Gastrointestinal Cancer

Microsatellite Instability Linked to Longer Colon Cancer Survival

Damjanov and Meropol review the status of several oral fluoropyrimidine drugs that are currently undergoing clinical testing for the treatment of colorectal cancer. Meta-analysis indicates an 8% improvement in the overall response rate and a survival advantage of 0.8 months with infusional vs bolus fluorouracil (5-FU)-arguably small differences. The incidence of grade 3-4 diarrhea, mucositis, and myelosuppression is < 10% with infusional 5-FU, although hand-foot syndrome is commonly associated with this therapy. The prevailing strategy for the development of oral 5-FU drugs employs multiple daily dosing for periods of 2 to 4 weeks followed by a 1- or 2-week break in order to mimic the protracted infusional schedule.UFT

The article by Damjanov and Meropol elegantly outlines the rationale behind the preclinical development of several potential new oral chemotherapy options for patients with advanced colorectal carcinoma and the available data from clinical trials in advanced colorectal cancer that evaluated the activity and safety of these agents. The authors relate the history of fluorinated pyrimidine therapy in colorectal cancer and the pharmacologic challenges to delivering effective oral therapy in a such a way that the chemistry behind the processes becomes readily intelligible. They note that the erratic absorption and blood levels associated with orally administered fluorouracil (5-FU) led to the current approaches to oral therapy.

Hepatocellular carcinoma (HCC) is one of the world’s most common cancers. It is closely associated with cirrhosis, especially that due to viral hepatitis. The incidences of viral hepatitis and HCC are rising steadily in the United

The US Food and Drug Administration (FDA) has approved irinotecan (Camptosar) as first-line therapy for patients with metastatic colorectal cancer in conjunction with fluorouracil (5-FU) and leucovorin. The approval follows unanimous

SAN FRANCISCO-Research conducted at New York Medical College, Valhalla, shows that acetaminophen may prevent early biologic changes that can lead to colon cancer.

ORLANDO-A number of therapies now in clinical trials may make a difference in outcome for patients with pancreatic cancer, and some may indefinitely prolong survival, Alexander S. Rosemurgy II, MD, said at the Joint Cancer Conference of the Florida Universities. The conference is sponsored by the Univerity of South Florida College of Medicine and presented by the H. Lee Moffitt Cancer Center & Research Institute, University of Florida Shands Cancer Center, and University of Miami Sylvester Comprehensive Cancer Center..

Hepatocellular carcinoma is a major public health problem worldwide, although at present it remains a relatively uncommon cancer in the United States. As pointed out by Dr. Venook in his elegant review of the topic, most hepatocellular carcinomas progress locoregionally. Hepatic failure is the most common mode of death for patients with this disease. For this reason, regional management strategies would appear to be attractive. Dr. Venook is to be commended for an accurate review of the literature regarding this issue. Unfortunately, that literature suffers from many limitations.

In his review, Dr. Venook correctly argues that, in the majority of pa;tients, hepatocellular carcinoma results from underlying liver disease; the most common culprit is cirrhosis, which, in turn, is frequently related to hepatitis B and/or hepatitis C exposure and alcohol abuse. Given that patient outcomes are determined by the “interplay between tumor growth and adequate hepatic reserve,” and that most patients with hepatocellular carcinoma eventually die of liver failure, Dr. Venook argues that there is a good rationale for locoregional tumor control of hepatocellular carcinoma. Locoregional therapies may include hepatic intraarterial (HIA) chemotherapy, transarterial chemoembolization, Lipiodol chemo-embolization, radiation therapy (conformal external radiation therapy or intraarterially delivered radiation), or ablative procedures. These therapies are less aggressive than conventional resectional therapies, such as cryosurg-ery, percutaneous ethanol injection, radiofrequency ablation, and other intratumoral therapies.

Since hepatocellular carcinoma almost always develops in patients with underlying hepatitis or cirrhosis of the liver, it cannot be viewed as a single disease. Not only does the biology of the cancer vary depending on the underlying etiology of the liver disease-hepatitis B, hepatitis C, or cirrhosis of another etiology-but also patient outcomes are determined by the interplay between tumor growth and

CHICAGO-Using a patient’s own tumor cells to produce immunity against further cancer growth may improve survival in some patients, researchers have found in the first randomized multicenter test of immunotherapy in colon cancer. The 7-year, 412-patient trial, conducted by the Eastern Cooperative Oncology Group, shows the promise of adjuvant active specific immunotherapy in stage II/ III colon cancer, said lead author Jules E. Harris, MD, of Rush-Presbyterian-St. Luke’s Medical Center.

NEW YORK-Patients with advanced colorectal cancer have a median survival of only 12 months with single-agent chemotherapy. New drugs and new drug combinations are being tested in an attempt to find more effective treatments for the disease. A panel of researchers discussed trials of raltitrexed (Tomudex) in combination with other drugs at the Chemotherapy Foundation Symposium XVII.

NEW YORK-A monoclonal antibody (MoAb) is being studied as monotherapy and in combination with standard fluorouracil (5-FU) in two large phase III trials of stage III colon cancer. The drug is edrecolomab (Panorex), a murine IgG2a MoAb that recognizes the 17-1A antigen, which is preferentially expressed on adenocarcinomas.

NEW YORK-Gemcitabine (Gem-zar), approved for the treatment of advanced pancreatic cancer, may have value as a modulator of standard chemotherapy in advanced colorectal cancer, Stefan Madajewicz, MD, said at the Chemotherapy Foundation Symposium XVII. Dr. Madajewicz, professor of medicine and chief of neoplastic diseases, Division of Medical Oncology, SUNY Health Center, Stony Brook, NY, reported on phase I/II trials of gemcitabine in colorectal cancer used in combination with fluorouracil (5-FU) and folinic acid.

Although surgery remains the only curative option for patients with gastrointestinal (GI) malignancies, the use of adjuvant chemotherapy and/or localized radiation is considered standard therapy for patients who present with

Preliminary clinical data presented at a poster session of the 1999 annual meeting of the American Society of Clinical Oncology (ASCO) revealed that a significant number of patients with advanced colorectal cancer respond to first-line treatment with raltitrexed (Tomudex) in combination with oxaliplatin. The response rate of 59% suggests that this regimen may be one of the more active combinations under current investigation for the disease.

NEW YORK-Although it is often not possible to offer curative treatment in pancreatic cancer, significant improvements have taken place nonetheless, said Ephraim S. Casper, MD, chief medical oncologist, Memorial Sloan-Kettering Cancer Center at St. Clare’s Hospital, Denville, NJ.

NEW YORK-A new oral combination chemotherapy regimen is as effective as intravenous fluorouracil (5-FU) and leucovorin, the current treatment standard, but with a superior safety profile. Speaking at the Chemotherapy Foundation Symposium XVII, Paulo Hoff, MD, assistant professor of medicine, M.D. Anderson Cancer Center, described the use of an oral regimen combining uracil/tegafur (UFT) and leucovorin as first-line treatment of metastatic colorectal cancer.

NEW YORK-The folate antagonist trimetrexate (TMTX) may be useful as a biochemical modulator of fluorouracil (5-FU) in the treatment of advanced colorectal cancer, according to preliminary results of a phase III trial conducted by the European TMTX Study Group and discussed at the Chemotherapy Foundation Symposium XVII

BUFFALO, NY-Colorectal cancer is caused by a multistep process, taking up to 25 years for an adenocarcinoma to develop. This offers multiple opportunities for prevention strategies to intervene and decrease the incidence of this disease.

NEW YORK-A regimen of twice-weekly gemcitabine (Gemzar) plus radiation therapy in patients with unresectable pancreatic cancer appears promising, according to results of a phase I dose escalation study presented at the Chemotherapy Foundation Symposium XVII. The twice-weekly delivery may be more cytotoxic than standard once-weekly dosing, and gemcitabine may act as a radiation sensitizer, said A. William Blackstock, MD, assistant professor of Radiation Oncology, Wake Forest University, Winston-Salem, NC.

VIENNA, Austria-The combination regimen of 5-fluorouracil (5-FU) and levamisole is one of the National Cancer Institute’s recommendations for adjuvant treatment of stage C colorectal cancer. However, results from the first 5,000 patients enrolled in the QUASAR trial suggest that this advice may be open to question. “There is no improvement in survival or recurrence rate with levamisole, and there is no worthwhile benefit from high-dose folinic acid as compared with low-dose folinic acid,” QUASAR investigator R.G. Gray, MD, of the University of Birmingham (UK), said at the 10th European Cancer Conference (ECCO).

BUFFALO, NY-Recent advances in colorectal cancer detection and treatment planning are improving quality of life and disease control in colorectal cancer patients, according to research discussed at the Roswell Park Cancer Institute Surgical Oncology Symposium.

ORLANDO-At the Digestive Disease Week meeting, University of Tokyo researchers reported on the largest single-institution study of the use of percutaneous ethanol injection therapy (PEIT) in hepatocellular carcinoma (HCC). The research group studied 849 patients hospitalized for HCC at their institution between 1985 and 1997.

BUFFALO, NY-Over the past several years, the focus of breast cancer treatment has shifted from late detection and radical surgery to early detection, breast-conserving surgery, and multimodality treatment. This “paradigm shift” may also be applicable to colorectal cancer, Glenn D. Steele, Jr., MD, PhD, dean of the Biological Sciences Division, Pritzker School of Medicine, University of Chicago, said at a surgical oncology symposium hosted by Roswell Park Cancer Institute. Dr. Steele was the recipient of the Roswell Park Centennial Award.

This article by Yao, Shimada, and Ajani accurately describes the current state of the art of adjuvant therapy for gastric cancer. The authors’ primary conclusion and current recommendations are as follows:

Yao and colleagues present a concise, yet complete review and analysis of adjuvant therapeutic approaches for gastric adenocarcinoma. They confirm a fact known to all clinical oncologists who manage patients with resected gastric cancer: No adequate data support the value of postoperative (adjuvant) or preoperative (neoadjuvant) therapy in managing patients with locally advanced adenocarcinoma of the stomach.

Gastric carcinoma is a discouraging disease. Although we can clearly identify patient- and tumor-related variables that predict outcome, the only reproducible treatment- related variable associated with an improvement in survival is a complete (R0) resection.[1]

Gastric cancer is often advanced and unresectable at diagnosis. Even when a curative resection is possible, the 5-year survival rate for patients with T2 or higher tumors is less than 50%. Survival rates are even lower if lymph node metastases are present at surgery. Many phase III trials of adjuvant therapy have been conducted around the world during the past 4 decades, but their interpretation varies in the East and West. In the West, postoperative treatment modalities have not proven to be superior to postsurgical observation alone. Thus, at present, the routine use of postoperative therapy should be discouraged. In the Orient, however, routine use of postoperative chemotherapy and/or immunotherapy is common after a surgical procedure. Further investigations that correlate treatment response with molecular markers are needed. Improved clinical trial designs, including better preoperative staging, standardized surgical techniques, inclusion of adequate numbers of patients, and the continued use of a surgery-alone control group, are essential. In addition, the incorporation of newer active agents, radiotherapy, and new strategies, such as preoperative therapy and selection of patients based on tumor biology, would result in much-needed advances. Less toxic approaches with novel mechanisms of action, such as antiangiogenesis therapy, tumor vaccines, monoclonal antibodies, and matrix metalloproteinase inhibitors, also hold promise. [ONCOLOGY 13(11):1485-1494, 1999]

ORLANDO-Researchers in Germany have found that in cases of advanced colorectal cancer that has metastasized to and destroyed more than 30% of the liver, surgical removal of the colorectal tumor does not benefit the patient. On the contrary, said Sandra Mitic, MD, “these seriously ill patients, who are soon to die anyway, are better off if surgeons perform the most limited procedure possible.” Dr. Mitic described the study in a poster presentation at the Digestive Disease Week meeting.