Sunday, August 28, 2016

Docetaxel with primary radiation therapy for high risk prostate cancer


In 2004, the FDA approved docetaxel as the first chemotherapy drug proven to extend survival in metastatic hormone-refractory prostate cancer. Although the survival benefit was a modest 2.5 months, researchers launched clinical trials to determine whether the survival advantage could be increased by using docetaxel earlier in disease progression or by combining it with other therapies. Those trials are beginning to mature now.

Last year, the CHAARTED study demonstrated a 17-month survival advantage stemming from starting docetaxel at the same time as ADT in men with multiple metastases. However, another trial, GETUG-AFU 15, did not demonstrate a benefit. Last month, early reports of the STAMPEDE trial confirmed the benefit, which was 22 months among men with any metastases upon initial diagnosis. As in the CHAARTED trial, the evidence of benefit has not yet emerged among men with advanced cancer who did not yet evince metastases.

Several trials looked at combining docetaxel with radiation among men diagnosed with high risk localized prostate cancer. RTOG 0521 showed that the 4-year overall survival was 89% without docetaxel and 93% with it -- a statistically significant difference, but perhaps not as meaningful as we would have liked to see. There was a significant improvement in disease-free survival (65% vs. 55% at 6 years), and incidence of metastases at 6 years (9% vs 14%). It’s possible that with longer follow up, the difference in overall survival will increase in magnitude.

Another clinical trial, GETUG-12, was designed to find out whether chemotherapy (docetaxel + estramustine) pretreatment would provide a survival benefit when added to 3 years of ADT and RT begun 3 months from the start of chemo (in 87% of the patients). The study was described and early results given in 2010, so I will not go into the details again. However, some follow-up results have recently been published. (Update 12/4/2018Fizazi et al. report that after 9.6 years median follow-up, relapse-free survival was 11.6 years among those who received chemo versus 8.1 years among those who did not. Clinical/radiographic relapse-free survival was 13.9 years among those who received chemo versus 12.5 years among those who did not. Metastasis-free survival, prostate cancer- specific survival, and overall survival were not significantly different. They further report equal levels of late-term high-grade side effects in both groups, and no deaths attributable to the chemotherapy.

These are not yet the improvements in long-term survival that we eventually hope to see by adding docetaxel. The long wait for differences in survival once again highlights the very long natural history of the disease, even in men diagnosed with high-risk prostate cancer.


(Update: 6/28/2018) A Scandinavian trial (SPCG-13) reported no benefit to adding docetaxel after ADT+RT in unfavorable risk patients. 376 patients with unfavorable intermediate risk or high risk prostate cancer were randomized to receive either:

A. RT (at least 74 Gy) +ADT followed by docetaxel (75mg/m2) every 3 weeks for 6 cycles
B. RT (at least 74 Gy) +ADT

After 5 years of follow-up:
  • The rate of biochemical failure was the same for both groups, at about 30%.
  • There were 20 deaths in Group A, 9 attributable to prostate cancer
  • There were 23 deaths in Group B, 7 attributable to prostate cancer
  • Febrile neutropenia, which can be life-threatening, occurred in 17% of Group A.
Five years should be long enough to start seeing a difference in biochemical failure rates, but none was observed and the survival curves showed no signs of diverging. Based on this clinical trial, there was no benefit, but substantial risk to adding docetaxel after RT+ADT in unfavorable risk patients.

(Update 10/16/2018) A small (n=132) Spanish trial  (more details here) also found no benefit to adding docetaxel to RT+ADT in high risk men. Patients were randomized to one of two groups:

A. RT (74 Gy) +ADT (LHRH agonist for 3 years)
B. RT+ADT (as above) followed by 9 weekly cycles of docetaxel (20 mg/m2)

Patient characteristics were:
  • Stage T3/4: 81%
  • Gleason score ≥ 8: 77%
  • PSA>20: 29%
  • positive lymph nodes: 18%
After 5 years of follow-up:
  • Biochemical recurrence-free survival was not statistically different: 93% for Group A, 85% for Group B
  • Progression-free survival was not statistically different: 93% for Group A, 84% for Group B
  • Overall survival was not statistically different: 93% for Group A, 94% for Group B



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