Survival benefit of dose escalation for higher risk patients

As discussed in a previous article, there is a seeming discrepancy between the findings of Kalbasi et al. and RTOG 0126, at least for intermediate-risk patients. Kalbasi et al. found that higher dose radiation is associated with higher overall survival rates for intermediate and high-risk patients (but not low-risk patients), while RTOG 0126 found no such association. Kalbasi et al. was a retrospective database analysis, while RTOG 0126 was a randomized clinical trial. Which is right?

I’ve had a chance to review the full text of the Kalbasi et al. study, but the RTOG 0126 trial has not yet been published. This article provides some additional observations based on what is currently available.

One shortcoming common to both is that they were attempting to find differences in overall survival after just 10 years. Because prostate cancer is often detected very early, has a long natural history, and there are many medicines now that extend survival, 10 years may not be enough to observe a difference. They also both used overall survival rather than cause-specific survival as endpoints, so we don’t know how many of the deaths were incidental to rather than because of prostate cancer. The database analysis did not include data on prostate cancer–related deaths, while in RTOG 0126, the prostate cancer-specific mortality was only 3%. RTOG 0126 did find differences in biochemical failure, distant metastases, and local progression related to higher doses of radiation. It is likely that differences in survival may emerge with longer follow up.

RTOG 0126 excluded the least favorable intermediate risk patients from their study. Those with Gleason score of 7 and stage T2c, and those with a PSA of 15-20 were excluded, and may be the group most likely to benefit from dose escalation.

Kalbasi et al. point out that RTOG 0126 may have been underpowered to detect the dose response. They also conjecture that the highly selected clinical trial patient sample of RTOG 0126 may not reflect the wider patient population – over 300,000 patients - in their data analysis. On the other hand, the retrospective nature of their study allows for confounding. Those patients who received lower doses of radiation may be the ones who had serious co-morbidities that precluded a higher dose. We can never establish a cause/effect relationship based on a retrospective study.

As often happens with long-term radiation studies, the findings become irrelevant by the time we get them. The finding that low-risk patients don’t need the higher dose is becoming increasingly irrelevant as those patients are more safely managed with active surveillance. The finding that intermediate risk (at least unfavorable intermediate risk) and high-risk patients do better with higher doses is irrelevant because IMRT doses of at least 80 Gy have become the standard of care already.

Kalbasi et al. suggest that even higher doses of radiation may improve survival. The problem with their suggestion is a limitation of IMRT – doses beyond 80 Gy become increasingly toxic. The solution is not to push the envelope on IMRT, but to use other methods. In a recent article, we saw that the combination of low dose rate brachytherapy and external beam radiation was able to push the effective radiation dose higher than IMRT alone, and resulted in increased oncological control. Toxicity, however, was higher than with monotherapy. As discussed there, adding a high dose rate brachytherapy boost has proven to be an equally effective technique for escalating dose. While SBRT has been used to increase the effective dose in intermediate-risk patients, and does so with extremely low toxicity, it has not yet been widely used in high-risk patients. In a recent article, we discussed the clinical trials that may prove to be a game changer in the management of such patients.

The multi-factorial nature of SBRT safety

In a previous article, we looked at the experimental use of extreme hypofractionated radiation therapy, SBRT or SABR, to treat high-risk patients. Here, we take a closer look at an early safety study by Bauman et al. that shows why radiation safety is more complicated than just setting the treatment dose.

Bauman et al. treated 15 high-risk men who were either frail and elderly, or who refused a long course of IMRT. They were all given 12 months of ADT beginning 2 months before SBRT.

After 6 months of follow up, the following rates of genitourinary (GU) and gastrointestinal (GI) toxicity were observed:

• ·      Acute GU toxicity: Grade 2: 27%, none higher
• ·      Acute GI toxicity: no Grade 2 or higher
• ·      Late-term GU toxicity: Grade 2: 33%, Grade 3: 7%
• ·      Late-term GI toxicity: Grade 2: 27%, Grade 3: 20%, Grade 4: 7%
• ·      Toxicity was not correlated with patient frailty

All of the toxicities were higher than expected, and the high rates of high-grade late-term GI toxicity were particularly troubling. As a result, the treatment plans have been altered. They eliminated the dose to the pelvic lymph nodes entirely, extended the ADT treatment to 18 months, and reduced the dose to the prostate to 35 Gy across 5 treatments, with only one treatment per week. This is similar to the plan that Dr.Katz has been using for his high risk patients with 6 years of reported follow up with very low rates of toxicity (see Katz and Kang 2014).

Dr. King has been using the same prostate dose that Dr. Bauman used -- 40 Gy across 5 treatments (NCT02296229). Dr. King has used this dose for all his patients (not just high-risk ones) since 2008 with low rates of toxicity, and he is now treating pelvic lymph nodes on select high-risk patients with 25 Gy. Both King and Bauman use an arc radiation therapy machine, although the brands they use differ – Varian and Elekta, respectively. So what accounts for the very different toxicity outcomes they are getting? Let’s look a little closer.

The following table highlights key dosimetric differences between King and Bauman’s high-risk SBRT protocols.

	Bauman	King
Prescribed dose to prostate	40 Gy (8 Gy x 5)	40 Gy (8 Gy x 5)
Margin treated	5 mm all around	5 mm, except 4 mm posterior
Prescribed dose to SV	40 Gy (8 Gy x 5) in first cm of SV	25 Gy (5 Gy x 5) to entire SV
Margin treated	5 mm	No margin
Pelvic lymph nodes	25 Gy (5 Gy x 5)	25 Gy (5 Gy  x 5)
Margin treated	5 mm	none
Bladder dose constraints:	≤50% receives >29 Gy ≤30% receives >35 Gy	<10 cc receives >25 Gy Max. point dose= 40 Gy
Rectal dose constraints:	≤50% receives >27 Gy ≤20% receives >35 Gy	<5 cc receives >25 Gy Max. point dose= 42 Gy (additional specific constraints for each side of the rectal wall)
Small bowel dose constraints:	<2 cc receives >27.5 Gy <190 cc receives >25 Gy	<10 cc receives >20 Gy Max. point dose= 25 Gy
Imaging for planning	CT	CT/MRI fused images
Inter-fractional motion tracking	Cone beam CT	Cone beam CT with fiducials
Intra-fractional motion tracking	none	Stereoscopic X-rays. Fiducials were realigned every half-arc, approximately 40 seconds.

In comparing the treatment parameters of the two plans, we begin to see why the original Bauman plan would have greater toxicity in spite of the fact that the prescribed dose to the prostate was the same. Perhaps the single biggest drawback to the Bauman plan was the lack of tracking of intra-fractional motion. The prostate can move quite a bit during the treatment. With the low doses of IMRT (1.8-2.0 Gy each) it would not matter so much, but with the higher SBRT doses (8 Gy each), significant amounts of radiation may inadvertently hit the bladder and rectum if the motion is not controlled for.

The other advantages of the King plan include:

• ·      Smaller margins where the prostate abuts the rectum
• ·      No margins around the pelvic lymph nodes that could impact the small bowel
• ·      No margins around the seminal vesicles that might hit the bladder neck
• ·      Tighter bladder and rectal dose constraints
• ·      MRI for more precise planning
• ·      Fiducials for more precise image alignment
• ·      Alignment is frequent and automatic. It’s not dependent on human intervention.
• ·      Optional selection of patients suitable for nodal radiation (e.g., no anatomic abnormalities, presence of visceral fat, high risk of nodal involvement)
• ·      Only 9 months of optional ADT are used

Dr. King has so far treated 19 high-risk patients on his protocol, 10 with nodal radiation. So far there have been no Grade 3 or higher toxicities of any kind. King uses Varian’s Truebeam with RapidArc and realigns four times during each fraction. The total treatment time is about 5-10 minutes each, with hundreds of beams emitted during each 40 second arc. Accuray’s CyberKnife, the most prevalent platform for SBRT, realigns the beams with the fiducials every few beams, and there are hundreds of beams. That extends the treatment time to about an hour each. While many different brands of linear accelerator platforms and image-guidance systems can be used for SBRT, it is vital that continual motion tracking or prostate stabilization (e.g., using a rectal balloon) be incorporated.

Other clinicians have sought the optimal SBRT treatment dose while all the other treatment parameters are held constant. Katz et al. (2011) tried two different doses, 36.5 Gy and 35 Gy, and found the lower dose had similar oncological results. While urinary toxicity was lower for the lower dose in a matched pairs analysis, the difference was not statistically significant. In contrast to Katz,  Bernetich et al.  found that there was a better oncological response to higher doses (37.5 Gy) for higher risk patients, but they also observed an increase in persistent GU toxicity, while GI toxicity remained low and unaffected by dose.  In a study that I consider to be of questionable ethics, Kim et al. experimented with SBRT doses as high as 50 Gy to find the SBRT dose limit for rectal tolerance, and not unexpectedly, found very high amounts of rectal toxicity associated with it. Currently, Dr. Zelefsky is the lead investigator on clinical trial at Memorial Sloan Kettering Cancer Center where he is raising the dose incrementally in successive cohorts of low and intermediate risk patients after insuring the safety of each lower dose. He has so far raised the SBRT treatment dose as high as 45 Gy. Clearly, there are many factors that affect SBRT toxicity, and there are still many details to be learned about SBRT dosimetry.

 note: Thanks to Dr. King for supplying the details of his protocol for high-risk patients and his update so far.

Radiation therapy may improve survival even when PSA≥75 ng/ml

Sometimes when patients originally present with very high PSA levels, a negative bone scan, and CT, they are put on permanent hormone therapy because the doctor just assumes it is micrometastatic. A closer look at the data demonstrates that an attempt at curative radiation may improve outcomes.

Lawrence et al. screened the 2004-2008 SEER database, and found 75,539 patients diagnosed with non-metastatic prostate cancer, and excluded those treated with surgery or brachytherapy. The patients had a median age of 70 years. Their findings based on a median of 60 months of follow up were:

• ·      Use of RT was associated with a reduction in prostate cancer mortality of 59%.
• ·      4-yr prostate cancer survival was 94% in those who had RT vs. 77% in matched patients who had no local therapy.
• ·      The benefit held even for those with PSA≥75 ng/ml

Three important caveats:

(1) This is a retrospective study and is subject to selection bias. This means that those who received no local therapy may have done so for reasons not readily apparent in the available records. Although the authors made an attempt to account for age, grade, PSA level, stage and perhaps other variables, there may have been signs of greater progression that the doctor was aware of.

(2) The PSA values recorded in the SEER database have recently been called into question. Interested readers may read more about it here. In fact, the National Cancer Institute has withdrawn PSA data from the current files. This analysis was evidently performed before that withdrawal on April 29, 2015. This does not affect the survival data.

(3)  A median of 60 months of follow up is not long enough to determine whether survival benefits are sustained in the long run. Neither the radiation-treated cohort nor the non-treated cohort reached median survival during the time period of observation so far available.

Given those caveats, we can only conclude that there may be something to this, but that can only be determined by a clinical trial where patients with extremely high PSA levels are randomized to radiation therapy or hormone therapy only, and they are tracked for ten years or more. The study does suggest that PSA alone is not a good risk factor on which to base the decision about whether to pursue curative therapy.

Docetaxel with primary radiation therapy for high-risk prostate cancer

(Updated)

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.

(update 7/28/2022) STAMPEDE reported results of the use of docetaxel in 230 newly diagnosed high-risk men compared to 460 who only received standard-of-care (SOC). SOC  consisted of ADT ± prostate radiation. "High-risk" also included men with pelvic lymph node metastases (in about half the men) but no distant metastases. After 6.5 years of follow-up:

• 5-yr metastasis-free survival was 82% with docetaxel vs 77% without docetaxel -> no significant difference
• no evidence of prostate cancer survival benefit
• no evidence of overall survival benefit
• it did lower PSA

Several trials looked at combining docetaxel with radiation among men diagnosed with high-risk localized prostate cancer. RTOG 0521 showed that the 10-year overall survival was 64% without docetaxel and 69% with it -- a statistically insignificant difference. There was insignificant improvement in disease-free survival, and incidence of metastases at 10 years.

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 12/4/2018) Fizazi 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

There is a ten-year update of RTOG 9902, a clinical trial begun in 2000 and closed to accrual in 2004 because of excess toxicity. Although the study ended before it met its accrual goal, patients continued to be tracked. The study protocol included:

• 380 high-risk patients were randomized to two arms
• High Risk = Gleason score≥7 and PSA from 20 to 100 ng/ml or 
• Gleason score≥8 and stage≥T2 
• Two arms: 
• Chemo + ADT + RT 
• ADT + RT 
• Chemo= Paclitaxel + Estramustine + Etoposide
• ADT= LHRH agonist (24 months) + anti-androgen (4 months), both begun 2 months before RT
• RT= 70 Gy to prostate only

The ten-year results were as follows:

• Overall survival: 63% with chemo, 65% without chemo (no sig. difference)
• Local progression: 7% with chemo, 11% without chemo (no sig. difference)
• Distant metastases: 14% with chemo, 16% without chemo (no sig. difference)
• Disease-free survival: 26% with chemo, 22% without chemo (no sig. difference)

This trial was begun before docetaxel became available. Docetaxel is far more effective and far less toxic than the chemo used in this study. They also used a radiation dose of only 70 Gy, and did not include the pelvic lymph nodes, which we now know to be inadequate for high-risk patients.

Taken together, all of these trials tell the same story - docetaxel provides no benefit before there are distant metastases.

Androgen deprivation therapy (ADT) and escalated dose in radiation therapy (RT)

Several recent studies shed light on the optimal use of androgen deprivation therapy (ADT) used in conjunction with radiation therapy (RT), including new learning about timing of ADT, RT dose, and their use in various risk categories.

When external beam radiation doses of around 70 Gy were used in the 1990s, it was shown that androgen deprivation therapy (ADT) used with it could improve oncological outcomes. However, it was not at all clear that ADT provided any additional benefit when higher doses radiation of about 80 Gy were used. DART 01/05 (Zapatero et al.) was a randomized clinical trial to determine the optimal duration of ADT supplementation.

DART 01/05 was a multi-institutional Spanish trial among intermediate and high risk men receiving primary treatment with 3D conformal radiation therapy (3DCRT) between 2005 and 2010. The patients were randomized to receive either 4 months (short term) or 28 months (long term) of ADT.

• Everyone received 2 months of ADT before and 2 months during their 3DCRT
•  Everyone received goserelin, an LHRH agonist, throughout, and also received 2 months of anti-androgen therapy (bicalutamide or flutamide) at the beginning.
•  173 patients received short-term ADT, 171 patients received long-term ADT

o   90 were high risk on long-term ADT

o   91 were high risk on short-term ADT

o   83 were intermediate risk on long-term ADT

o   78 were intermediate risk on short-term ADT

• Everyone received a median radiation dose of 78 Gy.

The 5-year outcomes were as follows:

• Biochemical disease-free survival was significantly better with long-term compared to short-term ADT: 90% vs. 81%

o   The difference was only significant among high risk patients: 88% vs. 76%.

•  Metastasis-free survival was significantly better with long-term compared to short-term ADT: 94% vs. 83%.

o   The difference was only significant among high risk patients: 94% vs. 79%.

• Overall survival was significantly better with long-term compared to short-term ADT: 95% vs. 86%.

o   The difference was only significant among high risk patients: 96% vs. 82%.

o   There were 5 deaths due to prostate cancer, all among men on short-term ADT.

• There were no significant differences in acute or late term rectal or urinary toxicities.

The authors conclude:

“Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation.”

For high risk patients, at least, this establishes that dose-escalated RT with long-term ADT is preferable to short term. It leaves several open questions about optimum radiation treatment for this group:

• What is the optimal duration of ADT? We know from an earlier randomized clinical trial (Nabid et al.) that 18 months of adjuvant ADT is as good as 36 months, even with lower dose RT. So the optimal duration is somewhere between 6 months and 18 months.
•  Is IMRT with a brachytherapy boost preferable, and is that enhanced by ADT? (See this link)
•  Is SBRT monotherapy preferable, with or without adjuvant ADT? (This was discussed in a recent article.)
• What is the effect on erectile function?
• Should the pelvic lymph nodes be treated as well? This is the subject of an ongoing clinical trial.

Another randomized clinical trial presented at the Genitourinary (GU) Conference found more support for the addition of ADT to RT for intermediate risk patients. While DART 01/05 looked at long-term vs, short-term ADT with RT and found no difference for the intermediate risk subset, Nabid et al. looked at short-term vs. no additional ADT with RT for intermediate risk patients. They also examined the effect of radiation dose.

Their study consisted of 600 intermediate risk men treated with external beam radiation at several hospitals in Quebec between 2000 and 2010. The 3 arms of their study were treated under the following protocols:

1.    Arm 1: 6 months of ADT + 70 Gy of RT
2. Arm 2: 6 months of ADT + 76 Gy of RT
3. Arm 3: 76 Gy of RT

Those who received ADT were treated with 6 months of both goserelin and Casodex (bicalutamide) beginning 4 months before their RT began. After a median follow up of 76 months, the researchers found that:

• Biochemical failure was significantly higher in Arm 3, but not statistically different between arms 1 and 2.

o   Arm 1: 12.5%

o   Arm 2:   8.0%

o   Arm 3: 21.5%

• 10-year disease-free survival was significantly lower in arm3, but not statistically different between arms 1 and 2.

     

o   Arm 1: 77%

o   Arm 2: 90%

o   Arm 3: 64.5%

• 10-year overall survival was not statistically different between any of the arms.

o   Arm 1: 64%

o   Arm 2: 70%

o   Arm 3: 78% 

• There were only 6 deaths (1%) attributable to prostate cancer, not enough to discern a difference among treatment arms.

The authors conclude:

“In patients with intermediate risk prostate cancer, the use of short term ADT in association with RT, even at lower doses, leads to a superior biochemical control and DFS as compared to dose-escalated RT alone. These outcomes did not translate into an improved overall survival.”

I hope the authors will attempt a sub-group analysis to determine if there were significant differences when favorable vs. unfavorable intermediate risk (see below) is taken into account. It will also be interesting to look at the side effect profile in the 3 arms.

A randomized clinical trial (RTOG 0126) of low dose (70 Gy) vs. high dose (79 Gy) radiation in intermediate risk patients, but without ADT, found improvements in the risk of biochemical failure, distant metastases, and time to local progression in those treated with the higher dose. However, they found no improvement in overall survival with 10 years of observation. Those treated with the higher dose did experience higher rates of urinary and rectal toxicity, however.

One must consider whether the higher rates of urinary and rectal toxicities are still applicable with modern IGRT/IMRT techniques. The men in the above studies were treated with 3DCRT – an older, less precise radiotherapy. As often occurs with long-term clinical trials of radiation therapies, the results may become irrelevant by the time they are reported because of technological advances.

I think 10 years is too short a follow-up period to detect significant differences in survival among intermediate risk men, and especially among favorable intermediate risk men. It also begs the question of whether those men require immediate treatment at all. Some of the sub-groups, including some who are older with co-morbidities, some with favorable PSA kinetics, low volume of cancer, and some with Gleason score≤ 3+4, may be better off with expectant management.

In contrast to the lack of survival benefit to the escalated dose found in RTOG 0126, a retrospective analysis reported at the GU Conference by Kalbasi et al. looked at 12,848 low risk patients, 14,966 intermediate risk patients, and 14,587 high risk patients After a median 73 months of follow up, they found a significant dose response for both the intermediate risk and the high risk patients, but not the low risk patients. For every 2 Gy increase in dose, there was a reduction in the hazard of death of 9% and 7% among the intermediate and high risk patients, respectively.

Perhaps sub-group analysis will explain the difference in the dose response between the two studies. I will report on both further when more detailed findings become available.

I don’t think it will come as any surprise that radiation added to androgen deprivation has better oncological outcomes than androgen deprivation alone. In a randomized clinical trial among 1,205 locally advanced prostate cancer patients treated between 1995 and 2005 with ADT and with or without low dose (64-69 Gy) RT, Mason et al., with median 8 years of follow-up, found that the addition of RT reduced prostate cancer mortality by about half.

Favorable vs. Unfavorable Intermediate Risk

In an earlier article, we noted that Dr. D’Amico raised a caution that the results may look very different if the intermediate risk men were divided into favorable and unfavorable groups. It may be that with further follow-up time, significant differences will appear among the intermediate risk men, and particularly among those with unfavorable features. In a retrospective study by Castle et al. where intermediate risk men were divided into favorable or unfavorable intermediate risk, favorable risk patients had no discernable benefit from the addition of ADT. Unfavorable intermediate risk patients had significantly higher 5-yr freedom from failure if they also received ADT, 74% vs. 94%, respectively. Similarly, Edelman et al. found that ADT combined beneficially with RT only in intermediate risk patients with GS 4+3, more than 50% positive cores, or multiple intermediate risk factors.

Another retrospective study by Keane et al. confirming that finding was presented at the recent Genitourinary Conference. They analyzed the oncological outcomes of 2,668 intermediate risk men (71% favorable, 29% unfavorable) treated between 1997 and 2013 with dose-escalated RT and with and without adjuvant ADT (median 4 months). After a median follow-up of 7.8 years, they found that there was a significant amelioration of the risk of prostate cancer-specific mortality among the unfavorable risk patients who also received ADT, but adding ADT did not make a difference to prostate cancer-specific mortality in those men categorized as favorable intermediate risk.

ADT Sequencing

The conventional wisdom is that neo-adjuvant ADT (ADT started at least two months before the start of radiation) and ADT given concurrently with RT have a different functional benefit from adjuvant ADT (ADT given after the completion of RT). Neoadjuvant and concurrent ADT is thought to radiosensitize the cancer to the radiation treatment, while the adjuvant ADT is thought to function as “clean-up,” killing off small amounts of hormone-sensitive stray cancer cells that may already be systemic. A new study by Weller et al. is calling that model into question.

They analyzed the records of intermediate and high risk patients treated from 1995 to 2002 who had either neoadjuvant and concurrent ADT with their dose-escalated RT (311 patients) or only adjuvant ADT immediately after their dose-escalated RT (204 patients). Ten-year biochemical recurrence-free survival was 61%, distant metastasis-free survival was 80%, and overall survival was 66%. There were no significant differences in any of those measures based on the sequencing of ADT.

The authors conclude:

“the synergy between RT and androgen deprivation is independent of the sequencing of both modalities and the initiation of RT does not need to be delayed for a course of neoadjuvant ADT.”

I think these findings have to be confirmed by a randomized clinical trial. It raises interesting questions about the way ADT and radiation interact to kill cancer cells, perhaps supporting the hypothesis that ADT sustains the immune response to the radiation-induced increase in cancer antigens. If the abscopal effect turns out to be of major importance in the ADT/radiation killing of cancer cells, various immunotherapies, like Provenge, Prostvac, Yervoy, and Keytruda, may improve the oncological benefits still further.

SBRT for High Risk Prostate Cancer

Treatments for high risk prostate cancer are limited. Surgery is usually considered a poor option if the cancer has already escaped the prostate capsule (stage T3/4). External beam radiation is often given with hormone therapy for high grade cancers, or with a brachytherapy boost. Because of the radiological similarity between stereotactic body radiation therapy (SBRT) and high dose rate (HDR) brachytherapy, several radiation oncologists have wondered whether it can be used in a similar way.

Starting in 1996, HDR brachytherapy was used as a monotherapy for favorable risk prostate cancer. The early results were impressive. In 2003, Dr. Christopher King at Stanford first used SBRT (on a CyberKnife machine) to mimic HDR brachytherapy monotherapy in its use for prostate cancer. With brachytherapy, the X-rays travel from the inside out; with SBRT, they travel from the outside in. Dose per treatment and doses to the prostate and nearby organs at risk are very similar. Out of prudence, its use was initially restricted to favorable risk patients. Unsurprisingly, reported oncological and toxicological outcomes have been nearly identical between the two treatments.

For high risk patients, HDR brachytherapy has, since its early days, been used as a way of boosting the dose to the prostate while IMRT has been used to widen the treatment area. While there have been no randomized comparisons between IMRT monotherapy and IMRT with an HDR brachytherapy boost, Deutsch et al. at Memorial Sloan Kettering Cancer Center reported significantly better results in men treated with the brachytherapy boost than in men treated with IMRT alone, even at doses as high as 86 Gy. After five years of follow up, 93% of the high risk patients treated with the HDR brachytherapy boost were free of biochemical progression compared to 71% of the high risk patients treated with 86 Gy of IMRT alone.

It is tempting to look at the superior results reported for HDR brachytherapy boost therapy for high risk patients and wonder if that can be duplicated with SBRT alone. After all, SBRT can treat a wide margin around the prostate just as IMRT can, and it can be used at the same time to give a higher dose to the prostate itself. All of this could be done in five treatments instead of five weeks of IMRT, and without the anesthesia or hospital stay required for HDR brachytherapy. While SBRT promises increased convenience and lower cost, is it as effective and as low in toxicity?

The major differences between SBRT for high risk compared to favorable risk patients involve controversies about treatment margins, dose, use of androgen deprivation therapy (ADT) with it, and treatment of pelvic lymph nodes. Clinical trials have already started to explore these issues, and there is an SBRT registry that may provide some guidance eventually.

SBRT, as discussed in this article, is given with extreme hypofractionation only  – typically 6 Gy to 8 Gy per treatment in each of 5 treatments. There are several trials of more moderate hypofractionation, usually with 2.5 Gy per treatment.

There have been several pilot tests of IMRT with an SBRT boost to the prostate in high risk patients. Lin et al. reported on 41 patients. The 4-yr biochemical failure-free survival was 92%, with a mean PSA nadir of 0.05 ng/ml. Two of the 3 failures were distant metastases. No one suffered any Grade 3 or higher acute toxicity, and no one suffered any Grade 2 or higher late toxicity. Anwar et al. reported on 43 patients. The 5-yr biochemical control was 82%, with a mean PSA nadir of 0.1 ng/ml. None of the 4 failures were local.

Katz and Kang have published the largest and longest follow-up trial of SBRT for high risk patients, with 97 patients and 6 years of follow up. Of those, 45 were treated with an SBRT boost following whole pelvic IMRT radiation, and 52 were treated with SBRT monotherapy. The 6-yr biochemical disease-free survival was 69%. This did not differ significantly whether they received the SBRT boost or monotherapy. It also did not differ significantly whether they received adjuvant ADT. Several different doses were used, but none had significantly better performance. Higher stage and grade cancers were cured equally well. Only patients with high initial PSA, perhaps indicative of metastases, fared worse than patients with lower initial PSA. Late Grade 2 rectal toxicity was higher for the combo IMRT+SBRT treatment. Late urinary and rectal toxicity were low, and transient, with none after two years.  This was reflected in patient-reported quality-of-life scores, which declined immediately after treatment but returned to baseline in less than a year.

In a pooled consortium of 8 institutions and 1100 SBRT-treated patients, only 121 were high risk patients, and 97 of those were from Dr. Katz’s practice, and 16 were from Dr. Bolzicco’s practice (below). The 5-year biochemical recurrence-free survival for the high risk patients was 81%, so the 24 patients outside of Dr. Katz’s practice fared quite a bit better, but this simply reflects the more recent entries, mostly from Dr. Bolzicco’s practice. A recent study by Bernetich et al. included a small group of 18 high risk patients. Their 5-yr freedom from biochemical failure was 87%.  Bolzicco et al. treated 16 high risk patients as part of their SBRT clinical trial. After 3 years, only one (6%) had biochemically failed. Another small study by Oliai et al. included 12 high risk patients. Their 3-year freedom from biochemical failure was 77%. Two of the 3 patients who failed treatment had been given a lower radiation dose, and 2 of the 3 were diagnosed with distant metastases.

While the oncological control seems promising, and the toxicity is suitably low, there have not yet been enough high risk patients treated with SBRT to draw reliable conclusions. However, there are several single-institution clinical trials in progress:

·      Clinical Trial Number: NCT02296229

·      Lead Investigator: Dr. Christopher King

·      Institution: Jonsson Comprehensive Cancer Center, University of California Los Angeles

·      5 treatments, every other day

·      40 Gy to prostate, 25 Gy to pelvic lymph nodes (optional), 25 Gy to seminal vesicles (optional)

·      5 mm margin around prostate, 4 mm on rectal side

·      8 months of ADT starting 2 months before treatment (optional)

·      Goal: 5-year biochemical no evidence of disease – 85%

·      Enrollment: 220 patients

·      Study completion: November 2019

·      Status: enrolling patients

·      Clinical Trial Number: NCT01953055

·      Lead Investigator: Dr. Andrew Loblaw

·      Institution: Sunnybrook health Sciences Centre/University of Toronto

·      5 treatments over 4 weeks

·      40 Gy to prostate, 25 Gy to pelvic lymph nodes

·      3 mm margin around prostate, 6 mm margin around pelvic lymph nodes

·      Enrollment: 30 patients

·      Study completion: September 2019

·      Status: 30 patients, fully enrolled

·      Clinical Trial Number: NCT02229734

·      Lead investigator: Dr. Glenn Bauman

·      Institution: London Regional Cancer Program of the Lawson Health Research Institute

·      5 treatments over 5 weeks

·      35 Gy to prostate, no treatment of pelvic lymph nodes

·      18 months of ADT

·      Age > 70, or refusing other treatment

·      Enrollment: 60 patients

·      Study completion: November 2019

·      Status: enrolling patients

·      Clinical Trial Number: NCT01985828

·      Lead Investigator: Dr. Arica Hirsch

·      Institution: Advocate Lutheran General Hospital, Park Ridge, IL

·      50 Gy whole pelvic IMRT over 5 weeks + 21 Gy SBRT boost to the prostate in 3 treatments

·      6 months or 3 years of ADT

·      Enrollment: 72 patients

·      Study completion: December 2024

·      Status: enrolling patients

I encourage patients with a high risk diagnosis to consider enrollment in one of these trials.

Note: SBRT is sometimes known as Stereotactic Ablative Radiotherapy (SABR). SABR has a more euphonious abbreviation, and one suggestive of the sharp-edged precision also reflected in the brand names CyberKnife or GammaKnife. However, some find the knife imagery misleading, and the radiation, while ablative of the tumors within and around the prostate, is not ablative of the prostate itself.