According to the Norton-Simon hypothesis, chemotherapy results in a rate of regression in tumor volume that is proportional to the rate of growth for an untreated tumor of the same size. The hypothesis suggests that when treating micrometastases, high-dose short-duration treatment, either with a single drug or a drug combination, that is followed sequentially by a non-cross-resistant treatment may be preferable to prolonged-duration low-dose therapy.
This treatment model has proved effective in breast cancer, pointed out Harry Long, MD, professor of oncology at the Mayo Clinic College of Medicine in Rochester, Minn. "We were able to take doxorubicin and cyclophosphamide in a regimen that was well tolerated on a three-week schedule, move it up to a two-week schedule with bone marrow growth factor support, and achieve a higher time to progression and survival. Can we do the same with ovarian cancer?" Yes, according to Dr. Long, who spoke in favor of a dose-dense paclitaxel (Taxol) schedule at the 2009 Oncology Congress in San Francisco.
But taking up the argument for caution in interpreting data on a shorter, more intense therapeutic course was J. Tate Thigpen, MD, professor of medicine and director of the division of medical oncology at the University of Mississippi Medical Center in Jackson. "Only one trial to date suggests that weekly dose- dense paclitaxel is superior to every-three-week paclitaxel; whereas earlier studies of single agent weekly paclitaxel vs every three week paclitaxel in the recurrent disease setting suggested no significant difference between the two schedules. In addition, the population in the Japanese study was considerably less diverse than the typical U.S. or European study. Final conclusions must await a confirmatory U.S. trial that has been awaiting NCI clearance for activation for almost one year, GOG 262."
A shorter course: Reasonable but feasible?
"If you have a lower-dose therapy, given at certain intervals, you get so many log cells killed and tumor recovery between treatments," Dr. Long said. "If you give a higher dose of a drug, or a regimen that kills more cancer, you can accomplish more cell kill in a given period of time. And if you can move up the therapy so that you reduce the recovery, you can accomplish more total cell kill. So dose density certainly seems reasonable. The question is: Is it feasible?"
To answer that question, Dr. Long cited the results from several clinical trials, such as the Gynecologic Oncology Group (GOG) trial 097. In this study, ovarian cancer patients received the same total dose of cyclophosphamide and cisplatin that was delivered over four three-week cycles or eight three-week cycles. The trial leaders found no difference in overall survival (OS), progression-free survival (PFS), or response rate (Semin Oncol 24:S213-S216, supplement 2, 1997; Semin Oncol 23:40-47, supplement 12, 1996).
More recent studies out of M.D. Anderson Cancer Center and the Royal Marsden Hospital in London noted that weekly paclitaxel was well tolerated. The Houston-based researchers found that weekly paclitaxel at a dose of 80 mg/m2 turned in a 21% response rate in previously treated patients. In the UK study, the dose was between 80 mg/m2 and 100 mg/m2 per week in previously treated and untreated patients, and the overall response rate was 48%. The median PFS was 4.8 months and OS was 13.5 months (Gynecol Oncol 101:436-440, 2006; Gynecol Oncol 109:27-32, 2008).
"Weekly paclitaxel is certainly feasible," Dr. Long said, although he pointed out that "if you look at the per mg/m2 per week schedule, this isn't too far off from the 175 mg/m2 every three weeks that has been the standard of therapy."
However, in other trials, when paclitaxel was combined with carboplatin, toxicity was a major problem. Weekly paclitaxel doses included 90 mg/m2 and carboplatin with an AUC of 4, and paclitaxel at 100 mg/m2 per week with carboplatin with an AUC of 2. "The higher the dose of chemotherapy, the greater the toxicity," he said. "If you want to give carboplatin in probably the worst possible way, you can give it weekly. It has cumulative myelosuppression, and after one or two cycles you won't be able to give any more. And that was found in the weekly schedules."
The Japanese Gynecologic Oncology Group conducted a study that upped the paclitaxel dose to 180 mg/m2 and also gave carboplatin once every three weeks at an AUC of 6. "They got an overall response rate of 53%, a median PFS of 17 months, and a two-year OS of 77.7%," Dr. Long explained. "They used dose stacks,
paclitaxel-carboplatin with paclitaxel of 80 mg/m2 weekly and carboplatin every three weeks, so there was no attempt at a dose-dense increase in carboplatin. And they got an overall response rate roughly the same as the standard regimen, but they increased median PFS to 27.9 months, and two-year OS to 83.6%. Both were statistically significant" (Lancet 374:1331-1338, 2009; ASCO 2008 abstract 5506).
On the basis of these results, Dr. Long answered yes to the feasibility question. On a weekly schedule, the dose density of paclitaxel was increased by about 30%, although it came at the cost of a reduction in dose intensity per treatment. "The [Japanese] randomized clinical trial does convincingly show that dose-dense, dose-intense chemotherapy with paclitaxel and standard carboplatin is superior to standard once-every-three-week paclitaxel and carboplatin," he said.