SUMMARY: Sipuleucel-T (PROVENGE®) is a therapeutic cancer vaccine developed to boost the patients immune system to fight prostate cancer. In a double blind randomized phase III trial, 512 patients with metastatic castrate-resistant prostate cancer received PROVENGE® vaccine (341) or a placebo (171). There was a 4.1 month improvement in median survival for patients receiving the vaccine compared to those receiving a placebo (25.8 versus 21.7 months) and a 22% reduction in the risk of death in the vaccine group. Because of the slow onset of action of any vaccine therapy, this option may be appropriate for individuals with less aggressive disease. N Engl J Med 2010;363:411-422
Author: RR
Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy
SUMMARY: The FDA in January, 2011 approved rituximab (RITUXAN®) as a maintenance treatment for patients with advanced follicular lymphoma. Follicular lymphomas are a subset of Non Hodgkins Lymphomas and are very responsive to chemotherapy or chemotherapy given along with RITUXAN®. They are however incurable, despite treatment with RITUXAN® plus chemotherapy. This condition can therefore be considered as a chronic disease. For this reason, prolonging remission duration is important, as the length of remission tends to be shorter with each recurrence. The FDA approval was based on the PRIMA trial, which is a phase III study, in which 1217 treatment naive patients with stage III and stage IV disease requiring therapy were initially treated with RITUXAN® and chemotherapy (induction chemotherapy). Patients responding to initial therapy (n = 1018) were randomized to observation alone or maintenance RITUXAN® for 2 years. The first preplanned interim analysis at a median follow up of 25 months demonstrated a progression-free survival (PFS) of 82% in the RITUXAN® maintenance therapy group versus 66% for those in the observation group, which meant that the recurrence rate was 18% with RITUXAN® maintenance versus 34% for those who were observed. This benefit with RITUXAN® maintenance therapy was seen regardless of age, disease severity, and type of induction chemotherapy received. These findings are relevant, as these patients essentially have a chronic disease and are willing to pursue interventions that could potentially delay recurrence of their lymphoma and thus improve their quality of lives. J Clin Oncol 28:15s, 2010 (suppl; abstr 8004))
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
SUMMARY: T lymphocytes play an important role in cell mediated immunity. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) also known as CD 152 is a protein expressed on the surface of T lymphocytes and has an inhibitory role in T cell function. Ipilimumab (YERVOY®) is a CTLA-4 targeted monoclonal antibody which was studied in metastatic malignant melanoma. MDX010-20 is a large double blind placebo controlled trial in which 676 HLA-A*0201–positive patients, with pretreated advanced melanoma, were randomly assigned to one of the three treatment groups- YERVOY® along with a placebo (137 patients), YERVOY® administered along with a peptide vaccine gp 100 (403 patients) or peptide vaccine gp 100 along with a placebo (136 patients). Patients receiving YERVOY® along with a peptide vaccine had a median survival of 10.1 months compared to 6.4 months for those who received the vaccine alone. This survival benefit for YERVOY® plus vaccine compared to vaccine alone was seen at 12 months (46% vs 25% ) and 24 months (24% vs 14%) respectively. Approximately 10-15% of the patients treated with YERVOY® experienced Grade 3 or 4 immune-related adverse events compared to 3% when treated with gp100 alone. This landmark study is a significant advance in the treatment of metastatic malignant melanoma, with an overall survival benefit. N Engl J Med 2010; 363:711-723
Randomized phase III trial comparing FOLFIRINOX (F 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA) Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial
SUMMARY: Adenocarcinoma of the pancreas is one of the hard-to-treat cancers for which chemotherapy has not demonstrated any survival benefit – that is, until now. In a recently presented randomized phase III trial at the ASCO 2010 meeting, 250 patients with metastatic pancreatic cancer were assigned to receive either single agent Gemcitabine (GEMZAR®) or a combination of fluorouracil, leucovorin, Irinotecan (CAMPTOSAR®) , and Oxaliplatin (ELOXATIN®) – (FOLFIRINOX regimen). Following an interim analysis, this trial had to be closed earlier than planned, based on the significantly positive results noted with the combination regimen. The median overall survival for patients in the FOLFIRINOX was 11.1 months compared with 6.8 months for those receiving single agent GEMZAR®. At one year, 48% of patients in the FOLFIRINOX group were alive compared to 20% for those in the GEMZAR® group. The median progression free survival was 6.4 months for the patients treated with FOLFIRINOX compared to 3.3 months for those treated with single agent GEMZAR®. Quality of life was also superior in the FOLFIRINOX group compared to those who were treated with GEMZAR®. For the very first time, we now have a combination chemotherapy regimen for advanced pancreatic cancer that confers survival benefit. J Clin Oncol 28:303s, 2010 (suppl; abstr 4010)
Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC) A Gynecologic Oncology Group study
SUMMARY: The role of Bevacizumab (AVASTIN®) in the treatment of advanced ovarian cancer was evaluated in a large randomized double blind phase III trial. One thousand eight hundred and seventy three (1873) patients with stage III or IV disease, who were treatment naïve, were randomly assigned to one of three treatment groups – standard chemotherapy with paclitaxel and carboplatin given along with a placebo followed maintenance treatment with a placebo, standard chemotherapy given along with AVASTIN® followed by maintenance treatment with a placebo or standard chemotherapy given along with AVASTIN® followed by maintenance treatment with AVASTIN®. Patients receiving standard chemotherapy along with AVASTIN® followed by maintenance AVASTIN® had a median Progression Free Survival of 14.1 months compared to 10.3 months for those who received standard chemotherapy alone. Interestingly, outcomes in patients receiving standard chemotherapy along with AVASTIN® followed by placebo maintenance did no better than those who received standard chemotherapy alone. To date, addition of AVASTIN® to standard chemotherapy followed by AVASTIN® maintenance has not resulted in significant improvement in overall survival. J Clin Oncol 28:18s, 2010 (suppl; abstr LBA1)
Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia
SUMMARY: ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) is a phase III, randomized, open-label, multicenter study comparing the efficacy and safety of Nilotinib (TASIGNA®), either 300 mg or 400 mg bid with GLEEVEC® (Imatinib) 400mg qd, in patients with newly diagnosed Ph+ CML in chronic phase. Of the 846 patients enrolled, 282 patients received TASIGNA® 300 mg bid, 281 patients received TASIGNA® 400 mg bid and 283 patients received GLEEVEC® 400 mg qd. With a median follow up of 18 months, the MMR (Major Molecular Response) was 66% for the TASIGNA® 300 mg bid group and 62% for the TASIGNA® 400 mg bid group compared with 40% for the GLEEVEC® 400 mg qd group. The median time to MMR amongst the patients who achieved MMR was faster for TASIGNA® 300 mg bid (5.7 months) and TASIGNA® 400 mg bid (5.8 months) groups of patients compared with GLEEVEC® 400 mg qd (8.3 months). The rates of complete cytogenetic response at 18 months were also significantly higher for both TASIGNA® groups – 85% in the TASIGNA® 300 mg bid group, 82% in the TASIGNA® 400 mg bid group and 74% in the GLEEVEC® 400 mg qd group. Fewer patients in the TASIGNA® groups progressed to accelerated phase or blast crises compared with GLEEVEC® group. Adverse effects more often seen with TASIGNA® included skin rash, headache, liver function abnormalities, high cholesterol, hyperglycemia, increased serum lipase, abnormal electrolyte levels and prolongation of the QT interval. The authors concluded that TASIGNA® at both 300 mg bid and 400 mg bid induced significantly higher and faster rates of MMR and complete cytogenetic remission compared with GLEEVEC® 400 mg qd. J Clin Oncol 28:15s, 2010 (suppl; abstr 6501)
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial
SUMMARY: The TROPIC trial (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated With a docetaxel (TAXOTERE®)- Containing Regimen) involved 755 men in 26 countries with metastatic prostate cancer who were castration resistant. Patients were randomized to receive either Cabazitaxel (JEVTANA®) 25 mg/m2 or Mitoxantrone 12 mg/m2 three times a week and both groups received prednisone 10 mg daily through out the course of their treatment. The combination of JEVTANA® and prednisone resulted in median overall survival of 15.1 months compared to 12.7 months for the Mitoxantrone group. There was a 30% reduction in the risk of death for the JEVTANA® group. This led to the approval of JEVTANA® for the treatment of hormone-refractory metastatic prostate cancer, previously treated with a TAXOTERE® containing regimen. Lancet 2010;376:1147-1154
Results of a randomized, phase III trial of nab-paclitaxel (nab-P) and carboplatin (C) compared with cremophor-based paclitaxel (P) and carboplatin as first-line therapy in advanced non-small cell lung cancer (NSCLC)
SUMMARY: In this randomized phase III trial, the efficacy of nab-paclitaxel (ABRAXANE®) and carboplatin was compared with paclitaxel and carboplatin in advanced NSCLC of all histologic types. Patients enrolled were chemonaïve, with stage IIIb and stage IV non small cell lung cancer. Five hundred and twenty one (521) received ABRAXANE® without any premedications at 100 mg/m2 on days 1, 8 and 15 along with carboplatin given on day 1 at an AUC of 6. The control group of 525 patients received standard Paclitaxel 200mg/m2 and carboplatin at an AUC of 6 on day 1. The primary end point was overall response rate. The ABRAXANE® group had a response rate of 33% compared to 25% for the standard paclitaxel group. When broken down by histology, the response rates in those with squamous cell carcinoma was 41% in the ABRAXANE® group versus 24% in the standard paclitaxel arm and the non squamous subtypes had a response rate of 26% versus 25% in the ABRAXANE® and paclitaxel group respectively. It is hypothesized that the superior response rates in squamous cell histology may be due to the overexpression by this sub type of an albumin receptor called Caveolin–1. ABRAXANE® which is an albumin bound paclitaxel utilizes the albumin receptor Caveolin-1 (CAV1) pathway and thereby may achieve a higher intratumoral drug concentration. J Clin Oncol 28:18s, 2010 (suppl; abstr LBA7511)
New Biomarker to predict Cancer Recurrence or Metastasis
A protein variant of carboxypeptidase E has now been shown to induce tumor growth and metastases. By measuring the level of this protein in the tumor and surrounding tissue, we may soon be able to predict whether a tumor is likely to spread or has already spread. The predictability of tumor behavior, using this new novel biomarker, appears to trump the outcomes based on staging and grade of the tumor. The tempo of the disease even in patients with advanced cancer can be predicted measuring the levels of this biomarker, with tumors expressing high levels of this protein doing poorly. This may also help the clinician determine when to treat a patient with cancer and when to just monitor without pursuing aggressive chemotherapeutic intervention.
These findings were published in the Journal of Clinical Investigation, Feb 2011.
Environment and Cancer
More than a third of Americans will develop some form of cancer during their life time. Interestingly 80-90% of the cancers in the western hemisphere has been attributed to environmental factors. With cancer being the second common cause of mortality in the USA, prevention of cancer related morbidity and mortality can be accomplished by avoiding environmental pollution with carcinogens and eliminating exposure to existing carcinogenic agents in the environment. This sentiment was eloquently verbalized by Dr. David Christiani in the March 3, 2011 issue of the NEJM.
Despite the progress made in cancer treatment and Genomics, we cannot lose sight of the fact that prevention is better than cure.