SUMMARY: The American Cancer Society estimates that approximately 15,720 new cases of chronic lymphocytic leukemia (CLL) will be diagnosed in 2014 and approximately 4600 patients will die from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. There are two main types of lymphocytes, B and T lymphocytes/cells, and B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling.
This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s tyrosine kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the BCR, Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways and resulting B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). The RESONATE trial is a multicenter, randomized, open-label Phase III study in which single agent IMBRUVICA® was compared to single agent ARZERRA® (Ofatumumab) in patients with relapsed or refractory CLL or Small Lymphocytic Lymphoma (SLL). In this study, 391 patients who had measurable nodal disease and received at least one prior therapy, were randomized to receive 420 mg of IMBRUVICA® orally once daily until progression (N=195) or ARZERRA® at an initial dose of 300 mg followed by 11 doses at 2000 mg, given intravenously weekly (N=196). Patients randomized to the ARZERRA® group, on disease progression were allowed to receive treatment with IMBRUVICA®. The median age was 67 years, 40% of the patients enrolled in the study were 70 years of age or over and 30% of patients had deletion of chromosome 17p. The primary endpoint of this study was Progression-Free Survival (PFS) and the secondary endpoints included Overall Survival (OS), Overall Response rate (ORR) and safety. Following recommendations from the Independent Data Monitoring Committee (IDMC), the study was stopped earlier, as the primary endpoint as well as an important secondary endpoint of the study, were met. At a median follow up of 9.4 months, IMBRUVICA® significantly prolonged PFS compared to ARZERRA® (median not reached vs 8.1 months; HR 0.215, P<0.0001) with a 78.5% reduction in the risk of disease progression and also significantly improved OS (median not reached, HR 0.43, P=0.0049) when compared with ARZERRA®, with a 57% reduction in the risk of death. The Overall Response Rates were significantly higher in the IMBRUVICA® group compared to the ARZERRA® group (42.6% vs 4.1% (P <0 .0001). An additional 20% of patients treated with IMBRUVICA® had a partial response of their persistent lymphocytosis. The benefit with IMBRUVICA® was similarly high even in the two very high risk groups of patients such as those with 17p deletions and those refractory to purine analog chemoimmunotherapy. The overall survival was significant despite the crossover of 57 patients upon progression, from the ARZERRA® group to IMBRUVICA®. Treatment was well tolerated in both groups. Diarrhea, fatigue, nausea and atrial fibrillation were more frequent in the IMBRUVICA® group but did not result in frequent dose reductions or treatment discontinuation. The authors concluded that IMBRUVICA® significantly improved Progression Free Survival, Overall Survival and Overall Response Rates, in patients with relapsed/refractory CLL/SLL, compared with ARZERRA® and IMBRUVICA® should also be a consideration for elderly patients who often are unable to tolerate intensive chemotherapy. Byrd JC, Brown JR, O’Brien SM, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA7008)
Author: RR
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Of The Efficacy and Safety Of Siltuximab, An Anti-Interleukin-6 Monoclonal Antibody, In Patients With Multicentric Castleman’s Disease
SUMMARY: Castleman Disease (CD) also known as giant lymph node hyperplasia and angiofollicular lymph node hyperplasia is a disease of lymph nodes and related tissues and can be Unicentric (localized) or Multicentric. Younger individuals are more likely to have the localized form whereas older adults and those with HIV infection are more likely to have the Multicentric form. Unicentric CD only affects a single group of lymph nodes and curative resection of the affected lymph nodes is feasible. Multicentric Castleman Disease (MCD) behaves like a lymphoma and is classified as a lymphoproliferative disorder and requires treatment intervention. The number of people diagnosed with MCD has been increasing with the rising incidence of HIV infection. Even though retroviral therapies have improved survival in patients with HIV infection, this has not impacted the incidence of MCD. Approximately 50% of the MCD cases have been attributed to Kaposi's Sarcoma-associated Herpes Virus (KSHV), also known as HHV-8, a gamma herpes virus which is a causative factor for Kaposi's sarcoma and Primary Effusion Lymphoma, while the cause of the remainder of the MCD cases is unknown.
There are three microscopic subtypes of CD – The hyaline vascular type which is localized (Unicentric) type, the plasma cell type which is more likely to be Multicentric, and the mixed subtype which occurs less often. The microscopic findings are less important when it comes to treatment whereas treatment is based on whether the disease is Unicentric or Multicentric. KSHV is closely associated with plasmacytic form of MCD while the hyaline vascular type is generally negative for KSHV. Patients with Multicentric CD usually experience fevers, night sweats, weight loss, fatigue as well as leukocytopenia, hypergammaglobulinemia, generalized lymphadenopathy and possible splenic involvement. It resembles angioimmunoblastic lymphadenopathy and the symptoms and signs have been attributed to dysregulated interleukin (IL)-6 production. Some patients with CD may have normal IL-6 levels and present with microcytic anemia without iron deficiency, which resolves after effective therapy. MCD is seen in patients with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes) and has been implicated in 10% of cases of paraneoplastic pemphigus. Based on the preliminary data demonstrating the efficacy of SYLVANT® (Siltuximab), a chimeric monoclonal antibody targeting human IL-6, in MCD patients, an international, multicenter, randomized phase II trial was conducted. Patients with Multicentric Castleman Disease (MCD) who were Human Immunodeficiency Virus (HIV) negative and Human Herpes Virus-8 (HHV-8) negative (N=79) were randomized 2:1 to receive SYLVANT® (Siltuximab) given every three weeks, as an IV infusion at a dose of 11 mg/kg along with Best Supportive Care (N=53) or Placebo plus Best Supportive Care (N=26). The median age was 48 yrs, 30% were on corticosteroids and 58% had prior systemic therapy. Primary endpoint was durable tumor and symptomatic response defined as PR or CR by independent review and improvement or stabilization in MCD-related symptoms for 18 weeks or more. Secondary endpoints included additional predefined efficacy measures and safety. The durable tumor and symptomatic response rates (Primary endpoint) were 34% versus 0% for the SYLVANT® and Placebo groups respectively (P=0.0012). With regards to secondary endpoints, tumor response rates were 38% versus 4% for the SYLVANT® and placebo groups, respectively (P<0.05), the median time to treatment failure was 134 days in those receiving placebo and had not been reached in the SYLVANT® (P=0.0084), an increase in the hemoglobin of at least 1.5 grams/dL at week13 in anemic patients was seen in 61% of the patients receiving SYLVANT® vs 0% in those receiving Placebo (P=0.0002). There were sustained decreases in C-Reactive Protein (a marker of IL-6 activity), ESR, and fibrinogen as well as an increase in albumin in the SYLVANT® group. The common adverse reactions (>10% compared to placebo) during treatment with SYLVANT® were pruritus, weight gain, rash, hyperuricemia and upper respiratory tract infections. The authors concluded that this is the first randomized study involving patients with Multicentric Castleman Disease, that has demonstrated significant efficacy with SYLVANT®, resulting in durable tumor and symptom responses and added clinical benefit. Wong RS, Casper C, Munshi N, et al. Abstract #505. ASH Annual Meeting and Exposition, 2013
Human Papillomavirus and Overall Survival After Progression of Oropharyngeal Squamous Cell Carcinoma
SUMMARY: The CDC estimates that more than 2,370 new cases of Human Papilloma Virus (HPV) associated Oropharyngeal Squamous Cell Carcinomas (OPSCC) are diagnosed in women and nearly 9,356 are diagnosed in men each year in the United States and this has been on the rise. Recent studies have shown that over 70% of the OroPharyngeal Squamous Cell Carcinomas (OPSCC) are caused by HPV and HPV-16 is the predominant type present in the tumor cells. The malignant behavior of these tumors is dependent on the expression of viral E6 and E7 oncoproteins that inactivate the tumor suppressor proteins p53 and the retinoblastoma protein (pRb), respectively. HPV-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) is more common among never smokers or light smokers and patients tend to be younger with better performance status.
To address this further, the authors examined the influence of tumor HPV status (tumor p16) on patterns of failure and survival after disease progression, by performing a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression, amongst patients enrolled in the Radiation Therapy Oncology Group (RTOG) trials 0129 and RTOG 0522. Eligible patients from these two trials had stage III-IV OroPharygeal Squamous Cell Carcinoma. Their tumor p16 status was known and these patients had local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy. Of the 181 patients included in this analysis, 105 patients had p16 positive OPSCC and 76 patients had p16 negative OPSCC. Tumor p16 expression was evaluated using immunohistochemistry methodology. Even though the patterns of failure and median time to progression were similar for patients with p16-positive and p16-negative tumors, after a median follow up period of 4 years after disease progression, patients with p16-positive OPSCC had significantly improved Overall Survival (OS) rates compared with p16-negative patients (2-year OS, 54.6% vs 27.6%; median, 2.6 vs 0.8 years; P <0.001). This meant that patients with HPV positive recurrent OPSCC had nearly twice the overall survival rate compared to HPV negative patients. Further, salvage surgery after disease progression in HPV positive patients reduced the risk of death. Factors associated with improved survival in multivariate analysis included, HPV positive status, salvage surgery, locoregional progression vs distant progression, lower T stage at enrollment and less than 20 pack year smoking history.
The authors concluded that patients with HPV positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) have tumors with different molecular behavior, compared to HPV negative and tobacco related OPSCC and tumor p16 status is independently associated with Overall Survival among OPSCC patients with disease progression. This important information should be a stratification factor for clinical trials and the benefits of salvage surgery dictates close surveillance as these patients are followed up. Fakhry C, Zhang Q, Nguyen-Tan PF, et al. Published Ahead of Print on June 23, 2014 as 10.1200/JCO.2014.55.1937
CYRAMZA® Improves Overall Survival in Advanced Gastric Cancer
In a multinational double-blind phase III trial, targeting VEGFR-2 signaling with CYRAMZA® , improved overall survival in patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. CYRAMZA® is the first biological treatment that has demonstrated survival benefit when given as a single agent in this patient population. This study was published in the Lancet, 2014.
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD) an international, randomised, multicentre, placebo-controlled, phase 3 trial
SUMMARY: It is estimated that there were approximately 21,600 new cases and 10,990 deaths from gastric cancer in the United States in 2013. The biology of gastric cancer appears to be different in different parts of the globe. Following progression after first line treatment for metastatic disease, the median survival is approximately 3 months.
Ramucirumab (CYRAMZA®) is a recombinant human IgG1 monoclonal antibody that binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D and thus inhibits ligand-induced proliferation and migration of endothelial cells. This is unlike AVASTIN® (Bevacizumab) which inhibits VEGF-A. REGARD is a multinational double-blind phase III trial, in which 355 patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma were randomly assigned in a 2:1 ratio to receive CYRAMZA® at 8 mg/kg, IV (N=238) or Placebo (N=117) every 2 weeks. Both groups also received best supportive care. The median age was 60 years and the ECOG performance of the patient population was 0 or 1. Patients received a median of four doses of CYRAMZA® or a median of three doses of Placebo. The primary endpoint was Overall Survival. The median Overall Survival in the CYRAMZA® group was 5.2 months vs 3.8 months in the Placebo group (HR = 0.78, P=0.047). The median Progression-Free Survival was also prolonged in the CYRAMZA® group (2.1 vs 1.3 months, HR = 0.48, P <0 .001). The most common adverse events of any grade in the CYRAMZA® group were hypertension, diarrhea, headache and hyponatremia. The authors concluded that VEGFR-2 signaling is an important therapeutic target in advanced gastric cancer and CYRAMZA® is the first biological treatment that has demonstrated survival benefit when given as a single agent in patients with advanced gastric or gastroesophageal junction adenocarcinoma, progressing after first-line chemotherapy. Fuchs CS, Tomasek J, Yong CJ, et al. Lancet. 2014;383:31-39
Treatment of Advanced Non–Small-Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Mutation or ALK Gene Rearrangement Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology
SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society’s estimates that over 224,000 new cases of lung cancer will be diagnosed in the United States in 2014 and over 159,000 will die of the disease. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, adenocarcinoma now is the most frequent histologic subtype of lung cancer. In the mid 1990’s, following a meta-analysis of 52 randomized clinical trials, platinum based doublet chemotherapy became the accepted standard, for patients with Stage IV Non Small Cell Lung Cancer (NSCLC), after this combination demonstrated a 27% reduction in the risk of death compared to supportive care. Since then, significant advances have been made and it is now established that Platinum/Pemetrexed (ALIMTA®) combination results in superior survival in those with non squamous histology tumors whereas Platinum/ Gemcitabine (GEMZAR®) combination is superior in patients with squamous cell histology. In 2004, the discovery of Epidermal Growth Factor Receptor (EGFR) mutations in some advanced NSCLC cases with adenocarcinoma histology and the favorable responses with EGFR Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib) and IRESSA® (Gefitinib), changed the treatment paradigm in favor of targeted therapy for this patient subset. Subsequently, the discovery of rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, led to the development of agents such as XALKORI® (Crizotinib) and ZYKADIA® (Ceritinib), with promising results. It has become clear that appropriate, molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. This new paradigm lead to the development of evidence based recommendations by a panel of experts in thoracic oncology taking the “driver oncogenes and driver mutations” into consideration. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8% as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive and the presence of two simultaneous mutations, are rare. The following guidelines have been put together, to better manage patients with advanced adenocarcinoma of the lung. 
EGFR Mutations and EGFR TKIs
• All patients with advanced NSCLC with the exclusion of pure squamous cell carcinoma should be tested for EGFR mutations before first line treatment decision is made. Because EGFR mutations and ALK rearrangement are mutually exclusive, routine testing of the other is not required for those patients with one known genomic abnormality.
• Patients should be tested for the most common sensitizing mutations such as deletions in exon 19 and L858R point mutations in exon 21, as these patients clearly benefit from first line EGFR TKIs. EGFR expression by IHC (ImmunoHistoChemical) staining, EGFR gene copy by FISH (Fluorescence In Situ Hybridization) and blood based proteonomic testing by VERISTRAT® is currently not recommended for the selection of first line EGFR TKIs.
• Any one of the three available agents, TARCEVA® (Erlotinib), GILOTRIF® (Afatinib) or IRESSA® (Gefitinib) are recommended for first line treatment, as per the regulatory label, because of the absence of data on direct comparisons.
• Platinum based chemotherapy should be considered after EGFR TKI failure in eligible patients and there is no evidence to recommend a preferred chemotherapy regimen in EGFR mutation positive patients.
• If EGFR mutation positive results become available after commencement of first line chemotherapy, early interruption of chemotherapy is discouraged. However maintenance therapy with EGFR TKI should be considered after completion of first line chemotherapy.
• In patients with unknown EGFR mutational status, first line platinum based chemotherapy is the standard of care.
• Continuing EGFR TKI beyond disease progression after its use as first line treatment is not recommended.
ALK Rearrangements and Treatment Selection
• Currently, ALK status is determined by FISH technique although ALK testing by IHC analysis is gaining momentum.
• All patients with advanced NSCLC with the exclusion of pure squamous cell carcinoma should be tested for ALK rearrangement before decision about first line treatment is made. Because EGFR mutations and ALK rearrangements are mutually exclusive, routine testing of the other is not required for those patients with one known genomic abnormality.
• In the US, XALKORI® (Crizotinib) is approved for use in any line of treatment.
• Chemotherapy is allowed in any line of treatment although it is preferable to use it following treatment failure with XALKORI®.
• ZYKADIA® (Ceritinib) is approved in the US for treatment of patients with disease progression on or who are intolerant to XALKORI® (Crizotinib).
• If ALK positive results become available after commencement of first line chemotherapy, early interruption of chemotherapy is discouraged. In these patients, XALKORI® should be used as second line treatment following disease progression on chemotherapy. Maintenance therapy with XALKORI® is not recommended.
• In clinical practice, a repeat biopsy is not recommended at disease progression after treatment with EGFR TKIs or ALK inhibitors.
Gridelli C, de Marinis F, Cappuzzo F, et al. Clinical Lung Cancer 2014;15:173-181
CALGB/SWOG 80405 Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC)
SUMMARY: The American Cancer Society estimates that approximately 137,000 new cases of colorectal cancer will be diagnosed in the United States in 2014 and over 50,000 are expected to die of the disease. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival and Overall Survival.
The benefit with anti EGFR agents however is only demonstrable in patients with metastatic colon cancer, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now becoming clear that even amongst the KRAS Wild Type patient groups, about 15% to 20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Therefore, pan RAS (expanded RAS) testing may become relevant. To determine the optimal combination treatment regimen, this phase III intergroup trial evaluated the addition of ERBITUX® or AVASTIN® to physician’s choice of standard first line chemotherapy such as FOLFIRI or mFOLFOX6. Even though the original study included unselected metastatic colorectal cancer patients and randomization to a third arm (combination of ERBITUX® and AVASTIN®), this study was amended to include only pts with KRAS Wild Type tumors and the combination ERBITUX® and AVASTIN® arm was deleted. Patients were randomized to either ERBITUX® 400 mg/m2 week one and then 250 mg/m2, weekly or AVASTIN® 5 mg/kg every 2 weeks given along with FOLFIRI or mFOLFOX6 chemotherapy (physicians choice at the time of enrollment). The median age was 59 years and treatment groups were Chemo plus AVASTIN® (N=559) and Chemo plus ERBITUX® (N=578). Approximately 27% of the patients received FOLFIRI chemotherapy regimen and 76% received mFOLFOX6 chemotherapy regimen. Treatment was given until disease progression and median follow up was 24 months. The primary endpoint was Overall Survival. The median Overall Survival was similar in the ERBITUX® combination and the AVASTIN® combination groups (about 29 months) and so was the Progression Free Survival in both groups (about 10.5 months). The chemotherapy used with either of the antibodies had no influence on the outcomes. The toxicity profiles were different as expected, with increased incidence of Grade 3-4 rash (7% versus 0%) and diarrhea (11% versus 8%), in the ERBITUX® group and increased incidence of Grade 3-4 hypertension (7% versus 1%) and gastrointestinal events (2% versus 0.5%), in the AVASTIN® group. The authors concluded that either ERBITUX® or AVASTIN® in combination with chemotherapy have equivalent overall survival benefit, when given as first line therapy, for patients with metastatic colorectal cancer, whose tumors are KRAS Wild Type. It remains to be seen however, if pan RAS (expanded RAS) testing and other molecular studies will identify subsets of patients who will benefit from specific antibody chemotherapy combination regimens. Venook AP, Niedzwiecki D, Lenz H, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3)
Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC) Joint analysis of IBCSG TEXT and SOFT trials
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 233,000 new cases of invasive breast cancer will be diagnosed in 2014 and 40,000 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues.
Presently available therapies include Tamoxifen and other Selective ER Modulators, which modulate ER alpha activity, Aromatase Inhibitors and Ovarian ablation that decrease estrogen production and FASLODEX® (Fulvestrant) that down regulates Estrogen Receptor. Aromatase Inhibitors (AI’s) are often prescribed, due to their superiority over Tamoxifen, for postmenopausal women with Hormone Receptor positive breast tumors, in adjuvant as well as metastatic settings. AI’s however, are not effective in premenopausal women, as these individuals derive their estrogen mainly from ovaries and not extragonadal tissues. The 2000 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview, as well as subsequent studies comparing adjuvant ovarian ablation/suppression with adjuvant chemotherapy in premenopausal women with hormone positive breast tumors, have demonstrated similar magnitude of benefit. The TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) are two phase III randomized trials, conducted at the same time and included premenopausal women (average age was 43 years) with hormone receptor positive early breast cancer. In the joint analysis of these two trials in which 5738 women were enrolled, the authors set out to answer 2 important questions – whether adjuvant AI improves outcomes in this patient group when their Ovarian Function is suppressed and whether there is any benefit with Ovarian Function suppression in premenopausal women suitable for adjuvant Tamoxifen. TEXT randomized patients (N=2672) within 3 months of surgery to 5 years of AROMASIN® (Exemestane) plus Ovarian Function Suppression (OFS) or 5 years of Tamoxifen plus OFS. The SOFT study randomized patients (N=3066) to 5 years of AROMASIN® plus OFS or 5 years of Tamoxifen plus OFS or 5 years of Tamoxifen alone. OFS choices included oophorectomy, ovarian irradiation or 5 years of TRELSTAR® (Triptorelin), a GnRH (Gonadotropin Releasing Hormone) agonist. The primary endpoint of these two studies was Disease Free Survival (DFS). In this joint analysis the outcomes for 4690 women randomized to receive AROMASIN® plus OFS or Tamoxifen plus OFS for 5 years, were analyzed. The 5 year Disease Free Survival was 91.1% in the AROMASIN® plus OFS group and 87.3% in the Tamoxifen plus OFS group (HR=0.72, P<0.0002). Compared to patients receiving Tamoxifen plus OFS, AROMASIN® plus OFS reduced the relative risk of premenopausal women developing a subsequent invasive breast cancer by 28% and the relative risk of breast cancer recurrence by 34%. The authors concluded that this largest joint analysis, evaluating adjuvant AI therapy with OFS in premenopausal women with Hormone receptor positive breast cancer, has demonstrated that 5 years of highly effective adjuvant endocrine therapy without chemotherapy can result in excellent outcomes. Further, AROMASIN® may be better than tamoxifen, when given with Ovarian Function Suppression. Pagani O, Regan MM, Walley B, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA1)
The ASH Choosing Wisely® campaign five hematologic tests and treatments to question
SUMMARY: CHOOSING WISELY® is a quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States such as the American Society of Hematology (ASH). This organization was established to improve quality of medical care, after it was noted that about 25% of the tests ordered at the time of hospital admission and 65% of the tests ordered on subsequent days were avoidable. Further, there is ample evidence to suggest that reducing unneeded investigations can decrease costs, increase patient satisfaction and quality of care. CHOOSING WISELY® has challenged medical societies to identify 5 tests, procedures or treatments, within each specialty's clinical domain, that are offered to patients, despite the lack of evidence demonstrating its benefit. The goal is to make positive changes in the actual delivery of patient care. The ASH identified 5 tests and treatments that practicing hematologists should give due consideration to, that in some situations are not evidence based and which in certain cases are associated with risks that outweigh the benefits and are not cost efficient.
Multitarget Stool DNA Testing for Colorectal-Cancer Screening
SUMMARY: The American Cancer Society estimates that approximately 137,000 new cases of colorectal cancer will be diagnosed in the United States in 2014 and over 50,000 are expected to die of the disease. It is the third leading cause of cancer death in the U.S. and the lifetime risk of developing colorectal cancer is 1 in 20. Implementation of screening programs in the U.S. has resulted in a 46% decrease in the rate of death from colorectal cancer, from its peak. The U.S. Preventive Services Task Force recommends annual screening with high sensitivity Fecal Occult Blood Testing (FOBT), sigmoidoscopy every 5 years with high-sensitivity FOBT every 3 years and screening colonoscopy every 10 years. Fecal Immunochemical testing (FIT) measures intact human globin protein as opposed to heme. Animal heme from meat will not trigger a false positive test with FIT and as such dietary restrictions are not necessary. Further, FIT is superior to FOBT in detecting advanced adenomas and only requires one stool specimen, as opposed to three specimens for FOBT.
COLOGUARD® is highly sensitive, noninvasive, multitarget, stool based DNA test, for colorectal cancer screening ie.early detection of colorectal cancer and precancerous lesions. This test takes advantage of the genetic and epigenetic alterations that leads to the development of colorectal cancer and analyzes the altered DNA signatures of cancerous and precancerous cells that exfoliate into the colon. In addition, this test includes an immunochemical assay for human hemoglobin. The stool samples can be easily collected, mailed from home, and requires no bowel preparation, medication restrictions or dietary change. The purpose of this study was to determine the sensitivity of COLOGUARD® as compared with FIT, for the detection of screening-relevant colorectal cancer. The study was conducted at 90 medical centers throughout the United States and Canada and evaluable patients (N=9989) were asymptomatic individuals between ages 50 and 84 years who were required to provide a stool sample and undergo screening colonoscopy within 90 days. Enrollment was weighted toward those aged 65 years or older. The primary outcome was the ability of COLOGUARD® to detect colorectal cancer and secondary outcomes were the ability of COLOGUARD® to detect advanced precancerous lesions, polyps with high grade dysplasia and serrated sessile polyps measuring 1 cm or more, when compared to FIT. (Sensitivity is defined as the proportion of persons with disease who have a positive test and Specificity is defined as proportion of persons without disease who have a negative test.) The sensitivity for detecting colorectal cancer was 92% with COLOGUARD® and 74% with FIT (P=0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% vs 23.8% (P<0.001), polyps with high-grade dysplasia was 69.2% vs 46.2% (P=0.004) and serrated sessile polyps measuring 1 cm or more were 42.4% vs 5.1%, (P<0.001) with COLOGUARD® and FIT respectively. Specificities with COLOGUARD® were lower compared to FIT (P<0.001). The authors concluded that COLOGUARD® can detect significantly more colorectal cancers and precancerous lesions than FIT. The high sensitivity of this non-invasive, stool DNA test, to detect curable stage of colorectal cancer, may increase the number of people, who will choose to be screened for colorectal cancer. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. N Engl J Med 2014; 370:1287-1297