Thursday, April 28, 2022

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 lower 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").

Saturday, January 22, 2022

Optimal duration of adjuvant ADT depends on the type of radiation used for high-risk patients

No one wants to have androgen deprivation therapy (ADT), even if it is for a limited time. It has been known for a long time that it improves oncological outcomes when given with ("adjuvant to") radiation therapy in patients with high-risk prostate cancer. Several randomized clinical trials (RCTs) have tried to find the best duration to use it, but it is difficult to arrive at reliable optimization points- it would involve varying the duration for a large number of high risk patients. Kishan et al. have taken an innovative approach to solving this problem by combining several RCTs and a multi-institutional observational study. Unlike typical "meta-analyses," they compared similar patients across three studies.

The three studies they used in their analysis were:

  1. The high-risk patients in the DART 01.05 GICOR RCT (see this link), which randomized patients to 28 months or 4 months of adjuvant ADT in patients getting high dose external beam radiation (EBRT-only). They found that 28 months is better than 4 months, but is there a duration that is less than 28 months for EBRT-only?
  2. The patients in the TROG 03.04 RADAR RCT (see this link), which randomized patients to 18 months or 6 months of adjuvant ADT in patients getting varying doses of EBRT or high dose rate brachy boost therapy (BBT). They found that 18 months is better than 6 months for BBT, but is there a duration that is less than 18 months for BBT?
  3. The patients in a multi-institutional (retrospective, non-randomized) study who received varying durations of adjuvant ADT and EBRT-only or brachy boost therapy for their high risk PCa (see this link).

They used distant metastasis-free survival (DMFS) as the endpoint of interest because it has been found to correlate well with eventual overall survival. They went back to the original patient-level data to extract comparable patients when comparing them across studies. This retained many of the advantages of each of the three studies. While this innovative approach does not constitute the highest level of evidence (Level 1), it offers a degree of reliability that goes beyond simple observational studies.

They used two statistical methods to look at the data. In one analysis, they divided the durations into three parts: 

  • ≤6mo.
  • >6 - 18 mos
  • >18 mos

In another analysis (called "cubic splines") they found the best fit for the continuous data. Both analyses led to similar conclusions.

The best estimates for the best minimum adjuvant ADT duration are:

  • at least 26.3 months for EBRT-only
  • at least 12 months for BBT

But, one might object, didn't Nabid's PCS IV trial show that 18 months is as good as 36 months (see this link)? Kishan points out that only about half of the cohort in that trial who were supposed to get 36 months of ADT actually got that much. And nearly a quarter of the 36-month cohort actually received less than 21 months. The only data we've seen so far has been analyzed by the dose they were intended to get, not by what they actually got. Also, why were the drop-out rates so high? The DART RCT had 95% compliance with the full 28 months, even though the radiation doses given were much higher.

There is a trade-off: BBT can come with severe late-term urinary side effects (among 19% in the ASCENDE-RT RCT), while the late-term urinary side effects are milder for EBRT-only (only 2.5% in DART). Only the patient can decide if he is willing to take on 12 months of ADT with BBT vs over twice as long for EBRT-only, given the higher expected radiation toxicity with BBT.

There are several unanswered questions:

  • As we have seen (see this link), brief intense use of abiraterone or other advanced hormone therapy may obviate the need for longer ADT.
  • Decipher genomic analysis may indicate which patients may be able to get away with less hormone therapy, and which need more. The PREDICT-RT RCT will eventually answer this question.
  • Does SBRT monotherapy or HDR brachy monotherapy still require adjuvant ADT? Those therapies can have almost as high a biologically effective dose as BBT but with fewer side effects. This study suggests that 12 months of ADT is beneficial with even the highest dose radiation, but future clinical trials will give a more reliable answer.
  • Standard-of-care dictates 2-3 years of adjuvant ADT when enlarged pelvic lymph nodes are found by CT or MRI. What is the optimum duration when cancerous pelvic lymph nodes are only detected with a PSMA PET scan and not by CT? What about when they are too small to be detected by any kind of imaging, and their presence is only suggested by risk characteristics?
  • What duration of adjuvant ADT minimizes biochemical recurrence-free survival and the need for any salvage treatment?
  • Will these estimates hold up if tested in an RCT?