodgkin's disease from 1975 through 1986. Twenty-three reports with 2999 patients were entered into matched study analysis. Data on extended-field radiotherapy (EF), involved-field (IF), chemotherapy alone, combination chemotherapy and radiotherapy (CM), disease stage, laparotomy staging, and complications were gathered. A proportional hazard rate was used to estimate and compare relapse-free (RFS) and overall survival rates (S). Iteratively reweighted least square analysis was used to estimate survival curves. Twelve-year RFS for CM (889 patients) was significantly superior to EF (1350 patients) (P less than 0.01). Twenty-year RFS in EF was better than IF (760 patients) (P less than 0.01). Twelve-year S for CM was not significantly different than for EF but was better than for IF (P less than 0.05).

Sequential methotrexate, 5-fluorouracil, and leucovorin in metastatic measurable colorectal cancer. Does it work?

Four single-arm trials using methotrexate (M), 5-fluorouracil (5FU), and leucovorin (L) were sequentially performed in metastatic measurable colorectal cancer using different dosing and timing schedules for the three drugs. A total of 99 patients were entered into the trials, 92 (49 men and 43 women) of whom were evaluable for response. Although the first trial appeared to have a 36% response rate, the overall response rate seen in the four trials was not higher than historical reports of 5FU alone. We could find no correlation with dose intensity or patient characteristics to account for the apparent good results of the first trial. It is our conclusion that MFL is not an active combination in colorectal cancer. After progressing to the fourth trial, four patients were placed on 5FU alone (supported by a grant from Lederle, Canada). This resulted in one response in a patient who had not responded to the three-drug combination and stable disease in two patients previously progressing. Although there are many reports of this combination working, the possibility is raised that M may be inhibitory to the combination despite the in vitro data.

Lonidamine and human lymphoblastoid alpha interferon in metastatic cancer: a phase I study.

The purpose of this study was to test the qualitative and quantitative toxicity of lonidamine (L) and alpha-interferon (IFN alpha) when used together, and to observe any apparent synergistic activity in conventionally untreatable measurable metastatic cancer. Eleven patients (8 males and 3 females) were enrolled. There was one response seen as measured by conventional criteria. There is no evidence that these agents are additive at this dose schedule, nor is their apparent synergistic activity.

Staging and prognosis of chronic lymphocytic leukemia: the Manitoba experience.

Three hundred ninety-one cases of chronic lymphocytic leukemia (CLL) from the Tumour Registry of Manitoba, spanning a 20-year period from January 1960 to December 1979, were reviewed. Survival curves were developed using the staging systems of Rai and Binet. A clear separation in survival was found utilizing the system of Binet. Also, there was a significant increase in the development of secondary malignancies (observed, 53; expected, 31, p less than 0.01). However, there was no significant increase in secondary malignancies if only those malignancies occurring at least six months after the diagnosis of chronic lymphocytic leukemia was made were analyzed (observed, 38; expected, 29, p = 0.26). This suggests that the increase in secondary malignancies is not treatment-related, and may be due to the underlying disease.

Lymphatic metastasis and its treatment.

The treatment of lymphatic metastasis depends on an understanding of its basic biology. We are still uncertain as to how human cancer cells enter lymphatic vessels and as to what reactions if any in the draining lymph node inhibit metastasis. We are uncertain as to whether lymphatic metastasis is an indicator or a governor of rapid dissemination, and poor prognosis. We are uncertain as to whether it is worth attempting to treat lymphatic metastases by means supplementary to those used in treating systemic tumour dissemination. It may be possible to obtain local cure of a local lesion by local lymphatic therapy and to concentrate therapy locally by intralymphatic infusion of a chemotherapeutic agent or encapsulation in liposomes. This is at best accessory to obtaining systemic cure of systemically disseminated neoplasm. Optimal results could be expected from appropriate combinations of local and systemic immunotherapy, chemotherapy and radiotherapy, after appropriate surgical reduction in tumour bulk.

Toxicity of oral N-methylformamide in three phase II trials: a report from the National Cancer Institute of Canada Clinical Trials Group.

Three National Cancer Institute of Canada phase II studies of N-methylformamide (NMF), given in a three times/week oral schedule, closed early because of frequent and occasionally severe toxicity. Eighteen of 41 (44%) cycles of treatment were not completed because of problems with NMF-induced hepatic and gastrointestinal toxicity. Several other reactions occurred, including skin rashes, abdominal pain, and gastritis, which were drug induced. One death occurred on study and was thought to be due in part to NMF toxicity. Further work exploring alternative schedules is needed before phase II studies of oral NMF can be done.

Phase II study of lonidamine in patients with metastatic renal cell carcinoma: a National Cancer Institute of Canada Clinical Trials Group Study.

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of lonidamine, given in an escalating oral daily schedule in patients with measurable advanced renal cell carcinoma. Two responses were seen in 25 evaluable patients. Toxicity was mild or moderate in most patients and included myalgia, nausea, vomiting, somnolence, and testicular pain. Lonidamine was not myelosuppressive. This agent had only minimal activity against renal cell carcinoma when given in this oral schedule.

Low-dose (diagnostic-like) x-ray as a cocarcinogen in mouse colon carcinoma.

To test the hypothesis that low-dose (diagnostic-like) radiation may play the part of a cocarcinogen in inflammatory bowel disease, we used four groups of BALB/C mice, (a control, dimethylhydrazine, dimethylhydrazine plus low-dose radiation, and low-dose radiation). We found no protective or carcinogen effects of the radiation in combination with dimethylhydrazine compared to dimethylhydrazine alone. This type of negative experimental finding is important in that individuals with inflammatory bowel disease have many diagnostic x-rays throughout life.