Brachy boost therapy and surgery extend survival about the same in high risk patients, but brachy boost does more

Two retrospective studies were published in the last week, and they had some similar findings, but some dissimilar things to say about which treatment is best for high risk prostate cancer. The three therapies they looked at were the combination of brachytherapy and external beam radiation (brachy boost therapy - BBT), external beam therapy alone (EBRT), and surgery (RP).

Kishan et al. reported on 1,809 men with Gleason score of 9 or 10 who were treated between 2000 and 2013 at 12 tertiary cancer care institutions (UCLA, Los Angeles VA, California Endocurie Therapy Center, Fox Chase, Mt. Sinai, Cleveland Clinic, Wheeling Jesuit University, University of Michigan, Johns Hopkins, Oslo University, William Beaumont Hospital, and Dana-Farber).

Patient characteristics:

• 639 were treated with radical prostatectomy (RP).
• 734 were treated with EBRT only.
• 436 were treated with BBT (BT was either low dose rate in 62% or high dose rate in 38%).
• All patients were Gleason 9 or 10 on biopsy.
• Pelvic LN involvement was discovered in 17% of RP patients ; 40% had positive surgical margins.
• RP patients were younger (61 years of age) compared to EBRT or BBT patients (68 years of age)
• RP patients were lower stage ( 87% clinical stage T1/T2) compared to EBRT (70% clinical stage T1/T2 ) or BBT patients (79% clinical stage T1/T2)
• RP patients had lower pre-therapy PSA (7 ng/ml) compared to EBRT or BBT patients (10 ng/ml)
• RP patients had lower percentage of Gleason score 10 (4%) compared to EBRT (6%) or BBT patients (9%)

Treatment specs

• Among the RP patients, 43% had adjuvant or salvage radiation therapy (68 Gy).
• Among radiation patients, about 90% had adjuvant ADT
• Median dose of EBRT was 74 Gy.
• adjuvant ADT continued for 22 months, median.
• Median equivalent dose of EBRT+BT was 92 Gy
• adjuvant ADT continued for 12 months.

Oncological outcomes

After a median follow-up of 4.2, 5.1 and 6.3 years for RP, EBRT, and BBT, respectively, the oncological outcomes (adjusted for age and disease characteristics) were as follows:

• The 10-year rates of distant metastases were
  • 46% for RP 
  • 44% for EBRT
  • 13% for BBT
  • Differences between BBT and the two others were statistically significant.


• The 10-year rates of prostate cancer-specific mortality (PCSM) were
  • 23% for RP
  • 26% for EBRT
  • 13% for EBRT + BT
  • Differences between BBT and the two others were statistically significant.


• The 10-year rates of all-cause mortality (ACM) were
• 32% for RP
• 39% for EBRT
• 31% for BBT
• None of the differences were statistically significant.
• There was a difference at 7.5 years in favor of BBT that vanished by 10 years.

In additional analyses, the authors looked at outcomes by duration of androgen deprivation for those receiving any kind of radiation. They found that ADT duration made no significant difference in detected metastases or PCSM within EBRT or BBT, and did not account for the difference between them. They also looked at radiation doses. EBRT patients who received <70 Gy had PCSM significantly worse than those who received ≥ 78 Gy. The rates of metastases did not differ. Notably, very few (11%) of the EBRT patients had both ≥ 78 Gy and ≥2 years of ADT, a combination that is now considered standard of care. Those that did had superior outcomes compared to RP. The use of LDR-BT or HDR-BT as part of BBT made no difference.

The authors conclude:

Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer–specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

In an analysis of the National Cancer Database, Ennis et al. reported on the overall survival of patients who were treated with RP, EBRT, and BBT for high-risk PC from 2004 to 2013. The database covers about 70% of all new prostate cancer patients treated in the US. The patient profile was:

• 24,688 patients treated with RP, at least at first
• 15,435 patients treated with EBRT
• 2,642 patients treated with BBT.
• All EBRT patients also had adjuvant ADT
• BBT patients may or may not have had ADT
• All were high risk by the NCCN definition: Either Gleason score 8-10, stage T3/4, or PSA≥20 ng/ml
• RP patients were younger (62 years of age) compared to EBRT (70 years of age) or BBT patients (67 years of age)
• RP patients were lower stage ( 89% clinical stage T1/T2) compared to EBRT (84% clinical stage T1/T2 ) or BBT patients (85% clinical stage T1/T2)
• RP patients had lower pre-therapy mean PSA (19 ng/ml) compared to EBRT (23 ng/ml) but the same as BBT patients (19 ng/ml)
• RP patients had lower percentage of Gleason score 8-10 (70%) compared to EBRT (78%) or BBT patients (73%)
• Comorbidities were similar among groups.
• The above risk factors as well as socioeconomic factors and year of diagnosis were used to adjust the raw data.
• It is unknown what percent of RP patients had adjuvant or salvage radiation.
• There was no data available on post-reatment metastases or prostate cancer-specific survival

Because surgery is sometimes aborted when pelvic LN cancer is discovered, they estimated the probability that patients had positive nodes, and included it as a risk factor. This would seem to double count those risk factors, but the authors say it had little effect. Based on their model, they estimated that the percent who had positive nodes was 10% of RP patients, 34% of EBRT patients, and 23% of BBT patients.

After a median follow-up of 36 months, the relative oncological outcomes (adjusted for age and other patient and disease characteristics), expressed as hazard ratios were as follows:

• RP: 1.0
• EBRT: 1.53 (i.e., 53% worse survival vs. RP)
• EBRT with < 79.2 Gy: 1.68
• EBRT with ≥79.2 Gy: 1.33
• BBT: 1.17 (not significantly different from RP)
• not different if ADT included
• no interaction between comorbidities and treatment effects

The authors conclude:

This analysis showed no statistical difference in survival between patients treated with RP versus EBRT plus brachytherapy with or without AD. EBRT plus AD was associated with lower survival. 

In an accompanying editorial, Ronald Chen discusses the problem of drawing conclusions about comparative effectiveness from this kind of registry data in the absence of clinical trial data. He points out that patient selection criteria are not completely reflected in comorbidity data. He believes that those who are selected for EBRT are just less healthy than those who can undergo anesthesia for surgery or brachytherapy. Other unmeasured confounders include burden of disease, and patient and physician preferences.

The two studies had similar conclusions, but tell us different things. They both found no effect of treatment on overall survival. Lest one walk away thinking it then doesn't matter, the experience of living with painful, crippling metastases and the experience of dying from prostate cancer are horrific in themselves. In the Kishan study among top institutions, there is greater confidence than in many studies that deaths due to prostate cancer could be distinguished from death from other causes. Still, overall survival is impaired in patients with cancer, even if the cancer itself isn't the ultimate cause of death.

Although several randomized clinical trials (RCTs) have demonstrated significant improvements in progression-free survival from BBT compared to EBRT, none have yet demonstrated improvements in overall survival. We saw this recently in the 2005 Sathya RCT. But the prostate cancer-specific mortality advantage of BBT has been confirmed in another study. In a recent analysis of the SEER database, PCSM was 40% higher among patients who had EBRT compared to those who had BBT.

Other than the lack of metastasis data and PCSM in the NCDB, there were other important differences between the two studies. In the Ennis study, only 25%-35% were gleason 9 or 10, whereas all were in the Kishan study. Other differences included the lack of comorbidity data in the Kishan study, and the lack of adjuvant/salvage radiation data in the Ennis study.

Prostate cancer-specific mortality rates were cut in half by BBT, and metastases were only a fraction compared to the other treatments. While this does not prove causality (only a randomized clinical trial can do that), it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high risk patients may have to forgo brachy boost therapy in favor of high dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy will probably be the best choice. Patients who are treated with EBRT only, should receive a radiation dose of at least 79.2 Gy and two years of adjuvant ADT.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

- with thanks to Amar Kishan for allowing me to see the full text.

Erectile Function after SBRT

Erectile function after radiation is of great interest to many men trying to decide between surgery and radiation, and to decide among the several radiation treatment options. Dess et al. reported the outcomes of men who received stereotactic body radiation therapy (SBRT), often known by the brand name CyberKnife.

Between 2008 and 2013, 273 patients with localized prostate cancer were treated at Georgetown University. All patients filled out the EPIC questionnaire at baseline, which includes several questions on erectile function. The authors focused on the question asking whether erections were firm enough for intercourse, irrespective of whether they used ED meds. A similar questionnaire, SHIM, was also used, but results were similar. Answers were tracked over time with analyses at 2 years and at 5 years. Importantly, the median age at baseline was 69 years. At 2 years:

• About half the men had functional erections at baseline
• Among those with functional erections at baseline, 57% retained potency
• The largest loss occurred by 3 months after treatment, with about 2/3 retaining potency at 3 months
• 2/3 retained potency at 3 months regardless of age
• Men under 65 suffered no further loss of potency, even after 5 years
• Men 65 and over continued to lose potency
• About half retained potency at 2 years
• About 40% retained potency at 5 years

The authors also looked at other causes of erectile dysfunction, including partner status, BMI, diabetes, cardiovascular disease,  depression, baseline testosterone levels, and baseline use of ED meds. None of those, except BMI, had a statistically significant effect in this patient population at 2 years post treatment.  Some gained importance by 5 years, but because they are age dependent, and also affect baseline ED, none except BMI were independently important after baseline function and age were accounted for. A few known risk factors for ED were not included: medications (e.g., beta blockers, testosterone supplementation, etc.), smoking, and substance abuse. Some of that data was collected and may be included in a subsequent analysis.

There is a source of statistical error called colinearity, which arises when 2 variables, like baseline potency and age, are substantially interlinked. Although they were independently associated with erectile function, there is considerable overlap, especially when patient age was over the median (69). It may be useful to separate the effect of one from the other. This is accomplished by using age-adjusted baseline erectile function in the same way that economists look at inflation-adjusted GNP. I hope the authors will look at this. As we saw, an analysis of brachytherapy utilizing a different technique showed that half of the loss of potency among men who had brachytherapy was due to aging.

The effect of age on potency preservation cannot be overemphasized. Undoubtedly, radiation can cause fibrosis in the penile artery, and fibrosis is worse in older men. But, contrary to a prevalent myth, those radiation effects occur very early. Following that early decline, the declines in potency are primarily attributable to the normal effects of aging (which include occlusion of the vasculature supplying the penis.) As we've seen in other studies, most of the radiation-induced ED will show up within the first two years, and probably within 9 months of treatment. This was shown for 3D-CRT in the  ProtecT clinical trial,  for brachytherapy, for SBRT, and for EBRT.

Looking at other reports of potency preservation following SBRT, the Georgetown experience (57% potency preservation) seems to be on the low end. There has only been one report of lower potency preservation: 40% at 3 years among 32 patients. An earlier report from Georgetown reported 2-year potency preservation at 79% at 24 months. Dr. Dess explained that the earlier report included men with lower potency at baseline. However, because baseline potency is highly associated with post-treatment potency, the outcomes should be in the other direction. The discrepant data are puzzling. At 38 months post treatment, Bernetich et al. reported potency preservation in 94% among 48 treated patients. Friedland et al.  reported 2-year potency preservation at 82%. Katz reported potency preservation of 87% at 18 months. Although, different patient groups may respond differently, it is difficult to understand why potency preservation was so much lower in the current study. These discrepancies argue for a more standardized approach to analyzing erectile function after treatment, and the present study makes a good start towards that goal.

Compared to other radiation therapies, SBRT fares well. Evans et al. looked at SBRT at Georgetown and two 21st Century Oncology locations and compared it to low dose rate brachytherapy (LDR-BT) and IMRT as reported in the PROSTQA study. At 2 years, among patients who had good sexual function at baseline, EPIC scores declined by 14 points for SBRT, 21 points for IMRT, and 24 points for LDR-BT( the minimum clinically detectable change on that measure is 10-12 points). There has been only one randomized trial comparing extreme hypofractionation to moderate hypofractionation. In that Scandinavian trial, they used an older technique called 3D-CRT, which would never be used today to deliver extreme hypofractionation (at least I hope not!). In spite of the outmoded technology, sexual side effects of of the two treatments were not different. In an analysis from Johnson et al. comparing SBRT and hypofractionated IMRT, the percent of patients reporting minimally detectable differences in sexual function scores was statistically indistinguishable in spite of the SBRT patients being 5 years older.

Dess et al. also looked at sexual aid utilization in a separate study on the effect of SBRT. They found:

• 37% were already using sexual aids at baseline
• 51% were using sexual aids at 2 years
• 55% were using sexual aids at 5 years
• 89% of users say they were helped by them at baseline, 2 years and 5 years
• 86% used PDE5 inhibitors only (i.e., Viagra, Cialis, Levitra or Stendra)
• 14% combined a PDE5 inhibitor with other sexual aids (e.g., Trimix, MUSE, or a vacuum pump)

Erectile function is well-preserved following SBRT, and seems to be as good or better than after IMRT, moderately hypofractionated IMRT, or LDR brachytherapy. Based on reports of a protective effect of a PDE5 inhibitor, patients should discuss their use with their radiation oncologist starting 3 days before radiation and continuing for 6 months after. High levels of exercise and frequent masturbation may have protective effects as well.

With thanks to Daniel Spratt and Robert Dess for allowing me to see the full texts of their studies

A PSMA-based PET scan can change salvage radiation treatment decisions

The new PSMA-based PET scans provide a way to locate exactly where the cancer has spread to after an unsuccessful prostatectomy. Formerly, the only tools we had were scans that could only detect very large or rapidly growing tumors at PSAs well above the levels most radiation oncologists would be comfortable treating with salvage radiation; that is, there is widespread agreement that success rates improve the lower the PSA is when SRT is used. Even the newly approved Axumin PET scan only detects cancer in 38% of patients if their PSA is in the range of 0.2-1.0 ng/ml. By contrast, as we saw recently, the Ga-68-PSMA-11 PET scan has detected cancer in half of men when their PSA was still below 0.2, and in about two-thirds of men whose PSA was 0.2 - 0.4. The PSMA-based PET scan has the power to change SRT treatment decisions.

Calais et al. reported the results of a multi-institutional study of the Ga-68-PSMA-11 PET/CT in 270 men with biochemically recurrent prostate cancer after prostatectomy while their PSAs were still below 1.0 ng/ml (median 0.44). The institutions comprised UCLA, Technical University of Munich, Ludwig-Maximillian University of Munich, and University of Essen. Patients received PET scans from 2013-2017. Researchers painstakingly mapped all sites of cancer to find the locations of cancer that would have been missed if they had just blindly treated the prostate bed and/or the pelvic lymph node field recommended by RTOG guidelines.

The following table shows how treatment decisions might change based on their findings.

So, all in all, about half of treatment decisions might change - 30% in a minor way, 19% in a major way. The major changes would be: 

• forgoing SRT entirely in up to 12%
• consider metastasis-directed radiation in 8% - a treatment of unknown significance
• changing from prostate bed-only to whole pelvic SRT in 11%, so as to potentially render curative what would have been a non-curative treatment
• expanding the pelvic treatment field in 7%, so as to potentially render curative what would have been a non-curative treatment

At the above institutions, extended pelvic lymph node dissection (ePLND) is common practice - 81% of patients had a PLND. Consequently, 20% of patients already had detected pelvic LNs (N1) before the scan. At many institutions in the US where ePLND is less common in intermediate and high risk patients, this can cause a much larger and potentially curative change in the treatment plan from prostate bed-only to whole pelvic radiation. The researchers are to be congratulated for the painstaking work in contouring and comparing so many pelvic scans.

As one might expect, PSMA-based cancer detection was higher for those with Gleason score more than 7, and those with pathological stage N1 and T3. The patient's PSA at the time of the scan played a major role. While almost two-thirds had a PSA ≤ 0.5 ng/ml, the detection rate was 41% for those patients vs. 60% for those with higher PSAs. While detection improves with higher PSA, it is important for patients to understand that it is unwarranted (and potentially unsafe) to wait for PSA to rise just so that more cancer can be detected. That would be a self-fulfilling prophecy: by waiting for the cancer to put out more PSA, one is virtually ensuring that the cancer will grow, spread, and possible metastasize. Although we await definitive clinical trial data, most radiation oncologists recommend early treatment (before PSA reaches 0.2 ng/ml) for men with adverse pathology or for those evincing a distinct pattern of PSA progression after prostatectomy.

While a previous analysis showed that the Ga-68-PSMA PET had little effect on SRT decisions, and no patients were upgraded from incurable to potentially curable, this larger, more detailed study indicates that about 1 in 5 patients can be upgraded, and 1 in 6 can be spared SRT. This would seem to justify the cost. UCLA charges $2650 for recurrent (and high risk) patients. NIH is recruiting recurrent and high risk patients for an improved PSMA-based PET scan (called DCFPyL) that  is free (and transportation to Washington D.C. is covered as well).

What to expect immediately after prostate radiation

Urinary, rectal and sexual side effects of treatment are usually mild and transient, although they may be worse if you are especially sensitive to radiation, are an older man, or had symptoms before you started radiation therapy. Some side effects described below may occur in many men starting anytime from a week to a month after treatment and continuing for weeks or months. These are called "acute" side effects. The duration and intensity vary greatly between men.

If any of those symptoms interfere with your day-to-day living, call your doctor. He may be able to prescribe medication that can help alleviate those symptoms.

Urinary

Total incontinence is uncommon. There may be some leakage or dribbling. Other common side effects are irritation, burning or bleeding while urinating, feeling like you have to urinate immediately even when you know your bladder isn’t full, having to wake up several times during the night to urinate, or having to urinate frequently during the day. You may pass small amounts of blood or blood clots; however, if you are bleeding copiously when you urinate, contact your doctor immediately.

A rare but potentially serious side effect is urinary retention. If you find that you can’t urinate even though your bladder feels full, go to the Emergency Room of the nearest hospital immediately and tell them you are suffering from urinary retention. They must catheterize you to allow the urine to flow out.

Rectal

There may be a feeling like you have to pass a stool but you cannot, and this feeling may recur often. This is called tenesmus. You should be aware that that feeling is from inflammation in your rectum (proctitis), not from actual stool there, and if you strain, you may create hemorrhoids. You may have frequent bowel movements. There may be blood in your stools or blood may drip out. Hemorrhoids may occur. Sometimes stool may leak out, especially when you are passing gas. Stool may be loose, or it may be especially hard.

If you have diarrhea for more than a few days, call your doctor. If the bleeding is copious, call your doctor.

Sexual

Semen will usually dry up soon after treatment, although there may be small amounts of fluid. Occasionally, you may see some blood in that fluid or a few drops of blood may drip out after orgasm.

You may notice that, over time, erections are not as hard or as long-lasting. To protect the blood vessels supplying your penis with blood, your doctor may have prescribed Viagra or a similar medication. You should continue to take that medication for at least 6 months after the end of treatment, even though it seems like you don’t need it.

Testosterone levels often drop following radiation, but may eventually return to normal levels. Because of this, you may notice a drop in the level of your sexual desire/libido. Some men experience difficulty reaching orgasm.

If any of the symptoms are bothersome, you may want to consult with a doctor who specializes in Sexual Medicine.

Inexpensive screening for germline mutations to personalize treatment

Pritchard et al. last year discovered that certain rare germline mutations that interfere with DNA-repair mechanisms occur with greater than expected frequency in men with aggressive prostate cancer. A "germline mutation" means that it is inherited from one's parents and is part of a man's normal genetic profile, for better or worse. By contrast, a "somatic mutation" means that it occurs only in tumor tissue and not necessarily in normal cells. There are several genes responsible for repair of our DNA. Their job is to fix random replicative errors as they crop up, and to cause cells that cannot be repaired to commit suicide (apoptosis) before they can become cancerous. When our inherited germline DNA repair genes are faulty, cancers may appear at any time and grow unchecked. They also can result in radio-toxicity because healthy cells can't fix the X-ray damage to their DNA and die off en masse. This is the case for ATM and ATR mutations that occur in both copies of the inherited genes (called "bi-allelic") When tumor DNA repair is faulty, as it often is, the cells become immortal, DNA errors proliferate and lead to such phenomena as EMT (cells able to exist outside of the prostate and migrate easily), castration resistance, and drug resistance.

The table below shows the incidence of several of the most important DNA-repair genes and their prevalence (1) in men with metastatic prostate cancer (2) in men with localized prostate cancer, and (3) in men in the general population who don't have prostate cancer. About 1 in 8 (12%) men who have detected metastases have a germline DNA repair defect. That falls to only about 1 in 22 men who have localized prostate cancer, and 1 in 37 men without prostate cancer.

It is only worth knowing about if there is something we can do about it. Someday we may have gene editing tools that can correct those aberrations throughout the body. CRISPR and Zinc Finger technology are in their infancy, and have only just started to be used in clinical studies for prostate cancer. The two medicines we have in our armamentarium against prostate cancer in those with germline DNA-repair defects are PARP inhibitors (e.g., olaparib, rucaparib, talazoparib, etc.) and platinum-based chemotherapy (e.g., carboplatin, oxaliplatin, etc.). (Update Oct. 2019) Recent trials suggest that only those with the BRCA1/2 mutations (and maybe CHK2) respond to current PARP inhibitors see this link).

Color Genomics

Color Genomics is a division of Genome Dx, the same company that offers the Decipher test. They are now offering a 30-gene panel listing the most frequently observed mutations in DNA-repair genes. It includes all of the genes listed in the table above plus other genes that have been implicated in other cancers (see the list here). They also look for aberrant TP53 and PTEN - two gene mutations that have been implicated in the loss of tumor suppression and loss of apoptosis, and are prognostic for aggressive prostate cancer variants. What is astounding is the price -- only $249! A full genomic analysis of BRCA2 would cost somewhere between $2,000 to $3,000. By limiting  their analysis to the most common site mutations, they are able to make it affordable, albeit not as thorough. It can be ordered by a physician (they will provide one if necessary). It is a simple saliva test that the patient mails in, and genetic counseling is included with the results.

(Update) The Color Genomics test is available free of cost to men who have a diagnosis of prostate cancer - they are building a registry database.  Interested patients can obtain it by putting their contact info in the website below. They mail a saliva test kit and pay for the return postage.

https://www.prostatecancerpromise.org/

Associated with other indicators of poor prognosis

A team at Johns Hopkins reported on their use of the Color Genomics test in 150 patients to determine whether germline DNA-repair defects were associated with two rare and aggressive prostate cancer variants: ductal and intraductal prostate cancer. They also looked for associations with lymphovascular invasion discovered at pathology. Velho et al. reported:

• Ductal/intraductal histology was discovered in 48% who had the defects vs only 12% who were free of those defects.
• Lymphovascular invasion was discovered in 52% who had the defects vs. only 14% who were free of those defects.
• 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines. (update note: NCCN has changed its guidelines)

Other tests

While 23andMe offers a germline test that the consumer can order without a doctor, it is inferior. There are, say, 10,000 or more genetic mutations that can occur within a single BRCA2 gene. 23andMe only looks at a narrow pre-defined range of genomic abnormalities, using a silicon SNP array. Color Genomics uses "next generation sequencing" to look at many more types of genomic aberrations. There are other tests available from AmbryGenetics and Myriad.

Those who test positive may wish to investigate a clinical trial of a PARP inhibitor:

• Olaparib (multiple US & Int'l locations)
• Niraparib + Zytiga vs Zytiga alone for mCRPC -multiple locations
• Olaparib + Keytruda (cohort A) mCRPC- multiple locations
• Olaparib + durvalumab recurrent - Memorial Sloan Kettering
• Olaparib + abiraterone - multiple sites
• Olaparib+ AZD6738 (ATR inhibitor) - U Mich
• Rucaparib (Phase 2) mCRPC - multiple sites
• Rucaparib +abiraterone or enzalutamide - sites TBD
• Rucaparib vs Zytiga/Xtandi/Taxotere(Phase 3) mCRPC - multiple sites
• Niraparib mCRPC - multiple sites
• Bavencio (PD-L1 inhibitor) + Talazoparib -mCRPC -multiple sites
• BGB-290 + Temozolomide - locally advanced/metastatic - multiple sites
• Olaparib + Xofigo -mCRPC - UCSD & Ohio State U
• Olaparib - recurrent - Baltimore, Omaha, Phila & Pittsburgh
• Jevtana, carboplatin then olaparib - aggressive variants - MD Anderson
• Talazoparib + Zytiga/Xtandi - mCRPC - multiple locations
• Talazoparib + Avelumab -locally advanced/metastatic - NY & AZ
• Talazoparib - mCRPC - multiple locations
• Rucaparib -mHSPC & ADT-naive- Johns Hopkins
• Rucaparib + carboplatin + docetaxel - mCRPC (allows somatic mutations)- UWashington Seattle
• Rucaparib - germline or somatic- UOP

Carboplatin trials specifically for men with DNA-repair defects:

• Docetaxel + Carboplatin - mCRPC - VA Hospitals, LA & Puget Sound
• Docetaxel + Carboplatin - mCRPC - UWashington Seattle
• Carboplatin - mCRPC - Zurich
• Carboplatin - mCRPC - UK

Most (7 out of 8) metastatic patients will learn nothing from this test and it will be a waste of money. But for some who seem to have an unusually aggressive prostate cancer variant, have ductal/intraductal histology, or have had lymphovascular invasion identified at pathology, it may be worth paying for the relatively inexpensive test. It may indicate that a platin may be a preferred form of chemo, or that a clinical trial of a PARP inhibitor may be warranted.

New Study: Adjuvant Radiation Saves Lives vs. Salvage

A major new study adds to several other studies that show that, for men with adverse pathology, adjuvant radiation (ART) within 3-6 months of prostatectomy saves more lives compared to waiting until the PSA rises into the range of 0.1-0.5 ng/ml - salvage radiation (SRT).

Three previous randomized clinical trials have shown an advantage to adjuvant radiation over a "wait-and-see" approach. However, only one of them (SWOG  S8794) showed that there was an improvement in freedom from metastases and overall survival attributable to earlier treatment. That study was limited in its generalizability because only a third of the "wait-and-see" cohort ever received salvage radiation. ARO-96-02 was designed to detect differences in progression-free survival (which were significant), but it was underpowered to detect overall survival differences. EORTC 22911 was designed to detect differences in progression-free survival (which were significant), but although it had a larger sample size, overall survival did not improve. Sub-group analysis showed the survival benefit was limited to men under the age of 70. A recent meta-analysis of the three trials showed that freedom from biochemical failure, freedom from life-long ADT,  and freedom from distant metastases were significantly improved by adjuvant treatment. But less than half of the men in the wait-and-see arms ever received salvage radiation, and 20-40% of  them never suffered a recurrence. All three trials used salvage radiation doses that would now be deemed too low. ART utilization rates are at an all-time low of 17% in men with adverse pathology.

What we really want to know is: what is the downside of waiting until the PSA rises to some arbitrary level, say 0.2 ng/ml? That is the subject of three randomized clinical trials, but we will not have the findings for several years. Meanwhile, some researchers looked at historical data in a new way to determine whether there is any evidence that might aid in decision-making.

Hwang et al. have pooled the databases from ten top institutions: Massachusetts General, Cleveland Clinic, University of Michigan, Duke University, Washington University, Mayo Clinic, University of Chicago, University of Miami, Virginia Commonwealth University, and Thomas Jefferson University. There were 1,566 patients who were treated between 1987-2013. Patients either had fully contained prostate cancer (T2) with a positive margin or extraprostatic extension (T3a)/ seminal vesicle invasion (T3b) with or without a positive margin.

They used a statistical technique called "propensity score matching" that in some respects resembles what would have resulted from a prospective randomized trial. Every patient who had ART was matched, in terms of patient characteristics, to a patient who had SRT. Patients are chosen randomly from among those with matched characteristics.  Patients were matched on age at surgery, year of surgery, Gleason score, T stage, margin status, postoperative ADT, and pelvic nodal RT. In this way, they were able to generate 366 matched pairs of patients. This technique works quite well in predicting outcomes of prospective randomized trials as long as there is a large enough sample size, considerable overlap in patient characteristics (which there was) and there aren't any prognostic patient characteristics that were missed.

The researchers found that all measured outcomes were significantly better among those who received ART:

• 12-year freedom from biochemical failure: 69% for ART vs. 43% for SRT
• 12-year freedom from distant metastases: 95% for ART vs. 85% for SRT
• 12-year overall survival: 91% for ART vs. 79% for SRT
• Patients who suffered biochemical failure were more likely to have had SRT, have been stage T3b, have had higher Gleason score, had not been treated with lymph node radiation, and had not had postoperative ADT.
• The advantage of ART was only lost if more than 56% of them would have been overtreated, but based on nomograms, no more than 46% would have been overtreated (using the assumption that 2/3 were GS 3+4 and 1/3 was GS 4+3).

Pending confirmation by the randomized clinical trials, this study is our best evidence to date that ART is preferable to SRT. However, there are a few very important caveats:

• They defined SRT as treatment when the PSA is in the range of 0.1 - 0.5 ng/ml. (They actually call this "early" salvage -- a term I would prefer to reserve for radiation when the ultrasensitive PSA (uPSA) is below 0.10 ng/ml.) For uniformity reasons in this 10-institution study, any PSA below 0.10 ng/ml on an uPSA test was deemed "undetectable," and those treated at very low PSAs were considered to have had ART. They had to use those definitions in their analysis because of the heterogeneous data set with PSAs recorded as early as 1987 (before there were any ultrasensitive PSAs). Because the risk of overtreatment with ART is high (they estimate 33%-52%), it behooves patients to track their post-prostatectomy PSA with an ultrasensitive test. We have seen that for men with adverse pathology,  any uPSA over 0.03 ng/ml reliably predicts that it will keep going up to 0.2 ng/ml (see this link). In men without adverse pathology, only a convincing pattern of PSA rises is prognostic.
• Adverse pathology in this study included anyone with positive margins, but others advocate that the length of the positive margin and the Gleason score at the margin are important considerations. A patient with focal positive margins and GS 6 at the margin may never need additional ART or SRT.
• They lumped together men whose PSA was undetectable but then climbed higher and men whose PSA was persistently elevated after prostatectomy. Persistent PSA with adverse pathology is a clearer indicator that gross amounts of cancer were left behind and calls for some quick action.
• The Decipher genomic test was not available throughout most of the study period. For those sitting on the fence, it may be a decisive factor.
• The newer PET scans (Axumin and PSMA-based) can find metastases if PSA is greater than 0.2 ng/ml. Multiparametric MRI may be able to find sites in the prostate bed or among the pelvic lymph nodes where tumor size is longer than 4 mm. Because of the advantage of earlier treatment, most men will require treatment before metastases become detectable. Some will be overtreated if the cancer is already systemic.
• Among very high risk patients (i.e., GS 8-10, seminal vesicle invasion (T3b) or invasion of nearby organs (T4), and very high persistent PSA) the probability that ART or SRT will be curative may be very low. Patients should understand what the population-based risk is from a nomogram.
• The radiation doses delivered were at a median dose of 66 Gy. More recent evidence suggests that higher doses may be necessary to achieve a cure. The value of adjuvant ADT and whole pelvic radiation suggested here has also been suggested by a number of other studies.
• This study excluded patients with detected positive lymph nodes. That is a clear indication for ART.

There are many factors to consider including comorbidities, continence and potency recovery. This will seldom be a straightforward decision. Patients with adverse pathology and uPSA over 0.03 ng/ml should be talking to a radiation oncologist and not a urologist.

Hyperthermia and Radiation

Many years ago, it was discovered that a moderate increase in tissue temperature can markedly improve the cancer cell killing power of ionizing radiation. The temperature increase needed is not extreme. It is only necessary to increase temperature from 37°C (98.6°F) to something in the range of 41-43°C (106-109°F), which is the just a little warmer than a hot shower. Like a hot shower, it brings more blood into the warmed tissues, which may be the reason for its benefit.

The Theory

Blood flows to warm tissue in an effort to carry away the excess heat. Skin and muscle can easily tolerate temperatures of 44-46°C for an hour or more in a limited volume. But cancerous tissue does not have a good blood supply, so the heat accumulates preferentially there and cripples those cells. Those cancer cells are more susceptible to killing by radiation (or chemotherapy). The increased blood flow also increases the oxygenation that is necessary for radiation to work,  while protecting healthy cells. There is also be a direct cancer cell killing effect attributable to protein denaturation and inhibition of DNA repair. By denaturing the proteins that activate DNA repair, the cancer cells undergo "mitotic catastrophe" when they try to replicate. Sublethal radiation damage becomes lethal. At the same time, cancer cells are directly destroyed via several other mechanisms: senescence, apoptosis, and necrosis.

When subjected to heat stress, cells, whether cancerous or healthy, release protective heat shock proteins (HSP) both inside the cell and into the extracellular space. HSP is responsible for thermal resistance, which is why hyperthermia is not used at every radiation sessions in most studies. (Negating the protective effect using HSP inhibitors is an active area of oncological research.) In the studies below, hyperthermia was given only a few times during the course of an extended radiation schedule. On the other hand, HSP in the extracellular space chaperones cancer antigens to the immune system. Much of the benefit is thought to arise from a bystander or abscopal effect.

Hyperthermia would ideally be delivered at the same time as radiation (see the brachytherapy study below). But it can also be delivered up to 3 hours before radiation. It has also been used within a short time after radiation because it renders lethal what would otherwise be sublethal damage, and because of immune stimulation.

Not all types of cancer cells are vulnerable to hyperthermia. In a lab study, it was shown that prostate cancer cells were sensitive to hyperthermia (and hypothermia). A mathematical model showed that raising the tumor temperature to 42°C and delivering 76 Gy of radiation would be equivalent in cancer killing to raising the radiation dose to 86 Gy - effectively adding 10 Gy of cancer-killing power without increasing toxicity.

While it's important to have a theoretical framework showing why it should be beneficial, it is more important to demonstrate that benefit in clinical practice. There are four situations in which combining hyperthermia and radiation may be useful in  prostate cancer treatment: (1) Primary prostate treatment, (2) Salvage prostate bed treatment, (3) whole pelvic treatment, and (4) Palliative treatment of metastases.

Primary Prostate Treatment

Many of the studies on hyperthermia + radiation occurred in the 1990s when radiation doses were usually inadequate for cure, and there have been no randomized studies. The few studies tell us more about treatment-related toxicity than efficacy.

Hurwitz et al.  used just two transrectal ultrasound hyperthermia treatments before radiation on 37 locally-advanced patients who also received 66 Gy of radiation and 6 months of ADT. They found that heating the rectal wall to 42°C for about an hour was tolerable, and they allowed the interior temperature probe to go up to 43°C for 10 minutes. Toxicity was mild, with no patients suffering from serious (Grade 3) urinary or rectal toxicity. There was no relation between late-term rectal toxicity and rectal wall temperature. There was a relationship with acute rectal toxicity, although there was no toxicity greater than grade 2 (see this link). The same authors also found that perfusion of blood into the prostate increased most among those with the most hypoxic prostate tumors.

With longer follow-up, Hurwitz et al. reported that two-year recurrence-free survival was 84% with hyperthermia compared to only 64% in historical controls without hyperthermia. 7-year recurrence-free survival was 61% with hyperthermia (they didn't have a comparable 7-year historical control). The authors noted a relation existed between the maximum heating achieved in a patient and his recurrence-free survival.

Maluta et al. reported on 144 patients with locally advanced prostate cancer treated with 74 Gy of conformal external beam radiation, with ADT used short term in more than 60% of those patients. Hyperthermic therapy was given once a week for the first four weeks of EBRT. They noted no significant side effects, other than those associated with ADT and radiation. There was no toxicity greater than grade 2.

Kukielka et al. reported on 73 prostate cancer patients  (54 primary therapy for low- and intermediate-risk, 19 locally recurrent after primary EBRT) treated with hyperthermia + high dose rate brachytherapy. They found no complications other than those normally associated with brachytherapy. There was no toxicity above grade 2.

It has been proposed that tumors within the prostate, identified with mpMRI or PET scan, can receive a hyperthermia boost prior to radiation. Tis may prove useful in overcoming hypoxia.

Salvage Prostate Treatment

Kukielka et al. separately reported on 25 locally radio-recurrent patients treated with hyperthermia + high dose rate brachytherapy. The brachytherapy dose was 30 Gy in 3 fractions, and hyperthermia was applied before each fraction. There were no complications higher than grade 2. Two-year biochemical control was 74%.

There is an ongoing trial in Europe of hyperthermia in patients receiving salvage radiation (70 Gy) using 41°C for 60 minutes in the prostate fossa.

With Dr. King's analysis that suggests that current post-prostatectomy salvage radiation doses (of about 70 Gy) are inadequate, there may be a unique opportunity to raise the biologically effective dose without increasing radiation toxicity.

Whole Pelvic Treatment

In 2005, Tilly et al. reported on 22 patients who received regional hyperthermia along with 68.4 Gy of radiation for locally advanced or recurrent prostate cancer. None had positive lymph nodes. Acute toxicity was high, while late toxicity was mild. Thermal parameters were not correlated with toxicity, but higher temperatures were associated with better PSA control.

This reflects an underexplored opportunity in both primary and salvage treatment, and especially when cancerous lymph nodes have been detected by pelvic lymph node dissection (PLND) or imaging. Because of toxicity considerations, the pelvic lymph node area is only treated with about 50 Gy of conventionally fractionated radiation, which may be inadequate to kill all traces of the relatively radioresistant cancer. Hyperthermia may be able to boost the effective cancer-killing dose. In addition, it can be used less broadly to radiosensitize any specific positive lymph nodes that have already been identified.

Metastasis-directed Treatment

Chi et al. reported the first clinical trial where 57 patients were randomized to receive hyperthermia along with their radiation (30 Gy in 10 fractions) of painful bone metastases. Those who received hyperthermia, received it within 2 hours after radiation treatments twice weekly for 2 weeks. Their hyperthermia system used radiowaves (RF) to heat the metastases to the target temperature for 40 minutes. Pain palliation was the goal. The trial was ended early because the adjuvant hyperthermia was clearly superior. Complete pain palliation after 3 months was achieved in 59% of those who received hyperthermia, but only 32% of those who received radiation alone. Among those who had a complete pain response, median time to return of pain was 55 days among those who received radiation alone, but was not reached in the 24 weeks of follow-up among those who received hyperthermia.

Hyperthermia Technologies

Historically, technology kept hyperthermia therapy from gaining wide acceptance. Patients often suffered burns.The hyperthermia did not penetrate deep enough, and could not be accurately maintained. There were no guidelines for its use, and it was labor intensive to closely monitor each treatment. With low-toxicity radiation dose-escalation achieved with IGRT/IMRT, there was less need for the adjuvant thermal treatment. There are several technologies used to achieve hyperthermic temperatures. Hurwitz et al. used transrectal ultrasound with multiple temperature probes. Kukielka used RF implants directly into the prostate done at the same time as the brachytherapy implants. Others have investigated implanted ferromagnetic seeds that heat up when exposed to an alternating magnetic field. Chi et al. used RF at the surface to warm metastases.

Temperature inside the body can now be monitored from measurements taken from the surface, rather than internal temperature probes. Hyperthermia is prescribed in terms of cumulative equivalent minutes at 43°C achieved in 90% of the target area (CEM43T90). For each °C above 43°C, the time required for an equivalent effect is halved; for each °C below 43°C, the time required for an equivalent effect is fourfold higher. Typical CEM43T90 is at least 10 minutes. It is difficult to maintain the hyperthermic temperature because blood flow is continuously trying to carry away the excess heat. The patient typically spends about an hour on the table.

The problem with RF and MW energy is that much of their energy is deposited at the skin, causing burns. Microwaves do not penetrate deeply but can pinpoint a small area. RF can go deeper, but can only be used in wider areas. Ultrasound (US) is the technological breakthrough that enabled hyperthermia to treat deeper and wider areas, and it allows for greater accuracy. Low frequency US can penetrate deeply. Multiple US beams can be made to converge at the target tissue without overheating adjacent tissue. The only drawbacks of US are that it is strongly absorbed by bone, and it is interrupted and reflected by air pockets. This means that the spine and bones of pelvis must be avoided. It can also not be used across the rectum, unless the rectum is filled with a water balloon.

Treating the pelvic lymph node area may be problematic. It is large area deep within the body which may be difficult to heat and keep heated for a therapeutic length of time. Also, pelvic bones must be avoided.

Many hyperthermia clinics use the Sonotherm 1000. Its US can penetrate up to depths of 8 cm, which should be adequate to reach the entire prostate, and prostate bed. Similar to a multileaf collimator and intensity modulation used in radiation, it has an array of US transducers that can shape and focus the beams.

Research Directions and Treatment Centers

Because radiation technology has progressed so rapidly, it is now usually possible to curatively treat most patients with dose-escalated radiation without dose-limiting toxicity. Still, there may be instances where gross tumors have been identified within the prostate. Those tumors may exhibit a relatively radioresistant Gleason pattern 5, or they may have poor blood flow. There are opportunities for using hyperthermia to increase the biologically effective dose in the post-primary radiation and post-prostatectomy salvage situation and, if the technology can be worked out, to the whole pelvic region where radiation doses have historically been held low to avoid toxicity. Adjuvant hyperthermia for metastasis-directed therapy for pain palliation looks like a very promising use.

Although adjuvant hyperthermia is more popular in Europe, there are several centers in the US that are using it, notably UCSF, Washington University, Cleveland Clinic,  Dana-Farber,  Duke, and Thomas Jefferson University. One private clinic I spoke with suggests daily treatments, for which there is  no substantiation, may render the therapy less effective, and seems to be a money-grabbing ploy.

It seems that the technology has improved to the point that randomized clinical trials should be instituted. There seem to be only two clinical trials currently running in the US. Mark Hurwitz at Thomas Jefferson University is lead investigator on a trial using salvage high dose rate brachytherapy with interstitial hyperthermia in patients who are recurrent after radiation. Joe Hsu at UCSF is running a similar trial that is no longer open to recruitment.

Adjuvant hyperthermia is now Medicare-approved. If not covered by Medicare or insurance, patients may pay about $900 per treatment.

Thanks to BJ Choi at The Center for Thermal Oncology for explaining their protocol.

Salvage SBRT after Prostatectomy

UCLA has announced a new clinical trial using SBRT for treating recurrent prostate cancer after failure of initial prostatectomy. This is the third such trial in the LA area, adding to the ones at USC and  City of Hope (no longer recruiting). The advantages to the patient are completing salvage radiation in just 5 treatments, and at a lower cost. But there are many issues that the lead investigators, Amar Kishan and Chris King, explored in a very detailed document that they kindly allowed me to see. The hope is that the increased biologically effective dose possible with extreme fractionation will increase cure rates without adding undue toxicity.

Eligibility

Patients are eligible if they had adverse pathological findings (i.e., Stage T3/4, positive margins, Gleason score 8-10, tertiary pattern 5), or PSA rising over 0.03 ng/ml. They are excluding anyone who exhibits distant metastases on a bone scan (M1) or positive pelvic lymph nodes discovered by dissection (pN1). They are allowing patients with non-surgical evidence of pelvic lymph node invasion (i.e., suspected because of a CT or a PET/CT).

Radiation Dose / adjuvant ADT

The treatment plan is:

• All patients will receive 34 Gy in 5 fractions to the prostate bed. 
• There may be a simultaneous boost dose of 40 Gy to any detected tumors in the prostate bed.  
• Optionally, they will also receive 25 Gy in 5 fractions to the pelvic lymph nodes. 
• Optionally, they will also receive 6 months of ADT beginning 2 months before radiation begins. 

While whole pelvic radiation and adjuvant ADT improve salvage radiation outcomes on the whole (see this link), they may not be necessary in all cases. A recent analysis suggested that adjuvant ADT only benefits those with post-prostatectomy PSA ≥ 0.4 ng/ml, Gleason score 8-10, Stage T3b/4, and those with high Decipher scores (> 1 in 3 probability of distant metastases in 10 years).

The prostate bed dose is biologically equivalent to 85 Gy using conventional fractionation (about 1.8 Gy per fraction). It is much higher than the typical salvage radiation dose of 67 Gy - 72 Gy in 37-40 fractions. It also exceeds by about 9% the dose used in a trial of moderate hypofractionation (discussed here). At the last ASTRO meeting, Dr. King presented the rationale for increasing the salvage radiation dose (see this link).  At the time, he proposed a randomized clinical trial using a dose of 76 Gy with conventional fractionation. The new protocol far exceeds that dose on the basis of biologically effectiveness, but they will compare outcomes to historical controls. The goal is to achieve a 5-year biochemical recurrence-free survival rate of 72%, compared to the historical level of 56%.

Toxicity

Salvage SBRT isn't just another form of salvage IMRT; IMRT is more forgiving. With IMRT, if there is a small misalignment, it is not a big deal -- the dose per fraction is small enough that a target miss caused by organ motion will not materially affect outcomes and will average out over time.

• Only devices that continuously track prostate bed motion during, and not just at the start of, each treatment, and that operate with extremely fast treatment times may be able to avoid all of the geographic misses. Image guidance is complicated when there is nothing for fiducials to grab onto.  This becomes an important consideration only at higher dose rates.
• Although the biologically effective dose (BED) for oncological control is higher with the SBRT protocol, the BED to healthy tissues (which causes toxicity) is lower. 
• For the tissues that may cause acute toxicity, the BED is a third lower compared to a 72 Gy conventionally-fractionated treatment. In a recent trial of 70 Gy salvage radiation, acute grade 2 and 3 urinary toxicity was 18%; acute grade 2 and 3 rectal toxicity was 18% as well.
• For the tissues that may cause late-term toxicity, the BED is about the same. Serious late-term toxicity was a rare event when 76 Gy was used for salvage in one study, but late term grade 2 toxicity was about 20% urinary toxicity and 8% for rectal toxicity. It is unknown whether the late-responding tissues of the bowels and urinary tract will suffer increased damage from the higher dose rates after longer follow-up.

SBRT as a primary treatment is different from SBRT as a salvage treatment.  There are also several considerations that arise more in the salvage radiation therapy setting than in the primary therapy setting:

• The bladder and rectum are no longer shielded by an intact prostate, so they are potentially exposed to greater spillover radiation. The prostate bed without the prostate is highly deformable, and rectal distension can change its shape markedly within seconds during the treatment. This increases the amount of toxic radiation absorbed by healthy tissues.
• The scar tissue of the anastomosis may become inflamed, leading to a higher risk of urinary retention or tissue destruction.
• The bladder neck, which may be spared during primary radiation and surgery, receives a full dose during salvage radiation therapy, increasing the probability of bladder neck contracture, urethral strictures, pain and incontinence. These problems may be amplified at higher doses per treatment.
• Erectile function is probably already impaired from the surgery. Neurovascular bundles, if spared by surgery, are far more exposed during salvage radiation.

We have had a couple of cautionary cases where SBRT toxicity has been extraordinarily high. In one, it was because the delivered radiation dose was too high. In the other, there may have been multiple causes.

There has been a study where conventionally fractionated salvage IMRT with a dose as high as 80 Gy has been used with low toxicity. A recent study using moderate hypofractionation for salvage (51 Gy/ 17 fx) also boasted low toxicity levels among treated patients.

They will monitor both physician-reported toxicity and patient-reported toxicity (urinary, rectal, and sexual). If the rate of grade 3 (serious) toxicity is higher than 20%, accrual will be halted and the study subjected to careful review. If the rate is higher than 30%, the study will be terminated.

Dose Constraints

The investigators have put together a set of very tight dose constraints for organs at risk. Organs at risk include the bladder, the front and back of the rectum, the small intestines, the penile bulb and the femoral head. They also included "point dose constraints": the maximum radiation exposure to even a millimeter of the organ at risk. Because of individual anatomy, it may not always be possible to simultaneously meet all dose constraints. In those cases, the physician will decide if the deviation is material, and if it is, he may lower the dose as low as 30 Gy.

Image Guidance

The prostate bed consists largely of loose and highly deformable tissue. Although some radiation oncologists (e.g., at UCSF) use fiducials or transponders for salvage image guidance, most find that they do not stay in place. This has not been a big issue for salvage IMRT because a few "misses" will not contribute materially to toxicity, but it may be a larger issue for salvage SBRT. One way around this is to have the doctor monitor the position of the soft tissue throughout each treatment, and manually realign the beams whenever the position of the tissues deviates from the planning image. The problem is that  manual realignment is time consuming. The patient is lying on  the bench with a full bladder, which may be difficult to hold in. Also, the more time that passes during a treatment, the more opportunity for bowel motion to occur. The lack of intrafractional image guidance remains a concern in this clinical trial that the investigators are well aware of.

A related issue occurs when the pelvic lymph nodes are simultaneously treated. The lymph nodes may move independently of the prostate bed, so it may be impossible to hit both areas simultaneously with pinpoint accuracy. The investigators are using the pelvic bones as landmarks.

Most importantly, all patients must have a full bladder to lift it up and help anchor organs in place. in addition, enemas are required before each treatment, and if the bowels are at all distended, treatment will be discontinued.

Risks

As with any clinical trial, patients take a risk in trying a new treatment. There is also a learning curve that doctors go through in trying out a new therapy.  I, myself, chose to participate in a clinical trial of primary SBRT when there were only 3 years of reported data. I judged the potential benefits worth the risk for me. It was also important to me that the treating radiation oncologist (Dr.King) had been using SBRT for prostate cancer longer than anyone else. Every patient should be well aware of the risks before agreeing to participate in a clinical trial. Patients who are looking for a shorter duration treatment with less toxicity risk may wish to be treated at the University of Wisconsin or in a clinical trial at the University of Virginia (discussed here).

Ac-225-PSMA-617 (update)

We now have some details of the clinical trial of Ac-225-PSMA-617 in advanced prostate cancer patients. Kratchowil et al. reported on 40 patients who received this treatment at the University of Heidelberg. All patients had failed multiple therapies and were expected to have 2-4 months median survival (see this link). They received 3 cycles of Ac-225-PSMA in two-month intervals.

• 11 patients did not complete 3 cycles
• 5 discontinued due to non-response
• 4 discontinued due to xerostomia (dry mouth)
• 2 did not survive 8 weeks.

Among the 38 surviving patients:

• 87% had some PSA decline
• 63% had a PSA decline greater than 50%
• Tumor control lasted 9.0 months (median)
• 5 patients had a response lasting more than 2 years
• Previous therapies with abiraterone lasted 10.0 months, docetaxel lasted for 6.5 months, enzalutamide for 6.5 months, and cabazitaxel for 6.0 months

These outcomes are impressive for a therapy given when all other therapies have failed. It is unclear whether it is better than Xofigo, the only approved radiopharmaceutical for metastatic castration-resistant prostate cancer. Xofigo only attacks cancer in bones, whereas Ac-225-PSMA attacks prostate cancer anywhere in the body.

(Update 5/19/2019)

Sathekge et al. reported the outcomes on 73 mostly chemotherapy-naive and abiraterone/enzalutamide-naive metastatic castration-resistant patients treated with Ac-225-PSMA-617 in South Africa. Most patients had 3 treatment cycles (every 2 months). Subsequent doses were lower to prevent side effects. PSA and metastatic activity was tracked using Ga-68-PSMA-617 PET scans.

• 83% of patients responded to treatment
• in 70% of patients, PSA declined by over 50%
• PSA declines of over 50% predicted longer progression-free survival and overall survival
• In 29% of patients, all lesions disappeared
• During follow-up, 23 patients (32%) had disease progression and 13 (18%) died of prostate cancer
• Progression-free survival was 15 months (median)
• Overall survival was 18 months
• Xerostomia (dry mouth) occurred in all 85% of patients, but it was not severe enough to stop treatment
• Anemia occurred in 27 patients (37%); none grade 4
• Grade 3 or 4 renal toxicity occurred in 5 patients with pre-existing renal impairment

This study suggests that Ac-225-PSMA-617 can be beneficial in patients who have not been heavily pre-treated. It also shows that xerostomia can be mitigated by reducing the subsequent doses given, and that for most patients, side effects are not severe enough to stop treatment. Lu-177-PSMA is now in a Phase 3 clinical trial at multiple sites in the US.

When can ADT be safely avoided with salvage radiation therapy?

Two randomized clinical trials (GETUG-AFU-16 and RTOG 9601) proved that adding at least some ADT to salvage radiation (SRT) improved outcomes. "Some ADT" was 6 months of goserelin in the GETUG-AFU-16 trial, and two years of bicalutamide in the RTOG 9601 trial. Retrospective studies suggest improved outcomes as well (see this link and this one). On the whole, adjuvant ADT improves SRT outcomes. But is there a subgroup of patients, especially those treated early enough, in whom adjuvant ADT can be safely avoided?

This was the subject of a retrospective analysis by Gandaglia et al. They examined the records of 525 post-prostatectomy patients treated with SRT at six international institutions between 1996 and 2009. Inclusion criteria were:

• Undetectable PSA (<0.1 ng/ml) after prostatectomy
• Biochemical recurrence - two consecutive PSA rises above 0.1 ng/ml
• PSA mostly ranged from 0.2 to 0.9 ng/ml (median 0.4) at the time of SRT
• No detected lymph node metastases

There were 178 patients who received adjuvant ADT (median 15 months) and 347 who had SRT without ADT. Compared to those who received no ADT, those that did were:

• Similar in age, initial (pre-op) PSA, and Gleason score
• More likely to be stage T3b/4
• Less likely to have positive margins
• Received higher SRT dose (70 Gy vs 66 Gy)

There were 8 years median follow-up for those who had no ADT, and 12 years median follow-up for those who had adjuvant ADT. The authors compared the actual 10-yr metastasis rate to the predicted 10-yr metastasis rate based on PSA at SRT, Gleason score, stage, positive margins, SRT dose, and whether lymph nodes were treated. They found that:

• Only those with a 10-year probability of distant metastases greater than 1 in 3 benefited from the addition of ADT
• The benefit grew exponentially with increasing risk
• Adjuvant ADT only benefited those with higher PSA (≥0.4 ng/ml), Gleason score 8-10, stage T3b/4. 
• Higher SRT dose and whole pelvic SRT improved outcomes independently of whether adjuvant ADT was used.

It should be noted that high-dose SRT and whole pelvic treatment were used in a minority of cases, and there is a significant risk of selection bias in this study.

The authors conclude that a higher radiation dose alone may be sufficient to treat many patients with a recurrence detected early enough, but for those with aggressive tumor characteristics, adjuvant ADT will improve outcomes measurably. While this was not proved with a randomized trial, it does suggest that adjuvant ADT will not be necessary in all cases of SRT. Patients who are undecided may wish to have a Decipher genomic classifier done on their prostate tissue to determine their 10-year risk of metastases.