What we learned on Monday June 7, 2004
Julia Draznin Maltzman, MD
Abramson Cancer Center of the University of Pennsylvania
What follows are highlights of the day on Monday June 7th. A more detailed review of selected presentations can be found on OncoLink.
Most of the breast cancer presentations today focused around the issue of Her2/neu. A retrospective analysis comparing a dose dense schedule of the three-drug regimen 5-fluorouracil (5FU), epirubicin, and cyclophosphamide, to the more conventional every three-week schedule was presented. The trial was done previously and negative results were reported. The presentation today differed in that it focused on the Her2/neu positive patients exclusively. Those patients in fact had a better event free survival. The overall survival for this high-risk group did not reach statistical significance but a trend was noted.
Following along similar thoughts, another group of investigators looked at stage II and III Her2/nue positive patients after completion of four cycles of Taxol with and without Herceptin followed by four cycles of 5FU, epirubicin, and cyclophosphamide with and without Herceptin. This trial was a prospective analysis that was terminated early due to the tremendous superiority of the Herceptin arm. However, this trial is very small and we can not extrapolate to the population at large. What is most notable about this trial is the lack of congestive heart failure seen even in the women receiving Herceptin with either the taxane or the anthracyclin.
A separate trial, however, did remind us that the combination of Herceptin with a taxane or an anthracycline could cause heart failure.
Another trial showed that the combination of Taxol, carboplatinum, and Herceptin does improve time to disease progression but has no significant difference in overall survival.
Finally, another trial pointed out that Her2/neu analysis is still problematic and not uniform throughout many laboratories. This issue is quite problematic as therapeutic decisions are made based upon this information.
An EORTC trial showed that cure rates in limited stage small cell lung cancer are not improved with vaccine therapy in addition to the conventional chemotherapy of cisplatin and etoposide.
Another trial asked the question of whether or not there is a good third line chemotherapy option for non small cell lung cancer. The combination of gemcitabine and navelbine was found to be non toxic and comparable in efficacy to a carboplatin doublet.
Once again most of the attention was focused on the EGFR inhibitors. Along with the INTAC I and II trials that were presented last year at ASCO, this year, the TALENT and the TRIBUTE studies confirmed lack of benefit of small molecule tyrosine kinase inhibitors when added to conventional chemotherapy in advanced disease.
The phase II trial examined combination chemotherapy (cisplatinum and vinorelbine) with and without Erbitux for non small cell lung cancer. The monoclonal antibody arm was well tolerated and did slightly better, however, the patient size was very small and the investigators are currently pursuing a large scale clinical trial.
Another interesting trial examined what kind of patient stands to benefit from Iressa the most. It seems as though bronchoalveolar carcinoma (BAC) histology, female sex, and never having smoked, portends a response to this agent. Similarly, we were reminded once again of the two recent papers in the New England Journal of Medicine and Science that identified the EGFR mutation which predicted response to Iressa.
The main conclusions that we should walk away with are: (1) EGFR small molecule inhibitors should not be administered in combination with cytotoxic chemotherapy, but on their own they do provide symptom relief possibly prolong survival. (2) Consider Iressa for BAC, female patients, and those who do not have a history of smoking. (3) The EGFR mutations predict response to small molecule tyrosine kinase inhibitors. (4) And, stay tuned for the role of monoclonal antibodies in lung cancer.
Great news was reported in renal cell carcinoma. Several new agents were reported to have had an impressive response rate in this previously dismal disease. Encouraging trials were presented with SU 11248, Avastin, PTK 787, Bay43-9006, mTOR inhibitors, Infliximab, and various combinations of these agents. All showed positive responses but none showed a survival advantage.
The biggest news was in prostate cancer, which had two presentations in the plenary session. Both presentations recommended Taxotere for the treatment of hormone refractory prostate cancer based on a survival advantage seen in two large scale randomized clinical trials. The discussant was so impressed with these data that he offered the possibility of looking at Taxotere for earlier stage disease. It is possible that the novel agents now widely used in lung and gastrointestinal malignancies will be applied to this disease as well. These findings received notoriety in the plenary session because these are the first trials to show benefit of cytotoxic chemotherapy in prostate cancer.
Strides were made in testicular cancer as well. Stage I seminoma is a highly curable disease however the treatment . external beam radiation can leave men with unpleasant, long term, side effects. An English study looked at the possibility of giving single dose carboplatinum instead of radiation therapy and found both two and three year survival to be about the same. However, the follow-up is short, thus we need to await further results before this treatment can be recommended.?
A study looked at three different options for advanced gastric cancer: epirubicin, cisplatin, and 5FU (ECF), (which is the standard of care in Europe for this disease), versus Taxotere, cisplatinum, (TC) as opposed to a third arm of Taxotere, cisplatinum, and 5FU (TCF). TCF seemed to be perhaps more effective that TC. However, due to trial design a fair comparison between TCF and ECF could not be done. Despite all this, the toxicities seen with TCF were so severe; that even the authors concluded that perhaps this combination should not go further in clinical trials.
Pancreatic cancer received much attention with multiple clinical trials examining various agents with gemcitabine versus single agent gemcitabine. Some examples of the regimens studied include: gemcitabine with and without Exatecan (a new topoisomerase I inhibitor), gemcitabine with and without oxaliplatin, gemcitabine with and without Pemetrexed, and the combination cisplatinum, epirubicin, 5FU, and gemcitabine versus gemcitabine alone. Some combinations showed a higher response rate, however, none of them showed a statistically different survival advantage over monotherapy with gemcitabine. Single agent gemcitabine has much less toxicity than any of the combinations evaluated and therefore remains the standard of care in advanced pancreatic cancer.
Colon cancer prevention was discussed in the plenary session where a retrospective analysis showed that HMGCoA reductase inhibitors, such as the .statin. drugs used to flight high cholesterol, might have a role in preventing colon cancer. This trial needs prospective validation and statins should not be given to patients as colon cancer prophylaxis.
Finally, hepatocellular carcinoma was examined and the combination of cisplain and interferon alpha was compared to the standard of care of adriamycin. The benefit was not statistically significant and the toxicity was profoundly worse. Adriamycin continues to be the standard of care in this difficult disease.