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Several studies have been performed and published.  A phase II study (Templeton et al., 2011) investigating the activity of everolimus 10mg/daily as first-line treatment found that in 37 enrolled patients, 12 (32%) remained progression-free at 12weeks. Other phase II studies of everolimus, alone or in combination with bicalutamide, bevacizumab, or chemotherapy, as well as trials testing other mTOR inhibitors such as temsirolimus and ridaforolimus, are currently recruiting patients.  More studies are awaited.

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There is currently limited evidence to support the use of Xtandi for patients who had not or cannot receive docetaxel, before the PREVAI results become available. Median time to radiographic progression in one phase II study by Scher, 2010, was 56 weeks for chemo-naive patients and 25 weeks for patients previously treated with chemotherapy.

Several studies, in addition to Prevail, are looking at Xtandi before docetaxel. There is a phase II trial began in March 2011 comparing MDV3100 with Casodex in patients  patients who have progressed while on LHRH analogue therapy (e,g., leuprorelin) or surgical castration. This ASPIRE trial is an an open-label study intended to evaluate the effects of enzalutamide in about 150 men who are theoretically eligible to receive chemotherapy but have chosen not to do this. Another phase II study, STRIVE trial is a randomized, double-blind, multi-center clinical study of the efficacy and safety study of enzalutamide (160 mg/day) compared to bicalutamide (50 mg/day) in men with recurrent prostate cancer who have serologic and/or radiographic disease progression subsequent to primary androgen deprivation therapy (ADT). The TERRAIN trial, is a randomized, double-blind, multi-center, Phase II trial designed to test the efficacy and safety of enzalutamide compared to bicalutamide (Casodex) in men with metastatic prostate cancer already controlled by either bilateral orchiectomy (surgical castration) or ongoing androgen deprivation therapy with an LHRH agonist or an LHRH antagonist at a stable dose. There are also combination trials.

The evolution of Zytiga(arbiterone) suggests that Xtandin will show itself very effective in non-docetaxel treated patients once trials are completed, but study results to confirm this widely shared opinon are not yet in. It has the advantage of not requiring steroids which Zytiga does require.

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Currently, there are no randomized controlled trials of IMRT compared with other radiation techniques for treatment of prostate cancer. This means that the evidence to support IMRT is less than conclusive. It can be said that it causes less toxicity but that it produces beter outcome cannot be concluded. Non-randomized studies consistently demonstrate reduced rates of toxicity in IMRT-treated patients. The 2010 Agency for Healthcare Research and Quality (AHRQ) comparative evaluation of radiation treatments for clinically localized prostate cancer concluded that data on comparative effectiveness between different forms of radiation treatments are inconclusive with respect to overall or disease-specific survival. In addition, the AHRQ technology assessment states that more studies of better quality are needed to confirm or refute the suggested findings in the studies that compared outcomes in patients treated with different forms of radiation therapy.

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MDV3100 is an androgen receptor antagonist drug developed with promise for hormone refractory prostate cancer, and it is in Phase 3 clinical trials and for breast cancer. MDV3100 has binds five times stronger to the androgen receptor (AR) than Casodex, a popular hormonal drug that is currently used. It also interacts with the cancer cels in other ways.

Median time to radiographic progression in a phase II study was 56 weeks for chemo-naive patients and 25 weeks for patients previously treated with chemotherapy. A phase III trial AFFIRM (NCT00974311), in men with metastatic castration-resistant prostate cancer (CRPC) who had progressed after treatment with docetaxel-based chemotherapy, was stopped in November 2011 after a planned interim analysis showed a 37% reduction in the risk for death with MDV3100 over.Based on this the drug was approved under teh name Xtandin in mid 2012.

Another phase III trial, PREVAIL(NCT012129  is ongoing in patients who are chemo naive. There is also a phase II trial began in March 2011 comparing MDV3100 with Casodex in patients who have progressed while on LHRH analogue therapy (e,g., leuprorelin) or surgical castration.

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Several studies have found activity for Taxotere and carboplatin combinations.

The recent review of various taxane combination by Oh et al concluded: “More recent Phase II studies of carboplatin suggested a moderate level of clinical and palliative activity when it was used as a single agent. However, when carboplatin was combined with a taxane and estramustine, high response rates were observed in several recent clinical trials. ….Several preliminary reports suggested that carboplatin and oxaliplatin may have activity as second-line chemotherapy. Platinum chemotherapy drugs historically have been considered inactive in HRPC, although a review of the data suggested otherwise. Carboplatin, in particular, induced very high response rates when it was combined with estramustine and a taxane, but it also appeared to have activity in patients who progressed after docetaxel.”

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Another disadvantage of proton beam therapy (PBT)is that the equipment that can produce it is very expensive, ensuring that it is only available in a limited number of academic centers.

Australia and New Zealand Horizon Scanning Network (2006) stated that PBT “may be of particular benefit” in the treatment of patients with intermediate depth tumors such as those in the head, cancers that are located in difficult or dangerous-to-treat areas, and tumors in locations where “conventional radiotherapy would damage surrounding tissue to an unacceptable level” (e.g., central nervous system (CNS) and head). PBT “may be ideal for use in the treatment of pediatric patients where the need to avoid secondary tumors is important due to the potentially long life span after radiation treatment when they may develop radiation induced malignancies.

A report by the American Society of Therapeutic Radiology (ASTRO) Emerging Technologies Committee states that there is reason to be optimistic about the potential developments in proton beam therapy (PBT) and the prospective research that is ongoing at centers worldwide. Current data do not provide sufficient evidence to recommend PBT outside of clinical trials in lung cancer, head and neck cancer, gastro-intestinal malignancies (with the exception of hepatocellular(liver) cancer) and pediatric non-Central Nervous System malignancies. In hepatocellular carcinoma and prostate cancer, there is evidence of the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies, there is a suggestion from the literature that PBT is superior to photon approaches, but there is currently insufficient data to support a firm recommendation for PBT. In the setting of craniospinal irradiation for pediatric patients, protons appear to offer a dose measuring benefit over photons but more clinical data are needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. In all fields, however, further clinical research is needed and should be encouraged (ASTRO, 2011).

American College of Radiology (ACR) appropriateness criteria state that the physical characteristics of the proton beam would seem to allow for greater sparing of normal tissues, although there are unique concerns about its use for lung tumors. The small amount of clinical data on its use consists of small single institution series. These data as a whole can be challenging to interpret, as various different techniques have been used by these institutions, making comparisons between studies difficult. Results from larger, prospective, controlled trials that are underway will clarify the role of proton beam and other particle therapies for lung cancer (ACR, 2010).

A Blue Cross Blue Shield technology assessment evaluated health outcomes following proton beam therapy compared to stereotactic body radiotherapy (SBRT) for the management of Proton Beam Radiation Therapy: Medical Policy 12 non-small-cell lung cancer. The report concluded that, overall, evidence is insufficient to permit conclusions about the results of PBT for any stage of non-small-cell lung cancer. All PBT studies are case series, and there are no studies directly comparing proton beam therapy (PBT) and stereotactic body radiotherapy (SBRT). In the absence of randomized, controlled trials, the comparative effectiveness of PBT and SBRT is uncertain (BCBS, 2011).

The only guideline that I found that offers a qualified support is NCCN. The National Comprehensive Cancer Network (NCCN) states that the use of more advanced radiation technologies, such as proton therapy, is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints (NCCN, 2012).

It is quite clear from limited studies that proton beam is not inferior to other radiotherapy techniques. What has not been proven is that it is superior and that its ability to spare the tissues translates to a better outcome. It makes sense that it should, but in science that would be called a hypothesis that needs to be proven. Because PBT is only available in limited centers and is much more complex and expensive than other tissue sparing radiation therapy techniques, it should still be considered investigational.

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There is no legal obligation for doctors to use drugs on label. On the other hand, one should not automatically assume that this drug can be used in any cancer, whether FDA indicated or not. The thirteen member Oncologic Drugs Advisory Committee(ODAC), reviewed a study funded by the manufacturer, Amgen on 1,435 patients with castration-resistant prostate cancer. They found that the drug did prevent metastasis for the excess of four months over placebo (29 months vs 25 months). However, Xgeva did not increase expected lifespan, and the side effects were severe and judged to be too common for routine use. A measurement of the drug’s effectiveness known as bone metastasis free survival (BMFS) was increased, but this was offset by the increase in serious reportable events (SRE) the worst classification of side effects. Side effects were notable for including a form of bone destruction called osteonecrosis of the jaw in 33 (4.6 percent) of the patients treated with Xgeva. Other side effects included hypocalcemia, rashes and several types of infections. Based on this, ODAC did not recommend FDA approval for prostate cancer and the FDA did not include prostate cancer as an indication. It is not known whether there is something specific about breast cancer that led to this results or whether this was really an aberration and Xgeva is as usefull impressive cancer as this in other solid tumors cancers with bone metastasis.

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