Category: PCa Commentary

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].

PCa Commentary Vol. #103: The (18)F-fluciclovine Total-body PET/CT Scan (Trade named “Axumin,” aka FACBC) is Now Approved for Recurrent Prostate Cancer; It’s availability is likely to impact clinical management decisions.

This article was co-written by David Djang, MD, specialist in Nuclear Medicine, Swedish Medical Center, Seattle, WA

Basic Background:

The spread of cancer from the prostate into the lymph node system has been regarded as an orderly and sequential involvement of the “regional” pelvic nodes near the prostate gland spreading further peripherally as the nodal burden increases. Based on nomograms indicating the likelihood of spread to lymph nodes, surgeons perform a pelvic lymph node dissection (PLND) and follow a standard template for nodal excision. In an extended PLND the external iliac, obdurator, hypogastric, and common iliac nodes are removed. In some cases nodes from the pre-sacral region are included. Surgical outcome studies have shown that when only one or a few nodes near the prostate are involved and excised, the outcome can be very satisfactory. Correspondingly, when radiation is employed, it also focuses on this conventional pattern and treats the same areas. The downside of adhering to these set patterns is that, even at diagnosis, as the burden of nodal disease increases, as it often does in aggressive high-risk cancer, nodal metastases have already spread to areas beyond the convention treatment targets. Depending on the cancer’s aggressiveness, spread beyond the usual treatment pattern may occur in as many as 40% of instances based on studies with the (11)C-choline or (11)C-acetate total-body scans. These more widespread nodal metastases remain untreated and can serve as the source of PSA relapse.

Unfortunately, useful as the choline and acetate scans are, these scans have limited practical availability because of requiring a nearby cyclotron. This limitation results from the short half-life of these tracers which limits their transit, i.e. 20 minutes for radioactive choline.

An Unmet Need:

There is clearly a pressing need for an available and accurate total body scan. As only one example, Garcia et al., Quarterly Journal of Nuclear Medicine and Molecular Imaging, 2015 Sept, using (11)C-choline PET/CT in the study of 61 patients with medium-to-high-risk prostate cancer found nodal involvement beyond the usual template in 21.3%. This information is essential for appropriate radiation therapy treatment planning and surgical management. Studies have found that when this information about the unexpected extent becomes known, radiation and surgical management changes. At PSA recurrence this wider nodal spread is often not imaged by the usual CTs and bone scans.  “Impact of (18)F-choline PET/CT in Decision-Making Strategy …[for] Radiation Therapy,” Clinical Nuclear Medicine, 2015 Nov, “ reported that in 57 men with low-, intermediate-, and high-risk prostate cancer the Choline PET/CT shifted treatment indication in 13 cases (21%).”

The Current Status is About to Change:

A new radiotracer for total body scanning, trade named (18)F-fluciclovine (also referred to as (18)F-FACBC, and trade named Axumin) was approved by the FDA in May 2016 for the diagnosis of suspected prostate cancer recurrence after primary therapy. It will likely have widespread availability in many nuclear medicine departments across the nation and already is available in 11 pilot locations.

18F-fluciclovine is a synthetic amino acid analog taken up and concentrated by prostate cancer cells through an amino acid transporter. The 18F-fluciclovine PET/CT scan can help identify a recurrence of prostate cancer at an early stage.

The half-life of 18F-fluciclovine is 110 minutes, which allows it to be produced and then distributed. This longer half-life allows the tracer to be produced at a centralized location, so that imaging centers would not need to have cyclotrons on site, a significant logistical advantage over the 11C tracers. From the patient’s perspective, the scan itself can be completed in less than one hour.

18F-fluciclovine was developed at Emory University, commercialized by Blue Earth Diagnostics, and is being distributed by PETNET. 18F-fluciclovine is only minimally excreted by the kidneys, which allows for accurate imaging of the prostate bed. The 18F-fluciclovine PET/CT scan can detect prostate recurrence in both bones and soft tissue, which has been routinely assessed by a combination of CT and bone scans.

Comparison of [18]F-fluciclovine PET/CT with (11)C-choline PET/CT for recurrence:

This comparison was reported by Nanni et al., European Journal of Nuclear Medicine and Molecular Imaging, Mar 2016, based on 86 men with CRPC and a rising PSA after prostatectomy. The men were off androgen suppression and the comparison between the two scans was made within 1 week.  The scans were compared on a per-person and per-lesion basis yielding an accuracy of 38% for the FACBC and 32% for the choline study. The positive predictive value was 97% and 90%, respectively.

In an earlier article based on the same cohort of men (Nanni et al., Clin Nucl Med 2015 Aug) the authors expressed their findings more forcefully: “On a patient-based analysis, (18)F-fluciclovine detection turned out to be significantly superior to (11)C-choline ( P<0.00001)” in men with low, intermediate, and high PSA levels. Their conclusion: “The 18F-FACBC can be considered an alternative tracer superior to 11C-choline in the setting of patients with biochemical relapse after prostatectomy.”

A study of 115 patients at Emory University found a whole-body positivity rate of 39.0% (7/18) at PSA 0 – 1; 76.9% (10/13) at PSA 1.1 –  2;  and 90% (27/30) at PSA 2 – 3.5 ng/mL.

One review article (von Eyben, Ann Nucl Med. July 2016) found the two scans to be equivalent in the detection of metastatic sites when scanning at a median PSA of 3.6+/- 2.7 ng/ml ( range 0.5-10.7).

However, the thrust of this article is not to detail a comparison of the fluciclovine and choline scans but rather to indicate the importance of having the forthcoming availability of the the Axumin scan in an accessible facility. Up to now, evaluation of recurrent prostate cancer has been made using ultrasound, CT of abdomen/pelvis, and bone scanning.

In 2016 the guidelines by the European Association of Urology and the National Comprehensive Cancer Network (NCCN Version 3.2016) changed their recommended studies for selected patients with recurrent disease from those studies to the (11)C-choline PET/CT.  When the Axumin scan enters the clinical scene, their recommendation is likely to extend to this scan.

What management decisions might follow from early and accurate information as to the location of recurrence diagnosed on an Axumin scan in men with prostate cancer?

  1. Awareness of the location of persistent disease at the time of PSA recurrence, if exclusively found within or in the region of the prostate, could provide the indication for further local therapy. Disease found beyond the primary treatment target could strengthen the case for the earlier application of androgen deprivation, chemotherapy, or immunotherapy, a promising emerging modality under current study. Repeat scans could augment the PSA test in monitoring the effectiveness of early therapy.
  1. In carefully selected cases of PSA recurrence with minimal sites of metastases (“oligometaststic,” i.e optimally 3 but <5 sites, ) and low and slowly rising PSA values, targeted CyberKnife treatment to the affected sites could be offered — a treatment whose effectiveness is under active study.

A recent check of ClincialTrials.gov found nine clinical trials addressing the treatment of oligometastatic prostate cancer in Phase II one-arm studies, some with accompanying ADT, and one with immune therapy (prembrolizumab).  They are mostly single institution trials, but promise useful information.

  1. If the scan were employed at the time of initial diagnosis, the information could result in choosing a wider field of nodal resection or a selectively widening of coverage by radiotherapy, as is already being done in Europe.

BOTTOM LINE:  

The local availability and accuracy of the Auxmin scan will very likely have significant influence on management decisions in the treatment of recurrent prostate cancer, the indication for which it is approved. In the future after further study, it may well become approved in the US for use at the time of initial diagnosis for high-risk aggressive prostate cancer.

[The PCa Commentary will notify its readers of the availability of the Axumin scan and how to order the study.]

PCa Commentary Vol. #102: An MRI Protocol for “One-Stop-Shopping” for Staging in Newly Diagnosed Prostate Cancers

Assistance in the composition of this article was provided by Dr. Udo Schmeidl, staff radiologist, Seattle Radiologists; and by Dr. Jim Borrow, formerly staff radiologist, First Hill Diagnostic Imaging, Seattle, now a consultant in MRI radiology.

The appropriate staging protocol after the diagnosis of prostate cancer is undergoing progressive evolution in keeping with the increasing sophistication of imaging technology. A recent article in the American Journal of Radiology reports that a multiparametric MRI of the prostate and pelvis combined with an MRI of the lumbar spine serves well as a single staging study for high-risk intermediate and high-risk prostate cancer. This one study can supplant the current customary CT of the pelvis often in conjunction with a Technetium or NaF PET/CT imaging of the skeletal system.

“Identification of Bone Metastases With Routine Prostate MRI: A Study of Patients with Newly Diagnosed Prostate Cancer,” by Woo et al, AJR, June 2016, reports on 308 newly diagnosed patients among which 21 were found to have metastases to bone on the basis of imaging of the entire skeleton. The AJR study protocol MRI was limited in scope and explored “most of the pelvic bone and proximal portion of the femoral head” and the lumbar spine.

The rationale for limiting the imaging to only the pelvis and lumbar spine is the many prior studies that have shown that “the possibility of isolated peripheral metastases is negligible and even distant bone metastases without pelvic and lumbar spinal involvement is unlikely.”

In the study the MRI findings were compared to the results of biopsy or surgical specimens from abnormal areas or a “comprehensive review of bone scanning, prostate MRI, CT, or a combination of these modalities, follow-up imaging studies for equivocal lesions (targeted radiology, dedicated CT or MRI and PET) and clinical follow-up … .”

Study Results:

“According to the reference standard [as described above] 12 of 21 patients (57.1%) had bone metastases in areas not explored with the prostate [and lumbar] MRI, that is, the cervical spine, sternum, skull, ribs, scapula, and humerus. However, “Only 1 of the 21 (4.8%) patients had bone metastases only in an area not explored with the prostate MRI, that is, the thoracic spine.”

There were 119 patients considered to be at high risk for bone metastases. In this group the sensitivity and specificity of the imaging protocol was 95% and 100%, and the positive predictive and negative predictive values were 100% and 99%, respectively.

Previous studies have reported the superiority of whole-body MRI scans and scans of the entire spine compared to bone radioisotope scanning (such as with Technetium)  or a sequential work-up. However, whole-body and axial spine MRI have the disadvantage of unavailability, high cost, and scanning time. There is no reported difference between MRI and CT in establishing the size of regional lymph nodes.

The authors of the AJR article contend their protocol offers a practical technique as “one-stop-shopping” for the staging of men newly diagnosed with prostate cancer.

In Addition to Patients at High Risk Which Other Patients are Most Likely to Benefit from this Extended Protocol?

Appropriate candidates for this comprehensive approach are high-risk and high-risk intermediate-risk patients. In European Urology. 2013 Dec Zelefsky et.al. proposed a new risk classification system for the heterogeneous intermediate risk group. The high-risk group was defined as primary Gleason score 4, > 50% positive biopsy cores, and two or more of the three NCCN risk factors in the current intermediate-risk grouping.  Favorable intermediate-risk was defined by a single NCCN risk factor combined with Gleason < 3 + 4, with <50% of the biopsy cores containing cancer. The Gleason score is the most consequential element in both high- and favorable-risk definitions. NCCN intermediate criteria are Clinical stage T2b or T2c, or Gleason score 7, or PSA 10 – 20 ng/mL.

The Distribution of Metastatic Spread to Bone and the Biology of Cancer Growth in Bone:

The credibility of the assessing metastases in the lumbar spine and pelvis as a surrogate for metastatic spread to the entire skeleton is based on: 1) the biologic pattern of prostate cancer migration from the prostate gland, and 2) the biology of cancer growth in the bone.

Distribution:

The distribution of metastatic sites has been well studied. The consensus favors dissemination, probably upward through Batson’s venous plexus from the pelvis, upward via these vertebral veins and rising sequentially through the lumbar vertebra into the higher levels of the axial skeleton, i.e. spine. Although cancer cell can spread directly from the prostate into the blood stream, spreading into the bone appears to be the preferential pattern in early dissemination.

Wang C, et al., Nuclear Medicine Communications. 2012, in “Studies on the distribution features of bone metastases in prostate cancer,” found that in the presence of widespread skeletal metastases, 99% (903/912) also occurred associated with sites in the pelvis and vertebra.”  “In [instances of] fewer bone metastases, the proportion of metastatic lesions in the lumbar vertebra was the highest … . Accordingly, tumor lesions frequently encroached on the lumbar vertebra at first; the lumbar vertebrae were the most important predilection site in early bone metastases.”

Similar data in support of the preferential metastatic spread to pelvis and lower spine was expressed by Larbi et. al. in “Whole Body MRI (WB-MRI) Assessment of Metastatic Spread in Prostate Cancer: Therapeutic Perspective on Targeted Management of Oligometastatic Disease,” The Prostate, 2016. [oligo = few; i.e. 3 or fewer sites] In 96 patients “No patients were diagnosed with exclusive non-axial bone metastases in the absence of axial metastases. The three most commonly involved areas were the left ilium 38%, lumbar spine, 38.5% and thoracic spine, 35%.

These authors expressed a strong preference in imaging modality: “MRI is highly sensitive for detecting BM [bone metastases] ; its superiority over [the Technetium scan] has been repeatedly demonstrated in multiple studies and meta-analysis [six references provided].”

Biology:  

The biology of the growth of prostate cancer in the bone gives an advantage to MRI over the Technetium scan for early detection. After cancer cells or clusters of cells have been seduced to home to the bone marrow, the cross talk between the microenvironment and the cells promotes proliferation. It is this mass, denser than surrounding tissue, that can be detected by the MRI. Later, the proliferating cancer effects degradation of the surrounding bone matrix, a process not visualized in radiotracer scans. Later an osteoblastic response follows in an attempt to replace the lost bone, and remodeling takes place. The increased cellular activity involved in bone remodeling can now be detected by, say, a Technetium scan.

This biology is the basis of the greater sensitivity of MRI for early bone marrow metastases. This process is discussed in detail in a review in the Asian Journal of Andrology (2009) by Clark, NW, “Molecular mechanisms of metastases in prostate cancer.”

The Protocol in Greater Detail: What Does the Protocol Entail, What Does it Image, and What Study to Order:

The routine protocol used by Woo et al. includes multiparametric MRI sequences (T1, T2, diffusion weight pre-contrast;  and T1-weighted gradient echo pre- and contrast-enhanced) MRI sequences targeted to the prostate and a single, non-contrast, T1-weighted sequence of the lumbar spine in the axial plane. The mpMRI prostate and lumbosacral sequences can be accomplished without moving the patient and performed in a single session.

The prostate study provides the best available imagine information about the location and size of the largest tumor mass, the “index” lesion, within the prostate and serves as a guide for a targeted re-biopsy if necessary. Properly interpreted, the mpMRI in conjunction with PIRADS ( Prostate Imaging Reporting and Data System ) classification allows assigning the index lesion a likelihood of showing cancer or biopsy — PIRADS 1, very low; to 5, very highly likely. The diffusion weighted sequence can additionally suggest a Gleason grade for the lesion.

Lumbar spinal bone marrow, virtually all pelvic marrow is imaged, and lymph nodes are included. As described by Wang et al. and as found by Woo et al, few patients with bone metastases will be missed with this as a standard protocol. Recognizing that a very small number of patients with isolated thoracic spine lesions will be missed with this protocol, a thoracic spine study can be added to capture these lesions.

BOTTOM LINE:   After a biopsy diagnosis of high-tier intermediate-risk or high-risk prostate cancer, staging of the disease can be accurately gained with a multiparametric MRI of the prostate and pelvis supplemented with a limited MRI of the lumbar spine.

PCa Commentary Vol. #101: Androgen Deprivation Therapy: A cautionary note for cardiac patients

Except for men presenting with the most advanced stages of prostate cancer, there is general agreement that most men — the vast majority — diagnosed with this disease will die of cardiac complications … and not from prostate cancer. When the association of testosterone suppression and cardiac death is assessed in large studies, studies not specifically focusing on cardiac issues, there is controversy questioning this association. But even in these analyses the risk of a cardiac complication is increased by about 10% or more for users of androgen deprivation therapy (ADT) vs non-users.

However, in meta-analyses of large observational studies that permit consideration of types of androgen suppression, duration, patient age, and comorbidity — especially the extent pre-ADT cardiac disease, the association of ADT with cardiovascular disease (CVD) is strong. The incidence of ischemic heart disease, congestive heart failure, myocardial infarction, stroke, and cardiovascular mortality (CVM) in those men with pre-ADT cardiovascular disease is markedly increased.

The essential quest is to properly evaluate the use of ADT in consideration of the benefit/loss equation. This may be best served in some instances by avoiding ADT altogether, a decision that may be challenging for a clinician to feel comfortable with acknowledging the understandable urge to respond to a rising PSA.  An important consideration for reducing the cardiovascular risk may be choosing the best agent for androgen suppression. Overriding these details is the clear imperative for the prescribing physician to review a man’s cardiac history and assess his cardiac risk factors before commencing ADT.

The plausibility of a causal association between testosterone (T) suppression and cardiovascular disease (CVD) and cardiovascular mortality (CVM) is strengthened by acknowledging the biologic consequences of a T lowered to subcastrate levels (20 – 30 ng/dL). Metabolic aberrations associated with castrate T levels include: decreased insulin sensitively and overt diabetes, hypertension, elevation of cholesterol and low-density lipoprotein, abdominal obesity, increasing arterial wall thickness, and proinflammatory and prothrombotic states, all of which predispose to cardiovascular disease.

A normal T level may actually exert a cardioprotective effect and this may be interrupted by ADT. Gonadotropin releasing hormone receptors (GnRHr) have been identified in cardiac muscle and their inhibition may lead to lower cardiac contractility ( Conteduca et al. Crit Rev. Oncol Hematol. 86 2013 ). 

One of the puzzling questions was what mechanism might explain heart attacks occurring so early — within 6 months – of starting Lupron. A potential answer seems to be indicated in “Treatment with a GnRH receptor agonist but not with the GnRH antagonist degarelix, induces atherosclerotic plaque instability in ApoE(-/-) mice. The study found that within 4 weeks of Lupron treatment the mooring of stable plaques within the arteries was disrupted.

Their conclusion: Destabilizing of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH agonists,”  Knutsson et al. Scientific Reports May 18, 2016.

On the basis of these concerns, in 2010 the FDA issued a safety warning regarding GnRH agonists, i.e., Lupron, Zoladex, and Eligard, cautioning about the increased risk of diabetes, heart attack, sudden cardiac death, and stroke associated with ADT.

  1. THE FINDINGS OF TWO MAJOR ARTICLES ON THE CARDIOVASCULAR COMPLICATIONS OF ADT:“Risk and Timing of Cardiovascular Disease after Androgen-Deprivation Therapy in Men with Prostate Cancer,” O’Farrell et al. (Kings College London, School of Medicine), Journal of Clinical Oncology. March 2015.

This Swedish study “investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched PCa-free comparison cohort.”

  • Antiandrogens (i.e., Casodex and Flutamide) were used in 10,656 men
  • GnRH agonists in 26,959 and
  • Surgical orchiectomy in 3747

The indication for ADT was a rising PSA after primary therapy or the initial use of ADT without primary therapy. The men were stratified as to risk categories, age, duration of ADT, the number of previous CVD events, and stratified as to the extent of comorbidities, such as myocardial infarction, congestive heart failure, peripheral vascular disease, and cerebrovascular, dementia, chronic pulmonary disease, and diabetes.  Having two or more of these conditions should raise concern. (J Chron Dis Vol. 40, 1987)

The major findings:

  • CVD was increased in GnRH agonist users 21% compared to non-ADT users.
  • CVD risk was highest — a 90% increased risk — during the first 6 months of ADT for those who had experienced two or more cardiovascular events within a year before therapy.
  • Orchiectomy was associated with a 16% increase in risk of CVD.
  • Men on antiandrogens (AA) were at a reduced risk — by 13% — compared to non-ADT users.

Their conclusion:

“There should be solid indication for use of ADT so that the perceived benefit outweighs possible harm. This is particularly important in men with a recent history of CVD.”

2. “Androgen Deprivation Therapy for Prostate Cancer Is Associated with Cardiovascular Morbidity and Mortality: A Meta-Analysis of Population-Based Observational Studies,” Zhao et al., (Tianjin, China) PLoS ONE (Public Library of Science) Sept 2014.

The major findings:

After identifying 836 unique articles on the subject, strict selection criteria yielded 6 studies suitable for evaluating the association of ADT (with GnRH agonists) with CVD. Based on 129,802 ADT users compared to 166,605 controls the incidence of CVD was increased 19%.  The combination of a GnRH agonist with an antiandrogen increased CVD 46%. Neither AA alone nor orchiectomy increased CVD incidence.

The evaluation of CVM was based on 119,625 ADT users compared to 150,974 controls. The incidence of CVM in men using GnHR agonists alone was increased 36%. When combined with an AA the increase was 44%. There was no increase in CVM when antiandrogens were used alone.

Their conclusion:

GnRH agonists alone and combined with an antiandrogen increase the risk of cardiovascular disease and mortality. This association underlines the need to “define populations for whom benefits from ADT outweigh risks and to develop strategies to prevent ADT-related cardiovascular events.”

STUDIES COMPARING THE RISK OF CARDIOTOXICITY OF ADT: GnRH ANTAGONIST (degarelix) versus GnRH  AGONISTS ( i.e. Lurpon, Zoladex, Eligard )   

  1. Research on this important issue was reported in “Risk of cardiovascular events with degarelix versus leuprolide [Lupron] after biochemical relapse of prostate cancer: Exploratory analysis of a randomized controlled trial,” Higano, Crawford, Klotz et al. Journal of Clinical Oncology, March 1 Supplement, 2015.

Their study of 175 men compared the incidence of non-fatal CV events in men with prostate cancer having pre-existing CV disease. Of interest, in the group of men in their mid-70’s 35% had a history of CVD at study entry. The arms were well matched for both cardiac and prostate cancer risk factors.

Their findings:  “During the observation period [of one year] a subsequent CV event occurred in 3 (3.4%) men treated with degarelix and 8 (14.5%) treated with leuprolide ….”

2. At ASCO Genitourinary Symposium 2016, abstract 232, a German group reported on cardiovascular events in three groups of cancer patients: 4436 men treated with GnRH agonists; 133 with the antagonist; and 37, 367 who received no ADT.

Myocardial infarction or ischemic stroke occurred in 6.27%, 3.76%, and 4.62% in the agonist, antagonist, and no-ADT group respectively. Cardiovascular events were seen in 11.27%, 7.52%, and 8.38% of men in the agonist, antagonist, and no-ADT groups.

Their finding: “Our results indicate that ADT with GnRH antagonists is associated with fewer CV events in PCa patients than treatment with GnRH agonists.”

3. In European Urology, March 1014, Albertsen, Klotz, Tombal et al. reported the results of six phase 3 prospective randomized studies (including the study cited above by Higano): “Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist.”

Their analysis was based on 837 receiving an agonist and 1491 receiving degarelix.  Treatment was administered for 1 year in 72% of patients, and for 3 – 7 months in the other men.  The study end points were death from any cause or a new occurrence of a cardiac event during 1 year of observation. Study entry required an excellent or good performance rating.

As also noted in the Higano article, in this age group, i.e. in their mid-70 years, a history of cardiovascular disease was already very prevalent in 30% including:  myocardial ischemia, 11%; myocardial infarction, 7%; coronary artery disease, 8%; stroke, 4%; angina, 3.3%; and history of coronary artery bypass, 3.1%.

Their findings: During the year there was a 40% decrease in death or a new cardiac event favoring degarelix compared to a GnRH agonist.

“No difference in the incidence of either death from any cause or the incidence of cardiac events was seen among men who had no preexisting CV disease at baseline.”

The biologic explanation for the claimed superiority of a GnRH antagonist over an agonist is unclear. Both agents lower pituitary secretion of luteinizing hormone (LH) resulting in T suppression. However the antagonist also reduces pituitary secretion of follicle-stimulating hormone (FSH) thought to exert a protective effect on blood vessel wall function.

Their conclusion: “Our study [finds] that among men with preexisting CV disease, those receiving GnRH agonists had twice the incidence of cardiac events when compared to men receiving a GnRH antagonist.

BOTTOM LINE:   Although still a controversial issue, multiple studies report persuasive evidence for an adverse association of ADT and cardiovascular toxicity. This association is especially strong in men with preexisting CV disease. The adverse consequence of ADT may be lessened by using a GnRH antagonist as opposed to an agonist. Considering the common prevalence of preexisting CV disease, a thorough screening of men for CV risk factors or prior CV events is essential. With this information a clinician has an opportunity to attempt to modify risk factors, and in some cases decide to avoid ADT altogether.