Is a possible benefit from longer-term docetaxel-based chemotherapy real?


A new paper in JAMA Oncology has suggested that longer docetaxel-based chemotherapy may be associated with longer survival for at least some men being treated for metastatic, castration-resistant prostate cancer (mCRPC).

These new data are reported by Morrée et al. based on a follow-up analysis of data from the Mailsail trial.

The Mailsail trial was initiated several years ago and showed that adding lenalidomide to docetaxel + predinisone (DPL) did not improve the median overall survival of men being treated with mCRPC compared to treatment with docetaxel + prednisone + a placebo (DP). However, in this trial, patients were all treated wither DPL or DP “until progressive disease or unacceptable adverse effects occurred.” Because of this, mant patients received much more than the customary standard of 6 cycles of DP chemotherapy.

Morrée et al set out to investigate whether the total number of docetaxel cycles delivered to the patients in this trial was an independent factor that affected overall survival of the patients. Here are their findings:

  • Data from all 1,059 patients enrolled in the Mainsail trial were included in the analysis.
  • The average (mean ± SD) age of these patients was 68.7 ± 7.89 years.
  • Compared to treatment with 6 cycles of docetaxel, treatment with 8 or more cycles of docetaxel was associated with superior overall survival (hazard ratio [HR] = 1.909), whether the patients also received lenalidomide or not.
  • Patients who received a greater number of docetaxel cycles had superior overal survival.
    • Men given 5 to 7 cycles of docetaxel had a median overall survival of 22.8 months.
    • Men given 8 to 10 cycles had a median overall survival of 26.9 months.
    • Men given > 10 cycles had a median overall survival of 33.0 months.

The possible implications of these data are significant — not only for men with mCRPC receiving initial chemotherapy for prostate cancer but also for men who are receiving first-line chemotherapy for newly diagnosed, metastatic prostate cancer, in combination with androgen deprivation therapy (as indicated by the CHAARTED and the STAMPEDE trials).

As the authors note, longer-term docetaxel chemotherapy appears to be associated with an increased survival benefit, but this is really going to need to be proved in prospective, randomized clinical trials. The improvement in overall survival probably needs to be carefully balanced against any risks for increased side effects in the patients, and so patients entered into any prospective trial to study the impact of longer-term chemotherapy would need to be stratified in some way to take account of the potential risk for side effects.

 

8 Responses

  1. Men who had more cycles must have been in better physical condition than those with fewer. Docetaxel is toxic and the effects are cumulative. 10 cycles is an astounding performance.

  2. This isn’t really surprising. While Doce+6 is the standard, many patients are put on additional rounds or switched to Jevtana for additional rounds already today. I would like to see a trial take this not just to additional rounds but also a head to head of docetaxel vs. cabazitaxel. We already know cabazitaxel patients experience fewer side effects. And seemingly with similar positive results.

  3. Let’s make sure we are all seeing the above two comments in an appropriate context:

    (1) All forms of chemotherapy come with inherent toxic side effects. Some men are much more able to deal with this than others. Clearly it would be inappropriate to continue to give more than 6 cycles of docetaxel to men who were already suffering from severe, docetaxel-related toxicities. However, it should be appreciated that docetaxel has a relatively low level of toxicity when compared to older forms of chemotherapy such as adriamycin that are still widely used today in the treatment of other forms of cancer.

    (2) The relative value of first-line cabazitaxel (Jevtana) as compared to first-line docetaxel has never been well studied in a large randomized trial. Cabazitaxel is still only actually approved for use as a second-line form of chemotherapy after docetaxel chemotherapy. It is a little odd that the manufacturer has never invested in a major Phase III trial to see if cabazitaxel might be a better first-line option than docetaxel. This would certainly be a trial that many in the advocacy community would support, and it could be conducted in such a way that appropriate patients could have > 6 cycles of either drug depending on how well they were able to cope with the differing toxicities.

    (3) While the findings above may not be surprising to some highly informed advocates, these data may well come as a surprise to many prostate cancer patients and to some of their doctors too.

  4. I do know of cases where carbazitaxel used instead of docetaxel with the intent of preserving dexterity in the hands and feet. Neuropathy in fingers and toes is far more common with docetaxel. I know I would certainly support a trial that would give us a less harsh chemotherapy drug.

  5. I had 21 doses of low-dose docetaxel (40 mg/weekly) …perhaps a big advantage re remission and survival. Additionally, the benefit of minimal side effects which is positive for elderly patients.

    Question: Why are there so few patients receiving low-dose chemo?

  6. Dear David:

    I would suspect that the simple answer to your question about why relatively few patients received low-dose chemotherapy is that the trials which proved that chemotherapy worked to extend survival were done with doses of more like 75 mg every 3 weeks.

    For many men, weekly visits to an oncologist can be a problem because of the distances they may have to travel and the costs involved. And many community oncologists are going to follow the guidelines issued by organizations like the National Comprehensive Cancer Network (NCCN) that are based on the results of the Phase III clinical trials.

    Frankly, we still don’t know what the “best” dose schedule is for treatment with docetaxel in men with mCRPC because this would require a very large randomized trial in which men were randomized to one of about three or four different dose schedules to see what the lowest dose of docetaxel might be to achieve the safest result while still maintaining the survival benefit. It might be very difficult to get men to enroll in a trial like that … and it would probably need about 1,500+ mCRPC patients to get us meaningful results reasonably quickly.

  7. Dear David:

    I would suspect that the simple answer to your question about why relatively few patients received low-dose docetaxel chemotherapy is that the trials which proved that chemotherapy worked to extend survival were done with doses of more like 75 mg every 3 weeks (more than 15 years ago now).

    For many men, weekly visits to an oncologist can be a problem because of the distances they may have to travel and the costs involved. And many community oncologists are going to follow the guidelines issued by organizations like the National Comprehensive Cancer Network (NCCN) that are based on the results of the Phase III clinical trials.

    Frankly, we still don’t know what the “best” dose schedule is for treatment with docetaxel in men with mCRPC because this would require a very large randomized trial in which men were randomized to one of about three or four different dose schedules to see what the lowest dose of docetaxel might be to achieve the safest result while still maintaining the survival benefit. It might be very difficult to get men to enroll in a trial like that … and it would probably need about 1,500+ mCRPC patients to get us meaningful results reasonably quickly.

  8. Hi David.

    Consider yourself lucky.

    I took along the 2- vs 3-weekly docetaxel study from 2013 (see this link) to my father’s oncologist. He hadn’t read it when it was published, but he gave it a very cursory glance before saying, “Yeah, we do it every 3 weeks.” I left him the full paper in the hope that he reads it (long story short = equally efficacious but fewer side effects).

    I was hoping to minimize the side effects for my father, who is now suffering with them significantly.

    Cheers

    Jonathan

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