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SPECIAL SECTION |
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AGGRESSIVE CHEMOTHERAPY USE COULD REDUCE MORTALITY, RESEARCHER SAYS |
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 Top Aggressive Chemotherapy Use... U.S. National Cancer Institute...BCG Vaccine and Letrozole... |
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Due to the fact that even high-risk patients were often not appropriately treated with chemotherapy, and the fact that mortality statistics take as long as 10 to 15 years to mature, proof of the benefit of chemotherapy was not available until the 1990s, Greenspan said. Mortality rates began to fall in 1989, and have continued to progressively decline in England and the U.S. Referring to the use of tamoxifen, as well as chemotherapy, he said, "Now, at long last, there is proof of the benefit of chemohormonal therapy." Between 1989 and 1993, mortality dropped more than 14% among white women 40 to 50 years of age in Great Britain. In the U.S. during the same period, the largest reduction was 13.5% among white women 30 to 40 years of age. Overall reductions in breast cancer mortality for all age groups during that six-year period were 7% in England and 5.8% in the U.S. Unfortunately, black women and those in Third World ethnic groups did not experience similar reductions in mortality, at least up to 1994.
Despite encouraging data demonstrating that stage III disease was highly responsive to combination chemotherapy and that long-term survival and "virtual" clinical cure were surprisingly high, the media and advocacy groups appeared to have targeted chemotherapy for intense negative publicity, Greenspan said. Focusing on the toxicities and hazards of chemotherapy for women with breast cancer, the media obscured the overall risk-versus-benefit picture, Greenspan said. Moreover, increased utilization of mammography during the 1980s has led to more frequent detection of low-risk early stage tumors and has contributed to the public’s perception of a breast cancer "epidemic," he said. According to Greenspan, the flat survival curve in years 10 to 20 after successful treatment for breast cancer represents what is essentially clinical cure of the disease. Mortality 20 to 30 years after treatment is confounded by noncancer-related deaths, he observed. The public needs to be informed that virtual clinical cure can be achieved in the majority of women with breast cancer, Greenspan said. Even when the disease is advanced, he pointed out, 30% to 40% of high-risk patients are successfully treated. "The mere designation of breast cancer as a potentially curable disease will accelerate the more widespread application of aggressive and improved methods of therapy," Greenspan concluded. 
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U.S. NATIONAL CANCER INSTITUTE EXPANDS TAXOL® AGREEMENT |
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TopAggressive Chemotherapy Use...U.S. National Cancer Institute...BCG Vaccine and Letrozole... |
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Though the new CRADA between BMS and NCI will expire in December 1997, officials at the company and the Institute said the door would be open to extending the collaboration. "Taxol® is one of the most significant cancer therapies available today, and we’ve only begun to scratch the surface of the drug’s full benefit for cancer patients," NCI Director Richard Klausner said in a statement. "Taxol® has proven to be a far more important drug than was originally envisioned in 1988, when a CRADA partner was first sought by the NCI," said Michael Loberg, president of BMS Oncology and Immunology division. "BMS remains committed to the research and development of Taxol® in order to further realize the drug’s cancer-fighting potential."
NCI and BMS collaborated in the development of Taxol®, obtaining FDA approval for the ovarian cancer indication at the end of 1992, only 24 months after the original CRADA partnership was approved. Since initial approval, BMS and the NCI have sponsored an additional 500 clinical trials involving 25,000 patients, the company said. Taxol® is approved in the U.S. for breast and ovarian cancer indications, and is available in more than 50 countries, the company said.
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BCG VACCINE AND LETROZOLE ON TRACK FOR U.S. APPROVAL |
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TopAggressive Chemotherapy Use...U.S. National Cancer Institute...BCG Vaccine and Letrozole... |
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TICE BCG, an attenuated, live culture preparation of the Bacillus of Calamette and Guerin strain of Mycobacterium bovis, was approved by the FDA in 1990 for carcinoma in situ of the bladder. However, TICE BCG is widely used in the U.S. off-label for prevention of bladder tumor recurrence.
To obtain FDA marketing approval for this indication, Organon Teknika submitted data from two prospective, randomized, controlled studies to the agency. The trials were the Nijmegen study, conducted in the Netherlands, and a trial conducted in the U.S. by the Southwest Oncology Group (SWOG). Both studies compared TICE BCG with Mutamycin (mitomycin C, MMC), by Bristol-Myers Squibb Co. Both enrolled patients with transitional cell carcinomas, the most common type of bladder tumor.
The SWOG trial (SWOG 8795) enrolled 469 patients, of which 447 were eligible. The recurrence rate for patients taking TICE BCG was 40.3%, compared to 54.3% for those taking MMC (p = 0.017). Median time to recurrence was 44 months for the BCG group, compared to 22 months for the MMC group. Of the BCG group, 7.8% progressed while on therapy, compared to 12.9% of those taking MMC. Nearly half the patients enrolled in the SWOG trial had TaG1 tumors, said Donald Lamm of SWOG. Of those patients, 52% recurred while taking BCG, while 60% recurred while taking MMC. The times to recurrence were 36 months for those on BCG and 13 months for those on MMC. The differences were not statistically significant, but indicated a trend favoring BCG, Lamm said. Of those patients with CIS, 55% responded to BCG, while 46% responded to MMC. TICE BCG resulted in more side effects than MMC, including dysuria, fever, malaise, and cystitis. About 5% of patients taking BCG will develop serious toxicity, Lamm said.
Organon recommends TICE BCG for selected patient groups: those with grade 3 TCC, Ta or T1; stage T1 TCC, grades 1 through 3; recurrent disease, grade 2; or multiple Ta, grade 1 tumors, with recurrence despite resection.
An analysis of the SWOG trial by the FDA agreed with the company’s presentation that TICE BCG was superior to MMC in reducing the tumor recurrence rate and median disease-free survival. However, FDA concluded that TICE BCG was not equivalent, but inferior to MMC in the Nijmegen study, agency reviewers Sheldon Morris and Richard Steffen said. In addition, it was concerned about the use of MMC as a comparison, because the drug has not been approved for this indication.
In the Nijmegen trial, with 469 patients, only 22% had TaG1 tumors. The trial compared three treatment arms: TICE BCG, BCG-RIVM, and MMC. Tumor recurrence rate was 44% for patients on TICE BCG, 34% for BCG-RIVM, and 29% for MMC. Median disease-free survival was 2.8 years for those on TICE BCG, and was not reached for the other two arms.
For patients with high grade tumors, those treated with TICE BCG had a 47% recurrence rate, compared to 36% for BCG-RIVM and 30% for MMC. The difference was statistically significant (p = 0.04). Michael Hanna, of Organon Teknika, noted that there were several differences between the studies, neither of which were sponsored by Organon. The Nijmegen study did not select patients, was not stratified, and had no provision for maintenance therapy of BCG.
The SWOG study selected for high-risk patients, based on the grade, stage, and rate of tumor recurrence. The SWOG trial also was stratified according to those patients with CIS and those without, and included nine months of maintenance therapy of BCG. In addition, the dose of mitomycin C used by the two groups ranged from 0.6 mg/ml in Nijmegen to 1 mg/ml in SWOG, Hanna said.
ODAC members said that although the Nijmegen trial did not prove TICE BCG activity in the prevention and recurrence of Ta and T1 tumors, the SWOG study did prove the drug’s activity, and, overall, the data supported the safety and efficacy of the drug. Many committee members said the indication should not be restricted, though they personally would not recommend using TICE BCG to prevent grade 1 tumors.
The FDA asked the committee for recommendations about methods to minimize the risk of nosocomial infection. The committee said labeling could include a warning about not mixing BCG under the same hood as chemotherapeutic agents. The company said the risk of infection is minimized by a new needle-free administration device for TICE BCG.
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FOOTNOTES |
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TopAggressive Chemotherapy Use...U.S. National Cancer Institute...BCG Vaccine and Letrozole... |
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