Letters

CTOS Op Ed: Questions, Comments & Counterpoint

Dr. Archie Bleyer sent us the following letter regarding Dr. Robert Maki's Op Ed piece, Sarcoma Alliance for Research through Collaboration (SARC): An effort to perform clinical trials efficiently and effectively for people with sarcoma, which appeared in the December 2007 issue of ESUN,

Letter from Dr. Archie Bleyer

Bruce,

The Op Ed by Dr. Maki entitled Sarcoma Alliance for Research through Collaboration (SARC): An effort to perform clinical trials more efficiently and effectively for people with sarcoma in the current issue of ESUN describes how "SARC clinical trials are designed ... to get to the correct answer faster than what one otherwise might." The Op Ed goes on to state that "One good example is the SARC study of gemcitabine with or without docetaxel in people with metastatic sarcomas. Thanks to the design of the clinical trial ..., 20% more people were given the better treatment in the study than would have occurred otherwise by putting half of people on one treatment and half on the other."

Isn't' there a problem with declaring the treatment that 20% more of the patients received "the better treatment" or "the correct answer"? A randomized phase II trial, which this study was, does not determine either. Moreover, as reported (J Clin Oncol 25;2755-63,3790:2007) "the better treatment" was significantly more toxic (p=0.001). Additionally, with greater toxicity "the better treatment" may have significantly compromised health-related quality of life (HRQOL), especially if the median delay in disease progression was only 3 months. HRQOL appears not to have been evaluated.

Archie

Reply by Dr. Robert Maki

I am in agreement with many of the points highlighted by Dr. Bleyer in his thoughtful reply to my recent editorial on the utility of a specialty trials group such as SARC.

In response, there is quite a bit that is not published regarding our Bayesian randomized clinical trial design that we could not publish owing to space considerations. For example, our SARC study was conducted as a phase III trial, but the reviewing biostatisticians felt it is best considered at the end a randomized phase II study, and rather than challenging the point and further delaying what we thought was an important observation, we changed the title of the paper during the review process.

SARC's intention was to perform a randomized trial that helped us choose which therapy was more effective. I agree with Dr. Bleyer; I should have used the phrase "more effective" rather than "better". In conducting our study, we are 98% sure that the combination of gemcitabine and docetaxel is "better" than gemcitabine alone, given our data. We are also 97% sure that, given our data, the combination leads to an improvement in survival in comparison to the single agent. In this study, people lived on average about 6 months (about 50%) longer when they received both drugs as opposed to the single agent. I would argue that the average person hearing about these data probably would not want to take part in a larger, traditional frequentist phase III study looking at the same question.

Furthermore, without quantity-of-life improvement, quality-of-life may be less critical for at least some patients. This is clearly an issue that is discussed by medical oncologists and their patients on a daily basis. Another example of this concept is the use of doxorubicin vs pegylated liposomal doxorubicin. While we see what appear to be more impressive responses with doxorubicin vs. pegylated liposomal doxorubicin in our own practice, the side effects of doxorubicin may mitigate against its use in certain patients.

The intention of our randomized study was to find the more effective therapy, without taking into account toxicity of the two regimens. Interestingly, adverse events such as anemia and thrombocytopenia were greater with higher doses of single agent gemcitabine vs. gemcitabine-docetaxel, while platelet transfusions were more common in people receiving the combination. Bayesian designs allow for the incorporation of toxicity as a metric for altering randomization. However, adding such a dimension would have very much put us into untested waters, and given the study was already challenging, we opted not to include such factors in the randomization model.

As we note in the discussion of our paper, the toxicity of the combination was significant, and off study I do not use 100 mg/m2 of docetaxel per cycle of therapy. As medical oncologists realize, therapy must be tailored to the individual patient. There are some data to support lower dose combination therapy for sarcoma patients. Leu et al. showed lower dose gemcitabine with 100 mg/m2 docetaxel was effective in a number of patients with soft tissue sarcoma. In our study, patients who had received prior pelvic radiation received lower doses of gemcitabine-docetaxel, and still had PFS and OS benefit from the combination in comparison to the single agent. Anecdotally, we see good responses in patients with MFH, leiomyosarcoma, and pleomorphic liposarcoma who receive this combination with lower doses of docetaxel. Proof of the utility of the combination, or of the utility of a single three-weekly dose of docetaxel vs. alternative schedules will require further study, be it phase II studies, or Bayesian or frequentist randomized studies.

In conclusion, we consider our Bayesian clinical trial a strong argument for improvement in survival of the combination of two drugs which themselves have limited activity. We agree with Dr. Bleyer that toxicity is an issue that has to be addressed in discussing chemotherapy options with patients. In that vein, we look forward to further exploration of this combination, both in preclinical models and in different schedules in patients, and hope this will further optimize the care for patients with sarcomas.

Sincerely,

Robert Maki, MD PhD

Memorial Sloan-Kettering Cancer Center