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Prostate Cancer
Prostate Cancer: Impact of BMI and C-peptide
A study published in the November edition of Lancet Oncology of 2546 men who were involved in the Physicians’ Health Study and had developed prostate cancer during the 24 years of follow-up. Body mass index (BMI) measurements were taken in 1982 at baseline and again in 1990. In addition, baseline c-peptide levels were available in 827 of these men. C-peptide concentrations represent a surrogate for insulin secretion. The study reports on the effect of BMI and C-peptide levels on prostate cancer–specific mortality after diagnosis. The data showed that 39% of the study participants were overweight and 3.4% were obese. When comparing the risk of prostate cancer death between men with a baseline healthy weight and those who were overweight or obese, those in the later categories had proportional risks of prostate cancer death of 1.46 and 2.66, respectively. C-peptide levels also independently influenced the risk of prostate cancer mortality. Patients with both factors (high BMI and high C-peptide) fared the worst with quadruple the risk of dying compared to men with a lower BMI and C-peptide level. The authors suggested that not only could androgens affect the growth of prostate cancer cells, but also the levels of insulin. They also suggest that these data support recommendations for men with prostate cancer to avoid becoming overweight and decrease their risk of metabolic syndrome through diet and physical activity. They propose that these data support the investigations of therapeutics that lower insulin levels or target insulin-like growth factor (IGF)–I.
Ma J, Li H, Giovannucci E, et al. Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol. 2008;9(11):1039-1047.
Prostate Cancer: Predictive effect of IGF-I levels
A similarly themed paper by Roddam, et al was published in the Annals of Internal Medicine in October 2008 and reported on an analysis of 12 prospective studies assessing the association between levels of IGFs and insulin-like growth factor binding proteins (IGFBPs). The analysis was performed on 3700 men with prostate cancer and 5200 control patients who did not have prostate cancer. Blood specimens were available on all of the men and on average were drawn approximately 5 years before the diagnosis of the prostate cancer. The analysis showed that men in the highest quintile for IGF-I were 38% more likely to get prostate cancer than men with the lowest quintile for IGF-I. The relationship between prostate cancer and IGF-I levels were independent of age, weight, BMI, smoking, and alcohol intake.
Roddam AW, Allen NE, Appleby P, et al. Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. Ann Intern Med. 2008;149(7):461-471, W83-8.
Prostate Cancer: Predictive Factors for Survival (CTCs)
Although much of the literature surrounding the measurement of circulating tumor cells (CTCs) has been related to therapeutic decision-making for breast cancer, the US Food and Drug Administration (FDA) approved this technology for estimating the prognosis for metastatic breast, prostate and colon cancers. A study was recently published regarding CTC levels measured before and during treatment for castration-resistant metastatic prostate cancer and if the levels were prognostic for survival. The multi-institutional study was performed on 231 evaluable patients with metastatic prostate cancer who were about to undergo chemotherapy. Circulating tumor cells and prostate-specific antigen (PSA) levels were assessed at baseline and prior to each course of therapy until progression of disease. The shortest median survival was seen in patients with unfavorable CTC counts at all time points (overall survival [OS] = 6.8 months), versus those with initially unfavorable counts which became favorable (OS = 21.3 months), versus those with favorable CTC counts at all time points (OS >26 months). When comparing the predictive capability of CTC to PSA levels, CTCs were superior with regards to survival, especially when considering post-treatment PSA reductions of >30% or even >50%. The use of CTC counts to predict for chemotherapy efficacy in metastatic prostate cancer is still under investigation.
de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302-6309.
NOCR ANNUAL MEETING - REGISTRATION NOW OPEN!
This is the premier annual event for community oncologists to update their clinical knowledge. This year’s meeting includes Meet-the-Expert sessions on the topics of breast cancer, leukemia, lung cancer, and myeloma.
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Prostate Cancer: Prevention
In 2001, a National Cancer Institute (NCI)–funded prostate cancer prevention trial (SELECT) was initiated. Over 35,000 men aged 50 and older were randomly assigned to 1 of 4 investigational arms in a double-blinded manner: selenium, vitamin E, the combination of the 2, or placebo. The study was undertaken to confirm observations in previous studies, that vitamin E or selenium supplementation could significantly reduce the risk of developing prostate cancer. The NCI released information after an independent interim analysis of the data. The analysis shows that neither vitamin E supplements, selenium supplements, nor the 2 of them taken together, reduced the risk of developing prostate cancer. If anything, there was a small trend towards an increase in the number of prostate cancer cases for the men randomized to take vitamin E, and a small increase in the number of cases of type II diabetes mellitus in men taking only selenium. The men who participated in the study are receiving information about these findings with a recommendation to stop their oral medication. An unblinding of the study arms is not currently being undertaken. The trial participants will continue to be followed for another 3 years to look for evidence of long-term benefit or harm, as well as long-term toxicity from their randomized medication. At the time the study was terminated, the participants had received an average of 5 years of study medication. Molecular analysis on stored blood samples from the participants will be performed to correlate outcomes with biologic specimens.
Hematologic malignancy: Indolent Non-Hodgkin Lymphoma
On October 31, 2008, bendamustine HCl (Treanda®) was approved for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab (Rituxan®) or a rituximab-containing regimen. Bendamustine is a purine analog/alkylator hybrid and was previously approved in March 2008 for the treatment of chronic lymphocytic leukemia (CLL). The efficacy in NHL was shown in an open-label trial of 100 patients with indolent B-cell NHL who had progressed during or within 6 months of treatment with rituximab. The response rate to bendamustine was 74%, which lasted a median of 9.2 months. Two additional phase II trials (1 as a single agent, and 1 in combination with rituximab) lent further safety data. Serious adverse events included myelosuppression, infections, infusion reactions, anaphylaxis, tumor lysis syndrome, and other malignancies. It is anticipated that further front-line data will be reported at the 2008 American Society of Hematology™ (ASH) symposium.
HPV Infection: Cancer Causation and Prevention
On November 3, 2008, the US Centers for Disease Control and Prevention (CDC) announced that the human papilloma virus (HPV) had caused 25,000 cases of cancer per year in the United States between 1998 and 2003. These cancers were not just limited to cervical cancer, with a significant finding of both anal and mouth cancers. Human papilloma virus has about 100 variants, and several of these variants are known to be the leading cause of cervical cancer. Since the virus is transmitted both sexually and by skin-to-skin contact, it is also known to cause cancers of the anus, penis, and various head and neck cancers originating in the mouth and throat. The CDC survey, which included 38 states and the District of Columbia, found about 7400 cases of mouth and throat cancers that could be linked to HPV and 3000 cases of anal cancer (1900 in women and 1100 in men).
Gardasil in Men
Data were presented in November 2008 at the European Research Organization on Genital Infection and Neoplasia (EUROGIN) International Multidisciplinary Conference. The HPV types 6, 11, 16, and 18 vaccine (Gardasil®) is currently approved in the United States as a preventive vaccination in females aged from 9 years through 26 years old in order to prevent infection with HPV types 6,11, 16, and 18. The study reported was a placebo-controlled phase III trial designed to determine the efficacy of Gardasil in males in preventing any of the following: genital warts, penile/perineal/perianal intraepithelial neoplasia, and penile/perianal cancer. Approximately 3400 heterosexual males between the ages of 16 years and 23 years, and 600 males aged 16 years – 26 years who had sex with other males were randomized to receive Gardasil or placebo at baseline, 2 months, and 6 months. The results of the study showed that Gardasil reduced external genital lesions from 31 in the placebo group to 3 cases in the vaccine group (90% reduction). Secondary endpoints of the study were also presented. Gardasil was very effective in reducing persistent infection (15 cases versus 101 cases) and the incidence of anytime HPV DNA detection (136 versus 241 cases) for the vaccine versus placebo, respectively. It is anticipated that Merck, the manufacturer of Gardasil, will submit a supplemental application to the FDA for the use of Gardasil in boys and men aged 9 years – 26 years for the prevention of external genital lesions caused by HPV types 6, 11, 16, and 18.
Oral TKI’s and Hypothyroidism
A satellite symposium held in conjunction with the annual meeting of the American Thyroid Association in November 2008, reported on the adverse effect of hypothyroidism for cancer patients taking oral tyrosine kinase inhibitors (TKIs). Dr Jerome Hershman from the University of California, Los Angeles provided an overview of the data from multiple trials using TKIs. He discussed the findings that TKIs may increase thyroxine requirements in patients with pre-existing hypothyroidism. He recommended that all patients have a baseline measure of thyroid-stimulating hormone (TSH), free T4, and T3 prior to initiating TKIs and that these labs be repeated at 2 to 3 month intervals while on therapy. One retrospective study and 3 prospective studies were discussed, all of which evaluated thyroid function in those undergoing sunitinib treatment. The retrospective study found that 42% of 50 patients developed an elevated TSH after a median of 5 months of therapy. The 3 prospective studies found between 27% and 46% incidence of clinical or subclinical hypothyroidism. Although many theories for the mechanism of this interaction have been purported, none have yet been proven. Sorafinib, another approved oral TKI, may also cause some thyroid dysfunction, but to a much smaller degree.
2008 Chicago Multidisciplinary Symposium in Thoracic Oncology
To complement our new Video OncoFacts, I’ll summarize 3 of the presentations made at the plenary session for this longstanding thoracic oncology conference which is now sponsored not only by the University of Chicago but also the American Society for Therapeutic Radiation and Oncology® (ASTRO), the American Society of Clinical Oncology® (ASCO), and the International Association for the Study of Lung Cancer.
AVAiL Trial:
This is a phase III double-blind trial that randomized 1043 patients with chemo-naïve locally advanced, metastatic, or recurrent non-squamous NSCLC, to cisplatin/gemcitabine with or without bevacizumab given either at 7.5 mg/kg or 15 mg/kg every 3 weeks. The primary endpoint was progression-free survival (PFS). The PFS endpoint that was originally presented by Manegold at ASCO 2007 was maintained. The risk of progression or death was reduced by 25% with bevacizumab 7.5 mg/kg and by 15% with bevacizumab 15mg/kg. However, even with longer follow-up, median overall survival was not statistically improved. The authors discussed the fact that OS may have been influenced by the unregulated heterogeneous subsequent therapies delivered to these patients when progressing on this trial regimen. It was also noted that the AVAiL trial did not support the OS findings of ECOG 4599 which showed a survival advantage for the addition of bevacizumab to carboplatin and paclitaxel.
BETA Trial:
The BETA (Bevacizumab in Combination with Erlotinib Compared to Erlotinib Alone) trial randomized 636 patients with advanced NSCLC who had failed standard first-line chemotherapy to bevacizumab + erlotinib (B+E) or erlotinib + placebo (E+P). The primary statistical endpoint was OS. The median OS for B+E was 9.3 months vs 9.2 months for E+P. However, median PFS was 3.4 months vs 1.7 months and overall response rate (ORR) was 12.6% vs 6.2% for B+E vs E+P, respectively. The authors concluded that although the addition of bevacizumab to erlotinib was not associated with an improvement in survival, there is evidence of clinical activity.
iPASS Trial:
The iPASS (IRESSA Pan Asia Study) was updated evaluating 1217 chemo-naïve patients who were never or light smokers with stage IIB/IV NSCLC to carboplatin/paclitaxel(C/P) versus gefitinib. The primary statistical endpoint was to assess noninferiority of gefitinib vs C/P for PFS. The PFS results showed that PFS was better for the C/P arm during the first 6 months, but with gefitinib being more favorable for the subsequent 16 months. Overall response rate favored gefitinib at 43% vs 32% for C/P. There were no differences in OS between arms. In the trial, 1000 of the patients agreed to have their tumor tested for EGFR mutations, and 683 had tissue that was analyzable. Over 60% of the tumors demonstrated an epidermal growth factor receptor (EGFR) mutation (M+). The ORR for EGFR M+ tumors was 71.2% for gefitinib and 47.3% for C/P. For the EGFR M- tumors, the ORR was 1.1% for gefitinib and 23.5% for C/P. The discussants suggested that if one were to consider single-agent EGFR TKI therapy in the front-line setting, then the cancer should be tested for EGFR mutations. These mutations are much more common in the Asian populations versus the North American or European populations.
OncoFacts™ Editor:
Christy Russell, MD
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