Clinical efficacy of oxaliplatin monotherapy: phase II trials in advanced colorectal cancer.
Becouarn Y. Rougier P.
Centre Regional de Lutte Contre le Cancer, Institut Bergonie, Bordeaux, France.
For the past 40 years, the mainstay of chemotherapy against colorectal cancer has been 5-fluorouracil (5-FU), often administered in recent years with folinic acid modulation. Traditional platinum derivatives have generally been ineffective in colorectal cancer therapy; however, the third-generation 1,2-diaminocyclohexane-platinum derivative oxaliplatin has shown good antitumor activity and a lack of cross-reactivity with cisplatin. Oddly, oxaliplatin was first developed as a combination therapy with 5-FU plus folinic acid administered as a chronomodulated infusion over 5 days. In subsequent phase II clinical trials, the activity of single-agent oxaliplatin was assessed in 63 previously untreated patients and 139 patients with metastatic disease refractory to 5-FU. In first-line therapy, the median overall survival was approximately 13 to 14 months, whereas in previously treated patients no longer responding to 5-FU, it was 8 to 10 months. The 18% objective response rate obtained with first-line therapy confirms that the activity of single-agent oxaliplatin is comparable to other anticancer therapies considered active against colorectal cancer. The 10% response rate obtained in second-line therapy in patients refractory to 5-FU provides a means for palliative care and suggests the possibility for a potentially active combination regimen with 5-FU.
Oxaliplatin plus 5-fluorouracil: clinical experience in patients with advanced colorectal cancer.
Bleiberg H. de Gramont A.
Unite de Chimiotherapie, Institut Jules Bordet, Bruxelles, Belgium.
Oxaliplatin was first introduced to the clinical setting as a combination therapy with 5-fluorouracil/folinic acid (5-FU/FA) in an attempt to improve the response rate obtained with 5-FU/FA against colorectal cancer. To dispel the impression that the improvements observed in objective response were somehow due to the chronomodulated regimen used, oxaliplatin was also tested in constant-rate infusion schedules and in regimens using bolus administration followed by 5-FU/FA infusion. The most current data comparing chronomodulated infusion and constant-rate infusion in untreated patients show a lower objective response rate for the latter (51 % v 29%), but comparable median progression-free survival and median survival (9.8 months and 15.9 months v 7.9 months and 16.9 months, respectively). The first trials using constant-rate therapy included pretreated patients with metastatic colorectal cancer, most of whom were refractory to 5-FU. In these studies, conducted using two different regimens or variations of them, objective response rates < or = 46% were obtained. The addition of oxaliplatin to 5-FU/FA in controlled, randomized phase III trials has resulted in a twofold or greater increase in objective response rate and a 3-month gain in time to progression, with survival differences blurred by crossover effect. Compassionate-use programs that included many heavily pretreated relapsing patients reported response rates of 15% to 25%, confirming the value of the oxaliplatin-5-FU/FA regimen and suggesting that oxaliplatin may act synergistically with 5-FU.
Reduction of nonresectable liver metastasis from colorectal cancer after oxaliplatin chemotherapy.
Bismuth H. Adam R.
Groupe de Recherche en Chirurgie Hepato-Bilaire et Transplantation Hepatique, Hopital Paul Brousse, Villejuif, France.
Until recently, approximately 30% of patients with resectable hepatic metastases from colorectal cancer survived 5 years after surgery. Additionally, many patients present with unresectable metastases and can look forward only to palliative care. Whereas therapeutic approaches such as cryosurgery appear to improve resectability, a key to resecting hepatic metastases is the ability to shrink the metastatic sites to make them more amenable to surgery. The administration of traditional chemotherapeutic modalities by conventional means or via intra-arterial or portal vein infusion has not provided significant improvements. The recent introduction of the combination oxaliplatin-5-fluorouracil/folinic acid administered as a chronomodulated regimen, however, has provided better response rates with minimal toxicity. Recent results show that the resection of previously unresectable metastases became possible in up to 16% of patients after chemotherapy with a chronomodulated regimen of oxaliplatin plus 5-fluorouracil/folinic acid. Of the patients who had successful resections, 54% and 40% were alive at 3 years and 5 years after surgery, respectively. The results of these studies demonstrate that this new approach can significantly prolong survival for patients with a previously bleak outlook. As a result, new treatment algorithms are evolving, integrating chemotherapeutic and surgical strategies for the treatment of patients with metastatic colorectal cancer.
Oxaliplatin for the treatment of advanced colorectal cancer: future directions.
Ducreux M. Louvet C. Bekradda M. Cvitkovic E.
Service de Gastroenterologie et d'Oncologie Digestive, Institut Gustave Roussy, Villejuif, France.
The introduction of oxaliplatin into the colorectal cancer setting represents a significant advancement in the treatment of the disease. Synergistic effects with traditional therapy 5-fluorouracil/folinic acid have increased response rates significantly, improved time-sensitive response parameters, and facilitated the removal of previously unresectable hepatic metastases, thus changing the natural history of the disease. Ongoing and planned trials are identifying various issues that need to be addressed to fully realize the potential of oxaliplatin. These include optimization of dosing and schedule of administration, determination of the most effective oxaliplatin-5-fluorouracil/folinic acid combination, definition of the role of new thymidylate synthase inhibitors with respect to oxaliplatin therapy, and identification of the most effective combinations of oxaliplatin with the new anticancer agents that have been recently introduced. Providing the answers to these questions will contribute to changing the attitude of the clinical oncologist regarding what strategy to adopt in treating colorectal cancer in the coming years.
Normal digestive physiology and the evaluation of digestive function.
Division of Gastroenterology, University of Colorado Health Sciences Cancer Center and Denver Veterans Affairs Hospital, 80262, USA.
Normal digestion is a complex and coordinated process that breaks food into constitutive molecules, some of which are absorbed and others passed through the body as waste. Many of the conditions associated with wasting syndromes alter normal digestive function and can lead to or exacerbate malnutrition. Digestive function can be defined by applying the principles of normal physiology. Our laboratory has developed a relatively comprehensive stable isotope method to assess function, which shows promise as a screening tool in evaluating patients with wasting syndromes. This and other tests of digestive function can be used to define the abnormalities associated with wasting and to direct or optimize antiwasting therapy.
Human immunodeficiency virus-related wasting: malabsorption syndromes.
Department of Medicine, St. Luke's-Roosevelt Hospital Center, College of Physicians and Surgeons, Columbia University, New York, NY 10025, USA.
Diarrhea and malabsorption are common findings in patients with the acquired immunodeficiency syndrome (AIDS). The pathogenesis and consequences of malabsorption in human immunodeficiency virus (HIV) infection are similar to those found in non-HIV-related conditions, and are related to both direct intestinal damage and alterations in the coordination of the body's response to feeding. The pathogenesis of malabsorption is multifactorial and includes primary enterocyte injury with partial villus atrophy and crypt hyperplasia, ileal dysfunction with bile salt wasting and fat malabsorption, and exudative enteropathy. Clinical studies show that intestinal cryptosporidiosis leads to excess fecal losses of about 20% for protein and fat. The consequences of malabsorption include decreased appetite; "enterogastrone" effects including dry mouth, decreased gastric acid secretion, decreased rate of gastric emptying, and slowed intestinal transit; anemia resulting from iron, folate, or vitamin B12 malabsorption; and metabolic effects including osteomalacia, gallstones, renal stones, and hypocholesterolemia. Few studies of nutritional therapy have been applied specifically to AIDS patients with malabsorption. Total parenteral nutrition promotes weight gain, although the response to this therapy depends on the underlying clinical problem, with body cell mass repletion noted in patients with malabsorption but predominantly fat gain in patients with systemic infections. Nutritional stabilization also was noted in response to oral administration of a semielemental diet.
Genetics and ovarian carcinoma.
Lynch HT. Casey MJ. Lynch J. White TE. Godwin AK.
Department of Preventive Medicine, Creighton University School of Medicine, Omaha, NE, USA.
Ovarian cancer is a disease that will affect approximately 1% of American women during their lifetime, and contributes to more than 14,000 deaths annually. If not detected early, this disease has a 5-year survival rate of less than 20%. Ovarian cancer develops predominantly from the malignant transformation of a single cell type, the surface epithelium. Although the biological mechanisms of transformation remain unclear, it is probably a multistep process requiring an accumulation of genetic lesions in a number of different gene classes. Several proto-oncogenes, such as AKT2 and Ki-RAS, are activated during ovarian cancer development, with putative oncogene-containing chromosomal regions showing imbalances and DNA amplifications. A number of chromosomal regions are also lost in ovarian tumors, indicating that the inactivation of tumor suppressor genes, such as TP53, may also contribute to cancer development. An important recent advancement in the field of ovarian cancer research is the identification of the breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2. Mutations in these two tumor suppressor genes are responsible for the majority of heritable forms of epithelial ovarian cancers. A second class of genes involved in DNA mismatch repair (MMR) are responsible for most cases of hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC or Lynch II cancer syndrome patients are also at an increased risk for developing ovarian cancer. Individuals in cancer-prone kindreds are currently being screened for germline mutations in BRCA1, BRCA2, and several MMR genes (eg, MSH2, MLH1), and mutant allele carriers counseled for cancer risks. Issues related to counseling and management of women at high risk for developing ovarian cancer are discussed. Although BRCA1, BRCA2, and a number of MMR genes have been identified, many more genes involved in gynecologic malignancies remain to be discovered and the clinical significance of the cancer genes already known is still in its infancy.