Docetaxel vs Surveillance After Radical Radiotherapy for Intermediate- or High-Risk Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•Docetaxel combined with androgen-deprivation therapy (ADT) has improved survival of patients with advanced prostate cancer. This study evaluated this combination in men with high-risk localized prostate cancer. A total of 376 patients were randomized to either six cycles of adjuvant docetaxel or to surveillance following radiation therapy for intermediate- or high-risk prostate cancer. Neoadjuvant/adjuvant ADT was mandatory for all patients. The 5-year estimated biochemical progression rates were 31% among the docetaxel arm and 28% among the surveillance group.

•Based on these data, adjuvant docetaxel did not appear to improve outcomes with ADT for patients with intermediate- or high-risk prostate cancer.

– Gautam Jayram, MD



Urology 

Written by Kenneth J Pienta MD

There continues to be great interest in treating men with intermediate- and high-risk prostate cancer with multimodality therapy to improve outcomes. This randomized study added docetaxel to standard therapy of external beam radiotherapy plus ADT to compare biochemical disease–free survival. The addition of docetaxel to standard therapy did not improve outcomes. This is not surprising given that the addition of docetaxel to standard hormonal therapy does not appear to improve survival in men with treatment-naïve, low-volume, metastatic disease as seen in CHAARTED and other studies. This suggests that, in patients with early, low-burden disease who benefit from temporary castration therapy, chemotherapy does not “wipe out” early castration-resistant clones or add significantly to the hormonal therapy benefits. We continue to need to understand why patients fail definitive local therapy (as ~30% of the men in this trial did) and to develop better treatment paradigms for these patients.

Reference

1.Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36(11):1080-1087. ascopubs.org/doi/full/10.12...

BACKGROUND

Docetaxel combined with androgen deprivation therapy (ADT) has improved patient survival for advanced prostate cancer (PCa).

OBJECTIVE

This randomised trial aimed to evaluate whether six courses of docetaxel improved biochemical disease-free survival (BDFS) after radical radiotherapy (RT) for intermediate- or high-risk PCa patients.

DESIGN, SETTING, AND PARTICIPANTS

A total of 376 patients were randomised in this multinational phase III study, and received either six cycles of adjuvant docetaxel 75 mg/m2 every 3 wk without continuous prednisone (arm A, n = 188) or surveillance (arm B, n = 188) after RT (NTC006653848). Neoadjuvant/adjuvant ADT was mandatory for all the patients. The primary endpoint was rising prostate-specific antigen (PSA) ≥2 ng/ml above the nadir PSA value. Intermediate- or high-risk PCa was defined as T2 with a Gleason score (GS) of 4 + 3, PSA > 10; T2, GS 8-10, ≤ 70 ng/ml; or any T3. The patients were followed for 5 yr by assessing PSA levels every 3 mo for 2 yr and every 6 mo thereafter.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

The study power was 89% to detect a difference in BDFS between groups, and the sample size calculation accounted for the T2/T3 distribution, where a 12%/15% difference in BDFS was assumed for the T2/T3 patients.

RESULTS AND LIMITATIONS

All six cycles were completed in 147 (78%) of the patients in arm A. The median age was 67 yr in both treatment groups, 75% had T3 disease, and 47% had GS 8-10. The median follow-up was 59 mo (range 1-111 mo). The primary endpoint was observed for 58 patients in arm A (docetaxel) and for 57 patients in arm B (surveillance). The Kaplan-Meier analysis showed no difference in the BDFS curves (p = 0.6) between the treatment groups. The 5-yr estimated biochemical progression rates were 31% for arm A and 28% for arm B. Febrile neutropenia occurred in 16% of the docetaxel patients. No deaths were related to the docetaxel treatment. There were 43 deaths during the trial, including 20 in arm A and 23 in arm B, of which nine and seven, respectively, were due to PCa. The hazard ratio from Cox multivariate analysis for PSA progression of arm A (docetaxel) versus arm B (surveillance) was 1.14 (95% confidence interval 0.79-1.64, p = 0.5).

CONCLUSIONS

Adjuvant docetaxel without prednisone did not improve BDFS after radical RT with ADT for intermediate- or high-risk PCa.

PATIENT SUMMARY

We compared six cycles of adjuvant docetaxel given after radical external radiotherapy plus androgen deprivation therapy to surveillance in intermediate- and high-risk localised prostate cancer. We found no overall benefit in this setting.

European Association of Urology

Docetaxel Versus Surveillance After Radical Radiotherapy for Intermediate- or High-Risk Prostate Cancer-Results From the Prospective, Randomised, Open-Label Phase III SPCG-13 Trial

Eur Urol 2019 Aug 20;[EPub Ahead of Print], PL Kellokumpu-Lehtinen, M Hjälm-Eriksson, C Thellenberg-Karlsson, L Åström, L Franzen, AS Fransson, MJ Leskinent, M Zeke, T Huttunen, C Ginman

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

[pjoshea13]

"Discussion

"This is the first published randomised trial of an adjuvant docetaxel treatment after radical RT compared with surveillance in PCa patients. Our result does not support the use of docetaxel after radical RT for intermediate- or high-risk PCa. This study used neoadjuvant/adjuvant ADT combined with RT, and still no beneficial effect of docetaxel in BDFS was observed. A recent publication of RTOG 0521 showed a significant overall survival gain with docetaxel [20]. In addition, improved disease-free survival and reduction in the rate of distant metastasis were observed. The study included more advanced patients, for example, locally advanced T4 tumours and with PSA values up to 150 versus 70 in our study. Among the patients in that study, 53% had GS 9–10 and 31% GS 8 (altogether 84% GS 8– 10), while only 47% of our patients had GS 8–10. Thus, RTOG 0521 patients had more advanced disease (Table 5). However, in our study, the interaction between treatment group and Gleason class was almost significant (p = 0.059), and the patients in the high-risk group (GS 9–10) had a tendency towards achieving a benefit (HR 0.67, 95% CI 0.34– 1.30, p = 0.2) from adjuvant docetaxel. RTOG 0521 used also prednisone with docetaxel. We did not use prednisone either in SPCG-12 or in SPCG-13 trial in order to avoid the known side effects of prednisone. The practice to use it with docetaxel comes from the trials of advanced PCa, where cortisone is also used to palliate symptoms. Thus, it was combined with mitoxantrone, which was compared with docetaxel in the early trials of mCRPC, such as in TAX 327. In addition, our treatment protocol with docetaxel and ADT was different from the sequential treatment protocols, which are used in adjuvant studies on breast cancer [13,14], where docetaxel was given before hormonal treatment.

In several studies, combining ADT with RT has been beneficial, and included in RT guidelines of high- and intermediate-risk PCa [4,21]. We chose the duration of the LH-RH analogue to be shorter than 3 yr to avoid permanent castration in these elderly men, and still their BDFS and overall survival were very good. Moreover, in the recently published phase III PCa trial, the shorter duration of ADT was used after RT [21]. However, long-duration ADT with RT remains the standard of care.

In an adjuvant study after RT in high-risk PCa patients with long follow-up and survival as an endpoint (RTOG 9902), no difference was seen in biochemical failure, distant metastasis-free survival, or overall survival after a median follow-up of 9.4yr [22]. This study used a probably less effective nontaxane triple chemotherapy in combination with ADT after RT. In addition, RTOG 9902 was closed early due to the toxicity of chemotherapy and slow patient accrual. In the GETUG-12 trial, docetaxel and estramustine phosphate, in combination with ADT, were compared with ADT alone after a curative treatment for high-risk disease and most of them after RT [23]. A significant difference in time to biochemical recurrence was found in favour of the combination therapy. The primary treatment was RT in combination with ADT, and ADT was given for 3 yr, and the progression was defined by PSA > 2.0 ng/ml above nadir as in our study. The difference in the outcome in the GETUG-12 study was seen in patients with a GS of 7, while no effect was seen in the GS = 8 or higher patients. In both RTOG 9902 and GETUG-12 studies, the primary endpoint was biochemical progression, and no conclusion was drawn about metastasis-free or cancer-specific survival [22,23]. Updated results of GETUG-12 were presented in ESMO 2018 [24]. According to these results, four cycles of docetaxel-based chemotherapy reduced the risk of clinical relapse or death in the long-term follow-up (12 yr). In the recently published STAMPEDE trial, there was no survival benefit from docetaxel combined with ADT compared with ADT alone for patients with locally advanced disease without proven metastasis at randomisation, but a positive effect on PSA was observed [11]. Both RTOG trials also had much more aggressive tumours (see Table 5, GS distribu- tion) than in our study explaining partly the difference in the outcome. Tosco et al [25] recently published a systematic review of therapeutic combinations with local treatments for high-risk localised PCa. They identified altogether 77 prospective trials. Many of these trials showed a benefit of combining ADT with external beam radiothera- py (EBRT) compared with EBRT alone; docetaxel showed to increase relapse-free survival with EBRT plus ADT in GETUG-12, RTOG 0521, and the nonmetastatic group in STAMPEDE; and according to the recent results of RTOG 0521, improved overall survival was observed. However, all these trials, similar to ours, should have longer follow-up time.

In a recent meta-analysis of the results from clinical trials on the use of docetaxel plus ADT in hormone-naive nonmetastatic locally advanced PCa, the gain in failure- free survival was highly significant (8%) [26]. However, the reduction in survival was 4%, which was not significant. In the SPCG-12 radical prostatectomy trial, no ADT and no daily prednisone were used, and likewise, as in our study, there was no benefit of six cycles of docetaxel. Similar findings were observed in the TAX 3501 radical prostatec- tomy study for the arm with the sequential docetaxel and hormonal treatment, but the number of patients and events was very low [27]. Thus, it seems that the beneficial effect of docetaxel in early PCa is not dependent on the docetaxel- ADT interaction. New therapeutic approaches and molecu- lar profiling as in TAILORx trial [15] should be studied, especially in the neoadjuvant situation before prostatec- tomy [28], allowing response evaluation more quickly. The toxicity profile of docetaxel was in line with the previous publications [11–14,16], and no toxic deaths occurred. Of the patients, 78% received all six cycles of docetaxel. However, more efforts should be made to avoid toxicity in this elderly patient population.

The limitations of our study include having a heteroge- neous risk profile in our study population, and that the primary endpoint is BDFS and not survival. However, the inclusion criteria were designed based on a 50% risk of relapse by nomograms. The trial might have been under- powered to detect subgroup differences. There were far fewer relapses than expected, lowering the planned statistical power of the study, even though most of our patients belonged to the high-risk group, and we will continue the follow-up of our patients.

In the main analysis for biochemical progression, the confidence interval of HR (docetaxel vs surveillance) spreads from 0.79 to 1.64, indicating that there is no clear difference in favour of either treatment arm. The lower limit of 0.79 does not indicate signs of considerable overall benefit of docetaxel over surveillance based on this study."

Kellokumpu-Lehtinen P-L, et al. Docetaxel Versus Surveillance After Radical Radiotherapy for Intermediate- or High-risk Prostate Cancer—Results from the Prospective, Randomised, Open-label Phase III SPCG-13 Trial. Eur Urol (2019), doi.org/10.1016/j.eururo.20...

ncbi.nlm.nih.gov/pubmed/314...

-Patrick

[pakb in reply to pjoshea13]

So this shows no benefit of using Docetaxel after radiation? I'm correct in seeing that the study was on men who had ADT plus Radiation first?

[timotur]

Big thanks for posting this study, I was looking for this pub to evaluate adjuvant chemo. This is a very, very significant result showing no benefit for T2-T3 patients. And very distinctly differentiates the results of RTOG 0521 showing benefit for patients with more advanced disease. Good info for discussion with my MO who was suggesting 4 rounds of taxotere for Gl-7 3tbN1M0 . This study says no.

[dadzone43]

First paragraph says improved survival; second paragraph says did not improve survival. The "take home message" is contradictory.

[Dd7757 in reply to dadzone43]

I think the second paragraph left out the word “ significantly” since there was only a 3 percent differential.

[dadzone43]

Thank you. I would not expect 3% to be significant with such a small number of participants.