Showing posts with label dose escalation. Show all posts
Showing posts with label dose escalation. Show all posts

Saturday, June 29, 2019

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.


Monday, January 7, 2019

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.


Monday, August 13, 2018

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.


Monday, March 19, 2018

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.


Monday, May 1, 2017

SBRT Dose Escalation

Is there an optimum treatment dose for SBRT? At the low end of the spectrum, Alan Katz found that 35Gy in 5 fractions gave equivalent oncological outcomes with less toxicity compared to 36.5 Gy. At the other end of the dose spectrum, a clinical trial pushed the dose as high as 50 Gy in 5 fractions with disastrous consequences (see this link).  A trial of high dose rate brachytherapy, which is radiologically similar to SBRT, failed to find an optimum dose.

But radiation safety is not only just about dose. We saw that two treatment schedules using the same prescribed dose (40 Gy in 5 fractions) had disparate toxicity outcomes (see this link). In fact, the 12 month toxicity outcomes of Dr. King's high-risk study were recently presented and look excellent (see this link). It's also worth noting once again the outcomes of the 5-year multi-institutional SBRT clinical trial that used 40 Gy in 5 fractions and had excellent oncological and toxicity outcomes (see this link).

Helou et al. reported the outcomes of their SBRT (they call it SABR, but it's the same thing) trials at the Sunnybrook Health Sciences Centre in Toronto, Canada. There were sequential trials conducted from 2006-2014:

  • 35 Gy/5 fractions/29 days - 82 low risk men only
  • 40 Gy/5 fractions/11 days or 29 days - 177 low and intermediate risk men

A few (12) men had up to 6 months of androgen deprivation to shrink their prostates prior to radiation.

As an early measure of oncological effectiveness, they used PSA at 3 years (PSA3Y) after radiation. After correcting for the other variables like age, baseline PSA, T stage, and ADT use, the dose received remained the biggest predictor of PSA3Y. Median PSA3Y was:

  • 0.64 ng/ml in those who received 35 Gy
  • 0.27 ng/ml in those who received 40 Gy
  • The difference was significant in both low risk men and intermediate risk men

The use of PSA3Y as a surrogate endpoint for biochemical recurrence is controversial. Because prostate cancer progresses very slowly and radiation, at the very least, reduces the cancer burden, it can take at least 5 years, and as long as 10 years, before we start to see concrete evidence that such therapy is curative. Also, a longer time until the nadir is achieved has been found to be correlated with failure-free survival (see this link). Nadir PSA has been proven to be a strong predictor of a lasting cure (see this link), but no one can tell when the nadir will be reached. In a recent study comparing the PSA at 1000 days after SBRT or HDR brachytherapy to the PSA at 1000 days after conventional IMRT, Kishan et al. reported that the PSA was lower for SBRT/HDR-BT. While the downward slope was about the same for the first 1000 days, the slope was steeper afterwards for SBRT/HDR-BT, indicating that a lower nadir would be achieved.

After correcting for confounders like age, baseline urinary function, and time between treatments, late term urinary toxicity of grade 2 or higher was 17 times greater among those who received 40 Gy compared to those who received 35 Gy.

The authors previously reported late term rectal toxicity. After 2 years, the cumulative probability of  grade 2 or higher rectal toxicity was suffered among:

  • 5% of the men who received 35 Gy with 4mm margins
  • 27% of the men who received 40 Gy with 5 mm margins
  • 42% of the men who received 40 Gy with 5 mm margins +  30 Gy to seminal vesicles received 

Grade 3 and 4 rectal toxicity was especially high (10%) in the group that had their seminal vesicles irradiated. There were 3 cases of fistulas that may be attributable to rectal biopsies. [Patients should be very careful about the use of any kind of instrumentation within at least 6 months of radiation. That includes cystoscopies and colonoscopies.] Since this study, the authors have changed their radiation planning to include faster (VMAT) linacs and improved rectal dose constraints. Other changes that might mitigate rectal toxicity may include use of intrafractional tracking, rectal immobilization, and a rectal spacer.

There was clearly a trade-off between SBRT dose and late-term side effects of treatments. Perhaps we will one day be able to identify those cancers that are curable with a lower dose, and treat only those with the more radio-resistant cancers with a higher dose. Some believe that such techniques as simultaneous integrated boosts or heterogeneous planning may cure the cancer in the prostate better with less damage to organs at risk. But they remain to be proved in randomized clinical trials.

Note: Thanks to Dr. Andrew Loblaw for allowing me to review the full text of the study.

Monday, November 28, 2016

Dose Escalation for Salvage Radiation


In the late 1990s and early 2000s, the advent of more accurate linear accelerators (linacs) and image-guidance technology for delivering therapeutic X-rays to prostate cancer changed the dose that could be safely given. In the late 1980s, the typical dose was only in the mid-60 Gy range. By the early 2000s most of the top prostate cancer treatment centers were delivering 80 Gy (at 1.8 or 2.0 Gy per treatment) with higher cure rates and lower toxicity. Dose escalation for primary treatment of prostate cancer was a resounding success and became the standard of care.

However, dose escalation was not utilized appreciably in salvage radiation treatment (SRT) after prostatectomy. The reasons doses were kept lower in the salvage setting were that:

  • Toxicity might be higher because radiation could be especially damaging when applied to tissue that had been cut or stressed by surgery.
  • Without the shielding effect of the prostate in place, sensitive structures like the bladder neck, the rectum, the penile bulb, and the urethra would receive the full brunt of the radiation.
  • Unlike the relatively large tumors in an intact prostate, the cancer in the prostate bed was small or microscopic and didn’t need as large a dose of radiation to eradicate it.

Current guidelines by the American Urological Association (AUA) and The American Society of Radiation Oncologists (ASTRO) establish a minimum dose of 64-65 Gy for SRT, but do not establish an optimum dose, citing lack of available evidence. At the top treatment centers, radiation oncologists routinely deliver doses as high as 70 Gy, but seldom higher. The outstanding question is: what is the optimum dose for SRT? That is, what dose offers the best chance at a cure with acceptable toxicity?

The Dose/Response Curve

Radiation oncologists talk about an S-shaped “dose/response curve.” At the bottom of the “S,” we know that at very low radiation doses there is very little “response,” meaning very few cancer cells are killed. At a certain radiation level, a lot more cancer cells are killed, and even a small increase in dose will kill a lot more cancer cells. This is called the “steep” part of the dose/response curve. After the steep part, adding more dose doesn’t kill a lot more cancer cells, but it begins to kill off healthy cells, increasing toxicity. The optimal dose is reached just before this happens at the top of the steep part. Below is what a dose/response curve looks like:


The Study

Dr. Christopher King (see this link) analyzed data from 71 studies, representing 10,034 patients treated who received SRT between 1996 to 2015 to see if the data conformed to a dose/response curve. He found an excellent fit:
  • SRT dose was the single most important factor correlated with recurrence-free survival
  • PSA at the time of SRT was the second most important factor
  • Other factors (stage, Gleason score, positive margins, lymph node invasion, and use of adjuvant ADT) were less important.
  • At an SRT dose of 66 Gy, half the patients were recurrence-free after SRT
  • Recurrence-free survival increased by 2 percentage points for each additional Gy of SRT dose.
  • The dose/response curve for SRT fit almost perfectly to the dose/response curve for primary RT.
Because the curves seem to be identical whether it was for primary therapy or for salvage therapy, it implies that even the microscopic prostate cancer cells lingering in the prostate bed require as much radiation to finish them off as the larger tumors within the prostate. This radioresistance will not surprise those of us who have noticed the improved cancer control patients get with a brachytherapy boost given for primary radiation therapy.

How much better cancer control can we expect?

It’s hard to know how high recurrence-free survival can get if the dose is increased. The statistics suggest that increasing the SRT dose from 66 Gy to 76 Gy will increase recurrence-free survival from 50% to 70% at 5 years of follow-up. But this is unknown territory, and in some patients, undetectable distant metastases will have already occurred. Of the 71 studies reviewed in this meta-analysis, only 4 included doses above 70 Gy. Dr. King is proposing a clinical trial where patients are randomized to receive 66 Gy or 76 Gy.

76 Gy for SRT – is that safe?

Only one study included a dose this high. Ost et al. treated 136 patients. 5-year biochemical recurrence-free survival was 56%, but patients were treated fairly late – median PSA had already reached 0.8 ng/ml by the time SRT began, and most had adverse pathology findings. They report reasonable late toxicity: 4 patients (3%) suffered a grade 3 urinary event, and 1 case of a grade 3 rectal adverse event. However, they do note that a lot of the grade 2 toxicity seemed to be chronic rather than transient. 39% suffered long-lasting grade 2 urinary toxicity, and 18% suffered from long-lasting grade 2 rectal toxicity. I assume patients will be excluded from Dr. King’s clinical trial if they still have urinary issues from surgery. There is no data on the effect of dose escalation on erectile dysfunction.

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.

Can SBRT be used instead of IMRT?

There have been a few clinical trials of hypofractionated SRT that seem promising (see this link). UCLA will be starting a trial next year as well. An IMRT dose of 76 Gy is biologically equivalent in its cancer control to 5 SBRT treatments totaling 33 Gy.

The challenges for SBRT are greater than for IMRT. Because the dose per treatment is so high, even a small “miss” can increase toxicity and reduce effectiveness. It is difficult to use fiducials in the prostate bed, and the soft tissue is highly deformable and subject to motion from the bowels and bladder. The radiation oncologist will have to use soft tissue landmarks and site them multiple times per treatment. A filled bladder and good bowel prep are important, as is a very fast linac. Careful planning and strict adherence to dose constraints to organs at risk are essential.

Implications for pelvic lymph node treatment

If prostate cancer in the prostate bed requires almost 80 Gy, what can we infer about microscopic cancer that has spread to pelvic lymph nodes? It would seem that that cancer would be equally radioresistant. The pelvic lymph nodes area is often treated with a dose of about 50 Gy. Unfortunately, as the radiation field increases to extend to the entire pelvic area, many more organs are subject to toxic reactions. The enteric tissue of the small bowel is particularly prone to late reactions. In a database analysis at Fox Chase Cancer Center, patients treated with 56 Gy to the whole pelvis for high-risk prostate cancer may have had gastrointestinal reactions as long as 9 years later. We await the findings of randomized clinical trials (RTOG 0534 and PRIAMOS1) to tell us whether such treatment is effective.

Discuss with your radiation oncologist

Although Dr. King’s meta-analysis is impressive in the amount of data represented, it is not a randomized trial that would change clinical standards on its own. Even so, it is certainly worth discussing with one’s radiation oncologist before committing to a treatment plan. There are many considerations for the patient  - especially his current status with regard to urinary and erectile function. For patients with few adverse pathology findings (e.g., long PSA doubling time, low Gleason score, no obvious capsular penetration), the risk of extra toxicity may not be worthwhile. It’s a judgment each patient must make for himself.



Note: Thanks to Dr. Christopher King for allowing me to see the full text of his study.




Tuesday, August 30, 2016

Safety limits of SBRT dose escalation

In a recent commentary, we saw that the lack of a standard of care for SBRT dose escalation may put patients at risk when dose limits are pushed beyond what is customarily considered effective and safe. Hannan et al. have now published their efficacy findings. Further details of the IRB-approved clinical trial specs are available here.

Between 2006 and 2011, the researchers at several institutions conducted a dose escalation trial utilizing SBRT on 91 men treated for low and intermediate risk prostate cancer. Among those men:
  • ·      64% were intermediate risk, defined as:

o   Either GS 6 and PSA between 10 and 20 ng/ml , or
o   GS 7 with PSA≤ 15 ng/ml and clinical stage ≤ T2b
  • ·      36% were low risk by the NCCN definition.

All patients received 5 treatments or fractions. The first 15 patients were treated with 45 Gy, the next 15 with 47.5 Gy, the next 15 with 50 Gy. Because that last group did not exhibit their predefined “maximally tolerated dose” in the short term, an additional 47 patients also received the 50 Gy dose.

The cancer control was excellent. At 5 years after treatment:
  • ·      98.6% were free from biochemical failure
  • ·      100% were free from metastases
  • ·      None had died of prostate cancer
  • ·      Overall survival was 89.7%

Toxicity was another matter. There were no reports of serious acute urinary toxicity. However, late-term urinary toxicity of grade 3 or greater was reported in 5.5% of patients. For the purposes of their analysis, acute toxicities were those observed within 9 months of treatment, and late-term toxicities were those observed between 9 and 18 months.

Rectal toxicity was reported in detail earlier by Kim et al. and merit a closer look:
  • ·      Among those who received 45 Gy there was no serious (grade 3 or higher) acute or late term toxicity.

o   No acute grade 2 toxicity was observed.
o   Late-term grade 2 toxicity was observed in 1 patient (of 15).
  • ·      Among those who received 47.5 Gy there was no serious (grade 3 or higher) acute or late term toxicity.

o   Acute grade 2 toxicity was observed in 4 of 15 patients (27%)
o   Late-term grade 2 toxicity was observed in 5 of 15 patients (33%).
  • ·      Among the 61 patients who received 50 Gy there was:

o   One case of serious (grade 3) acute toxicity and one case of life-threatening (grade 4) acute toxicity.
o   3 cases (5%) of serious (grade 3) late-term toxicity and 2 cases (3%) of life-threatening (grade 4) late-term toxicity.
o   2 of the patients developed rectourethral fistulae, and 5 required diverting colostomies.


We note that even at the lowest dose level given in this trial (45 Gy), they were delivering much more than the customary SBRT dose of 36.25 Gy. Because this study began with such a high dose, it did not succeed in its objective of finding an optimal dose. It did, however, find the dose that created dose-limiting toxicity. At 50 Gy, they were delivering a dose that is bioequivalent to more than twice the customary and safe IMRT dose (80 Gy in 40 fractions). This is especially troubling when we realize that 36% were low-risk patients who might have delayed treatment with active surveillance.

There are many aspects of this study that are hard to understand. It’s hard to understand why they didn’t start at a more reasonable dose level. Dr. Alan Katz reported excellent cancer control with extremely low toxicity using only 35 Gy (see this link). With the sharp increase in acute grade 2 toxicities at 47.5 Gy, it’s hard to understand why the researchers did not pull the plug before patients were seriously harmed. It’s also hard to understand how the internal review board (IRB) did not question the ethics of this study.

(Update 2/6/2019) In a small (n=26) prospective dose-finding study of 40 Gy (n=9), 45 Gy (n=10) and 50 Gy (n=7) among low and intermediate risk patients, Potters et al. reported freedom from biochemical failure of 92%, 100% and 100% respectively with 67 months of follow-up. There were no Grade 3 toxicities, and toxicity was about equal in all groups. Quality of life returned to baseline in all groups within 2 years.


We have observed (see this link) that there is a lot more to SBRT safety than simply setting the prescribed dose. Careful planning, image guidance and accurate delivery are equally important. In the right hands, SBRT is among the safest and most effective of all radiation therapies, with excellent convenience and relatively low cost. In fact, I chose it for myself.