Category: PCa Commentary

PCa Commentary #113: OLIGOMETASTATIC PROSTATE CANCER — METASTASES DIRECTED THERAPY: Where Do We Stand?

A clinically meaningful goal of MDT is the postponement of androgen suppression therapy, while the more lofty goals would be to prolong survival or affect a cure in some patients. Current research is refining the criteria for selecting those men who will benefit most.

MDT targets isolated lesions that emerge following primary therapy.  In most studies to date this involves treating three or less but possibly five lesions with surgery or “spot welding” the metastases with focused radiation such as CyberKnife.

It has been two years since the Commentary discussed this issue in the March-April 2015 volume PCa Commentary Vol 92, 2015 and concluded “MDT is a promising approach for oligometastatic recurrence … but should not be considered the standard of care.”  Many studies have been reported since then.

What has been learned? 

We’ve learned that MDT is still not applicable for most instances of recurrent cancer, but there may be some selected men where MDT may significantly delay the need for androgen suppression. An important current debate is whether MTD should stand alone or be accompanied by androgen suppression.

The evolution of more sensitive imaging techniques is altering the detection of “oligometastatic cancer.” Most early studies relied on CT and technetium bone scan imaging both of which lack sensitivity. Currently the 11C-choline PET/CT (and similar tracers such as 11C-acetate) are serving as the basis for more sensitive detection, but even these scans will be superseded by application of the 68Gallium-PSMA PET/CT, for which currently there are no reported study outcomes.

The issue of imaging accuracy was discussed by Dr. Piet Ost, Ghent University, Belgium, a leading investigator of MDT.  In his interview in Dr. Charles Myers’ Prostate Forum, Vol. 17, No. 7 Dr. Ost made the following points:

  • In contrast to CT and bone scans, which most often require the PSA to rise above 10 ng/mL for adequate detection, now metastases are detected at PSA levels of 2 – 5 ng/mL by PET/CT scans utilizing tracers incorporating Carbon (C)-11 Fluorine and  (F)-18 isotopes. Most recently, 68Ga-PSMA PET/CT appears to have lowered the PSA level at which metastases can be detected to around 1 ng/mL.
  • The result: “We’re diagnosing a higher percentage of patients with a limited number of metastases.”  “If you try to divide these patients into those with Oligometastatic [i.e., <3]  and poly-metastatic disease, we see up to 60-70% of our patients in a recurrent setting diagnosed with a limited number of metastases at very low PSA levels.”

Does an intermediate disease state — oligometastatic cancer — exist and can it be treated with localized therapy to the benefit of the patient?

The concept that there is an “oligometastatic state” — one with restricted metastatic capacity having unique biologic characteristics — interposed between cure and widespread metastatic disease was hypothesized in an editorial by Hellman and Weichselbaum, J Clin Oncol, 1995. A thoughtful recent editorial by Tran and Antonarackis of Johns Hopkins “Altering the Natural History of Oligometastatic Prostate Cancer with Local Therapies: Reality Versus Illusion, J Oncol Practice, 2017, addresses this question:  “… is there a biologic difference between hormone-sensitive oligometastatic prostate cancer and polymetastatic prostate cancer,” i.e., are the 3 – 5 lesions addressed with MDT only the forerunners of yet to emerge more widespread cancer?

To date, however, a molecularly distinct biologic or genomic profile for this condition has not been established. The authors point out the need for “an understanding of the early metastatic process before the inevitable changes have developed in men with metastatic castration-resistant prostate cancer after the heavy selective forces of multiple systemic treatment regimens.”

Therefore, currently the definition of “oligometastatic” remains clinical.

Unanswered questions:

On the clinical level, however, the major questions are:

  • Can MDT delay ADT and for how long?
  • Which men are the best candidates for MDT, and are there prognostic markers that can guide optimal patient selection?
  • Can the unresolved issue of whether to perform MDT with or without concomitant ADT be clarified?
  • And lastly, can MDT extend prostate cancer-specific survival and delay the on onset of castration-resistance in comparison to the conventional practice of commencing ADT at the onset of the diagnosis of metastatic disease?

Of the many reported studies, two examples will suffice.

  1. “Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study,” Trigging et al., British Journal of Cancer, April 2017.

This study reports the outcome of MDT in 100 men who relapsed following primary therapy and were diagnosed with < 3 isolated lesions based on a 11C-choline PET/CT (96%) or a combination of CT and bone scan (4%). The median PSA at initial diagnosis was 9.8 and at recurrence, 2.4 ng/mL. The risk categories of the men based on D’Amico staging were:  low, 5%; intermediate, 21%; high, 43%; and very high, 31%. The number of lesions treated was one, 87%; two, 9%; and three, 4%. The mean time from primary therapy to metastases was 43.9 months.

The distribution of lesions were 15.8% in bone and 84.1% in lymph nodes, the majority of which were in the template used for extended lymph node dissection, except for 24.4% in the paraortic nodes.

What was the outcome The median post SBRT PSA was 0.81 ng/mL. PSA doubting time (PSA DT) was a predictor of ADT-free survival. Of those men with a doubling time of <6.4 months 42.9% and 21.4% were free of ADT at 1 and 2 years. In those men with a PSA DT of >6.4 months, freedom from ADT was seen in 71.5% and 51.2% at 1 and 2 years. Those men with Gleason score 7 or less fared better than those with a higher Gleason scores.

Comment: This study, with its very well-studied and numerically sufficient patient cohort can easily serve as a model for patient selection and treatment outcome, offering in selected men a useful delay of ADT.

2. The second example comes from Dr. Ost and colleagues: “Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis,” European Oncology,

“We focused on patients who were treatment naive, with the aim of determining if SBRT could delay diseases progression” — both distant and local, with a goal of estimating the delay in the start of ADT.”  SBRT was used to treat 119 study patients with three or fewer lesions. The risk categories were skewed to higher risk men. Imaging was performed with 11C-choline PET/CT in 92 men and with 18F-FDG PET/CT in 24. One lesion was targeted in 72.3%; two in 18.5%, and three lesions in 9.2%.  The primary site of metastases was in lymph nodes in 60% of patients (10% beyond the pelvis) and in bone 36% and viscera 3%. The median PSA at the time of metastases diagnosis was 4 ng/mL and the median interval after primary therapy was 4.7 years. The median PSA DT at the time of metastases was 3.9 months (range 2.9 – 6.9). Half of the cohort received a median duration of ADT of 2 months.

What was the outcome?  The 3- and 5-yr distant progression-free survival was 31% and 15% before starting ADT.  Local control was achieved in 93% and 92% at 3 and 5 years. The median time before starting ADT was 28 months. No grade >3 toxicity was observed.

Their conclusion: “SBRT for oligometastatic PCa recurrence is safe and associated with a prolonged progression-free interval. This is likely to result in a clinically meaningful period without ADT in patients with metastatic disease.”

A Randomized Trial Is Needed …  and a well designed one has completed accrual and data is maturing.

A reasonable criticism of the studies to date is that all were retrospective and subject to “lead time bias,” a misleading conclusion that an earlier diagnosis yields a better ultimate outcome compared to the same disease detected at its usual clinical presentation.

These issues have been addressed in an important protocol conducted by Dr. Ost with European collaboration. The title of the trial is “Non-systemic Treatment for Patients with Low-Volume Prostate Cancer,” NCT01558427. In this small trial 58 men were imaged with a 11C-choline PET/CT after relapse following local treatment with curative intent. Those with three or fewer isolated lesions were randomized between half who received MDT and were followed for PSA progression and those followed for progression without MDT. Follow-up PET/CT imaging is prescribed at a set rise of PSA or symptoms. In the event of local or distant disease progression or symptoms ADT is started. Patients have been stratified on the basis of a PSA DT of greater or less than 3 months and the initial location of the metastases.

The primary endpoint is to determine the interval in each cohort before ADT is required. Secondary endpoints are prostate cancer-specific survival and overall survival. As described by Dr. Ost, “One of the goals of this approach is to delay the start of palliative androgen deprivation therapy (ADT), with its negative impact on quality of life.” “The inclusion of an active surveillance arm will improve our insights into the natural progression of oligometastatic PCa.” (Ost et al., BMC Cancer, 2014)

A protocol of similar design (NCT02680587), but using a PSMA tracer, is sponsored by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and is currently recruiting participants (target: 54 men). The study’s completion date is estimated to be October 2018. Contact physician: Phuoc Tran, MD, PhD at tranp@jhmi.edu

BOTTOM LINE:

Progress has been made in the last two years in defining the best candidates for metastases directed therapy. A meaningful delay in the start of ADT of more than 2 years has been estimated for those men. A currently maturing randomized trial is an effort to validate these findings.

PCa Commentary #112: (68)Gallium-PSMA-11 PET/CT: What Can It Tell Us That We Ought To Know (and Don’t)?

We are beginning to recognize that prostate cancer is a much more subversive adversary that we have conventionally thought. This awareness is largely coming from information from studies with the total body PSMA PET/CT. The (68)Ga-PET/CT is rapidly becoming the gold standard for prostate cancer imaging. There is ample support in the literature to establish that the PSMA PET/CT outperforms in accuracy the (11)C-choline, (11)C-acetate, the Axumin, and (18)F-FDG PDT/CT scans. Importantly, the PSMA PET/CT performs well at low PSA values, i.e. < 1 ng/mL, where the awareness of early disease spread allows appropriate management decisions.

A quote of Fabio Almeida, MD, the Medical Director of the Phoenix Molecular Imaging and Southwest PET/CT Institute and a guru in the field especially as regards the (11)C-acetate PET/CT, offered an assessment of the future of the PSMA PET/CT: “Despite some limitations, PSMA-targeted imaging appears to provide high sensitivity and specificity, and is likely to become part of the routine evaluation and management of men with prostate cancer in the near future,” December, 2016, in the Prostate Cancer Research Institute document “Overview of Positron Emission Tomography (PET) Scans.”

A very large number of reports have been published, especially in the European literature, regarding the results of the (68)Ga-PSMA PET/CT at various stages in the progression of the prostate cancer. This Commentary, however, will focus on the PSMA scan findings at points of high clinical relevance: 1) biochemical recurrence at a PSA of >0.2 ng/mL, the threshold for “biochemical failure” following surgery; 2) PSA values of <0.5 ng/mL, the point below which salvage radiotherapy is recommending following biochemical recurrences after surgery (RP); and 3), PSA values above the “Phoenix” criteria for biochemical failure, i.e. a PSA of 2 ng/mL above the nadir PSA after radiation therapy (RT).

Executive Summary

For those readers who need to cut to the chase, the 32 studies reviewed for this Commentary uniformly make two important points:
1) the (68)Ga-PSMA scan provides information about the location and extent of prostate cancer at clinically significant low PSA values      of <1 ng/mL , information not available with other scans based on cancer morphology or metabolism, and
2) this information can substantially change management decisions compared to pre-PSMA treatment plans.

What does the PSMA PET/CT reveal following surgery at PSA values above 0.2 ng/mL, the consensus threshold for biochemical failure?

  • A major study addressing this point came from Ali-Afshar et al. University of Heidelberg: “The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer,” Eur j Nuc Med Mol Imaging, 2015. A total of 319 patients were scanned after surgery (226) or radiation (89), 27 prior to salvage RT, and 38 prior to radioisotope therapy with 177-Lutetium radiolabeled PSMA. Of interest, the rate of positive scans in men being evaluated for suspected recurrence who had Gleason scores of 7, 8, and 9 were 80%, 79%, and 92.5%, respectively. In this group 82.8% (264/319) showed at least 1 lesion.

The probability of a positive scan in relation to the PSA at the time of the scan was:
50% (5/10) at PSA 0.21 – 0.5 ng/mL

58.3% (14/24) at PSA 0.51 – 1.0 ng/mL

71.8% (11/39) at PSA 1.1 – 2.0 ng/mL

85.9% (9/73) at PSA 2.1 – 5.0 ng/mL

Of the total of 910 individual lesions detected, 13 were local following RP, 328 were lymph node metastases, and 129 soft tissue metastases. Following radiation, lesions within the prostate gland were noted in 72 men either at recurrence post RT or as part of the initial work-up to exclude metastases.

Management decisions were guided by the PSMA scan findings: Of 116 patients where follow-up information was available 50 received local treatment (27 – focal radiation to PSMA positive sites, 19 – operated, 4 – HIFU); 34 were treated with 177-Lutetium-labelled PSMA; and 36 received ADT and/or chemotherapy.

  • Another major article was focused on: “Evaluation of Hybrid (68)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy,” Eiber et al. J Nuc Med, May 2015. Detection was greater in patients with Gleason score 7 or less vs 8 or more. The median PSA of the group was 1.99 ng/mL and 89.5% had suspicious lesions detected on the PSMA scan. The detection rate at PSA levels was: 0.2 – <0.5 ng/mL – 57.9%; 0.5 – <1.0, 72.7%; 1 – <2 ng/mL – 93.0%; and at PSA values > 2, 96.8%. These results are “substantially higher than those reported for choline-based tracers …”

The study observed that the PSMA PET/CT scan exclusively provided relevant diagnostic information” in 32.7% of patients and in 24.6% of patients “was able to identify additional involved regions compared to 6.9 % where the CT showed additional positive regions. At PSA > 2 ng/mL the detection rate in the Eiber study was 96.8%. This is toward to lower range for the Phoenix threshold of recurrence after radiation therapy.

The Eiber conclusion: “PSA relapse after RP is a common clinical scenario. In this context, biochemical failure defined by a confirmed PSA values of >0.2 ng/mL after RP occurs long before recurrent disease can be localized clinically or by imaging.”

What does the PSMA PET/CT reveal following radiotherapy with curative intent?

  • A study by Meredith et al., BJU Int, 2016, addresses this issue: “The use of (68)Ga-PSMA PET/CT in men with biochemical recurrence after definitive treatment of acinar [i.e., the common type] prostate cancer.” The detection rate in relation to the PSA values was reported in 107 men treated with either external beam radiotherapy or brachytherapy:

At PSA levels: 0.01 – <0.2 the detection rate was 33.3% (1/3);

At PSA between 0.2 – <0.5, 71.4% (5/7);

For PSA between 1 – <2, 93.3% (14/15); and

At PSA >2 ng/mL, 100% (82/82) had a positive scan.

At PSA values above 2 ng/mL 45% had suspected lymph nodes, of which 45% were outside the pelvis. These are small numbers, but the message is that well before the Phoenix criteria is met there is substantial spread, as was also indicated in the Ali-Afshar study.

  • Einspieler et al. (J. Nuc. Med., 2017) reported on the detection rate of (68)Ga-PSMA in 118 patients with biochemical failure after primary radiation defined by the Phoenix criteria. In the PSA range post treatment of 2 to <5 ng/mL 81.8% showed pathologic findings on scan. In their full study range of 2 to <10 ng/mL: 63.5% recurrences were local, 59.8% were only distant, and 23.4% were both local and distant.

To provide some perspective on the relatively poor effectiveness of the Phoenix criteria for detecting spread early there is a study from the Mayo Clinic (Klein, Tendular et al., Int J Rad Oncl, Biol, Phys, Jul 2016). They reported that 0.1 ng/mL was the median nadir at 6 months after highdose radiation therapy for men with intermediate- and high-risk cancer. At 6-months 58.3% had a PSA of < 0.1 ng/mL. A recent German Study of men treated with stereotactic radiation found the “median nadir for all patients was 0.3 ng/mL for all patients, and 0.6 ng/mL for patients without hormone therapy (Stralhlentherpaie und Onkologie, July 2016). These low median PSA nadir suggests that by employing the Phoenix criteria, the PSA is allowed to rise, with its consequent spread, in the majority of cases from PSA levels such as 0.1 ng/mL to slightly greater than 2 before “biochemical failure” is declared. The PSMA scans clearly show a greater extent of spread at or above the Phoenix definition of biochemical failure as compared to the surgical threshold of 0.2 ng/mL or less. Perhaps awareness of this difference led Merrick, Wallner et al. (Int. J. Rad. Oncol. Biol. Phys., 2007) in their study of brachytherapy therapy to set the criteria for biochemical failure following radiation at > 0.40 ng/mL after nadir and not at the Phoenix level.

(68)Ga-PSMA-11 PET/CT findings influence and change pre-scan management decisions.

Because of the current imaging inadequacy of the conventional CT and bone scans to detect early recurrences following primary surgery or radiation, clinicians have been deprived of the necessary information to make evidence based decisions. Multiple studies have shown that information exclusively available based on PSMA PET/CTs have changed clinical management in greater than 50%, or in one study in 76% of cases, from the treatment planned before the PSMA scan findings were known.

A variety of treatment options were offered in the Ali-Afshar study based on the finding of early spread. Among 116 patients with follow-up, “… 40% could be treated locally with resulting delayed systemic therapy.” Fifty patients received local treatment: 27 received focal radiation to PSMA positive sites, 19 were operated, 4 were treated with HIFU; and 34 underwent therapy with 177Lutetium-labelled PSMA; and 36 received ADT and/or chemotherapy. “We believe that such patients who can delay systemic therapy have a greater potential for improved quality of life.”

BOTTOM LINE:

It is likely that the (68)Ga-PSMA PET/CT will become the gold standard for early detection of lowvolume prostate cancer Emerging Technology Advances Staging Accuracy PCa Commentary Feb 2017 [control+click to follow] but, if detecting prostate cancer much earlier than is currently possible only leads to the earlier application of androgen suppression, not a great deal will have been accomplished, considering that ADT runs its course over middle range of 2 – 4 years before inviting castration resistance. Our efforts now should be directed toward treatments that can be effective at low tumor burdens, such as immunotherapy, alone or in combination, i.e., the clinical trial NCT02463799 combining Provenge with Xofigo; or targeted radiotherapy with stereotactic body radiation, or radioisotope therapy targeting the PSMA molecule, such a 177-Lu PCa Commentary March 2017 Lutetium-177 a promising radioisotope [control+click to follow] as offered on protocol at Cornell Medical College by Dr. Tagawa. The stem and progenitor cells should be next in line in the crosshairs.

PCa Commentary #111: The AR-V7 Splice Variant; Circulating Tumor Cells; and Prostate Management Decisions: Ready for Prime Time?

Blood analysis for the androgen splice variant 7 (AR-V7) in circulating tumor cells (CTCs) is now commercially available at Johns Hopkins. The possibility for a man to learn his AR-V7 status now directly focuses attention on the clinical importance of AR-V7 and how it might directly affect the choice between taxane (i.e. Docetaxel or Cabazitaxel) chemotherapy or androgen receptor inhibition with, say, Zytiga or Xtandi. This decision is commonly faced by many men whose PSAs are rising after primary treatment despite androgen deprivation therapy (ADT), i.e. men with “castration-resistant prostate cancer” (CRPC), non-metastatic or metastatic.

[An order form and instructions for sending a specimen to the Hopkin’s lab is available upon request to ecweber@nwlink.com.]

Circulating tumor cells:

CTCs are a rare population of cells in blood which are in dynamic equilibrium with the totality of the cancer, reflecting the genome of the primary tumor but also expressing the mutational landscape of the progressively evolving heterogeneous tumor burden. Sophisticated techniques permit genomic analysis of single cells, or aggregated pools of cells; but also snippets of messenger RNA, and even circulating free DNA.

The identification and enumeration of CTCs has been well studied (usually by the CellSearch method) and is recognized to offer important prognostic and predictive information. However, this article will focus on the molecular characterization of CTCs, in particular AR-V7 and its clinical consequence.

“All roads lead to Rome.”

The androgen receptor (AR) is the common nexus of all hormonal interventions directed toward subverting the AR signaling that promotes prostate cancer growth. It is the ligand binding pocket of this lengthy protein into which testosterone (T) and dihydrotestosterone (DHT) fit to initiate the AR signaling to its many androgen response DNA targets. And it is this pocket that antiandrogens such as Zytiga and Xtandi block to inhibit such signaling.

The AR-V7 splice variant:

AR-V7 is not a naturally occurring gene but a modification of the basic AR gene and codes for a “splice-variant,” a truncated form of the full-length AR. This variant form (there are > 20 AR splice variants) lacks the crucial binding pocket for T and DHT. The AR-V7 gene is present at a low percentage early in the disease but is increasingly over-expressed as the disease becomes more aggressive.

Additionally, its over-expression is progressively induced as a result of sequential anti-androgen therapy, i.e. Zytiga and Xtandi. The subversive behavior of these variants is that they are “constitutively” active, meaning that they promote adverse AR signaling even though lacking the ligand-binding pocket.

AR-V7 is not a mutation, so it is not captured on the standard genomic tests, such as Guardant360, FoundationOne Medicine, or Caris Life Sciences, which all report on the important mutations in genes; genes such as BRCA1 & 2, in which mutations might lead to the protocol use of the parp inhibitor, Olaparib; or the retinoblastoma (RB) gene which might alert to the transition to neuroendocrine differentiation.

Androgen-receptor variant 7 messenger RNA (mRNA) can be detected in circulating tumor cells by a quantitative reverse-transcriptase-polymerase-chain-reaction assay [RT-PCR] or by an antibody directed at the AR-V7 protein.

Clinical Application: What Does a Positive Test for AR-V7 imply?

The lead introduction to this issue was presented by Antonarakis and his colleagues from Johns Hopkins in the New England Journal of Medicine, Sept 2014: “AR-V7 and resistance to enzalutamide [Xtandi] and abiraterone [Zytiga] in prostate cancer.”

Their study prospectively analyzed men with metastatic CRPC (mCRPC)
 31 treated with enzalultamide (39% positive for AR-V7 in CTCs) and
 31 abiraterone treated patients (19% positive).
 The result: The PSA response (defined as > 50% PSA decline from baseline) was

  • 0% v 58% for AR-V7 positive v negative men in the enzalutamide group, and
  • 0% v 68% in the abiraterone cohort, respectively.
  • Poorer outcomes by various measures reflected these differences.

In JAMA Oncol, Aug 2015, the Hopkins group reported on men with mCRPC starting taxane therapy and concluded the presence of AR-V7 was “not associated with primary resistance to taxane therapy.”

  • “Of 37 taxane-treated patients enrolled 17 (46%) had detectable AR-V7 in CTCs.” The PSA response to taxane therapy in AR-V7-positive vs AR-V7-negative men was 41% vs 65%; P=.19, i.e., not considered statistically significant.
  • This 41% PSA response in AR-V7 positive patients is to be compared to the 0% PSA response to Zytiga or Xtandi in the men reported by the Hopkin’s group in the 2014 article (see above). However, “… in AR-V7 negative men, taxanes and enzautamide and abiraterone may have comparable efficacy.”

The original Hopkin’s study group of 62 was expanded to 202 men with mCRPC and reported on at the 2016 ASCO Annual Meeting in Abstract 5012.

  • They subcategorized the PSA response into three groups: men in whom CTCs were not identified; CTC+ AR-V7 negative men; and CTC+ AR-V7 positive men.
  • PSA responses were 75%, 52%, and 14%, respectively.
  • When either enzalutamide or abiraraterone were used first-line, those who were CTC+ AR-V7+ had a 27% PSA response; whereas when either drug was used secondarily the response was 5%.
  • Their finding showed, as have many other studies, that identifying CTCs (usually expressed as > or < than 5 CTC/7.5cc blood in the CellSearch system) conferred a poorer prognosis independent of AR-V7 status. In the Hopkins study. “CTC+AR-V7+ pts were more likely to have Gleason >8, M1 [metastatic] disease at diagnosis, higher PSA, prior Abi/Enza use, prior taxane [Docetaxel chemotherapy] use” and a poorer performance status.

In Abstract 183 (ASCO 2017, GU Cancer Symposium) by the Hopkins group their premise was “The AR-V7 splice variants may confer resistance to AR-directed therapies but not taxane chemotherapies” [Docetaxel and Carbazitaxel].

  • They queried 100 clinicians who had submitted blood for AR-V7 analysis from men with mCRPC and provided patient histories.
  • The data confirmed that the percentage of AR-V7 increases through sequential therapy.
    • Patients who had had neither prior Zytiga nor Xtandi were positive in 29%;
    • Those who had either of those drugs were positive 39%, and
    • If both drugs had been used, 62% were AR-V7 positive.
    • Finding: Clinicians most often chose taxane therapy in patients found to be AR-V7 positive.

Studies on this clinically important issue are ongoing. However, the observation of the adverse effect of response to hormone therapy in the circulating tumor cells of AR-V7 positive men was further confirmed by Scher et al. from Sloan-Kettering, JAMA Oncology, June 2016: “The results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS [androgen receptor signaling] – directed therapy in a clinical practice setting.”

Of interest, the analytic method used for the Scher study was different from the Hopkin’s technique. The Scher assay method was based on a rabbit monoclonal antibody staining of nuclear AR-V7 protein. This test will become commercial available later this year from EPIC/Genomic Health, Inc. It is easily conceivable that the two techniques measure slightly different forms of AR-V7 and might give different percentages of AR-V7 when tested on the same population. It is essential to know more about this. Dr. Antonarakis (personal communication) regards both tests as “extremely robust” in AR-V7 detection. Dr. Antonarakis indicated that a prospective head-to-head study is ongoing comparing the two methods in 120 patients who will each have both tests. Trial results are expected in 6 – 9 months.

So … Is assessing a man’s AR-V7 status test ready to bear the weight of clinical decisions?

… Maybe, … depending on the clinical situation. Clearly the application of this important test requires, and will get, additional validation. Validation studies will provide information about the prevalence of AR-V7 in different clinical situations and its effect on treatment outcome. This will allow physicians to better guide men as to their best treatment options.

However, on the basis of what is currently known, two scenarios can be imagined. A management decision might be based on the findings of the Abstract 5012 cited earlier. Envision a man with a history of Gleason 8 cancer who, at a later period in his disease during ADT, exhibited early mCRPC with a rising PSA and a doubling time of 9 months. If his blood showed circulating tumor cells (an adverse prognostic sign by itself) and he tested AR-V7 positive, his likelihood of benefiting from Zytiga or Xtandi would be low. The choice of taxane chemotherapy could be considered as a more likely pathway to response. On the other hand, if no CTCs were found, he has a reasonable chance of responding to the addition of Zytiga or Xtandi. Of course, there will be situations in the murky middle-ground where guidance from additional studies will be helpful and clinical judgment will be required.

These are the types of difficult decisions that patients and physicians are likely to face in the near future.

BOTTOM LINE:

Fully validated information about the clinical significance of CTCs positive for AR-V7 will become a valuable tool to guide prostate cancer management. The guidance in personalized treatment decisions available with AR-V7 testing, combined with the high-level accuracy in staging now possible with the PSMA based PET/CT total body scanning, and additionally with the emergence of potential treatment with 177-Lutetium PSMA targeted radioisotope therapy, taken all together, will have a marked positive effect on the management of prostate cancer.

For a discussion of PSMA PET/CT scanning see PCa Commentary #109 and for an introduction to PSMA targeted 177-Lutetium radioisotope therapy see PCa Commentary #110.

PCa Commentary #110: Lutetium-177, a promising radioisotope for the treatment of prostate cancer.

Lutetium-177 (177Lu), a radioisotope, can be linked with either a monoclonal antibody (J591) or alternatively a small molecule inhibitor (PSMA-617) both of which target the prostate specific membrane antigen (PSMA), a marker expressed on 95% of prostate cancer cells.  Both agents are under active study. When employed at therapeutic strength and targeted to the PSMA molecule, 177Lu becomes a “theranostic,” meaning that the low level gamma signaling of Lu177 identifies the PSMA target to the PET scanner while at the same time the beta emission treats the cancer.

The prior PCa Commentary, Volume #109, http://www.pctrf.org/pca-commentary-109 [control+click link to follow] discussed the targeting mechanism and the diagnostic potential of the emerging 68Ga-PSMA PET/CT. That article concluded with a brief example of two remarkable responses to the combination of the radioisotope Actinium 225 with PSMA targeting. This Commentary is a brief heads-up describing the radioisotope, 177-Lutetium, already much studied in Europe, which also holds great promise for the treatment of prostate cancer.

What is Lutetium-177 ?

Lutetium-177 is one of the 32 synthetic radioisotopes of the element Lutetium-175, a rare earth metal, and was chosen as a radiotherapeutic because of its appropriate half-life of 6.64 days, during which it decays to produce a gamma ray and low-energy beta particles (essentially electrons) with a cytotoxic range of about 125 cells (0.25 mm). The name Lutetium is derived from the Latin Lutetia, the Roman name for Paris, where it was discovered in 1907.  A nearby cyclotron is not required and the 6+ day half-life allows sufficient time for transportation from a manufacturing site to the nuclear medicine department for intravenous administration.

There are differences in the behavior of the monoclonal antibody (mAb) and the inhibitor relating their biodistribution. “The mAb’s have a long circulation time so will continue to deliver 177Lu (or whatever is attached) for many days, whereas the ligands [i.e. inhibitors] are gone from the circulation in hours. Also, because of their size, the mAbs do not target salivary glands, kidneys, and other such areas of low-level PSMA expression, but do have high circulation in the bone marrow (so lead to myelosuppression)”, personal communication, Dr. Scott Tarawa.

When either the antibody or the inhibitor is mated to the extracellular portion of PSMA the combination is quickly internalized to where the radioisotope effects its damage. The half-life allows sufficient time to carry out DNA injury from within the cell. The rapid internalization limits collateral damage to nearby normal tissue. Lutetium-177 therapy should be particularly effective on micro-metastases because of easier penetrance compared to large tumor masses, a feature that would seem to argue for its use early in the course of the disease.

What Do We know So Far About 177Lu Radioisotope Therapy ?

Considerable research on 177Lu therapy has been performed in the past few years in Europe and in the US particularly at Cornell Medical College by Dr. Scott Tagawa and colleagues. The early studies have been targeted to evaluate safety and short-term efficacy. In general, mild to moderate reversible hematologic toxicity has been reported. A dry mouth syndrome (xerostomia) can occur because of a low concentration of benign PSMA targets in the parotid glands. Clear evidence for short-term efficacy has been demonstrated.

Five European studies were reviewed. All the men had mCRPC. A PSA decline of >50% was a common measure of evaluation. These were not clinical trials with the requisite documentation of patient inclusion criteria and follow-up for toxicity, but collectively they document substantial PSA response and acceptable toxicity.

Early Studies of 177Lu in the United States:

Dr. Scott Tagawa and colleagues at Cornell Medical College, Memorial Sloan-Kettering, and Duke have conducted detailed research as to the toxicity profile of the agent, the best regimen for administration, selection of optimal patients to receive treatment, and consideration of combination therapy with chemotherapy. In their 2013 study, “Phase II Study of Lutetium-177-Labled Anti-Prostate Specific Membrane Antigen Monoclonal Antibody j591 for Metastatic Castration-Resistent Prostate Cancer,” Clin Cancer Research, they reported reversible hematologic toxicity in 47 patients from a single dose administration. At the highest dose (70mCi/m2) two cohorts showed median survivals of 16.3 and 27.3 months. PSA declines were seen in 46.9% of men at this dose level. Grade 4, i.e. clinically significant, platelet and neutrophil suppression, was seen in 46.8% and 25.5%. “Those with poor PSMA imaging were less likely to respond.”

The abstract #121 presented by this group of researchers at the 2013 GU Cancer Symposium added additional details. “12 of 15 pts had baseline and follow-up CTC [circulating tumor cells] counts at 4-6 weeks: 66.7% had >50% decline and 25% were unchanged …”  Although 93.3% had accurate targeting (imaging) of known sites of disease, as seen in initial analysis, a trend for fewer >30% PSA declines was seen with less intense PSMA imaging.”

In the conclusion of the 2013 article the authors stated: “Future directions in progress with anti-PSMA-RIT [radioimmunotherapy] include (i) studies to improve patient selection using imaging and CTC and immunohistochemical PSMA expression analysts; (ii) improving therapeutic margin with dose-fractionation; [and] (iii) using taxane chemotherapy radiosensitization and tumor debulking.”

Much of this work has already been accomplished. In abstract 194, ASCO supp 2015, Tarawa and colleagues reported results of 3 cycles of a two-dose fractionation of 177Lu-J591 combined with taxotere chemotherapy. A PSA decline of >50% was seen in 73.3% and a >30% in 80.0% of the patients.

[From personal communication with Dr. Tagawa]:  “A randomized phase III registration trial in men with metastatic CRPC is planned.” The Cornell lead study group currently has studies with 177Lu-j591 and 177Lu-PSMA-617 in non-metastatic CRPC with the hope of curing some men with micrometastatic disease. Studies are contemplated to employ 177Lu-j591 in the setting of biochemically recurrent prostate cancer.

Additional studies will open up in Texas and UCSF in 2017. A phase II trial of 177-PSMA-617 for men with advanced CRPC is expected to open at UCLA in the first half of 2017.

BOTTOM LINE:  The story of 177Lu in the treatment of prostate cancer is just at its beginning, with more work to come in refining the regimens. Early work, however, shows great promise that this radiotherapeutic agent will become an effective and safe member of our increasing armamentarium against prostate cancer.

PCa Commentary #109: EMERGING TECHNOLOGY ADVANCES STAGING ACCURACY – Introducing the 68Ga-PSMA PET/CT

Accurate staging is the keystone of appropriate managing decisions at initial diagnosis and at recurrence of prostate cancer. Recent advances in imaging technology are driving a tectonic shift toward improvement in both these areas. Added to this is the potential of improved treatment by the linkage of tracers accurately targeting prostate cancer joined with therapeutic radioisotopes. Just as prostate cancer treatment experienced a dramatic upgrade in recent years with the introduction of Zytiga, Xtandi, Xofigo, Provenge, and Xgeva, so now clinicians and patients can expect to benefit from promising advances in imaging accuracy and “theragnostics,” the newly coined term that refers to the linkage of the targeting tracer with a radioisotope, such as Actinium 225.

This leap forward in imaging technology has already begun with the available, but difficult to access, 11C-choline and 11C-acetate total body PET/CT scans. The recently approved Axumin PET/CT (18F-FACBC) will soon make this improved staging technology available at many nuclear medicine departments across the country. The next generation of this remarkable technology will be the targeting of a surface marker on prostate cells themselves, the prostate-specific membrane antigen (PSMA). 

The venerable staging tools of the past — the abdominal/pelvic CT and the Technetium bone scan, both until recently the best we’ve had to work with, are still being used because of their easy availability. However clinicians have recognized for some time that these tools are inadequate for the tasks assigned to them.

For example:

  • The CT definition of an “enlarged” lymph node is one having a short axis of >8 mm. 
  • “A recent 68Ga-PSMA-11 PET/CT study found 49 positive lymph nodes including 38 (78%) with a diameter of <8 mm.” The mean diameter of positive nodes in the study was 5.8 mm. 
  • The authors concluded that the PSMA scan detected nodal recurrence in two-thirds of patients who would have been missed using conventional morphological criteria. (Giesel, Eur J Nucl Med Mol Imaging, 2015) 

The Technetium scan is either overused in low-grade cancer or insufficiently sensitive in high-grade disease, as compared to the Sodium Fluoride PET/CT, which displays a significantly better sensitivity. Unfortunately, this scan is less utilized than warranted because of lack of availability and inconsistent insurance coverage.

The standard CT, being solely a morphological study (i.e. based on shape and size), fails to capture evidence of cancer in small lymph nodes or minimal bone metastases. Therefore it understages cancer. The multiparametric MRI, a remarkable functional study, is excellent in evaluating the prostate gland for the location, size, and, to some extent, the grade of cancer but, it is not a total body survey and is equally deficient as the CT in identifying malignancy in lymph nodes.

The 11C-choline, 11C-acetate, and the Axumin (based on amino acid uptake) PET/CTs  are extremely informative total body scans based on the metabolic cellular uptake of basic cellular building substrates choline, acetate, and lysine Their inherent weakness, which decreases their sensitivity, is their requirement for tumors to have sufficient cellular proliferation and tumor bulk to generate a signal adequate for PET detection. The golden ring of imaging, therefore, is a tracer that targets prostate cancer cells directly, independent of growth rate and bulk. This is the goal that PSMA imaging has the potential to achieve.

 So … clinicians and patients everywhere are more than ready to upgrade to the greater imaging accuracy of the 68Ga-PSMA PET/CT.

The research literature in the past several years has been bulging with articles from all over the world (with the notable exception of the USA) about this new staging technology and with studies comparing PSMA imaging with current methods. It would be challenging to summarize this. However, I am absolutely indebted to the authors of the article that I will review (with my added commentary): “Current Status of Prostate-Specific Membrane Antigen Targeting in Nuclear Medicine: Clinical Translation of Chelator Containing Prostate-Specific Membrane Antigen Ligands Into Diagnosis and Therapy for Prostate Cancer,” Seminars in NUCLEAR MEDICINE, 2016, by Kratochwil, Afshar-Oromieh, Kopka, Haberknown, and Giesel, all from Heidelberg, Germany. They are in the forefront of exciting research in this area. Their article examines the current imaging methods through the prism of the possibilities of emerging PSMA technology. 

What Characteristics Makes PSMA  So Ideal for Diagnosis and Therapy?

PSMA is a cell surface transmembrane protein, an enzyme (glutamate carboxypeptidase II), which wags its receptor tail in its surroundings, and after being bound by incoming signaling messengers moves into the cell’s interior where the information is passed on to nearby scaffold units that govern a variety of cellular responses, i.e., cellular proliferation, migration, and invasion. This internalization, “leads to enhanced tumor uptake and retention, and it results in high-image quality for diagnostic procedures and a high local dose of therapeutic applications” (Kratochwil, ibid).  PSMA is expressed on 90% of prostate cells and its expression increases in advanced stage cancers. Prostate cancer cells express PSMA 8-12 times more than non-cancerous prostate cells, and 1000 times more than other cells (i.e. in kidney, lung, liver, salivary glands and others). Of note, whereas the detection rate (sensitivity) in CRPC with the choline PET/CT declines with greater cancer aggressiveness (de-differentiation), in contrast, the expression of PSMA increases in more aggressive cancer, making it particularly useful for diagnosis and treatment of CRPC. This relatively high concentration in prostate cancer tissue, especially the feature of cellular internalization, is an advantage in reducing adverse effects on other organs when the PSMA tracer is linked with radioisotopes for treatment. As an additional bonus, PSMA is expressed on tumor neovasculature, an advantage for diagnosis and treatment.

For diagnostic imaging with PSMA a small molecule inhibitor of the PSMA enzyme is linked with the isotope 68Ga, the source of the positron sensed by the PET scanner. For treatment the PSMA tracer is linked to a therapeutic radioisotope such as the -emitter 225 Actinium.

The Seminars in NUCLEAR MEDICINE Review Article:

Kratochwil and colleagues usefully divided their review into three sections: PSMA scanning at diagnosis, at recurrence; and in the near future when the PSMA technology is developed as a “theragnostic.” I will follow their clue and add additional commentary.

  • PSMA-PET/CT for Primary Staging” (ibid)

The authors point out that there are FEW studies of PSMA PET/CT for evaluating the prostate itself. One study did compare tumor localization within the prostate gland seen on a PSMA PET/CT to that seen on a multiparametric MRI and found their accuracy similar, between 90% – 97%.  Considering the wide availability of the mpMRI and the accuracy of MRI based targeted biopsies to diagnose the lesion with the highest Gleason score, the mpMRI can serve quite well in finding these lesions. The PSMA PET/CT will be less utilized in evaluating the prostate gland.

However, in the staging of higher-risk patients the PSMA PET/CT can contribute significant guidance when information about lymph node spread is required.

PSMA PET/CT prior to radiation: The 68Ga-PSMA-11 PET/CT has been compared to conventional staging of the pelvis and abdomen. Two studies of 57 and 44 patients reported this comparison in men scheduled for primary radiation. In one of them “In 50.8% of the cases, therapy was changed;” and in the second the treatment plan was changed in 53.7%.

(Sterzine, Eur J Null Med Mol Imaging, 2016; Shakespeare, Radiat Oncol, 2015, respectively)

In the setting of salvage radiation after radical surgery, Heidenreich (Eur Urol 2007) reported management change in 29% based on PSMA-PET/CT findings.

PSMA PET/CT prior to surgery: Surgery on higher-risk patients is frequently accompanied by a limited or extended pelvic lymph node dissection. This procedure remains the gold standard for detection of positive nodes in advanced cancer. However, many studies have shown that positive lymph nodes in higher-risk patients often lie beyond the standard template of dissection. These nodes would only be detected with the fuller field imaging of the PSMA PET/CT, which has a greater application for imaging in recurrent disease.

An example: a small study was reported in the January issue of BJUI, van Leeuwen et al., of 30 patients (3 intermediate-risk and 27 high-risk) who underwent a PSMA PET/CT prior to surgery. Positive nodes were found in 37%. For the detection of positive nodes the specificity was 56%, specificity 98%, positive and negative predictive values 90% and 94%. One of 27 positive nodes was outside the ePLND template. The mean size of missed positive nodes was 2.7 mm. They concluded that the PSMA scan “had the potential to replace current imaging [i.e. CT and MRI] of LN staging of patient with PCa scheduled for RP.”

68Ga-PET/CT scans are currently available at a limited numbers of institutions. An academic consortium has been formed for joint study at Stanford, UCSF, UCLA, Iowa, Indiana, Wisconsin, Vanderbilt, MSKCC, Wash U, and more to come. Expect a barrage of reports from this research. However, it will be some time before this scan is fully vetted and available.

 Even though the forthcoming FDA approved total body Axumin scan has been shown to be somewhat less accurate than the 68Ga-PET/CT, none the less it represents a significant advance over convention imaging, and as it becomes generally available it can provide improved imaging in the near future.

  • PSMA Imaging of Recurrent PC” (ibid)

Compared to the use of the PSMA scan for primary diagnosis, there has been extensive reporting, especially from European centers, of the scan’s performance at biochemical recurrence.

Scan performance in two large studies of men with biochemical recurrence showed a sensitivity of 88.1% and 89.5%.  In one, detection did not correlate to PSA doubling time. In a second, “Among the patients with PSA <2 ng/mL, the detection rate was 85% if the PSAdt was <6.5 months, but only 19% if the PSAdt was >6.5 months. Three studies reported positive scans in “patients with PSA values between 0.2 and 0.5ng/mL. The detection rates were in good accordance: 57.9%, 50%, and 50%.”

Eiber et al., Journal of Nuclear Medicine 2015 reported on 393 patients with biochemical recurrence following surgery.  “The detection rates were 96.8%, 93.0%, 72.1%, and 57.9% for PSA levels of >2, 1 to <2, 0.5 to <1, and 0.2 to <0.5 ng/mL.”  Their conclusion: Hybrid 68 GA-PSMA ligand PET/CT shows substantially higher detection rates than reported for other imaging modalities. Most importantly, it reveals a higher number of positive findings in the clinically important range of low PSA values (<0.5 ng.mL), which in many cases can substantially influence the further clinical management.”  Detection at this low PSA value is especially informative since it is now conventional to offer salvage radiation to men with PSA recurrence following surgery before the PSA rises to >0.5 ng/mL.

 A recent study in BJUI, January 2017, Albisinni et al., reported PSMA scan findings in 131 men with persistent PSA elevations after surgery, or at biochemical recurrence after surgery, radiotherapy or both. At least one lesion suspicious for prostates cancer was identified in 75% of patients and the pre-scan management plan was changed in 76%. “The main modifications included continuing surveillance (withholding hormone therapy), hormone manipulation, stereotactic radiotherapy, salvage radiotherapy, salvage node dissection or salvage local treatment (prostatectomy, high-intensity focussed ultrasound).”

The essential point arising from all these studies is that the PSMA scan performs well at low PSA values and the results often change the pre-scan management plans. Kratochwil cites three studies in which the PSMA outperformed choline PET/CTs in this setting of biochemical recurrence.

  • PSMA-Targeted Radionucleotide Therapy of CRPC” (ibid) A View Towards A Promising Future, which is already in progress in some research centers.

“Theragnostics,” the linkage of PSMA targeting tracers and a therapeutic radioisotope has the potential of being a powerful and cancer-specific therapy. Examples of the effectiveness of this modality are encouraging, particularly as reported from the University of Heidelberg, Germany, the research site for the authors of this article.

Regarding their work, Kratochwil comments, “… it seemed more promising that PSMA ligands that target tumor cells directly and which are internalized into the cell will be effective in delivering high doses of systemic PSMA-Radiolabeled Therapy.”  A short range -emitter, 225 Actinium (Ac), seemed appropriate because of its lesser toxicity to the bone marrow, (as opposed to the -emitter 177 Lutetium).

Since the cancers of 10% of men with CRPC do not express PSMA, it is mandatory that a PSMA scan be positive before treatment.

An article by Kratochwil and colleagues from Heidelberg examples the promising research in theragnostics: “225Ac-PSMA-617 for PSMA-Targeted -Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer, J Nucl Med 2016. Although their case series is still ongoing, they thought it important to “report in advance about two patients in highly challenging clinical situations who showed a complete response to 225Ac-PSMA-617 therapy.”

       In both the post treatment scans showed dramatic responses.  In patient #1 after four bi-monthly cycles, the pretreatment PSA of 2923 fell to <0.1 ng/mL and the restaging scan was clear. Patient #2 had progressed after therapy with 177Lu-PSMA-617.  After three cycles of 225Ac-PSMA-617 the PSA fell from 419 to 0.1ng/mL and his scan showed a complete response. “No relevant hematologic toxicity was observed.”  The full reporting of this series and their longer-term follow-up will be very interesting. 

Of real practical importance, as noted in Seminar article, “the first 68Ga/68Ga generator system was approved by the European Medicines Agency and a single-vial kit solution for radiolabling 68Ga-PSMA-11 at room temperature has been developed.” This should allow the PSMA scan (not the theragnostic combination) to be available in nuclear medicine departments similar to the availability of the Technetium bone scan tracer.

BOTTOM LINE:  With the introduction of the 68Ga PET/CT a new era in prostate cancer imaging and therapy is underway with promising possibilities.

PCa Commentary #108: Adjuvant Deprivation Therapy Adjuvant To Radiotherapy: New Mechanistic Insights with Clinical Implications

A reasonable goal — especially from a patient’s point of view, in the use of androgen deprivation therapy (ADT) is capturing the benefits of androgen deprivation while reducing its well-recognized toxicity. This might be accomplished by reducing the duration of exposure or selecting and treating only those patients who will benefit.

Suggested regimens of ADT have varied widely, but even at this time the optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. The literature is replete with an extensive variety of schemas for combing ADT with radiotherapy. The duration of treatments prior to RT have ranged from 6 months to none at all. Therapy during and after RT ranged from of 4, 6, 18, 24,  36 months and 5 years — even for life. The focus has been on intermediate-risk (especially “unfavorable” intermediate-risk) and high-risk prostate cancer. These different regimens have for the most part been derived empirically in an attempt to build upon the best results of prior protocols. The current NCCN recommendation for adjuvant therapy for high-risk cancer is 2 – 3 years.

The Addition of ADT to Radiotherapy Improves Outcome — But Why?

A uniform finding throughout these various efforts is the firm observation that adjuvant androgen deprivation during and after radiation yields better outcomes as compared to no ADT. As summarized by Bartek et al. (Cancer Discovery, Nov 2013):

“In numerous clinical trials, such combined treatment showed improved disease-free and overall patient survival, for both high- and intermediate-risk prostate cancer when compared with radiotherapy alone. Although the clinical benefits of combining radiotherapy with androgen deprivation seem indisputable, this contrasts sharply with our lack of validated mechanistic understanding of the cellular and molecular basis for such synergistic therapeutic effects.”

Recent studies have provided deeper “mechanistic understanding” of both the counterproductive cellular response to radiation and the ameliorating effect of androgen deprivation.  Based on these observations (and likely more to come) the use and duration of ADT in association with radiation therapy in the future may be guided by a biologic rationale.

ADT enhances prostate cancer’s sensitivity to radiation therapy — Three studies:

Radiation damages DNA by creating double-stranded breaks causing a faulty transcription of the genome which results in cell death or promotion of tumorigenesis. Nature has provided rescue mechanisms — a repair process, to anneal this damage. The common message from these recent studies is that a suppressed testosterone works to thwart the repair process.

  • “Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand breaks repair,” Tarish et al., ScienceTranslationalMedicine, Nov. 2015: Tarish evaluated the DNA repair process based on prostate biopsies in 48 men with localized cancer undergoing radiation. Half had radiation only; in the others radiation was combined with ADT. They demonstrated that androgen suppression interrupted the repair process, thus “explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration.”
  • “Androgen receptor signaling regulates DNA repair in prostate cells,” Polkinghorn et al., Cancer Discovery, Nov. 2013: The research demonstrated that radiation therapy “enhanced DNA repair and decreased DNA damage” and, correspondingly, that androgen suppression inhibits this repair, “providing a potential mechanism by which androgen deprivation synergies with radiotherapy to prostate cancer.” 
  • “A hormone-DNA repair circuit governs the response to genotoxic insult,” Goodwin, Schweizer et al. Cancer Discovery, Nov. 2013: The authors reported their elucidation of the molecular biology underlying the relationship of the radiation induced upregulation of AR signaling, enhanced DNA repair, and therapeutic resistance to radiation. This study points up a mechanism by which radiation has an inherent counterproductive aspect: radiation upregulates the androgen receptor which in turn facilitates the repair of DNA damage.

A hint as to what was forthcoming in later research came in an early work by Vijayakumur et al., Radiology, 1992 Jul, who did a now-unusual check on sequential PSA levels during radiotherapy. The unexpected result was that of 23 patients “four patients had an increase in PSA levels during [a portion of] the course of RT.”  Since PSA expression is promoted by AR activity; the PSA increase in these few men suggested what is now known, that RT upregulates AR activity.

It is currently customary in some regimens to precede radiation with 2 months of ADT. However, early pioneering work on adjuvant hormone suppression by Bolla et al., NEJM  2009, for locally advanced cancer, and again by Bolla, JCO, March 2016, for intermediate- and high-risk disease, demonstrated increases in survival when AS was initiated only on the  first day of radiation and then continued for 6 months. Considering the accelerated action of degarelix (Firmagon) compared to Lupron, it may be possible to gain the benefit of ADT by using degarelex on day one of radiation. [An exception might be for those men with large prostates who need a period of gland shrinkage to facilitate brachytherapy needle placement.]

The Role of ADT Beyond Its Concurrent Use with Radiation Therapy — How Long and Why:

This issue was elegantly explored by Spratt, Polkinghorn, Sawyers et al. in “Androgen receptor upregulation mediates radioresistance after ionizing radiation” [italics mine], Cancer Research, Nov. 2016.

Spratt and colleagues acknowledged the role of ADT as radiosensitizer during RT, but they add “for unknown reasons adjuvant ADT [following RT]  provides further survival benefits,” begging the question as to why, how long, and in which patients. Their research demonstrated that RT durably upregulates the expression of the AR pathway (and its associated repair function) post-therapy “in nearly 20 percent of patients after RT,” and this elevation of AR activity persists beyond the completion of radiotherapy. Considering the clinical heterogeneity inherent in intermediate- and high-risk patients it would be expected that a spectrum of AR upregulation would be present among patients. They cited studies in which men experienced improved survival when ADT was applied only after radiation but had had none during treatment. This suggested that the timing and duration of ADT is important.

During the course of radiation (In preclinical and human studies) they tracked the response of the androgen regulated genes for PSA and its cousin, human glandular kallikrein-2 (hk2). They also monitored the cancer promoting gene fusion product TMPRSS2. Of 227 men with low- or intermediate-risk cancer treated with radiation, 40 showed a rise in these products persisting after the RT was completed.  “… we found that men with increased free-hk2 levels post-ERBT were three times more likely to experience a biochemical failure than those with unchanged or declining hK2 post-treatment,” 17.5% versus 5.3%, respectively. Since the AR governs the expression of thousands of genes, many other genes averse to cancer control may be unregulated in addition to TMPRSS2.

What Are the Clinical Implications of These Studies for the Use of ADT with Radiotherapy?

Much is yet to be learned regarding the upregulation of AR expression by radiation, and significant findings will require testing in clinical trials. The clinical implications of the studies, taken collectively, are best stated in the conclusion of the Spratt article:

“Our results suggest that AR activity during and after ADT/ERBT should be more closely studied with serum and imaging biomarkers to determine their prognostic significance. One potential implication is that adjuvant ADT may only be necessary for men whose tumors upregulate AR as a response to RT.  Alternatively, more potent AR inhibition using second generation ADT might prevent or mitigate the negative consequences of AR upregulation post-RT.”

BOTTOM LINE:  The studies cited here are poignant examples of significant advancements in the understating of the basic mechanisms underlying the relationship of radiation and androgen deprivation.  Successful translation of this basic research into clinical practice is essential for our better controlling prostate cancer while at the same time minimizing adverse effects of treatment.

[I appreciated the opportunity to discuss the Cancer Research article with Dr. Spratt.]

PCa Commentary #107: Adverse Effects: “Doctor, What Are the Side Effects of Your Treatment?”

Consideration of the adverse effects of different therapies for prostate cancer is integral to an informed decision about what treatment to choose — sometimes the most important issue. It’s basically the question of what am I willing to accept for what I get. This Commentary will address adverse effects associated with radical prostatectomy (RP), intensity modulated radiotherapy (IMRT, a term used to replace EBRT, which may include older techniques), and brachytherapy (BT, i.e., permanent seed implantation). IMRT combined with surgery (as employed in adjuvant or salvage treatment) and the combination of IMRT with BT will be reported. Also to be discussed is CyberKnife (hypofractionated radiation, i.e. 40 Gy delivered over 5 days).

The data has been drawn from a large number of major studies, a few of which will be summarized. A requirement for inclusion was that the data reported be based on patient reported information collated from validated questionnaires. It is acknowledged that patient reported assessments are the only valid way to gain unbiased and accurate information. The extent of functional decline must be adjusted for a man’s condition at baseline and his co-morbidities, which is especially necessary for evaluation of preservation of erectile function where an outcome compressed into a single numerical percentage inadequately accounts for the baseline variation in individual characteristics.

An example of a well-used validated questionnaire is the “Expanded Prostate Cancer Index Composite Index,” which asks about multiple aspects of the major domains of quality of life, i.e., urinary, erectile, and bowel function. Adverse effects are frequently reported as Grades 1 through 5, as in “Common Terminology of Criteria for Adverse Events” (CTCAE) in which Grade 3 is considered “severe or medically significant, but not immediately life threatening.” Grades 1 and 2 are considered “bother” and are temporary.

EXECUTIVE SUMMARY: (1-3 based on Zelefsky, Scardino et al., Sloan Kettering, in Radiation and Oncology, 2016.)

  1. “At 48 months, surgery had significantly higher urinary incontinence than others [IMRT and BT], but fewer urinary irritation/obstructive symptoms,” [i.e. painful urination/difficulty initiating urination].
  2. “Brachytherapy and IMRT showed better sexual function than surgery accounting for baseline function. Sexual bother was similar” [for all three]. … Sexual function was strongly affected in all groups yet significantly less for radiotherapy.”
  3. “Low levels of bowel dysfunction were observed and only small subsets in each group showed rectal bleeding… Using modern radiotherapy delivery, bowel function deterioration is less-often observed.” [The use of a spacer gel to temporarily separate the prostate from the rectum during radiation further reduces rectal injury as does sharper focus of radiation with modern technique, such as CyberKnife therapy.]
  4. Dr. Jaspreet Sandhu, a specialist in reconstructive surgery for voiding dysfunction at Sloan Kettering, confirms this data. “After surgery, the rates of urinary incontinence are on the order of 10% at one year,” [i.e. urinary stress incontinence, or incontinence after activity]. “After radiation therapy for prostate cancer, incontinence rate are actually quite low. On the flip side, you get some elements of obstruction, though the rates are quite low.” Quoted from Prostapedia, October 2016.

NOW … SOME NUMERICAL MEAT FOR THE BONES OF THESE ASSERTIONS:
Four Studies of Monotherapy and Combined Modality Treatment:

  • ProtecT Trial: “Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer,” NEJM, Sept 2016, Donovan et al.

Incontinence (% use of any pads): at 12 months — RP, 26 % v EBRT, 4%. At 36 months —RP 21% v EBRT, 4%, respectively. By year six 17% in the RP group were using pads versus 4% in the radiotherapy group.

Erectile function (% not firm enough for intercourse); at 12 months — RP, 85% v ERBT, 62%. At 36 months RP, 79% v ERBT, 66%, respectively. At baseline 67% of men reported erections firm enough for intercourse. By year 6 this figure was 17% after RP v 27% after EBRT.

  • Zelefsky et al. (Ibid): “Longitudinal assessment of quality of life [over 48 months] after surgery, conformal brachytherapy, and intensity-modulated radiation therapy for prostate cancer.”

Summary of decline of function between baseline (100 on the scale), and at 48 months:

Incontinence: RP, 95 falling to 82; BT, 96 then 91; and IMRT, 93 then 89.

Irritation or obstruction: RP, 87 improving to 92; BT, 88 then 86; and IMRT, 85 then 84.
[Prostatectomy can address obstruction from BPH and result in improvement.]

Erectile function: RP, 78 reduced to 49; BT, 63 then 50; and IMRT, 56 then 40. Age affects baseline performance. In their study the mean age for RP was 60 years; BT, 67; and IMRT, 70. Understandably, those men with the best baseline function lose the most.

  • Cooperberg, Carroll et al.: UCLA, “Long-term Health-related Quality of Life after Primary Treatment for Localized Prostate Cancer: Results from the CaPSURE Registry,” European Urology, 2015, report comparative toxicity outcomes for prostatectomy, brachytherapy, and external beam radiotherapy.

“Surgery had the largest impact on sexual function and bother and urinary function; radiation had the strongest effect on bowel function ….”

Expressed as clinically meaningful declines from baseline performance they reported outcomes at 2 and 5 years:

Urinary function — The declines for both nerve-sparing and non-NS RP were similar and at 2 years were 54%, and at 5 years 59%; for BT, 40% and 44%; and for EBRT, 24% and 37%.

Sexual function at 2 and 5 years —Nerve-sparing RP, 64% and 62%; non-NS RP, 68% and 67%; BT, 40% and 45%; EBRT, 38% and 41%.

  • Jarosek et al.: University of Minnesota, “Propensity-weighted Long-term Risk of Urinary Adverse Events after Prostate Cancer Surgery, Radiation, or Both,” European Urology, 2015.

This article sets the stage for consideration of a very consequential adverse effect — urethral stricture, that can follow surgery, IMRT, and brachytherapy. However, the message is clear: strictures are significantly increased with combined therapy, i.e. RP combined with IMRT or BT with IMRT. Currently radiation is often used after surgery as immediate or delayed (salvage) treatment at PSA recurrence. IMRT is now regularly combined with a brachytherapy “boost” to achieve optimal outcomes.

The actual incidence of strictures is very difficult to capture because of the complexity of their various causes. A stricture, a scar-like constriction, can occur at any location from the base of the bladder to the tip of the penis. For surgery it usually occurs at the location where the penile urethra is joined to the base of the bladder following the removal of the prostate. A stricture here is termed a bladder neck contraction (BNC). For IMRT or BT, with the prostate remaining in place, scaring can occur from the bladder neck to the base of the penis.

All strictures are not created equal. It is possible to achieve a correction of a surgically caused stricture at the bladder neck with a transurethral surgical repair. Obstruction resulting from radiation induced strictures may require dilation, repeated dilations, or a TURP (transurethral resection), which might help 70% of patients.

Jarosek presented information regarding the occurrence of strictures extracted from a national database based on the registration of hospital procedures. Their total figures included data on naturally occurring strictures. Since the period of their study, 1992 to 2007, techniques in all fields have improved, but the effect of combined therapy is clear: 38.7% for RP+ERBT and 28.4% for BT+ERBT. For monotherapy the incidence is lower: ERBT, 2.8%; BT, 5.2%; and RP, 12.7%.

More current data shows a marked decrease of strictures as presented by Peter Carroll et al. (UCLA), based on the CaPSURE data from urologists at 40 participating institutions. They note that data about BNC can vary from 2.7% to 25.7%! In their analysis stricture rate for RP was 8.4%, RP+EBRT 2.75%; BT, 2.5%; BT+ERBT 5.2%; and for EBRT, 1.7%. When reporting data from their own institutional base of 988 men at UCLA, Carroll et al., BJUI, 2010, cited an incidence of BNC following surgery of 2.2%, indicating the wide variability of this adverse effect and importance of high quality surgical technique.

In the practice of one experienced brachytherapist (personal communication) single dilations for obstruction were reduced to 2.5% and to 0.8% for multiple dilations. The stricture rate reported in the ASCENDE trail which combined IMRT plus a BT boost was 19%, although in this study BT was performed by a variety of physicians.

Measures to lessen this complication for surgery are a skillful use of the robot and excellence in a surgeon’s judgment and technique. Equal excellence is required for brachytherapists for whom the proper placement of seeds is an art form. Quality matters. For radiation therapy there is movement toward restricting the need to augment BT with ERBT and use more sharply focused radiation, such as with CyberKnife, to avoid, where possible, treatment to the base of the bladder.

CYBERKNIFE THERAPY (i.e. extreme hypofractionated radiation)

CyberKnife radiotherapy, sometime termed Stereotactic Body Radiation Therapy (so called because it can be used for cancers other than prostate cancer) is an emerging modality with considerable advantages for the treatment of prostate cancer.  Vol. 97.3 Cyberknife SBRT (control+click link to open or visit www.pctrf.org)

 It delivers intense high-dose radiation in a compressed interval of 5 days (40 Gy in five fractions) as compared to 38 – 39 days of treatment with IMRT. This highly focused radiation can constrain its beams to within 1 mm of the target’s margin as with treatment of the prostate and the seminal vesicles, a capacity that lessen its potential injury to the anterior rectum. Its beam width can be expanded to encompass the periprostatic regions and nearby lymph nodes, as might be indicated for higher-risk cancers. Used this way CyberKnife can be an alternative to brachytherapy plus EBRT.

CyberKnife therapy has been developing over 10 years. Although criticism early-on expressed concern about lack of information about adverse effects, two important recent reviews reported outcomes which allay these fears. To date there have been no randomized comparison with other modalities.

Two Studies:

 ·         Meier et al.  Recently reported in abstract form “Five-Year Outcomes from a Multicenter Trial of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Cancer, Int J Rad Oncol Bio Phys, 2016. The data summarized adverse effects from the treatment of 309 men in 21 community, regional, and academic hospitals. The median follow-up was 61 months. Adverse effects were stratified according to the CTCAE. Grade 1 and 2 urinary toxicity was seen in 53% and 35%, respectively; Grade 3 was 0% at less than 3 months and 2% > 3 months. Grade 1 and 2 gastrointestinal toxicity was seen in 59% and 10%; no Grade 3 adverse effects were seen. 

 ·         Hannah et al., in “Stereotactic body radiation therapy for low and intermediate risk prostate cancer — Results from a multi-institutional clinical trial,” European Journal of Cancer, 2016, reported adverse effects at a median follow-up of 54 months. A variety of doses were used, but the group that most closely resembles the men in the Meier study was the 15 men treated at 45 Gy over five days.  No Grade 3 urinary toxicity occurred before or after 3 months. No Grade 3 bowel toxicity was reported. The next study for this group will use a “biodegradable spacer gel injected between the prostate and the rectum to eliminate all rectal toxicity.”

BOTTOM LINE:  Men are understandably concerned about the loss of urinary and erectile function that can result from treatment. In this Commentary I have not focused on bowel toxicity since it is in that domain that improvement has steadily improved with modern techniques and older data is no longer applicable.  Clear differences among surgery, IMRT, and BT have emerged from these large studies of adverse effects in the domains of urinary and erectile function.

Many practitioners will feel that the published data do not reflect the outcomes experienced in the patients they have treated. In this case the patient must ask for a tally of patient reported outcomes to verify that discrepancy. Individual variation in patient characteristics and physician expertise plague any attempt to generalize. The data presented above is offered as a starting point for discussion.

PCa Commentary Vol. #106: COMPARING TREATMENT OUTCOMES – SURGERY VS RADIOTHERAPY: Is it Even Possible … or Necessary?

There is no lack of efforts to crack this very thorny and controversial nut. For this Commentary nineteen contemporary, peer reviewed studies from major institutions have been reviewed … resulting in a rather murky conclusion with conflicting strong claims for superior effectiveness for both modalities. Is an answer to this question necessary?  Clearly, yes!, since men facing treatment decisions want, need, and deserve credible information on this basic issue. Is such a comparison possible? “Aye, there’s the rub.” (Hamlet)

Comparisons between treatment regimens are fraught with many problems, some of which are listed here:

  • Controversy exists as to the choice of an appropriate, agreed-upon metric for comparison. This disagreement concerns using PSA failure at >0.2 ng.mL for surgery vs. the Phoenix definition for radiotherapy failure at a post treatment PSA nadir + 2 ng/ml. Surgeons contend this method gives an unwarranted advantage to radiation outcome.
  • The dosing and quality of radiation therapy in different studies can be different.
  • Unavoidable, unrecognized unevenness in the quality and experience of the treating physicians can influence outcome.
  • There can be significant disparity in the demographic composition of the groups being compared, notably patient age and comorbidity.
  • Unequal durations of ADT among studies contribute to incomparability.
  • And, yes, bias toward a preferred modality can unintentionally color the outcome.

But probably the most important and worrisome aspect of this effort to compare is that the results reported in these studies are the product of treatment techniques that are incrementally (fortunately) being improved over the course of the longer period of observation required in these trial to achieve a meaningful endpoint.

What really counts for men are:  the adverse effects of treatment (to be discussed in the December issue); the duration of freedom from metastases; and the rate of prostate cancer-specific survival, — best if collected over 5 and optimally 10 years of observation.

What Has Changed?

During the last 10 years or so radiation doses have been gradually increased, achieving superior cell kill; surgeons are becoming more expert with the robot; and new and more accurate imagining techniques are influencing management decisions. Information from multi-parametric MRIs combined with “targeted” biopsies is challenging the solidity of standard risk categories that have been based on conventional clinical parameters.

Genomic classifiers are parsing a cancer’s hidden biologic behavior and altering treatment decisions. Recent advances in systemic therapy, and those yet to emerge, are extending, bit by bit, survival for prostate cancer patients.

The older 3-D conformal radiotherapy (used at the beginning of some study periods) has been replaced and improved by intensity modulated (IMRT), or even image guided radiotherapy. External beam radiation combined with a brachytherapy boost seems to be on its way to supplant IMRT monotherapy in intermediate- and high-risk prostate cancer. And high-dose hypo-fractionated radiotherapy, even extreme hypo-fractionation, (i.e,“CyberKnife”) delivered over 5 days with their significantly greater cell killing power may supplant IMRT because of greater effectiveness and convenience.

The train of progress is leaving the station while we are looking back to see where we have been.

But an effort at comparisons, even considering all these important caveats, is still worth a shot. So here it goes.

Examples from the Reviewed Studies

The focus of most of these was upon intermediate- and high-risk prostate cancer, since it is generally conceded that in low-risk disease (which currently might be managed with active surveillance) there is little difference in the outcome between surgery and radiation.

It is important to note that all of these are retrospective studies from single-institutions or meta-analyses analyzing either organ confined or locally advanced disease. Their comparisons are based on prostate cancer-specific survival and overall survival.

This article does not analyze each of these studies individually but will summarize that there is no clear consensus as to which treatment is superior. It is becoming almost inappropriate to compare surgery with IMRT, as was done with most articles, since hypofractionated radiation and brachytherapy are emerging as more effective treatments, as was demonstrated in the ASCENDE trial outcome http://www.pctrf.org/pca-commentary-97-1-radiation-therapy-the-ascende-trial/ (control+click link to open or visit www.pctrf.org)

The following are samples of the conclusions of a few of the important studies just to give a flavor of the findings:

1)    Boorjian et al. from the Mayo Clinic, Urologic Onology, Oct. 2014: “Although comparisons between surgery and radiation in the setting of high-risk disease are comprised of retrospective analysis subject to the potential for significant bias, nevertheless these observational studies consistently have reported favorable oncologic outcome with surgery as the primary treatment modality.”

2)    Zelefsky et al. from Sloan-Kettering, Journal of Clinical Oncology, March 2010: “Metastatic progression is infrequent in men with low-risk prostate cancer treated with either radical prostatectomy (RP) or external beam radiotherapy (EBRT). RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer specific death than EBRT patients. These results may be confounded by difference in the use and timing of salvage therapy.”

3)    Crook, British Columbia Cancer Agency, Brachytherapy. 2015: “For intermediate- and high-risk prostate cancer, brachytherapy provides superior long-term oncologic and functional outcomes. … High-risk patient do very well with multimodality treatment combining external bean radiotherapy, a brachytherapy boost, and androgen deprivation for 9 – 12 months.”

4)    Kibel et al. from Harvard and Cleveland Clinic, Journal of Urology. 2012: (comparing RP, EBRT and BT): “After adjusting for major confounders, radical prostatectomy was associated with a small but statistically significant improvement in overall and cancer-specific survival [cancer death at 10 years: 1.8%, 2.9%, and 2.3%, respectively]. These survival differences may arise from an imbalance of confounders, difference in treatment related mortality and/or improved cancer control when radical prostatectomy is performed initial therapy.”

5)    Wallis et al. from Sunnybrook (Toronto) and Mayo Clinic, European Oncology. 2015: “Radiotherapy for prostate cancer is associated with an increased risk of overall and cancer-specific mortality compared to surgery, based on observations data with low to moderate risk of bias. This data, combined with the forthcoming randomized data, may aid clinical decision making.”

Results of the Much Awaited Randomized “ProtecT Trial”, … which has now “forth come.”

Published in the New England Journal of Medicine in September 2016, the study was prospectively randomized and designed to arbitrate the comparative effectiveness of prostatectomy, external beam radiotherapy, and active surveillance in PSA detected localized prostate cancer. The study ran from 1999 to 2009 and reported 10-year outcomes for freedom from metastases, prostate cancer-specific and overall survival. Participants were skewed to lower-risk disease: the median PSA was 4.6ng/mL; 77% had Gleason Score 6; 29% had disease spreading beyond the prostate (pT3), and 76% had non-palpable cancer. In all arms androgen suppression was initiated at PSA >20 and bone scans were performed at PSA >10 ng/mL.

The authors themselves pointed up the major limitations of the study: it was conceived 20 years ago; surgical techniques have changed; there was no use of multiparametric MRI; the less effective conformal 3D technique was used in the earlier period; brachytherapy was not included; and there was no sub-stratification between favorable and unfavorable Gleason 7 disease.

Findings:

1)    At a median follow-up of 10 years there was no difference in overall survival among the groups.

2)    Prostate cancer-specific mortality in the surgery arm ( 391 men) occurred at a rate of .9 men per 1000 person-years of observation compared to .7 for men in the radiotherapy arm (401 men) and 1.2 (482 men) in the surveillance arm. The prostate cancer-specific survival in all groups was 98.8%.

3)    Metastases were diagnosed in the RP arm at a rate of 2.4 men per 1000 person/years; 3.0 in the radiotherapy arm, and at a rate of 6.3 per 1000 person years in the active surveillance arm.

Conclusion: “At a median of 10 years, prostate cancer-specific mortality was low [~1%] irrespective of treatment assigned, with no significant difference among treatments.”

[Because of the acknowledged limitations of the study, the complexity of its schema, and its focus on lower-risk disease, it is unlikely by itself to settle the thorny “comparison” issue, although this study does make a useful contribution.]

A Credible Effort at Analyzing the “Comparison” issue:  

“Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer: How Good is the Evidence?” by Mack Roach III, MD Professor, Departments of Radiation and Urology, UCSF, et al., Int J Radiation Oncology, Biology, Physics, Aug 2015.

The article begins with a now-familiar caveat: “The optimal treatment of clinically localized prostate cancer is controversial. Most studies focus on biochemical (PSA) failure when comparing radical prostatectomy (RP) and radiation therapy (RT), but this endpoint has not been validated as predictive of overall survival (OS) or cause-specific survival (CSS).” Roach’s study reviewed 14 observational reports and focused on 10-year OS and CSS (as did all the studies cited above).

Since no randomized trials were available, the authors constructed a “reliability” scale (RS; range 5 – 18, detailed in the article) that allowed them to assign a weight as to the quality of each of the 14 studies. They defended the scale by saying: “We would argue that our analysis systematically takes on a whole host of biases not accounted for by any off the studies cited.”  [However, this system can easily evoke criticism from the urologic community.]

What Were Their Findings?

1)    At the median reliability scale of 12, “the median difference in 10-year OS and CSS favored RP over RT: 10% and 4%, respectively.

2)    “For studies with a RS > 12 (average RS 15.5), the 10-year OS and CSS median differences were 5.5% and 1%, respectively.

Conclusion:  “Reliable evidence that RP provides a superior CSS to RT with ADT is lacking. The most reliable studies suggest that the difference in 10-year CSS between RP and RT are small, possibly <1%.”

[Although PSA recurrence after initial treatment is not a validated metric for CSS or OS, none the less, it serves as a useful marker for some important management decisions: i.e., for considering the need of “salvage” radiotherapy following surgery; prompting a search for the source of the rising PSA with a view toward additional focal treatment; or as an alert to the possible need for hormonal intervention.]

BOTTOM LINE: Is This Controversial Issue Settled?  

Certainly not!  Improvements in techniques are emerging in all modalities of prostate cancer treatment that will influence outcome. Past studies have offered no clear consensus that radiation or surgery is the most effective management. However, in a very pertinent and important way these past studies provide only suggestive background data for men facing treatment decisions. Men are not being treated by a ‘collection’ of surgeons or radiation therapists, and clearly not by a ‘meta-analysis’ of physicians. Men are choosing or consulting with one particular practitioner equipped with his/her own unique skills and technique. This is where the rubber really meets the road. It is incumbent upon the patient to inquire about the outcomes in the men already treated by the physician he is facing in the consultation room. What is his experience history and outcome record? It is equally essential that the treating MD has collected his data and can discuss it with the patient. These must be components of an informed discussion …

… and this discussion of necessity involves the issue of the adverse effects of treatment on a man’s quality of life exacted by the treatment under consideration. This will be the subject of the December 2016 PCa Commentary.

PCa Commentary Vol. #105: FOLLICLE STIMULATING HORMONE (FSH): Its Suppression by Degarelix (Firmagon) May Contribute to the Drug’s Effectiveness in Androgen Suppression and Its Lesser Cardiotoxicity Compared to Leuprolide (Lupron.)

A potentially important difference between leuprolide and degarelix lies in the significant reduction of pituitary, FOLLICLE STIMULATING HORMONE, FSH secretion by degarelix, an action not shared by Lupron. While both drugs suppress serum testosterone by inhibiting the secretion of luteinizing hormone (LH), sustained suppression of FSH secretion is unique to GnRH antagonists such as degarelix. This has been hypothesized to be the basis of the superior inhibition of prostate cancer growth and the lesser cardiotoxicity of the drug.

Suppression of Pituitary FSH secretion:  Degarelix rapidly reduces serum FSH by 80% by day 1, 75% on day 15, and results in a sustained reduction of 89% below baseline over the ensuing year.  In contrast, leuprolide lowers the initial serum FSH levels by 76% by day 14, but then the level rises to stabilize at 55% of baseline thereafter. Other studies of leuprolide report a 66% reduction of FSH by 10 – 11 weeks followed by a sustained rise to 10 – 20% below baseline between weeks 25 and 97.

A comparison of FSH levels between degarelix and leuprolide was presented in poster form at the 2016 Society of International Urologists, October 2016 by Crawford et al., based on 1 year comparison data from the study by Klotz, BJU Int, 2008. Their findings:

  1. Both FSH and LH levels increase with age.
  2. At 3 months degarelix reduced FSH levels ~97%  from baseline and this reduction was sustained for 13 months. Leuprolide reduced FSH by ~55-60% at 3 months.
  3. “Greater FSH suppression is related to greater PSA suppression only for patients treated with [degarelix].”
  4. “… FSH suppression to very low levels may have a direct anti-tumor effect.”

Although not fully explained, but possibly due to loss of negative feedback on pituitary FSH secretion, orchiectomy dramatically increases FSH levels.

Tissue Location of FSH Receptors:

FSH receptors are present at low levels in normal and malignant prostate cells, in the inner lining of tumor blood vessels, on the surface of T lymphocytes, and in lymph nodes, testes, and at other locations. Prostate cells themselves secrete FSH.  FSH receptors are found in benign and malignant prostate cells and their abundance increases as the disease becomes more aggressive, increasing even more in metastases. Activation of these receptors and their downstream signaling leads to a variety of biologic consequences to be discussed below. Suppression of pituitary FSH secretion by degarelix results in reduction in these biologic responses.

What is the Biologic Function of FSH? How Might It Be Important in the Treatment of Prostate Cancer?

As with any cellular receptor when joined by its matching signal (termed a “ligand”), when FSH activates its specific receptor a cascade of molecular signaling follows. The biologic result of FSH receptor stimulation is 1), increased cellular proliferation (i.e. cancer growth), and 2), the promotion of new blood vessel formation (termed “angiogenesis”) at the advancing edge of the prostate tumor mass.

Angiogenesis: 

Extensive research on this issue was reported in the New England Journal of Medicine, 2010, by Radu et al., “Expression of Follicle-Stimulating Hormone Receptor in Tumor Blood Vessels.”  Although the best recognized action of FSH is the conversion of female testosterone into estrogen, of special interest to this article is the expression of FSH receptors in the inner lining of blood vessels at the periphery (the outer 10 mm) of the growing prostate tumor mass. This results in a proliferation of new blood vessels at the invasive front of the tumor. The abundance of these new blood vessels at the growing edge of the tumor offers a greater opportunity for malignant cells to enter the blood stream. The proposed mechanism underlying this angiogenesis is the up-regulation of vascular endothelial growth factor (VEGF). The research by Radu was based on prostate cancer tissue from 773 patients and confirmed this location of receptors in the blood vessel lining surrounding malignant, but not in normal, prostate tissue.

The authors’ conclusion: Stimulation of endothelial FSH receptors promotes angiogenesis which “may substantially enhance the proliferation and migration of endothelial cells in cancer,” promoting cancer growth and increasing the opportunity for migration of cancer cells into the blood stream.

FSH as a mitogen, i.e a promoter of cellular proliferation and cancer growth:

Work by Mariani et al. (J Urol. June 2006) established that minimal FSH receptor expression was seen in normal  or BPH prostate cells, but was increased in malignant cells. A study by Ben-Josef et al. (J Urol. 1999) found that the expression of FSH receptors was up-regulated in hormone-refractory prostate cancer. And Siraj et al. ( BioMed Central. 2013) reported that the microvasculature of metastases expressed more FSH receptors than the cancer deeper within the prostate. The conclusion of these studies and others indicates that there is an abundance of tissues displaying FSH receptors which are targets for activation by serum FSH secreted from the pituitary gland and prostate cancer cells.

What are the consequences of FSH receptor activation?

This question leads to pointing out an excellent review article by David Crawford, MD, Chairman of the Department of Surgery at the University of Colorado, in association with other prominent urologists and experts in prostate endocrinology: “The Role of the FSH System in the Development and Progression of Prostate Cancer,” American Journal of Hematology/Oncology, June 2016.

In addition to discussing the points mentioned above in detail, the article additionally indicates:

  1. An important negative regulator of FSH secretion, prostatic inhibin peptide (PIP), arises from the prostate itself and functions as a check on pituitary FSH secretion. PIP expression progressively decreases as the grade of prostate cancer increases thereby reducing its suppressive effect on FSH secretion.
  2. The article reported many of the studies showing the sustained reduction of pituitary FSH resulting from degarelix and the substantially incomplete reduction seen with leuprolide.
  3. Citing his own study comparing degarelix vs leuprolide, Crawford et al, J Urol. 2011, stated that “patients on degarelix had a lower risk (34%) of PSA failure compared with leuprolide, and the risk of PSA failure decreased in patients who switched from leuprolide to degarelix.” Interestingly, degarelix more effectively suppressed FSH by almost 35% compared to leuprolide.
  4. “A recent analysis of 6 phase 3 prospective randomized trials reported that the risk of developing adverse cardiac events was significantly lower [by 50%] in patients receiving degarelix when compared to those receiving leuprolide,” (Albertson, Klotz, Tombal, Eur Urol 2014). Cardiac events in this study included: arterial embolic or thrombotic events, hemorrhagic or ischemic cardiovascular conditions, myocardial infarction, and other ischemic heart conditions occurring within one year of initiating therapy. [Reviewed in PCa COMMENTARY June 2016/

The authors’ conclusion in the Crawford article: “Since one of the main differences between chronic agonist [leuprolide] and chronic antagonist [degarelix] treatment is their effect on FSH, it is plausible that the long-term benefits from antagonists may be due, at least in part, to their profound suppression of the FSH system.”

BOTTOM LINE:  The significant reduction in FSH levels by degarelix is well established. A beneficial effect of this FSH reduction on cancer growth and decreased cardiotoxicity is strongly suggested by data, but will be further clarified by additional studies.

PCa Commentary Vol. #104: A RISING PSA!…WHEN TO START ANDROGEN SUPPRESSION…No Clear Guidelines.

A major, and poorly defined, issue for both patients and clinicians regards the optimal start point for ADT when the PSA is rising after primary therapy with curative intent. Surprisingly, there have only been two major studies that attempt to answer this important question — and they offer opposite conclusions!

Perspective offered by studies on the natural history of prostate cancer after biochemical recurrence:

It is instructive to put the broad issue of the natural history of prostate cancer after a rising PSA into perspective. This insight has been offered by Antonarakis, Eisenberg, Walsh, Partin et al. in BJU Int. 2012 Jan, “The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up”, wherein they give further follow-up and analysis of the original patients in Walsh’s 1999 JAMA article. The purpose of their study was to provide better risk assessment models to identify men who might benefit from earlier additional treatment.

In their study no treatment was given to most patients after PSA recurrence until metastases developed, except for 14% who did receive androgen suppression prior to metastases. The median time to biochemical recurrence for the entire cohort was 3 years and the median metastases-free survival (MFS) was 10 years, “most strongly influenced by PSA doubling time and Gleason score.” The unique protracted natural history of prostate cancer is underscored by the study’s observation that the “Median survival has not been reached after 16 years of follow-up after biochemical recurrence.”

The median initial PSA for the 450 man study group was 8.5 ng/mL. The pathological Gleason scores were 6 (19.9%), 7 (53.1%), and 8-10 (27.3%).”Most patients had pathological non-confined disease and Gleason scores >7,” indicating a greater than average degree of aggressiveness.

The key finding of the study was that:

  • The risk of developing metastases from prostate cancer was strongly related to Gleason score (<7 vs 8-10) and prostate cancer specific antigen doubling time (PSADT).

The 5-year median metastases-free survival (MFS) was stratified according to PSA doubling times:  <3.0 months, 3 – 9 months, 9 – 15 months, and >15 months. The results varied markedly according the PSADT and Gleason score.

Table 3 in the article presents median metastases-free survival in years according to PSA doubling time and pathological Gleason score:

  • For the four categories of PSADTs the median MFS in years is 1, 4, 13, and 15 years, respectively.
  • The MFS stratified for Gleason score: GS 8-10, 4 years; GS 7, 11 years; and for GS 4-6, >15 years.

[Although it has been difficult to establish a benefit for ADT in prolonging overall survival, ADT can clearly postpone the onset of metastases and their attendant symptoms.]

Authors’ conclusion: “Therefore, identifying and treating patients at highest risk of metastases would probably have the greatest impact on patient outcome, especially since most prostate cancer deaths occur in men with metastatic disease.” Although the development of metastases based on PSA doubling time is a continuous variable, a reasonable dividing point for starting ADT based on this data would seem to lie somewhere between a PSADT of 6 to 9 months. For men with higher-risk Gleason scores a PSADT closer to 6 months might be more appropriate for starting ADT.

Two Recent Studies on When to Start ADT.

The question addressed in both these studies is whether there is an advantage to starting ADT “early,” or whether ADT can be delayed as long as possible so as to avoid the toxicity of androgen suppression.  A comparison of the findings in these two articles is presented below. The first of the two studies, based on CaPSURE (a national prospective registry) data, is more statistically solid and likely warrants greater credibility.

Article #1:     “Immediate vs deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An observational follow-up study,” Garcia-Albeniz, Cooperberg, Carroll et al., Eur J Cancer, 2015 May.

Reports a retrospective analysis of overall survival for 2096 men treated with radical prostatectomy (69%) or radiotherapy (31%). The Gleason score was >7 in 35%. Eligibility required the tumor stage to be <T3a, and lymph nodes and metastases negative. The mean interval for the total cohort from primary therapy to PSA relapse was 37.4 months. [Roughly similar to the figure in the Atonarackis article.]

This study focused on men with low- to moderate-risk prostate cancer — the category most commonly seen. Other studies focusing on higher-risk cancer have shown that earlier ADT intervention is warranted for this much smaller group of men with Gleason score 8-10, early relapse from primary therapy, and the 6% of men with PSA doubling times of < 3 months (Freedland, JAMA, 2005).

In the Garcia study design “We emulated [a randomized trial] by assigning patients to the “immediate” strategy if they initiated ADT within 3 months of PSA relapse and to the “deferred” strategy if they initiated ADT when they presented with metastases, symptoms, or a short [i.e. < 6 months]  PSA doubling time.”  An additional indication for starting ADT was a combination of PSA >10 ng/mL and a PSADT of < 12 months.  ADT could be accomplished with an LHRH inhibitor or orchiectomy.

Study results:  The estimated 5-year overall survival for “immediate “ADT was 85.1% vs 87.2% for “deferred.” The 10-year survival was identical in both groups, 71.6%. There were very few prostate cancer specific deaths.

Study conclusion: “Our study suggests little or no survival benefit for immediate ADT initiation compared with deferred ADT initiation (at clinical progression) among prostate cancer patients with PSA-only relapse.”

The authors cite ASCO guidelines: “The Panel cannot make a strong recommendation for the early use of ADT” … [and] “the critical issue is to determine whether there is benefit and how large it is for starting ADT while patients are asymptomatic.”

Article #2:    The second study: “Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA , [acronym] ”TOAD”: a randomized, multi center, non-blinded phase 3 trial, published in Lancet, June 2016, and was a collaborative effort by 29 oncology centers in New Zealand and Australia.

It had aimed at 750 registrants, but poor accrual led to its early closure, diminishing its statistical power to achieve a firm conclusion. The patient mix was heterogeneous: 261 men were treated at PSA relapse, 32 never had primary therapy and received ADT; some received continuous ADT and others intermittent ADT. For “delayed” ADT the study schema recommended that intervention be delayed for at least 2 years unless clinically contraindicated, i.e. development of symptoms, metastases, or a PSADT of 6 months or less.

At 5 years the immediate treatment group’s overall survival was 91.2% vs 86.4% in the deferred arm.

Terrence Friedlander, MD, prostate cancer specialist, UCSF, who reviewed the study for ASCO 2015, opined “This study is not practice changing, and if there is a benefit to early ADT the benefits are likely to be modest and have to be balanced with the considerable side effects of hormonal treatment.”

What does “Up To Date” Say About This Issue?

“Up To Date” is a subscription-only, highly regarded source of very current evidence-based recommendations for management of most types of cancer. Of interest for this Commentary article is the section written by Judd Moul, MD, Professor of Urologic Surgery, Duke Prostate Cancer Center,  and Mary-Ellen Taplin, MD, medical oncologist, Associate Professor of Medicine, Harvard Medical School: “Rising serum PSA after treatment for localized prostate cancer: Systemic therapy,” updated June 2, 2016. They make some major points:

  1. In the situation the rising PSA after primary therapy, “No adequate data from randomized trials have compared the role of ADT with observation in this setting.”
  1. Regarding “When to initiate ADT-based therapy: The optimal timing …is controversial.”  “Deferral is favored by some, commencing ADT upon the development of metastases or symptoms since there is no consistent evidence for a significant survival benefit with ADT in this setting … .” [ i.e. at the point of a rising PSA.]
  1. They cite the CaPSURE data [reviewed above] in which “there was [by some calculations] a 2 percent difference in overall survival when men were treated within three months after detection of PSA increase,” as compared to delayed ADT.
  2. Regarding the TOAD trial [reviewed above]: “ … the trial has too few events to date and will be underpowered to make any definitive conclusions.”
  1. Their suggestions:  For young men at high risk for metastases, i.e., Gleason 8-10 or PSADT of <6 months, they prefer early rather than delayed ADT. “For men with favorable features, such as PSA doubling time >12 months, initiation of ADT can be delayed, with careful informed consent and periodic imaging to assess for metastases.”
  1. What is “early” ADT?  “There is no consensus on what is “early” initiation of ADT, but a practical target is PSA <5.”

BOTTOM LINE When to start ADT if the PSA rises? There are no clear guideline. But there is information and perspective upon which to have an informed discussion with a patient. The PSA doubling time and the Gleason score are the best predictors for the onset of metastases and best inform the decision to begin ADT.

[As an assist for calculating the PSA doubling time here is a link. For accurate results the most recent 3 values, preferable more, should be entered. Also note, that in the high sensitivity PSA range of < .2 ng/ml, a rapid PSADT doubling time may not accurately predict the same rapid rate at higher PSA levels.

The link: https://www.mskcc.org/nomograms/prostate/psa-doubling-time [Memorial Sloan Kettering Cancer Center].