Radiation combined with Hormonal Therapy

According to the NCCN guidelines (go here) it is not necessary to combine radiation with hormone therapy (Lupron or Zoladex) for low risk patients (Gleason 6 and PSA less than 10) but may be considered for 4 to 6 months in the intermediate risk patients (Gleason 7 or PSA between 10 and 20) and definitely be used for 2 to 3 years in the high risk patients (Gleason 8 - 10 or PSA over 20).

In general, combining hormonal therapy with radiation will increase the chance of sterilizing the cancer:

Negative Prostate Biopsy at 24 Months
Treatment Regimen	Negative Biopsy
Radiation Alone (64Gy)	22%
3 mos hormones then XRT	72%
3 mos before, during and 6 mos after	90%

In general most of the studies show better control of the cancer but not overall survival (which may mean that when they relapse they are later given hormones and do just as well.) as in the RTOG 85-31 trial: (but like RTOG 92-02 there was a survival advantage for high Gleason Cancers) but not necessarily for those with lymph node spread (go here.)

T3 or N1, Zoladex concurrent and indefinitely continued. Lawton IJROBP 2001;49:937

the other RTOG trial (86-10) which used Zoladex and Flutamide for 2 months prior to and during radiation also showed better control but no survival benefit:

In the RTOG 9413 trial for high risk patients (high PSA or Gleason so that their calculated risk of node metastases was at least 15%) they found that radiating the lymph nodes is beneficial even if hormones are given, and they found that neoadjuvant (2 mos before and during) are better than post XRT 4 months of hormones. There was no survival advantage (but as noted this was a short course of hormones.) see the 2007 update here

RTOG 9413 High Risk Prostate Trial
Radiation Field	Hormones	DFS at 4 Years
whole pelvis	neoadjuvant	61%
prostate only	neoadjuvant	45%
whole pelvis	after XRT	49%
prostate only	after XRT	47%


They combined the data from RTOG 85-31 and 86-10 (Horwitz IJROBP 2001;49:947) to compare XRT alone (65-70Gy) with short hormones (4 mos) with long-term HORMONES (indefinite) and published as below (the relapse rates were much better with long term hormonal therapy, overall survival was no better but cancer survival was better)


Studies that used longer courses of hormonal therapy (2 years or longer) show a survival advantage, the EORTC trial used 70Gy of radiation and hormones concurrently and for three years in high risk patients (T1-2 tumours of WHO grade 3 or T3-4 N0-1 M0 tumours) (Bolla; Lancet 2002 Jul 13;360(9327):103-6) the results are noted:

Results	Radiation Alone	Radiation + Hormones (3 years)
prostate cure at 5 years	40%	74%
alive at 5 years	62%	78%
alive (from cancer death) at 5 years	79%	94%

also MD Anderson reported a survival advantage in high risk patients (high Gleason score or PSA) or patient with lymph node metastases (Node +) with combined therapy

A final trial randomized surgically staged patients to RT alone (46 patients) or RT and orchiectomy (45 patients). All eligible patients with T1-4N0-3M0 disease participating in this phase III prospective trial from Umeå University in Sweden underwent bilateral staging pelvic lymph node dissections. With a median follow-up of 9.3 years, disease-free survival was 39% in the RT-alone arm compared with 69% in the RT-plus-hormone group. Cause-specific survival was 56% versus 73% for the RT-alone group and RT-and-hormones group, respectively . J Urol 1998;159:2030-2034

Roach recently published long term survival data from the combined RTOG studies (IJROBP 2000;47:609) using the following prognostic groups:
Group I : Gleason 2-6, stage T1-2Nx
Group II: Gleason 2-6 and stage T3Nx; or GS 2-6 and N+; or Gleason 7 and T1-2Nx
Group III: Gleason 7 and T3Nx; or Gleason 7 and N+; or Gleason 8 - 10 and T1-2Nx
Group IV: Gleason 8-10 and T3; or Gleason 8 -10 and N+

A recent analysis of the RTOG hormonal/radiation studies (Roach IJROBP 2000;47:617) using the prognostic groups as described above concluded the following impact on survival:
   Group I : no advantage to hormones
   Group II: short term hormones (2 mos before and 2 mos during XRT) increased survival (83%/8y to 98%/8y)
   Group III: long term hormones increased survival (70%/8y to 88%/8y)
   Group IV: long term hormones increase survival (42%/8y to 69%)


Using hormone therapy may allow for high control rates with lower doses. As noted in the 3D/conformal section, may studies are now suggesting that high doses (>72Gy) are necessary for sterilize prostate cancer. A recent study from the Cleveland Clinic (Kupelian IJROBP 2000;46:567) with 1,041 men compared the results with radiation alone or combined with hormone therapy (median of 6 months) and noted that the impact of dose was less significant if hormones were used as noted below:

Control Rates for Early Stage Prostate Cancer


Combining hormonal therapy with high dose 3-D conformal therapy is being studied, a recent study from Memorial Sloan-Kettering, in a group of men (n = 213) with an average PSA of 15.3, showed that results were better if the PSA was reduced to <0.5 prior to starting radiation (relapse free rate at 5 years was 74% vs. 40%.) They also found that even with hormones and high dose XRT (75.6Gy) cure rates (relapse free at 5 years) were better if the original PSA was low: 93% (< 10), 60% (10-20) and 40% (if original PSA was > 20.) Zelefsky. J Clin Onc 1998;16:3380


A recent trial comparing immediate hormonal therapy versus observation after radical prostatectomy for node (+) prostate cancer patients by Messing noted: After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group. The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group. At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels. Conclusions. Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer. (N Engl J Med 1999;341:1781-8.)


Another recent trial from Harvard (D'Amico, JAMA. 2000;284:1280-1283) compared radiation alone with short course hormonal therapy as noted: The study population comprised 1586 men treated with 3-dimensional conformal external beam RT with or without AST at the Joint Center for Radiation Therapy, Boston, Mass, Radiation therapy was delivered using a 4-field technique and at least 10 mV photons to a total median dose of 70.2 Gy (range, 70.0-72.4) to the prostate gland after 95% normalization. Androgen suppression therapy was given for 6 months (2 months before, during, and after RT) and consisted of the combination of a luteinizing hormone-releasing hormone agonist and a nonsteroidal antiandrogen. Low-risk patients had a PSA of 10 µg/L or less and Gleason score of 6 or less and 1992 tumor category T1c or T2a. Intermediate-risk patients had a PSA of 10.1 to 20 µg/L or a Gleason score of 7 or 1992 AJCC tumor category T2b. High-risk patients had a PSA of more than 20 µg/L or Gleason score of 8 or 1992 AJCC tumor category T2c. The results are as noted:

Cure Rate (bNED) at 5 Years
Group	XRT + Hormonal Therapy	XRT Alone
Low Risk	92%	84%
Intermediate Risk	88%	62%
High Risk	68%	43%

Relapse Free Survival (PSA normal) After Treatment

D'Amico, JAMA. 2000;284:1280-1283

Conclusion and Opinions about Hormonal Therapy combined with Radiation
From the above, it seems clear that short course hormonal therapy (2 months before and continued during radiation) will increase the likelihood of local control. So any patient with a large gland or intermediate risk factors (e.g. Gleason of 7 or PSA > 10) should probably consider at least the short course. Patients with a higher risk of distant spread (PSA > 20, positive nodes or Gleason 8 or higher) probably need prolonged hormonal therapy if they hope to improve not just local control but survival. (For breast cancer it takes 5 years of the hormone blocking drug Tamoxifen to maximize survival.) The RTOG 92-02 trial (ASCO #1284/May, 2000) for high risk prostate cancer patients used short term hormone + radiation in all and then compared no further therapy with 24 months of continued hormones. The high risk groups (Gleason 8-10) who had the prolonged hormonal therapy had much better 5 year survival Perhaps if the hormones had been continued 5 years the results on survival may have been more significant. The DiAmico trial above has poor control rates for the high risk group with a short course ( 6 months) of hormonal therapy (bNED of only 68% at 5 years) which suggest these patients need long term hormonal therapy. Even the intermediate risk group results (88% bNED/5y) are probably not satisfactory and would suggest even this group be considered for a longer course of therapy. Ultimately prostate cancer patients (like breast cancer) may all end up receiving 5 years of androgen-suppression therapy.

Results	Radiation Alone	Rad + Hormones
prostate cure at 8 years	25%	36%
alive at 8 years	47%	49%

Results	Radiation Alone	XRT and Short Hormones	XRT and Long Hormones
prostate cured at 8 years	14%	27%	52%
alive at 8 years	44%	51%	50%

Results (High Risk)	Radiation Alone	Rad + Hormones
prostate cure at 5 years	18%	85%
alive at 5 years	81%	95%

Results (T3 Prostate)	Radiation Alone	Rad + Hormones
prostate cure at 6 years	33%	78%
alive at 6 years	79%	89%

Results	4 months hormones	2 years hormones
Cure at 5 years	54%	79%
Alive (DSS Survival) at 5 years	87%	92%

Results for Gleason 8-10	4 months hormones	2 years hormones
Disease specific survival at 5 years	80%	90%
Overall Survival at 5 Years	69%	78%