Steven E. Benner

Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer.

PURPOSE This phase III study was designed to demonstrate equivalence in survival of oral uracil/tegafur (UFT) and oral leucovorin (LV) to conventional intravenous (IV) fluorouracil (5-FU) and LV in previously untreated metastatic colorectal carcinoma. Safety was also compared. PATIENTS AND METHODS Eight hundred sixteen patients were randomized to receive either UFT (300 mg/m(2)/d) and LV (75 or 90 mg/d) for 28 days every 35 days or IV bolus 5-FU (425 mg/m(2)/d) and LV (20 mg/m(2)/d) for 5 days every 28 days. RESULTS UFT/LV produced survival comparable to the IV 5-FU/LV regimen. Median survival was 12.4 months (95% confidence interval [CI], 11.2 to 13.6 months) with UFT/LV and 13.4 months (95% CI, 11.6 to 15.4 months) with 5-FU/LV (P =.630). The hazard ratio for survival was 0.964 (95.6% CI, 0.826 to 1.125), supporting equivalent survival. The overall response rate did not differ between treatment arms (UFT/LV, 11.7%; 5-FU/LV, 14.5%; P =.232). Median time to progression favored 5-FU/LV (UFT/LV, 3.5 months; 5-FU/LV, 3.8 months; P =.011), but tumor assessment schedules differed between arms. UFT/LV significantly improved safety compared with 5-FU/LV. Diarrhea, nausea and vomiting, and stomatitis and mucositis were significantly less frequent with UFT/LV, as was myelosuppression. Patients treated with UFT/LV had fewer episodes of febrile neutropenia (P <.001) and documented infections (P <.05). Increased bilirubin, without other liver function abnormalities, was observed more often with UFT/LV (P <.001). Concomitant medications were more frequent with 5-FU/LV, including use of antibiotics, growth factors, and antiemetics. CONCLUSION UFT/LV provided a safer, more convenient oral alternative to a standard bolus IV 5-FU/LV regimen for metastatic colorectal cancer while producing equivalent survival.

Phase II study of docetaxel for recurrent or metastatic non-small-cell lung cancer.

PURPOSE We conducted a phase II study to determine the response and toxicity of docetaxel (Taxotere; Rhône-Poulenc Rorer Pharmaceuticals, Inc, Collegeville, PA) in chemotherapy-naive patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS We treated 41 chemotherapy-naive patients who had stage IIIb or IV non-small-cell lung cancer with 100 mg/m2 of docetaxel intravenously over 1 hour every 3 weeks. Responses were assessed after every one to two treatment courses. Responses of 39 of 41 patients were assessable. The patients median age was 63 years; 90% of patients had a Zubrod performance status of 0 or 1. The predominant histology was adenocarcinoma (54%), and 90% of patients had stage IV disease. RESULTS Thirteen patients (33%) achieved a partial response to treatment, and the median response duration was 14 weeks. Grade 3 or 4 neutropenia occurred in 97% of patient; this was usually of brief duration and was associated with serious infection in 17% of patients. Other acute toxic effects included easily treated hypersensitivity reactions (36% of patients) and dermatitis (74%). We also observed fluid retention (with peripheral edema or pleural effusion or both) in 54% of patients. This was a cumulative side effect that generally occurred late in treatment. CONCLUSION Docetaxel administered at 100 mg/m2 intravenously every 3 weeks has significant activity against non-small-cell lung cancer, with a 33% major response rate. Primary toxicities were neutropenia, hypersensitivity, and fluid retention.

Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer

PURPOSE AND DESIGN This review describes the early clinical development of uracil-ftorafur (UFT), an oral fluoropyrimidine, designed in 1978 by adding uracil to ftorafur. The review focuses on the treatment of colorectal cancer and summarizes the Japanese experience and the phase I and II trials performed in the United States and Europe. RESULTS Clinical trials of UFT published in the Western world have included 581 patients with colorectal cancer. UFT has been administered in these trials as a single agent or biomodulated by leucovorin (LV). UFT was administered daily in split doses for periods that ranged from 14 to 28 days. The activity of oral UFT in large-bowel cancer when administered with oral LV (approximately 50 mg/dose) has resulted in objective response rates of approximately 40%. Response rates of approximately 25% (range, 17% to 39%) were reported when UFT was administered as a single agent or with lower doses of LV. The highest dose-intensities of UFT are achieved with 28-day schedules of administration. The maximum-tolerated dose (MTD) of UFT with this schedule, when administered concomitantly with oral LV 150 mg daily, is 300 mg/m2 daily. The dose-limiting toxicity (DLT) of UFT has generally been diarrhea. Other commonly described toxicities include nausea and vomiting, fatigue, and stomatitis. Myelosuppression occurs infrequently. Typically, hand-foot syndrome and neurologic toxicity are lacking. CONCLUSION UFT is a fluoropyrimidine active in colorectal cancer. The oral route of administration and improved safety profile represent important advantages over both conventional and infusional fluorouracil (5-FU) regimens.

Chemoprevention strategies for the control of cancer

High incidence and low survival rates of many epithelial cancers remain beyond the control of established preventive and therapeutic modalities. Chemoprevention is a new approach under study that involves the intervention within the premalignant process with specific chemical agents to reverse carcinogenesis and prevent the development of invasive cancer. The two biologic concepts that underlie this research are multistep carcinogenesis and field carcinogenesis. Major clinical issues include trial design and drug development in head and neck, lung, and breast cancer chemoprevention. Within the area of trial design, intermediate end point biomarkers will become very important for providing biologic insights in the short term and greater trial efficiencies in the long term. Drugs that are under the strongest investigation include retinoids and β‐carotene in the head and neck and lung, calcium in the colon, and tamoxifen in the breast. This new field has the potential to make an important contribution toward increasing our control over many deadly epithelial cancers.

Epidemiology, biology, and chemoprevention of aerodigestive cancer.

Cancers of the aerodigestive tract are a major cause of worldwide morbidity and mortality. Long term survival rates for these epithelial cancers have not improved substantially in the past 20 years despite intensive efforts to improve the prevention and therapy of these diseases. Therefore, new approaches are needed. One new investigative approach is chemoprevention, the chemical prevention of cancer. Chemoprevention studies in the upper aerodigestive tract have focused on the reversal of pre‐malignant lesions and the prevention of second primary tumors. These chemoprevention efforts have resulted from an understanding of the multistep nature of epithelial carcinogenesis and the diffuse epithelial injury that results from carcinogen exposure. Ongoing research efforts are attempting to define these processes. The interaction between carcinogen exposure and host susceptibility in the development of cancers of the aerodigestive tract is being evaluated (e.g., with an assay of chromosomal sensitivity to the clastogen bleomycin). This review discusses several new aspects of the epidemiology, biology, and chemoprevention of aerodigestive tract carcinogenesis.

A phase II study of ifosfamide in recurrent squamous cell carcinoma of the head and neck.

Chemotherapy has not significantly altered the overall survival of patients with recurrent squamous cell carcinoma of the head and neck; therefore, the development of new agents is essential. The purpose of the current phase II study was to define the efficacy of ifosfamide in the treatment of recurrent squamous cell carcinoma of the head and neck. All patients were required to have squamous cell carcinoma of the head and neck that had recurred following surgery or radiotherapy or both. Patients may have received prior chemotherapy. Patients were initially treated with ifosfamide 2 g/m2/day for 4 days (dose level 0). Dose level-1 was 2 g/m2/day for 3 days, and dose level-2 was 2 g/m2/day for 2 days. All patients received mesna 400 mg/m2/day prior to and 1,200 mg/m2/day as a continuous infusion after ifosfamide. Thirty-eight patients were enrolled in the study. Five patients were inevaluable for toxicity or response. Overall, the regimen was well tolerated, with grade 4 granulocytopenia the only significant toxicity occurring in 16 patients. Overall, eight of 31 evaluable patients (25.8%) had a major response. Only one of the 10 patients (10%) with prior chemotherapy responded, but seven of the 21 patients (33.3%) with no prior chemotherapy had major responses. Ifosfamide is an active agent in recurrent squamous cell carcinoma of the head and neck. Further studies of ifosfamide in combination with other agents, particularly as induction therapy in patients with locally advanced disease, are warranted.

A Stopping Rule for Standard Chemotherapy for Metastatic Breast Cancer: Lessons from a Survey of Maryland Medical Oncologists

The sequential administration of standard chemotherapy regimens to treat metastatic breast cancer may keep patients and oncologists from considering other important, but more psychologically difficult, issues such as the patients declining health or approaching death. This practice also utilizes health care resources for ever-decreasing individual patient benefit. If generally agreed-upon rules or guidelines were developed about stopping standard chemotherapy after a limited number of regimens, oncologists could recommend treatment discontinuation with greater confidence. Also, resources could be redirected. To inform the development of guidelines on when to stop chemotherapy for metastatic breast cancer, we surveyed fully trained Maryland medical oncologists about their knowledge and beliefs about chemotherapy for metastatic breast cancer. The survey instrument included open-ended questions and clinical vignettes. There was consensus about the value of first-line chemotherapy. Even though oncologists employed second-line chemotherapy, they were unenthusiastic about it. The frequent utilization of second-line regimens probably reflects an effort to offer marginal regimens to patients who want them. Based on these data, it is suggested that standard chemotherapy be stopped after breast cancer fails to stabilize or respond on a standard regimen. Patients who wish further treatment could be referred for investigational therapy if it is available and if they are eligible.

Prevention of second head and neck cancers

Abstract Unfortunately, squamous cell cancer patients of the head and neck are at significant risk for development of SPT, and their prognosis is poor once a second tumor develops. The increased risk for these patients and their personal understanding of the effects of cancer makes this population well suited for developing prevention strategies. Because of their past experiences with cancer, these patients may be more tolerant of side effects and more compliant with the requirements of a study protocol. The marked increase in risk that these patients carry should make it possible to demonstrate the efficacy of a chemoprevention strategy in a study of reasonable size and duration. The needs of these patients represent not only an opportunity to develop a prevention strategy, but also a powerful model for understanding human carcinogenesis. The current 13- cis -retinoic acid SPT prevention protocol is closely integrated with a number of scientific projects designed to develop a basic understanding of retinoids in carcinogenesis and chemoprevention (Table 6). These related investigations, which will be performed in conjunction with the 13- cis -retinoic acid trial, will hopefully increase our knowledge of the biology of SPTs and further improve our prevention efforts.

Biology and reversal of aerodigestive tract carcinogenesis

Squamous cell carcinoma of the upper aerodigestive tract is a cosmetically, functionally, and economically devastating class of diseases yet to come under control with standard approaches to prevention, early detection, or therapy [1,2]. Three principle modalities are currently used to control this disease: tobacco/alcohol cessation programs, surgery and radiotherapy for early and local-regional advanced disease, and chemotherapy in advanced, recurrent, and metastatic disease.

The role of retinoids in preventing second lung cancers

The field cancerization hypothesis has guided the development of a series of retinoid chemoprevention trials in the upper aerodigestive tract (UADT) and lung. The hypothesis suggests that the entire epithelium of the UADT and lungs is exposed to inhaled carcinogens and at risk for the development of cancer. The term field cancerization was first used to describe the frequent occurrence of multifocal tumors and premalignant lesions in pathologic specimens from resected head and neck cancers [I]. Epithelial premalignant lesions occur most often in individuals who have been exposed to carcinogens, such as tobacco smoke. In the oral cavity, leukoplakia, whitish plaques that cannot be otherwise characterized, have been associated with the development of invasive cancer. In the lungs, squamous metaplasia, the replacement of the normal columnar epithelial lining with a squamous epithelium, frequently appears in tobacco users and in surgical specimens obtained during resection of a lung cancer. The presence of dysplasia is not necessary for the diagnosis of leukoplakia or squamous metaplasia but may be associated with the progression to cancer. The occurrence of second primary tumors (SPTs) is another important aspect of field cancerization (Table 1). The carcinogenic process that results in the initial cancer has also been associated with damage to the remainder of the epithelium. SPT’s develop in 2040% of patients successfully treated for squamous cell cancers of the head and neck and in lO-20% of patients after resection of early stage non-small cell lung cancers [2-51. SPTs develop predominantly within the exposed field, the lungs and UADT [6]. The initial description of field cancerization was based on the interpretation of histologic findings. Considerable attention is now being directed towards the molecular aspects of field cancerization. Identification of the changes that are crucial to the multistep process of carcinogenesis, would both define field cancerization and focus chemoprevention efforts.