Higher dose improves results in high-risk patients

GETUG-AFU-18 is another trial where the findings are obvious, and irrelevant, because radiation and hormone medication technology have improved far beyond what was available when this trial began 15 years ago, and long follow-ups are necessary to detect outcome differences in men with localized prostate cancer. A similar trial (RTOG 0126) in intermediate-risk patients found a curative benefit for the higher dose, although no increase in overall survival within 8 yearsd.

The trial randomized 505 high-risk patients in 25 French centers to receive a radiation dose of either 70 Gy or 80 Gy. 

• All patients received 3 years of ADT. (If started today, it may have been 2 years of ADT (see this link) with external beam radiation.) 
• All patients had no detectable cancer in pelvic lymph nodes (N0), but 83% received whole pelvic radiation.
• High-dose patients received IMRT, but many (41%) lower dose patients received 3D-CRT (which is seldom used anymore).

After 10 years of follow-up, only 92 men progressed, which was less than expected. The results were:

• 84% were progression-free in the 80 Gy arm, 72% in the 70 Gy arm. 
• 44% reduction in the biochemical failure rate
• 52% reduction in prostate cancer-specific mortality
• 39% reduction in overal mortality rate
• No difference in late-term urinary or rectal toxicity. Serious (grade 3) toxicity was rare (2-3%)
• No difference in patient-reported quality of life

It comes as no surprise that higher dose radiation to the prostate is more curative. Since there is no toxicity cost to giving the higher dose, it is the clear standard of care.

Several randomized clinical trials (ASCENDE-RT and TROG RADAR) have now proven that increasing the prostate dose with brachytherapy improves outcomes. Clinical trials using SBRT for high-risk patients are underway, and moderate hypofractionation is already standard of care. The FLAME trial showed results can be improved by targeting MRI-detected intraprostatic lesions with a radiation boost. POP-RT showed the importance of whole-pelvic treatment. The whole-pelvic treatment area was expanded (see this link).

STAMPEDE showed that 3 years of abiraterone+ 2 years of ADT improved results over ADT alone. Hormone treatment has been intensified and shortened in the AASUR trial. The PREDICT-RT trial investigates Decipher genomic scores to determine intensity and duration of hormone treatment with apalutamide. DASL-HiCAP tests darolutamide. 

The FDA approval of PSMA PET/CT for high-risk patients improves patient selection. Those found to have distant metastases might be better treated with hormone therapy alone. Those found to have only pelvic lymph node metastases might still be curatively treated with radiation and hormone therapy.

The importance of radiotherapy dose escalation and long-term ADT for success

 Localized prostate cancer (PCa) is highly curable. We usually divide localized PCa into 3 risk categories: low-risk, intermediate-risk, and high-risk of recurrence after treatment. Even high-risk PCa is highly curable - 80+% of patients are cured in clinical trials of various radiation therapy regimes (see this link, for example). With new PET scans recently approved for high-risk patients, patients who truly have localized PCa have every hope of achieving even better cure rates.

This begs the question: what do we mean by "cured." What most patients mean is that no recurrence will ever be detected. The first sign of recurrence is a rising PSA more than 2.0 ng/ml over the lowest PSA achieved (nadir). This is called a "biochemical recurrence" (BCR). Other deleterious events may happen. An undetected ("occult") metastasis may grow. The patient may die due to some other cause. If the former never happens, it is called "metastasis-free survival (MFS)." It is highly dependent on the technology used to detect occult metastases. If the latter never happens within the time patients are tracked after treatment, it is called "overall survival (OS)." It is highly dependent upon other diseases ("comorbidities"), treatments given, and the length of follow-up. Often, there are undetermined variables (called "confounders") that tilt OS in one direction or another. Only BCR is relevant for the patient making a therapy choice for his localized prostate cancer.

As we saw previously (at this link), the MARCAP consortium has found that the duration of androgen deprivation therapy (ADT) given along with ("adjuvant to") radiation therapy depends on how the radiation is delivered to high-risk patients - either 12 months for brachy boost therapy or 26 months for external beam radiation therapy. Kishan et al. has analyzed a large number of clinical trials to answer the following questions:

1. What is the role of radiation dose escalation in minimizing BCR?
2. What is the role of long-term vs short-term ADT in minimizing BCR?

• They defined "high dose" radiation as any dose equivalent to greater than or equal to 74 Gy (or its equivalent)
• They defined "long-term" (LTADT) as any duration longer than 18 months, while "short-term" (STADT) was defined as 3-6 months.

For high-risk patients, compared to treating them with low-dose RT without ADT:

• Adding high dose RT (without ADT) reduced BCR by 26%
• Adding short-term ADT reduced BCR by 36%
• Adding high dose RT and STADT reduced BCR by 55%
• Adding low dose RT and LTADT reduced BCR by 61%
• Adding high dose RT and LTADT reduced BCR by 69%

Intermediate risk patients were treated before NCCN distinguished "favorable" intermediate-risk from "unfavorable" intermediate-risk (see this link). For intermediate-risk patients, taken as a whole, compared to treating them with low-dose RT without ADT:

• Adding high dose RT (without ADT) reduced BCR by 21%
• Adding short-term ADT reduced BCR by 32%
• Adding high dose RT and STADT reduced BCR by 46%
• Adding low dose RT and LTADT reduced BCR by 55%
• Adding high dose RT and LTADT reduced BCR by 74%

In both risk groups, long-term ADT provided greater benefit than high dose RT, but combining LTADT with high dose RT provided the best cure rates. 

There are some seeming contradictions between this meta-analysis and the DART 01/05 randomized clinical trial. The purpose was to see if there was a difference in biochemical disease-free survival (bDFS) among intermediate and high-risk patients treated with high-dose radiation and either 28 months or 4 months of ADT. At 5 years of follow-up (see this link), the LTADT group had a significantly higher bDFS than the STADT group. The difference was particularly noticed among the high-risk subgroup. However, with 10 years of follow-up, the difference was no longer significant. 

• For the total, the bDFS was 70% for LTADT vs 62% for STADT (not statistically significant)
• For the high-risk subgroup, the bDFS was 67% for LTADT vs 54% for STADT (not statistically significant)

At least for the high-risk subgroup, the difference was large but not statistically significant. What happened?

What happened was a quarter of the men in the study died in the interim (median age was 72 at the start). Only 3% died of prostate cancer. Many of the men who would have shown no biochemical progression had they lived were eliminated from the trial because they died of other causes. This is called "survivorship bias." The high dropout rate due to death from other causes tells us that follow-up of such trials beyond 5 years will introduce bias into our most important endpoint. It is also another reason that "overall survival" is not a useful endpoint when patients are older. Men with less than 10 years of expected survival due to age or comorbidities should consider watchful waiting rather than any kind of radical treatment. Patients can determine their actuarial expected survival with this calculator: (scroll down to "Male Life Expectancy").

Lower salvage radiation dose - are outcomes the same?

A large randomized clinical trial, SAKK 09/10, found that a salvage radiation dose of 64 Gy over 32 treatments had equivalent biochemical outcomes compared to 70 Gy over 35 treatments.

They treated 350 patients from 2011 to 2014 at 28 hospitals in Germany, Switzerland, and Belgium. They were treated with either 3D-CRT (44%) or more modern radiation techniques. None had positive lymph nodes. Key patient characteristics were as follows:

• Biochemically recurrent after prostatectomy (median PSA= 0.3 ng/ml)
• Positive margins in 45%
• Gleason score ≥ 8 in 18%
• No detectable tumors

After 6.2 years of follow-up, outcomes were as follows:

• Freedom from biochemical progression (FFBP) was enjoyed by 65% of those who got 64 Gy vs 73% of the 70 Gy group. This difference is not statistically different (p=0.11).
• Local recurrences (only) occurred in 9% of the 64 Gy group vs 2% of the 70 Gy group. This difference is statistically significant (p= 0.005)
• Regional recurrences (only) occurred in 11% of the 64 Gy group vs 17% of the 70 Gy group. This difference is not statistically significant (p= 0.11)
• Distant recurrences (any) occurred in 15% of the 64 Gy group vs 15% of the 70 Gy group.
• In an earlier report, acute urinary toxicity of Grade 2 or greater occurred in 14% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• In an earlier report, acute rectal toxicity of Grade 2 or greater occurred in 17% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• Late urinary toxicity of Grade 2 or greater occurred in 29% of the 64 Gy group vs 30% of the 70 Gy group (not different)
• Late rectal toxicity of Grade 2 or greater occurred in 12% of the 64 Gy group vs 22% of the 70 Gy group (different)
• Patient-reported outcomes were not different between the two dose regimens.

Oncological Outcomes

The stated purpose of SAKK 09/10 was to detect a difference in 6-year FFBP, and they detected no difference. But is that enough to change practice? The ICECAP working group cautions  that 5-year metastasis-free survival, but not biochemical recurrence-free survival, is a good surrogate endpoint when overall survival would take too long to obtain in trials of primary therapy for localized prostate cancer. For trials of salvage therapy of recurrent prostate cancer after prostatectomy, some early analysis suggests that the 5-year occurence of distant metastases may be a good surrogate endpoint. 6-year FFBP used in this trial is probably not a good surrogate endpoint.

Focusing our attention on the actual cancer progression instead of just PSA progression, we see that the higher dose did significantly better at preventing local progression of the cancer. If the trial were to run 15 years, we might see a very meaningful difference between the curative powers of the two dose regimens. Furthermore, as shown in the SPPORT trial, salvage treatment of pelvic lymph nodes, even when none is detectable, may slow progression or possibly cure some patients with regional micrometastatic progression. 

There may be other ways to improve outcomes:

• Using the expanded prostate bed delineation guidelines may improve local control.
• As PSMA PET/CT becomes more widely available, it will be possible to detect more loco-regional cancer for boost doses, and eliminate salvage treatment from patients who already have small distant metastases (see this link). 
• The use of genomic tests, like Decipher Genomic Classifier (GC), may aid in selecting patients in whom higher doses are needed. In a subset analysis, among Decipher "high GC-risk" patients, FFBF was 51% for 70 Gy vs 39% for 64 Gy patients; among Decipher "low GC-risk" patients, FFBF was 75% for 70 Gy vs 69% for 64 Gy patients (update) FFBF was 45% for GC-high patients vs 71% for GC-low patients. 
• There is a clinical trial at UCLA that will determine whether raising the biologically effective dose (BED) using SBRT (34 Gy/ 5 fractions) gives good outcomes compared to historical controls. The BED is equivalent to 85 Gy if given in fractions of 1.8 Gy.
• There is a clinical trial in France that will determine whether adjuvant hormone therapy intensification with Erleada improves results.
• Keeping in mind that very few patients in this trial had Gleason scores of 8-10, and none had detectable gross tumors at or near the prostate, those patients may still be good candidates for dose intensification (as well as adjuvant ADT).

Toxicity Outcomes

If there is no cost to the patient in terms of increased toxicity, there is no reason not to increase the dose. The patients were unable to detect a difference in urinary, rectal, or sexual outcomes. There was a difference in physician-reported late-term rectal toxicity that deserves further attention.

Compared to acute urinary toxicity, late-term urinary toxicity is about twice as bad in both dosing regimens, although the ratings are not different between regimens. Compared to acute rectal toxicity, late-term rectal toxicity was 29% lower for the 64 Gy dose group, but marginally higher for the 70 Gy dose group. The authors believe that rectal dose constraints could be tightened with IMRT.

For comparison, MSK reported that using 70 Gy as a salvage dose, late-term urinary toxicity (Grade≥2) was 17% (vs 30% in this trial) and late-term rectal toxicity (Grade≥2) was 5% (vs 22% in this trial). They also reported that IMRT improved rectal toxicity over 3D-CRT, while no difference was observed in this trial.

The reason for these atypical results is mysterious, although physician-reported toxicities are notoriously unreliable.

So, lacking more reliable endpoints and considering that patients did not notice any difference in their quality of life based on dose intensification, the decision on what dose to use is best based on a discussion with the radiation oncologist.

(update 04/22/2022) Beck et al. report that adherence to treatment guidelines was poor in the SAKK 09/10 trial. This may explain the mysterious toxicity results as well as being responsible for worse freedom from biochemical progression.

Evidence for Dose Escalation in Adjuvant/Salvage Radiation

It is well known that prostate cancer is relatively radio-resistant compared to other kinds of cancer. While dose escalation (most recently by increasing the biologically effective dose using hypofractionated dose (more that 2.0 Gy per session) delivery or brachytherapy boost therapy) has become the mainstay in primary radiation therapy, doses delivered for adjuvant or salvage radiation has stayed about 10 Gy lower. Recently, Dr. King's analysis of the dose responsiveness of salvage radiation questioned this supposition (see this link). While his mathematical arguments provide us with intriguing plausibility, only clinical evidence from a randomized clinical trial can change practice.

We now have Level 1 evidence that expanding the adjuvant/salvage treatment field to include the pelvic lymph nodes improves the oncological outcomes in men with higher PSA at the time of salvage radiation.

Link et al. conducted a small, retrospective study among 120 locally advanced (stage T3/4) post-prostatectomy patients at the University of Heidelberg between 2009 and 2017. All were lymph node negative.

• 43 received whole pelvic radiation therapy (WPRT)- 62% received 79.3 Gy to the prostate
• 77 received radiation to the prostate bed only (PBO)- 70% received 79.3 Gy to the prostate
• Biologically equivalent dose (2 Gy) to the prostate was 79.3 Gy ("high dose") if they had positive margins or PET/CT/MRI imaging-detectable prostate bed tumors (62% of patients), 71.4 Gy ("low dose") if they had negative margins (38% of patients).

Median freedom from biochemical failure was:

• longer among those who got the higher dose: 76 months vs 21 months
• longer among those who received WPRT vs PBO: 68 months vs 32 months

There is a lot of overlap in treatments, so it is impossible to tease out the effect that each had on the oncological outcomes. Almost all of those who received the escalated dose also had positive margins - a known factor for predicting success of adjuvant/salvage radiation. Also, almost all men who had adjuvant radiation had positive margins and dose escalation - adjuvant radiation has proven to be more successful than "wait-and-see" in 3 major randomized clinical trials.

Toxicity increased with both dose and size of the treatment field. Grade ≥ 2 toxicity was reported by:

• 3.4% among those who received low dose and PBO
• 12.5% among those who received high dose and PBO
• 15.4% among those who received low dose and WPRT
• 36.7% among those who received high dose and WPRT
• No reports of Grade 3 gastrointestinal toxicity
• 13% Grade 3 urinary toxicity among high dose patients, none among low-dose patients

This is a far cry from the randomized clinical trial we need for practice-changing dose escalation for adjuvant/salvage radiation. However, we can't rule out that there is no oncological benefit to dose escalation. It remains unknown what proportion of these high-risk patients would have done just as well with lower doses and smaller treatment fields. The increase in toxicity with dose and treatment field means that patients ought not jump into this without understanding the risks and discussing them with their radiation oncologists.

SBRT: Optimal Dose

While excellent outcomes of stereotactic body radiation therapy (SBRT) have been reported since it was first used for prostate cancer in 2003, the delivered doses have ranged from 35 Gy in 5 treatments to 40 Gy in 5 treatments. We saw in a University of Texas Southwest (UTSW) study (see this link) that toxicity escalates when doses are greater than 45 Gy.

Memorial Sloan Kettering designed a clinical trial (described here) among low and intermediate-risk men. They started with about 35 men treated at 32.5 Gy and checked for dose-limiting toxicity. When most reached 6 months of follow-up, and fewer than 10% had dose-limiting toxicity, they increased the dose to the next group of 35 men by 2.5 Gy in 5 treatments. In all, they had 136 patients who were followed up for 5.9 yrs, 5.4 yrs, 4.1 yrs and 3.5 yrs with doses of 32.5 Gy, 35 Gy, and 37.5 Gy and 40 Gy, respectively.

Their toxicity and oncological outcomes are reported here and shown in the table below:

	Dose delivered in 5 treatments
	32.5 Gy	35.0 Gy	37.5 Gy	40.0 Gy
Acute toxicity
Urinary – grade 2	16.7%	22.9%	8.3%	17.1%
Rectal – grade 2	0%	2.9%	2.8%	11.4%
Late-term toxicity
Urinary – grade 2	23.3%	25.7%	27.8%	31.4% (1 grade 3 stricture)
Rectal – grade 2	0%	0%	0%	0%
Oncological outcomes
5-year PSA failure	15%	6%	0%	0%
2-year positive biopsy	47.6%	19.2%	16.7%	7.7%

Other than the one urinary stricture, there were no acute or late-term grade 3 (serious) toxicities.

Because follow-up decreased with increasing dose, it is unclear whether the zero biochemical failure rates for doses of 37.5 Gy and 40 Gy will be sustained, but in other studies, almost all SBRT failures had occurred within 5 years. The positive biopsy rates will probably continue to decline with longer follow-up because the non-viable cancer cells can take up to 5 years to clear out. Clearly, 32.5 Gy is too low because of its unacceptable oncological results.

A dose of 40 Gy in 5 treatments has very acceptable toxicity and excellent cancer control. It would be reasonable to use doses as low as 37.5 Gy in patients with insignificant amounts of low grade cancer (who would usually be excellent candidates for active surveillance). Based on the UTSW study, it would be reasonable to escalate the dose as high as 45 Gy in patients judged to have radioresistant cancers.

Optimal prostate dose is also discussed:

SBRT dose escalation trial at Sunnybrook 

SBRT dose escalation trial at UTSW

Potters et al. trial

The multi-factorial nature of SBRT safety

Why we should care about standards of care

Escalated radiation dose doesn't improve 8-year overall survival in intermediate-risk men (but does it matter?)

Survival benefit of dose escalation for higher-risk patients

Salvage Radiation Dose: Decision-Making Under Uncertainty

A large, well-done, confirmed randomized clinical trial (RCT) is the only evidence that proves that one therapy is better than another. According to current consensus, this is deemed "Level 1a" evidence. But this high level of evidence is seldom available. This is especially true of prostate cancer because it takes so long to achieve acceptable endpoints like overall survival, prostate cancer-specific survival, and metastasis-free survival. Such studies are very expensive and difficult to carry out.

Alexidis et al. analyzed the National Cancer Database for men treated with adjuvant or salvage radiation therapy (SRT) after prostatectomy failure from 2003 to 2012. SRT with doses above 66.6 Gy were labeled "high dose," and SRT with doses above 70.2 Gy were labeled "very high dose." Between 2003 and 2012:

• High dose SRT utilization increased from 30% to 64%
• Very high dose SRT utilization increased from 5% to 11%
• Utilization of high and very high dose rates was greatest at academic centers, lowest at community centers.

The authors decry the fact that this doubling of high dose SRT took place in the absence of RCTs that would definitively establish proof. They point out that the evidence for it is based on observational studies (see, for example, King and Kapp and Ohri et al.), which are fraught with confounding due to stage migration,  selection bias and ascertainment bias. Stage migration was the result of better imaging becoming increasingly available to rule out SRT from patients already harboring occult distant metastases. Also, three randomized clinical trials published in the middle of the observational period convinced many radiation oncologists that earlier SRT led to better tumor control than waiting. Selection bias occurred because the patients selected to get higher doses of radiation were healthier and those whose cancer was less progressed -- they would have done better regardless of the dose. Ascertainment bias resulted from the longer observational period for patients treated in 2003 vs. 2012 - the opportunity for treatment failure increases with the amount of time that has passed. The authors also doubt that biochemical recurrence-free survival (which is what was used in observational studies) is a good enough surrogate endpoint for overall survival. They are right that all these factors may be confounding the previous retrospective analyses, and the only way to know with certainty is to conduct a trial where patients are randomized to receive high or low SRT doses,  and follow patients long enough so that median survival or at least metastasis-free survival is reached in the low dose group.

There has been one randomized clinical trial of SRT dose escalation in the modern era. The SAKK 09/10 trial found little difference in acute toxicity symptoms at 70 Gy compared to 64 Gy, but patient-reported urinary symptoms worsened. Unfortunately, many patients were treated with three-dimensional conformal radiation therapy (3D-CRT), which had higher toxicity than the IMRT in widespread use now. Also, it uses freedom from biochemical failure (not yet reported) as its surrogate endpoint.

So, what is a patient to do in the absence of Level 1a evidence? Should he accept the higher doses with possibly added toxicity and better tumor control, or should he go for a lower dose with possibly less toxicity and less tumor control?

As a compromise, Mantini et al. recently reported 5-year biochemical disease-free survival (bDFS) and other outcomes for patients who received higher dose SRT (70.2 Gy vs. 64.8 Gy) depending on their post-operative pathology. They also may have received (depending on pathology) whole pelvic radiation and adjuvant hormone therapy. Those patients who received the higher dose had equivalent 5-yr bDFS in spite of their worse disease characteristics. Those who received only 64.8 Gy still had a 5-year bDFS as high as 92%. We do not know how many of those recurrent men with favorable disease characteristics actually needed any SRT. They were all treated with 3D-CRT and toxicity was not reported.

The other thing we can do when our information is imperfect is go through the Bradford Hill checklist. It can give us more confidence if we have to make a decision based on less than Level 1 evidence. The factors that ought to be considered are:

• Strength of Association (larger associations are more likely (but not necessarily) causal)
• Consistency of Data (independent studies all lead to the same conclusion)
• Specificity (a very specific population is differentially affected)
• Temporality (the effect has to occur after the cause)
• Biological gradient (too some extent, more drug/radiation dose leads to more effect) 
• Plausibility (one can come up with a plausible explanation)
• Coherence (lab studies demonstrate a plausible mechanism for the observed effect)
• Experiment (has the effect been prevented by modifying the cause)
• Analogy (similar factors may be considered)

Unfortunately, the authors did not refer to Dr. King's more recent analysis of SRT dose/response, which we discussed in depth here. He looked at 71 studies, demonstrating consistency. While it is not Level 1 evidence, it is Level 2a evidence. In it, he observes that the salvage radiation dose response conforms exactly to the primary radiation dose response.  In other words, the prostate tumor is equally radio-resistant whether it is in the prostate or the prostate bed. This increases the plausibility of a dose effect of SRT. What's more, dose escalation was proven to be beneficial for biochemical recurrence-free survival, metastasis-free survival, and freedom from lifelong ADT use, for primary radiation in intermediate risk men by a RCT (RTOG 0126). So, we also have greater confidence in SRT dose escalation by analogy.

RTOG 0126 did not find an increase with higher dose in 8-year overall survival or cancer-specific survival. This calls into question whether these longer-term effects are really useful endpoints if we are to be able to obtain and use the results of any clinical trial in a reasonable time frame.

Dr. King proposed a randomized clinical trial of 76 Gy vs. 66 Gy for SRT. Meanwhile, he is routinely giving his SRT patients at UCLA 72 Gy. Dr. Zelefsky at Memorial Sloan Kettering Cancer Center and other eminent radiation oncologists have also upped the radiation dose to 72 Gy. Such doses seem to be safe and effective, but it is one of many factors in the SRT treatment decision that must be carefully considered by patients and their doctors.

Escalated radiation dose doesn't improve 8-year overall survival in intermediate risk men (but does it matter?)

Last week, we saw that escalated dose did not improve 10-year overall survival in high-risk men (see this link). The latest published findings of the randomized clinical trial (RTOG 0126) prove that 8-year overall survival was not improved in intermediate risk men who received a higher radiation dose. In both studies, we are left wondering whether that matters.

Michalski et al. reported the results of RTOG 0126, a randomized clinical trial (RCT) designed to prove that escalated dose improves survival in intermediate risk men. It was a very large trial:

• 1499 men
• 104 sites in the US and Canada
• Patients treated from 2002 to 2008
• Median age was 71

The patients were all intermediate risk, defined as:

• Stage T1b-T2b, and
• Gleason score ≤ 6 and PSA ≥10 and <20 (16%), or
• Gleason score = 7 and PSA < 15 (84%)
• 71% were Gleason score 3+4

The treatment consisted of:

• either low dose 70.2 Gy/ 39 treatments 
• or high dose 79.2 Gy/ 44 treatments
• delivered using 3D-CRT (66%) or IMRT (34%)
• none had adjuvant ADT, but they may have had salvage ADT or other salvage therapies if RT failed

After a median follow-up of 8.4 years:

• 8-year overall survival was 75% for the low-dose group vs. 76% for the high-dose group (not significantly different)
• 8-year prostate cancer mortality was 4% for the low-dose group vs. 2% for the high-dose group (not significantly different)
• 8-year biochemical failure was 35% for the low-dose group vs. 20% for the high-dose group (significantly different)
• 8-year local progression (felt with DRE) was 6% for the low-dose group vs. 3% for the high-dose group (significantly different)
• 8-year distant metastases (bone scan/CT detected) was 6% for the low-dose group vs. 4% for the high-dose group (significantly different)
• 8-year salvage therapy was 22% for the low-dose group vs. 14% for the high-dose group (significantly different)

Toxicity outcomes were as follows;

• Acute grade 2+ urinary toxicity was 17% for the low-dose group vs. 17% for the high-dose group (not significantly different)
• Late-term grade 2+ urinary toxicity was 7% for the low-dose group vs. 12% for the high-dose group (significantly different)
• Acute grade 2+ rectal toxicity was 5% for the low-dose group vs. 7% for the high-dose group (not significantly different)
• Late-term grade 2+ rectal toxicity was 15% for the low-dose group vs. 21% for the high-dose group (significantly different)

In a separate analysis of the high-dose group:

• Acute grade 2+ urinary and rectal toxicity was 15% among those treated with 3D-CRT vs. 10% among those treated with IMRT (a significant difference)
• Late-term grade 2+ urinary toxicity was not significantly different among those treated with 3D-CRT vs. IMRT
• Late-term grade 2+ rectal toxicity was 22% among those treated with 3D-CRT vs. 15% among those treated with IMRT (a significant difference)

This RCT raises many important questions about the design of clinical trials and the validity of conclusions drawn from them. Dr. Michalski addressed some of these concerns in an audio interview presented with the published study. This was an enormous undertaking, running almost two decades from design to reporting, and coordinating the treatments and reporting of 1,500 men in over 100 sites spread throughout Canada and the US.

The results show that dose escalation was not needed to increase 8-year survival in these intermediate risk patients. But this probably won't change practice for a number of reasons.

The intervening endpoints are of considerable importance to patients: the anxiety associated with rising PSA, the toxicity of all the salvage therapies, and the pain and possible crippling due to metastases all impact quality of life.

The median age of the men at treatment was 71, and they were screened for good performance status. The actuarial life expectancy in the US for a 71 year-old men is 14 years. This implies that they ought not make a decision based on expected survival for only 8 years. Also, as radiation-treated men get treated at a younger age, the gap will become more pronounced. According to the Memorial Sloan Kettering Life Expectancy Nomogram, a 71 year-old intermediate-risk man in good health has only a 8% probability of succumbing to prostate cancer in 10 years (vs 3% in 8 years in this study), and 12% at 15 years if he had no treatment whatever. At the same time, his probability of dying from other causes is 30% in 10 years, and 51% in 15 years. The overall survival improvement may not become apparent until median survival is reached in 15 years. And differences in prostate cancer survival are difficult to discern when numbers are this low. But it is difficult and costly to track patients for 15-20 years. We have to look to surrogate endpoints.

While 8-year overall survival and prostate cancer-specific survival did not improve, all the intervening endpoints did. Biochemical failure, local progression, distant metastases, and use of salvage therapies were all worse in the low-dose group.  It is very costly and difficult to run an RCT long enough to see a survival difference in men with localized prostate cancer. As we've seen, the few RCTs that have run the longest for each type of therapy have been single institution studies with much smaller sample sizes. Distant metastasis-free survival is probably a better surrogate endpoint if the study can't run for 15-20 years. There were enough metastatic events to see a difference. A recent analysis by the ICECaP Working Group of 12,712 patients in 19 clinical trials of radiation in localized prostate cancer showed that 5-year metastasis-free survival was almost perfectly correlated with overall survival. By reducing the time needed to accumulate data, this might increase the relevance of such trials while reducing their costs.

As Dr. Michalski points out, survival in both groups was much better than expected when the study was designed in 2001. This is largely because life-extending salvage therapies (e.g., docetaxel, GnRH agonists, Zytiga, Xtandi, Xofigo, and Provenge) have become prevalent in the interim.

Toxicity was markedly reduced by the introduction of IGRT/IMRT technology that became increasingly available, especially in the US, in the last 20 years. With the improvement in beam accuracy and the knowledge of the dose/toxicity relation of organs at risk, tighter dose constraints for organs at risk have been utilized. Because of the technology changes, a high-dose regimen today is probably no more toxic than a low-dose regimen. So, if there is little toxicity cost to the more effective treatment, why not use it? Rapidly adopted changes in radiation technology in the last 20 years, especially the shift from 3D-CRT to IMRT, render many of the findings irrelevant to today's standard practice.

Another RCT reported by Nabid et al. at the 2015 Genitourinary Conference had similar findings. They found that 10 year overall survival was no different for higher dose (76 Gy vs 70 Gy) or the addition of short-term ADT. Biochemical failures were actually worse in the higher dose group, but only if short-term ADT was not used with it. Zaorsky et al. conducted a meta-analysis of dose escalation trials in intermediate risk men and arrived at a similar conclusion. A contrary finding was noted by Kalbasi et al. in their analysis of the National Cancer Database. They found that there was a significant survival increase associated with higher dose (hazard ratio = 0.84). In fact, for every 2 Gy increase in dose, there was an 8% reduction in the hazard of death in intermediate-risk patients. Being retrospective, their analysis suffers from selection bias - it may be that the frailest patients got lower doses. However, they did include more unfavorable intermediate risk patients, including those treated with adjuvant ADT.

We are now recognizing that unfavorable intermediate risk patients may benefit from adjuvant ADT and higher doses, whereas the favorable intermediate risk patients may not. EORTC 2291 and the Nabid et al. trial established that short term (6 month) ADT markedly improved progression-free survival. Several retrospective studies (like this one and this and this) suggest that the benefit is limited to those with less favorable disease characteristics. It may well be that higher doses are necessary to overcome the radioresistance of high volumes of Gleason pattern 4.

The degree to which RTOG 0126 is irrelevant to contemporary decision-making is heightened by the success of hypofractionated IMRT and SBRT in intermediate risk patients. Both provide much higher biologically effective doses, equal efficacy to conventional IMRT, and about the same toxicity. Also, their cost is lower and patient convenience is higher. Unless a patient has an anatomical abnormality such that dose constraints cannot be met, it is hard to come up with a reason why higher biologically effective doses should not be used.

Note: Thanks to Dr. Howard Sandler for allowing me to see the full text of the study.