GENOMIC APPROACHES TO GUIDE THERAPY IN PROSTATE CANCER Phillip Febbo is an Assistant Professor in the Dept. of Molecular Genetics and Microbiology in the Duke Institute for Genome Sciences and Policy at Duke University in Durham, N.C. He disclosed financial connections to Bristol, Myers Squibb, Genentech, and Novartis and is on the speakers bureau of Sanofi-Aventis. He opened his lecture by asking whether genomic analysis can: -Diagnose disease earlier? -Identify individuals at high risk for prostate cancer recurrence? Or prostate death? -Inform resistance mechanisms so as to inform future clinical intervention? -Help target specific therapy to pts more likely to respond? He then addressed these questions individually citing genomic studies that have provided some early answers. To the first question about diagnosis, he showed data that supports the argument that there are detectable changes in gene expressions that can be correlated with PC. With present techniques, the protein soups that can be analyzed require sophisticated approaches and hardware to affect the analyses. He illustrated this point with data showing how “auto-antibodies” can be used to detect PC. He then addressed the question of using genomics to identify individuals at high risk for PC. And again, he showed data in support of this. A group of identifiable genomic risk factors were shown along with correlations predicting PC recurrence published in the literature. In some studies he reported that “clinical predictors” did outperform genomic predictors. So the jury is still out regarding which is likely to be the most useful. He also discussed genomic analysis and its utility in identifying resistance mechanisms. These results might be useful in designing future clinical trials. Ongoing trials in this area were discussed briefly by Febbo. With respect to the usefulness of genomics in identifying patients most likely to benefit from a given therapy, the answer was a loud yes. He showed how selecting patients with Her2 vs unselected pts for a trial with Trastuzumab (Herceptin) greatly increased response rates. Dr. Febbo quoted from a study by Press and Seeling that showed a saving in clinical trial costs of some $35 million, increased income to the manufacturer of some $2.5 billion, and increased access to the drug of some 120,000 patients. These are significant benefits. He then went on to discuss Duke’s approach to biopsies for HRPC pts and also the genomic assays of HRPC. The goal is to predict the response of individuals to any of the available cytotoxic therapies. Professor Febbo then discussed some trials run to determine answers to this question. Preliminary data support the hypothesis that clinical responses to cytotoxic therapy may be predictable from genomics. He concluded his lecture by summing it up as follows: we don’t know yet what genetic factors will cause resistance to drugs. FINAL SESSION COMBINING RADIATION AND HORMONES: HOW CAN WE DO IT BEST? EVICENCE BASED TREATMENT GUIDELINES IN THE MANAGEMENT OF HIGHER RISK LOCALIZED AND LOCALLY ADVANCED PROSTATE CANCER Dr. Anthony D’Amico of Brigham& Womens’ Hospital in Boston delivered this lecture. He is a Professor of Radiation Oncology at the Harvard Medical School in Boston. No financial conflicts were submitted by Dr. D’Amico. [Ed Note: Of all the speakers, the ones involved in product development or product trials, seemed to report the most financial support by the Drug Industry]. Dr. D’Amico made an overriding point saying that in all cases of more advanced, or high risk PC, the combination treatment with hormonal therapy and radiation improved overall survival and time to progression of disease (TTP). He cited some trials or RT to which were added short courses of hormonal therapy (HT). In one instance with intermediate and high risk pts, 70 Gy plus 6 mos. HT resulted in a “25% PSA benefit at five years and a 10% survival benefit. Of the pts in the trial, 73% has GS >or= 7 and a median PSA = 11. In another case he discussed a trial involving 3 to 6 months of HT plus either 64 Gy or 74 Gy dosage. That trial showed a 12% PSA benefit at 5 years but no overall survival benefit. He also showed the increase risk for older men who experience HRT for longer periods of time, e.g., over 4 years. For men >65, prolonged treatment with HRT increases risk of death from non-cancer causes. He showed more data indicating that HT shortens the time to fatal coronary effects. Almost 10% of men who had undergone HRT for some six years had fatal coronary events. He showed additional data that indicated that after 6 months of hormonal therapy, PCSM (prostate cancer specific mortality) was greatly reduced if the testosterone level remained castrate at least two years. This was another way of reflecting the results when PSA remains at or near the nadir following HRT for 6 months. For higher risk cancers where the Gleason Score is in the 8 to 10 range, two – three years of hormonal blockade tx is “standard”. He quoted results of a small study wherein 19/51 men with GS 8-10 experienced two years of T suppression after just six months of hormonal treatment. In this same small group, PCSM was 0% for men whose T suppression lasted at least two years, versus 38% for men < 2years. Dr. D’Amico concluded by stating that the current best practice for T3 or T4 kind of disease should include 6 months of HRT with 70GY of 3D Conformal Radio Therapy. [Ed. Note: Although not stated directly, we assume that IMRT combined with 6 mos. Of HRT would produce similar, if not the same, results.] IMPACT OF RADIATION DOSE ESCALATION ON LOCAL CONTROL Dr. Howard Sandler, Professor and Senior Associate Chair, Dept. of Rad. Oncology, and Professor in Dept. of Urology at the U. of Mich Comprehensive Cancer Center gave this lecture. He disclosed being a paid consultant and/or Advisory Board Member for Cytogen, Genentech and Sanofi-Aventis. He also receives funding for some of his research by Sanofi-Aventis. His paper was essentially a review of current practice in radiation therapy for PCa. Given all the methods for delivering radiation to the prostate, he said that all results were essentially the same. He didn’t discuss the side effects issues as a function of delivery method. IMRT is the current “standard” for delivering controlled dosage to the gland. The greater the dose, the greater the cure rate. Dr. Sandler generalized by stating that for every increase of 1 GY in dosage, a 2% improvement in results occurs. He also stated that it can take up to three years for PC to disappear after radiation. This means that PSA must be tracked during that time until it reaches a nadir. Dr. Sandler also reviewed some literature showing dosage selected vs disease stage. NEOADJUVANT PRE-PROSTATECTOMY Dr. William Oh, Clinical Director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, delivered this lecture. Dr Oh disclosed being a paid consultant/Advisory Board Member of Abbott Labs, Abraxis Oncology, Berlex, Schering AG, Dedreon, Eyeteeth Technologies, Genomic Health, Imclone Systems, Novacea, Inc.,Roche Phmctcls, and Sanofi-Aventis. He also disclosed being on the speaker’s bureaus of Amgen, AstraZeneca, Lilly, Norvartis, and Sanofi-Aventis. Research funding is provided to Dr. Oh by Bristol, Myers, Squibb, Celgene, Genetech, Roche, and Sanofi- Aventis. [Ed. Note: Dr Oh also maintains an oncology clinical practice where he treats men with PCa. He must be a very busy researcher] Dr. Oh began his lecture by citing the relatively high rate of failure of local therapy in cases of high risk PC. When stage of disease has been identified as T3 or T4 and PSA = or > 20 with GS 8-10, there is a strong implication that the disease is already systemic and any local therapy is likely to fail. Most nomograms are structured to reflect this reality and they stratify patients by relative risk of being capsule confined, or have extra-capsular extension, or likely lymph node involvement, etc. He pointe out that cancer specific survival is poor in these high risk pts after any kind of local therapy. Oh briefly reviewed the multiplicity of local methods currently available that provide lots of options for local therapy but result in high failure rates for most high risk cases. He then used that observation to open a discussion of Neoadjuvant ideas prior to local tx. In the case of Neoadjuvant TX prior to radical prostatectomy, he listed as advantages such as: ability to assess in vivo chemosensitivity, ability to assess the molecular response in pathologic specimens, and the rapid ability to assess the effects of new agents compared to the adjuvant setting (where the tx is given AFTER the primary TX). He used as an example data from breast cancer trials that showed how pathological complete response rates were predictive of overall survival in BrCa. He then showed some data from Professor Soloway, U. of Miami, in which Neoadjuvant luprolide did NOT improve overall survival in patients with RPs following tx with the hormonal blockade. These results would seem to be contradictory to the same trials run with radiotherapy as the primary TX instead of RP. If the hypothesis of Neoadjuvant therapy combined with some acceptable primary TX was advantageous in overall survival, it would be evident in the Soloway data. These data showed that DFS was about the same (65%) with or w/o the Neoadjuvant tx. Dr. Oh showed an interesting table that summarized some seven trials involving combinations of chemotherapy with hormone regimes. Out of these seven trials only one involving 64 pts with Docetaxel plus HT showed three pts with pathological complete responses. He also showed some data on chemo neo trials witout hormonal regimens. These were Docetaxel trials w and w/out mitoxantrone. Even though these trials showed PSA declines ranging from 30 – 64%, there were no complete responses shown by pathology analyses. A total of 60 pts were involved in these trials. He reviewed the results of a trial using Neoadjuvant Docetaxel prior to RRP. This was a Phase II trial in which the primary endpoint was pathologically complete response. A PSA decline of =>50% occurred in 11/19 ots (58%) and a “measurable tumor response by erMRI was found in > or = 25% in 13/19 of pts, 68%. A pathologic response was found in 38% of pT2 pts, 63% in T3/T4 pts and 0% in pN(+) pts. The most common side effects mentioned in this trial included Grade 1-2 fatigue, no myelosuppression nor nausea or neuropathy. Some 68% of pts completed the trial. The median follow-up of 22 mos. Found that 3/16 pts were then on androgen deprivation therapy. The median PSA was <0.1. The conclusions from this study were the following: -Neoadjuvant Docetaxel is well tolerated -PSA declines of >50% seen in 2/3 of pts (independent of T) -Radiographic reductions of tumor seen in 2/3 pts -No evidence of CR pathologically Essentially, Neoadjuvant chemotherapy did some good but one might expect to see the tumor return in time. Additional trials are in the works for Neoadjuvant tx followed by RRP, e.g. CALGB 90203 by Dr. Eastham of MSKCC. Dr. Oh concluded this lecture with a brief review of trials involving GM-CSF and Thalidomide. [ Ed. Note: The spectrum of side effects in this trial would be enough to discourage all but the most eager to avoid it, at least until some less difficult regimen were to be offered.] NATURAL HISTORY OF RECURRENT PROSTATE CANCER The first speaker in this session was Dr. Mack Roach of UCSF who is a Professor of Radiation Oncology & Urology and is the Chair, Dept. of Radiation Oncology at the UCSF Mt. Zion Comprehensive Cancer Center. His topic was “ADJUVANT COMPARED TO SALVAGE RADIATION THERAPY. The title is self-explanatory: is it better to give radiation plus surgery first, or to hold off using radiation unless and until surgery has failed. He led off the talk by saying that some 50% of GS7 pts. fail a radical prostatectomy(RP) within 10 years! That is an alarming statistic. Others report that up to 60% of RP treated pts will fail in 10 years. Even some 15-25% of organ confined PC will have PSA failure, according to the Partin Tables. He then looked at the literature that defines treatment failure. Essentially, any PSA following RP that exceeds some level (ranging in the literature from 0.1 to 0.6 is considered to reflect failure of the surgery to totally eliminate the prostate cancer. Dr. Roach also discussed RT for salvage purposes following failed RP. He cited data that indicated an increase from 52% to 74% in 5 year “relapse-free survival” and 85% vs 75% in clinical progression free survival (data from Bolla, et al. Lancet 366, 572-578, 2005). This is a good reference to examine work done in a Phase III trial with N=1,005 pts. Conclusion of Bolla, et. al. is that salvage radiotherapy can be useful following failed RP. For side effects of this combination the original article should be consulted. His concluded that adjuvant RT : -For every solid tumor studied, local control is improved with post op RT in High risk pts. -When done well, the morbidity is low -If adjuvant RT does not prolong survival, what does this mean? [RT prior to surgery does improve time to disease progression when RP combination fails to cure disease, and post RP salvage RT also helps some men to gain longer DFS. Ed. Note] SALVAGE SURGERY FOR RADIORECURRENT CaP Dr. Graeme S. Steele in the Urology Division of Brigham and Women’s Hospital in Boston, delivered this lecture. He had no financial conflicts to be disclosed. Interesting to note that none of the surgeons reported financial conflicts. Compare this to the number of financial conflicts reported by the oncologists and researchers working in the areas of drug research and development. Dr. Steele discussed overall ex;perience with salvage surgery following failed RT, either brachy or XBRT. He was not optimistic about the results of this sequence of treatments. For highest success probability, the following initial disease parameters were identified: -GS < 7 -PSA = < 5 - 10 Life Expectancy He discussed the difficulties encountered in imaging cases of recurrent disease. If endorectal MRI identifies ECE or SV or LN involvement, then the odds of success drop sharply. He cited literature showing DFS following S-RP (salvage surgery) in a variety of PC conditions. The higher the initial T stage of the disease, the higher the degree of LN involvement, the higher the metastases identified, the lower the degree of S-RP success. [ ED. NOTE: In the case of salvage therapies following failed primary treatment the overarching conclusion is that they are not likely to succeed. RT post RP failure has better odds than RP after failed RT. No cryo surgery was discussed in salvage terms at this meeting but it is being attempted with increasing frequency.] PANEL DISCUSSION Following their individual lectures, the speakers held a Q&A Panel session. Dr. Roach cited some literature that claimed adjuvant RT was more successful than salvage RT. Issues of morbidity were discussed in the context of salvage procedures. The radiologists argued that “morbidity was not significant” but this was contradicted by the surgeons. This basic argument goes on. It was agreed by the RT Salvage promoters that the earlier salvage RT is applied, the higher the success rate. Dr. Eastham, a practicing surgeon at MSKCC stated that he will not perform a salvage RP if the initial PSA was >10. Also, Dr. Roach said he does not recommend HT for “low risk” pts. The “take-home-lesson” from the salvage therapy sessions was essentially not to have to resort to it. Early stage disease is least likely to fail after primary therapy and therefore is the least likely to require salvage treatments whose results are always uncertain. SECONDARY HORMONAL APPROACHES Dr. Charles Ryan, Assistant Prof. of Med, UCSF Comprehensive Cancer Center in San Francisco, disclosed only being on the Speaker’s Bureau for Sanofi, Aventis. He discussed secondary hormonal approaches that are typically used when PCa becomes HRPC. Dr. Ryan opened his lecture by identifying three possible interpretations of when PCa stops responding to hormonal blockade therapy. He phrased the question as follows: is it HRPC, AIPC as in androgen independent PC, or is it castrate resistant PC? The fundamental question of secondary HBT arises upon disease progression even in the face of castrate levels of serum testosterone. He used this provocative statement “…why truly androgen independent PC may not exist….” To open a discussion of the mechanisms that may be involved in both the response of the PC to HBT and in the ultimate development of HRPC in all cases. “Persistent AR signaling may be an early event associated with recurrence. AR copy number increases with disease progression. Androgen persisting in the serum may stimulate tumor growth despite ‘castration’ therapy and intratumoral androgens may stimulate tumor growth.” The persistence of androgen receptors in spite of blockade therapy may be an early signal of resistance to treatment in PC cases. Ryan pointed out that there are other androgens in the male such as androstenedione, DHEA, DHEAS, and of course Testosterone. His point was that despite reaching castrate levels of T, the other androgens may also be indicators of hormone resistant tumors. And these may predict the response to the use of secondary ketoconazole tx. He cited work by Page, et. al. that showed the presence of “intra-prostatic androgens” after “medical castration” in healthy men. Ryan indicated that the presence of these androgens are “modestly” associated with the probability of response to ketoconazole tx. Low levels of androstenedione are associated with shortened survival. He used ketoconazole as the only available anti-androgen with known effectiveness in treating AIPC as a secondary line. Some men who do not respond to ketoconazole may not have the requisite levels of non-T androgens. Ryan discussed the early work going on with Abiraterone as a new seconday line tx for HRPC. Is is described as an “adrenal androgen inhibitor”. See trials CALGB 7630, SWOG 9916, and TAX 327 to compare effectiveness of abiraterone with chemo and with keto. Some of the preliminary results are interesting. PSA declines of >90% were observed in 12% of pts, declines of >50% occurred in 48% of pts, with a median decline of 24% seven days after one dose of Abiraterone. Dr. Ryan concluded his lecture by making some interesting observations: emerging data suggests that androgen/AR interactions persist even in castration resistant PC. Also, intratumor steroid production suggests that these effects are not “endocrine” or even “hormonal” at all. And novel enzyme inhibitors may prove effective by inhibiting these pathways (either intrinsic or extrinsic). More clinical work is being done with abireterone and the Editor will follow it for further reporting on the web site www.jupiterprostategroup.org. CHEMO-HORMONAL THERAPY FOR BIOLOGICAL PROGRESSION This lecture was presented by Dr. William Oh, Dana-Farber Cancer Institute, Harvard Medical Service. See earlier talk for pertinent info on Dr. Oh. He reviewed biochemical (PSA) failure from the pts perspective: disappointment that “I wan’t cured”, confusion whether “I still have cancer”, fear “am I going to die”, and anxiety “what do I do now”. Dr. Oh reviewed the “standard” options for biochemical failure patients: -Observation -Salvage local therapies -RP or cryo for RT failure -XRT for RP failure -Hormonal TX -Castration -Non-castration -Diet/Alternative Trials -Chemo, hormonal biologic trials According to Dr. Oh, as many as 1/3rd of men who have been treated for localized PCa, will relapse. And this is manifested in a rising PSA. Dr. Oh stated “little is known about optimal management of rising PSA patients”. Given the large number of men in this category it is disturbing to hear one of the country’s leading medical oncologists say this. I quote Dr. Oh: “We really don’t know how to manage these patients”. To the editor’s knowledge, every man who experiences a rising PSA following some kind of primary therapy is exposed to hormonal blockade therapy. The implication of Dr. Oh’s remarks is that this is a purely empirical reaction to the problem. He cited some data from Johns Hopkins Hospital where 321 out of 1,997 men who underwent RRP relapsed (16%). They did not have hormonal blockade therapy until a + bone scan was obtained in a median oft 7.5 years. They all experienced rising PSA <2years post RP. These pts who had GS 8-10 and PSADT < 10 mos. had worse survivals. This study reported an average of 6.5 years between the + bone scan and death. In another study by D’Amico cited by Dr. Oh, some 8,669 pts (both RT and RP) were followed from 1988 – 2002. The median followup from PSA recurrence was approximately 4 years. Stratifying these pts in terms of PSA doubling time (PSADT) using 3 months as the dividing point, showed that those whose PSADT was < 3mos., had almost 20 times the risk of dying from PCa than those with the slower PSADT of > 3 mos. (see D’Amico, JNCI, 2003) He further reported that the literature has generally shown that earlier tx is better than delayed Tx but is not considered curative. More recent studies have used Neoadjuvant hormonal tx with XRT and reported better survival results. However, these advantages are generally in added months of survival vs. years. He reported that PSADT after local therapy is probably the best indicator of risk rather than PSA itself. There are no really good data supporting the idea of HBT in rising PSA cases. Considering that the world of practicing prostate oncologists routinely uses HBT in cases of post primary TX failure, it is no wonder most men consider it “curative”. Oh showed some data from the Lancet Journal that showed only an absolute survival difference of 0.7% between combined AA treatment and monotherapy in metastatic disease. Cost and toxicity were significant factors because the drugs used for antiandrogen effects are very expensive and have problematic side effects. Essentially, he concluded that monotherapy with LHRH agonists is best overall. Oh then spent some time describing some early results from trials combining androgen deprivation therapy and chemotherapy. These results are showing survival advantages but mostly in surrogate endpoints that are more quickly determinable than overall survival. [Ed Note: The empirical approaches that are taken designing trials with chemo and w/ and w/o ADT seem to be endless. When one considers the various combinations that might be tried in trials, it seems that the trialists are looking for the proverbial needle. Given two therapies that alone do not have curative properties so that combining them in various ways to achieve some kind of synergy, does not seem to be the most rational approach. But absent any real understanding of the basic mechanisms involved in prostate cancer metastasis and recurrence, we are left with fundable clinical trials supported by the drug manufacturers.] TARGETING HISTONE DEACETYLASE INHIBITORS Dr. M. Carducci of Johns Hopkins deliverd this lecture. Histone Deacetylase Inhibitors (HDI) are a relatively new class of compounts that may be useful in treating PC at different stages of the disease progression. Some seven pharmaceutical companies were identified as having candidate products in various stages of development ranging from phase I to phase III trials. HDI compounds have been studied for several years because of their ability to alter some critical cell processes. The HDI products can modulate gene expression, induce cell growth arrest, and cell differentiation. They can also help induce apoptosis, programmed cell death, a vital mechanism in cancer development. Tumor cells proliferate because their apoptotic capability has been lost or dramatically reduced. The work reported on by Dr. Carducci was all related to basic cellular mechanisms and the HDI role. There is also work going on with HDI products used in various combination strategies with other prostate cancer treatments. Dr. Carducci outlined some of the possible combinations that might result in better tumor control in PCa. Most of his presentation dealt with fundamental mechanisms believed to be involved with HDIs but no data were presented. This work should be followed by those interested in its potential usefulness in PC therapy. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. 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