Practice changing results….chemotherapy up front.

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Adding 6 cycles of docetaxel at the outset of hormonal therapy for prostate cancer has been shown to improve survival, especially in men with a high burden of disease. The much anticipated report was presented in detail today at the ASCO annual meeting. Those of you who have followed this blog will remember that I previously highlighted the CHAARTED trial when the trial was stopped prematurely because of the positive result.

The first author, Chris Sweeney, is a good friend and led the study in which several of our patients here in Denver were participants. Thanks guys !

This study randomized 790 men who presented with metastatic prostate cancer and who had never received hormone therapy (ADT) to receive ADT alone (393) vs ADT plus chemothrapy with docetaxel (397) starting up front at the time the ADT was started.  In patients with high volume disease, defined as those men with visceral metastases or >3 skeletal mets including one beyond the pelvis and spine, there was an improvement of 17 months in overall survival from 33 months to 49 months with a p value of <.0006 for significance between the two arms of the trial. The men with lower volume of metastases are also doing better, but the curves for the two treatment arms have not met significance. There was reasonable balance in age, race, psa values, etcetera between the arms. A key point is that 3/4 of the men initially treated with ADT alone went on to receive docetaxel at the time of progressive disease, meaning that this trial can reasonably be considered to reflect a “pay me now or pay me later” with docetaxel toxicity, and the men who were on the “pay me now” arm had the most benefit from the toxicity of the chemotherapy. There was good balance between the arms in terms of the number of men who received others of the newer treatments (abiraterone, enzalutamide, sipuleucel-T).

For prostate cancer, this is akin to the studies of using chemotherapy “up front” in the adjuvant setting that really got medical oncology going in the early 1970′s in women with breast cancer. It opens the door to the study of using aggressive multimodality treatment including the newer hormonal agents, and possibly vaccines, in men with high risk disease at the very outset of their therapy, which should be the next studies. The problems with designing such studies is the very long period of time it takes to get answers. CHAARTED was opened in 2006 and only now, 8 years later, do we have a result. The time could be dramatically shortened if more men would be placed on clinical trials. 1000′s of men were treated with same old same old treatment during the time we worked on CHAARTED. If 50% of them would have been put on this trial in the first two years, we could have had this result about 4 years earlier. Since that takes a major change in how medicine is practiced in the US, don’t hold your breath.

8 Comments

Filed under General Prostate Cancer Issues

8 responses to “Practice changing results….chemotherapy up front.

  1. Richard Stanton

    DoctorGlobe:

    From your report, it appears that men who benefit the most from the combined treatment of ADT and docetaxel are those with greater metastasis at the tme therapy is commenced. Is it correct to conclude that it is reasonable for men with progessive disease (e.g., just a few positive lymph nodes) and being ADT sensitive, to wait longer before starting ADT until there is more metastasis, but then start treatment with the combined ADT + docetaxel therapy? Thank you.

    Richard Stanton

    • That is an interesting possibility, but untested. Probably we won’t have a good idea about such an approach until the longer followup of the CHAARTED trial is reported with data on the men with low volume disease parsed out.

  2. JOHN CHARLES MILLER

    Circulate to group please. john Date: Mon, 2 Jun 2014 05:01:04 +0000 To: millerjc000@msn.com

  3. Dave Stevens

    Is there any known way to forecast an individual’s side effects and severity of side effects from docetaxel based on medical history and current physical characteristics? Thanks.

    • At present there is not an easy way to forecast. However, the molecular “personalized medicine” approaches now being taken hold promise, although they are often research, unless/until there is a direct link between a genetic profile that predicts response or one that predicts toxicity (or both). As you might imagine, such profiling is both complex and expensive (and will likely be carried out on the CHAARTED trial in due time) but here is an example of a result from a breast cancer trial that was looking at whether any biomarkers could predict response to docetaxel and cetuximab in women with triple negative disease:

      “We applied the ROC curve to identify the best cut-off value for Ki67, EGFR, MET, cytokeratin 5/6 and 8/18, p53, ALDH1, PTEN, P-cadherin and the FOXP3+ or CD8+ TIL counts. None of these biomarkers was predictive of pCR except for the CD8+/FOXP3+ TIL count ratio. pCR rate was higher in the pts with the ratio equal or higher than 2.75 than in the others (43% versus 0%, p = 0.047).”

      When these sorts of results are reported, it is seldom that everyday clinical practice changes – but in some cases, when the response to a drug is ZERO and it is a single biomarker that predicts that, the drug will nowadays be approved ONLY for those patients who have a possibility of responding. The same paradigm holds, in general, for toxicity prediction.

  4. Gzr

    Sounds like a very significant study.

  5. Ashton Villars

    Dr.Glode,
    Thank you for informative Blog. This study sounds very significant based on longevity. The unknown as discussed above are quality of life issues and the acceptable mix of longevity and quality of life varies with the patient.
    With that being said I am sensitive to quality of life issues and appear to be in the category of progressive disease Mr Stanton alluded to above. But based on your response there is not enough data at this time to help a patient make the decision of ADT or ADT plus docetaxel and when to start.

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