NCCN Annual Conference 2011

Testing for epidermal growth factor receptor mutations is an important step in the evaluation process for systemic therapy in patients with metastatic or recurrent non–small cell lung cancer according to updated recommendations issued by the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) on April 7 that patients with advanced non–small cell lung cancer (NSCLC) who are being considered for treatment with one of the tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) should undergo EGFR-mutation testing.

Oncologists have learned that NSCLC is "really a collection of genetically distinct diseases," ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to "treat patients with drugs that target the molecular drivers of their specific tumors rather than using a one-size-fits-all approach."

The NCCN earlier updated its clinical management guidelines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s annual conference.

Both groups based their endorsements on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy noted the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients delays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefitinib (Iressa) among EGFR mutation–positive patients.

The last question is of particular interest, because gefitinib is not Food and Drug Administration approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progression-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefitinib or standard carboplatin and paclitaxel chemotherapy.

IPASS demonstrated that EGFR mutation strongly predicted a lower risk of progression on gefitinib vs. chemotherapy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57).

Similarly, in a pooled analysis of clinical outcomes of NSCLC patients who were treated with erlotinib, EGFR mutations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a difference in overall survival among treated patients with and without EGFR mutations, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mutation in patients with NSCLC "confers a high level of resistance" to TKIs.

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an association between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommendation for sequencing, as well as a recommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lymphoma kinase (ALK) fusion gene, Dr. Ettinger said. "Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy," he said, noting that the investigational ALK-targeting drug crizotinib, in particular, has demonstrated positive results in early studies of NSCLC patients with echinoderm microtubule-associated proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic therapy, patients with adenocarcinoma, large cell carcinoma, or NSCLC "not otherwise specified" who have an Eastern Cooperative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line therapy should be treated with erlotinib, according to the NCCN guidelines. Alternatively, the guidelines state that gefitinib can be used in place of erlotinib "in areas of the world where it is available."

For patients in whom the EGFR mutation is discovered during chemotherapy, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment."

For patients whose EGFR status is negative or unknown, even in the presence of clinical characteristics that might be suggestive of a mutation (for example, female, nonsmoker, Asian race), conventional chemotherapy is recommended, Dr. Ettinger said.

The updated NCCN guidelines for NSCLC are posted at www.nccn.org.

The guidelines take a conservative stance on the National Lung Screening Trial finding that screening with low-dose helical CT was associated with a 20% reduction in lung cancer deaths vs. screening with standard chest x-ray. Despite this positive finding, "the NCCN panel does not recommend the routine use of screening CT as a standard clinical practice," said Dr. Ettinger; more conclusive data from ongoing national trials are needed to define the associated risks and benefits. "High-risk patients should participate in a clinical trial evaluating CT screening or go to a center of excellence to discuss the potential risks and benefits of a screening CT," Dr. Ettinger said.

Other notable updates include the following:

• The addition of EBUS (endobronchial ultrasound) as a work-up recommendation.

• The recommendation that bevacizumab (Avastin) and chemotherapy or chemotherapy alone is indicated in performance status 0-1 patients with advanced or recurrent NSCLC, and that bevacizumab should be given until disease progression.

• The recommendation against systemic chemotherapy in performance status 3-4 NSCLC patients.

• The guidance that chemoradiation is better than chemotherapy alone in locally advanced NSCLC, and that concurrent chemoradiation is better than sequential chemoradiation.

• The addition of denosumab (Xgeva) as a treatment option for patients with bone metastases.

• The recommendation favoring cisplatin/pemetrexed (Alimta) vs. cisplatin/gemcitabine (Gemzar) in patients with nonsquamous histology.

• The recommendation against adding a third cytotoxic drug, with the exception of bevacizumab or cetuximab (Erbitux), in treatment-naive performance status 0-1 NSCLC patients.

• The guidance that cisplatin-based combinations are better than best supportive care in advanced, incurable disease, with improvement in median survival and 1-year survival rates.

The ASCO PCO is available online.

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the growing clinical importance of molecularly defined subgroups of adenocarcinoma signals a "new era of personalized medicine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy."

The implementation of routine, simultaneous testing of multiple markers will likely be conducted on all patients prior to treatment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, including obtaining adequate tumor material at the time of diagnostic biopsy and developing testing platforms "that simultaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges."

Dr. Ettinger has consultancy agreements with the following companies: Biodesix, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Genentech, Merck, Novartis Pharmaceuticals, Poniard Pharmaceuticals, Prometheus Laboratories, Shin Nippon Biomedical Laboratories, and Telik. Dr. Keedy receives commercial research support from Ariad Pharmaceuticals, Ziopharm Oncology, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with Amgen, AstraZeneca, Abraxis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Syndax, Biodesix, Allos Therapeutics, Novartis, OSI/Genentech/Roche, Poniard, and Sanofi-Aventis. Dr. Doebele disclosed research funding from Lilly, ImClone Systems, and Pfizer.

Testing for epidermal growth factor receptor mutations is an important step in the evaluation process for systemic therapy in patients with metastatic or recurrent non–small cell lung cancer according to updated recommendations issued by the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) on April 7 that patients with advanced non–small cell lung cancer (NSCLC) who are being considered for treatment with one of the tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) should undergo EGFR-mutation testing.

Oncologists have learned that NSCLC is "really a collection of genetically distinct diseases," ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to "treat patients with drugs that target the molecular drivers of their specific tumors rather than using a one-size-fits-all approach."

The NCCN earlier updated its clinical management guidelines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s annual conference.

Both groups based their endorsements on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy noted the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients delays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefitinib (Iressa) among EGFR mutation–positive patients.

The last question is of particular interest, because gefitinib is not Food and Drug Administration approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progression-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefitinib or standard carboplatin and paclitaxel chemotherapy.

IPASS demonstrated that EGFR mutation strongly predicted a lower risk of progression on gefitinib vs. chemotherapy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57).

Similarly, in a pooled analysis of clinical outcomes of NSCLC patients who were treated with erlotinib, EGFR mutations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a difference in overall survival among treated patients with and without EGFR mutations, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mutation in patients with NSCLC "confers a high level of resistance" to TKIs.

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an association between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommendation for sequencing, as well as a recommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lymphoma kinase (ALK) fusion gene, Dr. Ettinger said. "Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy," he said, noting that the investigational ALK-targeting drug crizotinib, in particular, has demonstrated positive results in early studies of NSCLC patients with echinoderm microtubule-associated proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic therapy, patients with adenocarcinoma, large cell carcinoma, or NSCLC "not otherwise specified" who have an Eastern Cooperative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line therapy should be treated with erlotinib, according to the NCCN guidelines. Alternatively, the guidelines state that gefitinib can be used in place of erlotinib "in areas of the world where it is available."

For patients in whom the EGFR mutation is discovered during chemotherapy, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment."

For patients whose EGFR status is negative or unknown, even in the presence of clinical characteristics that might be suggestive of a mutation (for example, female, nonsmoker, Asian race), conventional chemotherapy is recommended, Dr. Ettinger said.

The updated NCCN guidelines for NSCLC are posted at www.nccn.org.

The guidelines take a conservative stance on the National Lung Screening Trial finding that screening with low-dose helical CT was associated with a 20% reduction in lung cancer deaths vs. screening with standard chest x-ray. Despite this positive finding, "the NCCN panel does not recommend the routine use of screening CT as a standard clinical practice," said Dr. Ettinger; more conclusive data from ongoing national trials are needed to define the associated risks and benefits. "High-risk patients should participate in a clinical trial evaluating CT screening or go to a center of excellence to discuss the potential risks and benefits of a screening CT," Dr. Ettinger said.

Other notable updates include the following:

• The addition of EBUS (endobronchial ultrasound) as a work-up recommendation.

• The recommendation that bevacizumab (Avastin) and chemotherapy or chemotherapy alone is indicated in performance status 0-1 patients with advanced or recurrent NSCLC, and that bevacizumab should be given until disease progression.

• The recommendation against systemic chemotherapy in performance status 3-4 NSCLC patients.

• The guidance that chemoradiation is better than chemotherapy alone in locally advanced NSCLC, and that concurrent chemoradiation is better than sequential chemoradiation.

• The addition of denosumab (Xgeva) as a treatment option for patients with bone metastases.

• The recommendation favoring cisplatin/pemetrexed (Alimta) vs. cisplatin/gemcitabine (Gemzar) in patients with nonsquamous histology.

• The recommendation against adding a third cytotoxic drug, with the exception of bevacizumab or cetuximab (Erbitux), in treatment-naive performance status 0-1 NSCLC patients.

• The guidance that cisplatin-based combinations are better than best supportive care in advanced, incurable disease, with improvement in median survival and 1-year survival rates.

The ASCO PCO is available online.

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the growing clinical importance of molecularly defined subgroups of adenocarcinoma signals a "new era of personalized medicine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy."

The implementation of routine, simultaneous testing of multiple markers will likely be conducted on all patients prior to treatment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, including obtaining adequate tumor material at the time of diagnostic biopsy and developing testing platforms "that simultaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges."

Dr. Ettinger has consultancy agreements with the following companies: Biodesix, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Genentech, Merck, Novartis Pharmaceuticals, Poniard Pharmaceuticals, Prometheus Laboratories, Shin Nippon Biomedical Laboratories, and Telik. Dr. Keedy receives commercial research support from Ariad Pharmaceuticals, Ziopharm Oncology, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with Amgen, AstraZeneca, Abraxis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Syndax, Biodesix, Allos Therapeutics, Novartis, OSI/Genentech/Roche, Poniard, and Sanofi-Aventis. Dr. Doebele disclosed research funding from Lilly, ImClone Systems, and Pfizer.

Testing for epidermal growth factor receptor mutations is an important step in the evaluation process for systemic therapy in patients with metastatic or recurrent non–small cell lung cancer according to updated recommendations issued by the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

ASCO issued a provisional clinical opinion (PCO) on April 7 that patients with advanced non–small cell lung cancer (NSCLC) who are being considered for treatment with one of the tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) should undergo EGFR-mutation testing.

Oncologists have learned that NSCLC is "really a collection of genetically distinct diseases," ASCO’s PCO panel cochair Dr. Vicki L. Keedy of Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said in a press release. The goal is to "treat patients with drugs that target the molecular drivers of their specific tumors rather than using a one-size-fits-all approach."

The NCCN earlier updated its clinical management guidelines to include a category 1 recommendation that EGFR testing should be undertaken after histologic diagnosis of adenocarcinoma, large cell carcinoma, or undifferentiated carcinoma.

The NCCN recommendation does not extend to patients with squamous cell lung cancer, because the incidence of EGFR mutation in this patient subgroup is less than 3.6%, Dr. David S. Ettinger said in March at the organization’s annual conference.

Both groups based their endorsements on studies demonstrating that mutations in two regions of EGFR gene appear to predict tumor response to chemotherapy in general, and to TKIs specifically.

Among the research priorities that were identified by ASCO, Dr. Keedy noted the trials that are designed to discern whether first-line treatment with a TKI in EGFR mutation–negative patients delays chemotherapy or affects outcome; whether chemotherapy prior to TKI treatment in EGFR mutation–positive patients affects outcome; and whether there are clinically significant differences between erlotinib (Tarceva) and gefitinib (Iressa) among EGFR mutation–positive patients.

The last question is of particular interest, because gefitinib is not Food and Drug Administration approved outside a special program in the United States, whereas erlotinib is currently approved as second-line therapy, she said.

Dr. Ettinger, chair of the NCCN’s NSCLC guideline panel and professor of oncology at Johns Hopkins University in Baltimore, cited findings from the landmark IPASS (Iressa Pan-Asia Study) investigation that compared progression-free and overall survival in 1,217 East Asian patients with advanced NSCLC that was treated with the gefitinib or standard carboplatin and paclitaxel chemotherapy.

IPASS demonstrated that EGFR mutation strongly predicted a lower risk of progression on gefitinib vs. chemotherapy (hazard ratio, 0.48), whereas wild-type EGFR predicted a higher risk of progression on gefitinib relative to chemotherapy (HR, 2.85) (N. Engl. J. Med. 2009;361:947-57).

Similarly, in a pooled analysis of clinical outcomes of NSCLC patients who were treated with erlotinib, EGFR mutations were associated with a median progression-free survival of 13.2 vs. 5.9 months (J. Cell. Mol. Med. 2010;14:51-69). Neither study demonstrated a difference in overall survival among treated patients with and without EGFR mutations, Dr. Ettinger said.

The updated NCCN guidelines also state that the sequencing of KRAS (a G protein involved in the EGFR-related signal transmission) could be useful for the selection of patients as candidates for TKI therapy. The KRAS gene can harbor oncogenic mutations that may render a tumor resistant to EGFR-targeting agents, Dr. Ettinger explained, noting that studies have shown that a KRAS mutation in patients with NSCLC "confers a high level of resistance" to TKIs.

Although the data – which primarily come from retrospective reviews with small sample sizes – are insufficient to make a determination about an association between KRAS mutation status and survival, he said, they are sufficient to warrant a category 2A recommendation for sequencing, as well as a recommendation that patients with a known KRAS mutation should undergo first-line therapy with an agent other than a TKI.

Individuals who test negative for EGFR and KRAS should also be screened for a mutation of the anaplastic lymphoma kinase (ALK) fusion gene, Dr. Ettinger said. "Patients who screen positive may not benefit from EGFR TKIs, but they may be good candidates for an ALK-targeted therapy," he said, noting that the investigational ALK-targeting drug crizotinib, in particular, has demonstrated positive results in early studies of NSCLC patients with echinoderm microtubule-associated proteinlike 4 (EML4)-ALK translocations (N. Engl. J. Med. 2010;363:1693-703).

With respect to first-line systemic therapy, patients with adenocarcinoma, large cell carcinoma, or NSCLC "not otherwise specified" who have an Eastern Cooperative Oncology Group/World Health Organization performance status grade of 0-4 and who test positive for the EGFR mutation prior to first-line therapy should be treated with erlotinib, according to the NCCN guidelines. Alternatively, the guidelines state that gefitinib can be used in place of erlotinib "in areas of the world where it is available."

For patients in whom the EGFR mutation is discovered during chemotherapy, the guidelines recommend either adding erlotinib to the current chemotherapy protocol or switching to erlotinib as maintenance treatment."

For patients whose EGFR status is negative or unknown, even in the presence of clinical characteristics that might be suggestive of a mutation (for example, female, nonsmoker, Asian race), conventional chemotherapy is recommended, Dr. Ettinger said.

The updated NCCN guidelines for NSCLC are posted at www.nccn.org.

The guidelines take a conservative stance on the National Lung Screening Trial finding that screening with low-dose helical CT was associated with a 20% reduction in lung cancer deaths vs. screening with standard chest x-ray. Despite this positive finding, "the NCCN panel does not recommend the routine use of screening CT as a standard clinical practice," said Dr. Ettinger; more conclusive data from ongoing national trials are needed to define the associated risks and benefits. "High-risk patients should participate in a clinical trial evaluating CT screening or go to a center of excellence to discuss the potential risks and benefits of a screening CT," Dr. Ettinger said.

Other notable updates include the following:

• The addition of EBUS (endobronchial ultrasound) as a work-up recommendation.

• The recommendation that bevacizumab (Avastin) and chemotherapy or chemotherapy alone is indicated in performance status 0-1 patients with advanced or recurrent NSCLC, and that bevacizumab should be given until disease progression.

• The recommendation against systemic chemotherapy in performance status 3-4 NSCLC patients.

• The guidance that chemoradiation is better than chemotherapy alone in locally advanced NSCLC, and that concurrent chemoradiation is better than sequential chemoradiation.

• The addition of denosumab (Xgeva) as a treatment option for patients with bone metastases.

• The recommendation favoring cisplatin/pemetrexed (Alimta) vs. cisplatin/gemcitabine (Gemzar) in patients with nonsquamous histology.

• The recommendation against adding a third cytotoxic drug, with the exception of bevacizumab or cetuximab (Erbitux), in treatment-naive performance status 0-1 NSCLC patients.

• The guidance that cisplatin-based combinations are better than best supportive care in advanced, incurable disease, with improvement in median survival and 1-year survival rates.

The ASCO PCO is available online.

In an editorial that accompanied ASCO’s PCO announcement, Dr. Paul A. Bunn Jr. and Dr. Robert C. Doebele of the University of Colorado Cancer Center in Aurora wrote that the growing clinical importance of molecularly defined subgroups of adenocarcinoma signals a "new era of personalized medicine for patients with advanced lung cancer, in which it will be imperative to match the specific mutations of a patient’s tumor with a specific therapy."

The implementation of routine, simultaneous testing of multiple markers will likely be conducted on all patients prior to treatment initiation, regardless of clinical features, they stated, acknowledging certain procedural challenges, including obtaining adequate tumor material at the time of diagnostic biopsy and developing testing platforms "that simultaneously analyze for the presence of somatic mutations, gene fusions, or other genetic challenges."

Dr. Ettinger has consultancy agreements with the following companies: Biodesix, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Genentech, Merck, Novartis Pharmaceuticals, Poniard Pharmaceuticals, Prometheus Laboratories, Shin Nippon Biomedical Laboratories, and Telik. Dr. Keedy receives commercial research support from Ariad Pharmaceuticals, Ziopharm Oncology, and Amgen Oncology Therapeutics. Dr. Bunn has a consultant or advisory role with Amgen, AstraZeneca, Abraxis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Syndax, Biodesix, Allos Therapeutics, Novartis, OSI/Genentech/Roche, Poniard, and Sanofi-Aventis. Dr. Doebele disclosed research funding from Lilly, ImClone Systems, and Pfizer.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.