Category: Meeting Updates

Recurrent VTE in Cancer Patients Treated with XARELTO®

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000 – 100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality. Patients with unprovoked DVT and PE are two to four times more likely to be diagnosed with cancer within the following 12 months compared to the general population. In patients with cancer associated thrombosis, COUMADIN® (Warfarin) and XARELTO® (Rivaroxaban) are often prescribed, despite guidelines recommending Low Molecular Weight Heparin (LMWH) in this patient population.

Recently published data suggests that the rates of major bleeding, with use of XARELTO® in a highly selected group of cancer patients with venous thromboembolic disease, compared favorably with those treated with LMWH. (Mantha S, et al. 2015 ASH Annual Meeting). There is however limited data comparing the efficacy of different anticoagulants for VTE treatment in cancer patients.

The authors conducted this study in cancer patients, to compare the VTE recurrence rates, following most frequently prescribed anticoagulants in the United States. Newly diagnosed cancer patients with a first VTE, who initiated LMWH, COUMADIN® or XARELTO®, were selected using healthcare claims from the Humana database. The study population included 2,428 patients (XARELTO®: N=707; LMWH: N=660; COUMADIN® N =1,061). VTE recurrences were defined as hospitalizations with a primary diagnosis of VTE. Outpatients with a primary diagnosis of VTE were added as a sensitivity analysis to the recurrence definition.

The median duration on initial LMWH treatment was 1 month, on COUMADIN® was 3.5 months and on XARELTO® was 3 months. When compared to LMWH, VTE recurrence rates were lower with initial XARELTO® treatment at 6 months (13.2% versus 17.1%; P=0.06) and at 12 months (16.5% versus 22.2%; P=0.03). When initially treated with XARELTO®, recurrent VTE was 28% less likely than with LMWH (HR=0.72; P<0.03).

When compared to COUMADIN®, VTE recurrence rates were again lower with initial XARELTO® treatment at 6 months (13.2% versus 17.5%; P=0.02) and at 12 months (15.7% versus 19.9%; P=0.02). When initially treated with XARELTO®, recurrent VTE was 26% less likely than with COUMADIN® (HR=0.74; P<0.03). This benefit with XARELTO® when compared with LMWH and COUMADIN® users, was also noted in the sensitivity analysis.

The authors concluded that based on this real world healthcare claims data in cancer patients, XARELTO® was associated with a lower risk of recurrent VTE than LMWH or COUMADIN® and this could be a reflection of a shorter duration of treatment with LMWH and difficult therapeutic anticoagulation with COUMADIN®. Recurrent VTE in cancer patients treated with anticoagulation. Streiff MB, Milentijevic D, McCrae K, et al. J Clin Oncol 34, 2016 (suppl; abstr 10024)

Late Breaking Abstract – ASCO 2016 Extended Adjuvant AI Therapy Improves DFS in Postmenopausal Hormone Receptor Positive Breast Cancer

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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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 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. These patients are often treated with anti-estrogen therapy as first line treatment. 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. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Postmenopausal women with hormone receptor positive early breast cancer are often treated with 5 years of Aromatase Inhibitor (AI) therapy either as up-front treatment or after 2-5 years of Tamoxifen. The benefit of extending treatment with an AI to 10 years may further reduce the risk of breast cancer recurrence, but this benefit was not previously known.

The Canadian Cancer Trials Group MA.17R is a double blind, placebo controlled, phase III trial, which tested the benefit of extending AI treatment, using FEMARA®, for an additional 5 years. This study involved 1,918 postmenopausal women with early stage breast cancer and included three patient groups – one group had no prior treatment with adjuvant Tamoxifen whereas the other two groups had adjuvant Tamoxifen for some duration of time. All patients however had recently received 4.5 to 6 years of adjuvant AI therapy. These patients were then randomly assigned to receive either extended adjuvant treatment with FEMARA® or placebo for an additional five years. The primary endpoint was Disease Free Survival (DFS).

After a median follow up of 6.3 years, the 5 year DFS rate for the extended FEMARA® group was 95% compared with 91% for the placebo group (HR=0.66; P=0.01). The improvement in DFS was significant among patients with node-positive disease, but not for those with node-negative disease. There was no difference in the 5 year Overall Survival between the two groups – 93% with FEMARA® versus 94% with placebo (HR 0.97; P=NS). The annual incidence rate of contralateral breast cancer was however significantly better in the FEMARA® group at 0.21%, compared with 0.49% with placebo (HR=0.42; P=0.007). Patients receiving extended treatment with FEMARA® had more frequent adverse events such as bone pain, elevation of alkaline phosphatase, and elevation of alanine transaminase. There was also a greater incidence of osteoporosis with FEMARA® than with placebo (11% vs 6%; P<0.0001) and fracture risk was higher in the FEMARA® group (14%) compared with 9% in the placebo group (P=0.001).

The authors concluded that this is the first study to show added benefit of improved Disease Free Survival, by extending an adjuvant AI beyond 5 years to 10 years, when compared with 5 years of AI treatment as initial therapy or preceded by 2-5 years of Tamoxifen. A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. Goss PE, Ingle JN, Pritchard KI, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA1)

Pacritinib for Myelofibrosis – A New JAK-2 Inhibitor with a Better Toxicity Profile

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SUMMARY: Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by a ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

Pacritinib is a potent JAK2 inhibitor, without significant JAK1 inhibition. Preliminary studies have shown minimal myelosuppression with Pacritinib. JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor and is not safe for patients with low platelet counts. PERSIST-1 is a phase III study in which 327 patients with intermediate or high-risk Primary MyeloFibrosis (PMF), Post–Polycythemia Vera MF or Post–Essential Thrombocythemia MF were enrolled. Patients were randomized in a 2:1 ratio to receive Pacritinib 400 mg once daily (N=220) or Best Available Therapy (BAT) excluding JAKAFI® (N=107). Patients in the BAT group received Erythropoietin Stimulating Agents, Immunomodulatory drugs such as THALOMID® (Thalidomide), REVLIMID® (Lenalidomide) and Hydroxyurea. Because patients with very low platelet counts were enrolled in this study, JAKAFI® therapy was excluded, as JAKAFI® is not considered safe for patients with low platelet count. Approximately 32% of the patients had a platelet count of less than 100,000/µL and 15% had a platelet count of less than 50,000/ µL. About 75% of the patients were JAK2V617F positive. The median duration of treatment was 16.2 months in the Pacritinib group and 5.9 months in the BAT group. The primary endpoint was the proportion of patients achieving 35% or more reduction in the spleen volume at 24 weeks. Secondary endpoints included the proportion achieving 50% or more reduction in MyeloProliferative Neoplasm symptom score at 24 weeks.

At 24 weeks of treatment, 19.1% of patients in the Pacritinib group experienced 35% or more reduction in spleen volume compared to 4.7% in the Best Available Therapy (BAT) group (P=0.0003). This benefit was even more so in the subgroup of patients with the lowest platelet counts (less than 50,000/ µL), with 33.3% in the Pacritinib group demonstrating spleen volume reduction, compared to none in the BAT group. Patients in the Pacritinib arm were much more likely to experience more than a 50% reduction in symptoms, compared to BAT group at 24 weeks (24.5% vs 6.5%; P<0.0001), with significant improvements in fatigue, early satiety, abdominal discomfort, pruritus, night sweats and bone pain. This symptom improvement was noted by 4-8 weeks. Approximately 25% of the patients in the Pacritinib group achieved transfusion independence compared with none in the control group (P=0.043). The most common adverse events associated with Pacritinib were diarrhea, nausea and vomiting.

The authors concluded that Pacritinib significantly reduces spleen volume and Myelofibrosis associated symptoms, and fulfills an unmet need for Myelofibrosis patients with low platelet count, in addition to achieving RBC transfusion independence. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). Mesa RA, Egyed M, Szoke A, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA7006)

FDA Approves DigniCap Cooling System for Prevention of Chemotherapy Induced Alopecia

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SUMMARY: The FDA on December 8, 2015 allowed the marketing of the first cooling cap in the US, Dignitana DigniCap Cooling System, to reduce hair loss, in female breast cancer patients undergoing chemotherapy. Alopecia (hair loss) is a common side effect of several chemotherapeutic agents and can be emotionally traumatic. Even though temporary, minimizing or alleviating hair loss, can have a significant impact on patients psychological well being and willingness to pursue necessary treatment. Presently available non-FDA approved cooling devices include Penguin Cold Caps and Paxman Scalp Cooling System, although the later is not available in the US. One of the major concerns with cold caps use has been the risk for scalp metastasis due to decreased chemotherapy access to the scalp tissue from vasoconstriction associated with cooling devices. It is clear now that that the risk of metastases to the scalp is extremely rare and low (1.2%) and even lower as an initial event for advanced disease.

The Dignitana DigniCap computer-controlled cooling system pumps liquid coolant through a head-worn silicone cooling cap during chemotherapy treatment. This cooling cap is covered by an outer insulating cap which holds the cooling cap in place. The circulating coolant inside the cap gradually gets colder. The cold and near freezing temperature constricts the blood vessels in the scalp, which, in turn reduces chemotherapy access in the hair follicles, as well as metabolic activity of the hair follicle cells, thus slowing cell division. This combined action impairs the effect of chemotherapy on hair follicles and reduces chemotherapy induced hair loss.

The FDA approval was based on a multicenter prospective open-label, nonrandomized study in which the efficacy of the cooling system was studied in 122 women with Stage I and Stage II breast cancer who were receiving chemotherapy regimens associated with hair loss. The primary endpoint was patient self-assessment of hair loss using standardized photographs at three to six weeks after the last chemotherapy cycle. A score of 0-2 (50% or less hair loss) was defined as treatment success. Patients who chose not to undergo scalp cooling were enrolled in a control group. It was noted that more than 66 percent of patients treated with the DigniCap reported losing less than half their hair whereas 94% had more than 75% hair loss in the control group. The most common side effects with the scalp cooling system included cold-induced headaches and neck and shoulder discomfort, chills and pain associated with wearing the cooling cap for prolonged period of time.

The authors concluded that the DigniCap System is highly effective in reducing chemotherapy-induced alopecia and the FDA approval of this scientifically proven option will provide a major relief for cancer patients receiving chemotherapy. Clinical performance of the DigniCap system, a scalp hypothermia system, in preventing chemotherapy-induced alopecia. Rugo HS, Klein P, Melin SA, et al. J Clin Oncol 33, 2015 (suppl; abstr 9518)

FDA Approves COTELLIC® in Combination with ZELBORAF® for Advanced Melanoma

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SUMMARY: The U.S. FDA on November 10, 2015, approved COTELLIC® (Cobimetinib) for the treatment of patients with unresectable or metastatic melanoma, with a BRAF V600E or V600K mutation, in combination with ZELBORAF® (Vemurafenib). The American Cancer Society estimates that for 2015, approximately 74,000 new melanomas will be diagnosed in the United States and about 10,000 people are expected to die of the disease. The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway, which enables the cell to respond to external stimuli. This pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas. In the BRIM 3 randomized, phase III study, ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF demonstrated significant improvement in Progression Free Survival and Overall Survival compared to Dacarbazine. Squamous cell carcinoma’s were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. MEK gene is downstream from RAF in the MAPK pathway. The addition of a selective inhibitor of MEK gene such as COTELLIC® (Cobimetinib) to a BRAF inhibitor such as ZELBORAF®, has addressed some of these limitations, in previously published studies, with improvement in Objective Response rates and decrease in the incidence of cutaneous secondary cancers.

coBRIM is an international, multicenter, randomized, phase III study in which the efficacy and safety of COTELLIC® combined with ZELBORAF®, was evaluated in previously untreated patients, with advanced BRAF-mutated melanoma. Four hundred and ninety five (N=495) patients were randomly assigned in a 1:1 ratio to receive ZELBORAF® 960 mg orally twice daily along with either COTELLIC® 60 mg orally once daily on days 1-21 (N=247) or matching placebo (N=248), of a 28 day cycle. BRAF V600 mutation-positive status was detected using the cobas 4800 BRAF V600 mutation test. The median age of the study group was 55 years and patient demographics in both treatment groups were well balanced. About 60% of the patients, had stage IV disease. The primary endpoint for the study was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), and duration of response.

The primary analysis published in NEJM demonstrated a significant improvement in the median PFS (9.9 months vs 6.2 months) as well as ORR (68% vs 45%) with the combination of ZELBORAF® and COTELLIC® compared to ZELBORAF® and placebo respectively. In this updated analysis submitted to the FDA, the median PFS with the combination of ZELBORAF® and COTELLIC® was 12.3 versus 7.2 months for ZELBORAF® alone (HR= 0.56; P <0.001). There was also a statistically significant improvement in OS based on an interim analysis, with the median OS not reached (NR) in the combination group versus 17 months in the single agent ZELBORAF® group (HR=0.63; P=0.0019). The ORR were 70% and 50% in the ZELBORAF® and COTELLIC® and single agent ZELBORAF® groups, respectively (P<0.001).

The most common adverse reactions were diarrhea, photosensitivity reaction, nausea, pyrexia and vomiting. Treatment-related discontinuation rates in the combination and single agent groups were similar at 13% and 12%, respectively. It was concluded that in patients with unresectable or metastatic melanoma, with a BRAF V600E or V600K mutation, a combination of COTELLIC® and ZELBORAF® delays disease progression and improves survival compared to single agent ZELBORAF®. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. Larkin JMG, Yan Y, McArthur GA, et al. J Clin Oncol. 2015;33 (suppl; abstr 9006).

The 2015 ASH CHOOSING WISELY® Campaign Five Hematologic Tests and Treatments to Question

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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 70 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 without harming the patient. The ASH CHOOSING WISELY® Task Force comprised of 13 individuals, represents a broad spectrum of hematologic expertise including malignant, benign, adult, and pediatric specialists. The five final recommendations of the 2015 ASH Choosing Wisely Campaign is an addition to the 10 prior recommendations made by ASH over the past 2 years. These top 5 recommendations were presented on December 7, 2015, at the 57th annual meeting of ASH, in Orlando, Florida. Practicing hematologists should give due consideration to these recommendations which are evidence based and cost effective.

Don’t image for suspected Pulmonary Embolism (PE) without moderate or high pre-test probability of PE

The American College of Radiology has recommended that assessment of the risk-benefit ratio is important especially with pulmonary embolism and imaging can be avoided for suspected PE, without moderate to high pre-test probability.

Don’t routinely order thrombophilia testing on patients undergoing a routine infertility evaluation

With Nearly 15% couples of patients receiving an infertility evaluation, the American Society for Reproductive Medicine has recommended that even though several population-based studies have found association of infertility or failure of assisted reproduction with thrombophilia, 2 large cohort studies have shown no association between thrombophilias such as Factor V Leiden or Prothrombin gene mutations and assisted reproduction failure or infertility. Further, thrombophilia is not a predictor of who will benefit from Low Molecular Weight Heparin (LMWH) treatment with respect to assisted reproduction and LMWH can be associated with adverse events.

Don’t perform repetitive Complete Blood Count (CBC) and chemistry testing in the face of clinical and lab stability

The Society for Hospital Medicine and Adult Hospital Medicine noted that ordering routine complete blood counts (CBCs) during hospitalization is common practice and is unnecessary. Critically ill patients do not have the bone marrow reserve or erythropoietin stimulus to compensate for iatrogenic blood loss. Reducing the frequency of CBC’s does not result in inferior outcomes and several studies have shown that there is no difference in readmission rates, length of hospital stay and rates of adverse events. In addition to the risks of phlebotomy, this practice is economically disadvantageous, as they may not be reimbursable and will be an additional avoidable cost to dispose the biohazard waste of the blood samples.

Don’t transfuse red blood cells for iron deficiency without hemodynamic instability

The American Association of Blood Banks has recommended against PRBC transfusions for patients with hemodynamically stable iron deficiency anemia. These patients when evaluated in the Emergency Department (ED) can be prescribed oral or IV iron with similar responses noted at 6-8 weeks. The compliance rate in those receiving oral iron may only be 50% due to GI side effects. Therefore parenteral iron may be a better treatment option for certain groups of patients seen in the ED.

Avoid using positron emission tomography (PET) or PET-CT scanning as part of routine follow-up care to monitor for a cancer recurrence in asymptomatic patients who have finished initial treatment to eliminate the cancer unless there is high-level evidence that such imaging will change the outcome

Professional organizations like ASCO, ESMO and NCCN do not include surveillance PET in disease-specific guidelines because, routine use of intensive surveillance does not improve survival or enhance quality of life. Besides cost implications, CT scans may in fact expose patients to small doses of radiation.

The ASH Choosing Wisely® Campaign: Top 5 Non-ASH Choosing Wisely® Recommendations of Relevance to Hematology. Presented on December 7, 2015, at the 57th annual meeting of ASH, in Orlando, Florida.

Late Breaking Abstract – ASCO 2015 Elective Neck Dissection Improves Overall Survival and Disease Free Survival in Early Oral Cavity Cancers

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SUMMARY: The American Cancer Society estimates that approximately 39,500 individuals will be diagnosed with oral cavity and oropharyngeal cancer in the United States in 2015 and about 7,500 will die of the disease. These cancers are more than twice as common in men as in women and tobacco and alcohol use are among the strongest risk factors. Routinely screening for oral mucosal lesions can improve survival in this patient group. The primary treatment of oral cavity squamous cell carcinoma is complete surgical resection with tumor free margins. Surgical management of the neck in patients with early stage oral cancers has remained unclear, with regards to the benefit of ipsilateral Elective Neck Dissection (END) at the time of primary surgery following diagnosis versus Therapeutic Neck Dissection (TND) after nodal relapse in the neck. To address this question, the authors conducted a prospective, randomized, controlled trial between 2004 and 2014, in which 596 treatment naïve patients with invasive squamous cell carcinoma of the oral cavity (tongue-85%, buccal mucosa-14%, floor of the mouth-1%) were enrolled and randomized to 1:1 to Elective Neck Dissection (END) or Therapeutic Neck Dissection (TND) following primary oral surgery. Patients had T1 (2 cm or less) or T2 (more than 2 cm and less than 4 cm) tumors that was lateralized to one side of the midline and were amenable to oral excision with adequate margins. Elective Neck Dissection (END) consisted of removal of submandibular (level 1), upper jugular (level 2)and midjugular (level 3) lymph nodes, with lower jugular (level 4) and posterior triangle (level 5) lymph nodes removed only if any of the lymph nodes in the first three levels showed intraoperative metastatic disease. Therapeutic Neck Dissection (TND) consisted of modified neck dissection (level 1-5) at the time of nodal relapse. All patients with high risk disease received adjuvant radiotherapy. The Primary end point was Overall Survival and Secondary end point was Disease Free Survival.

This publication summarizes the outcomes for the first 500 patients (245 in the END group and 255 in the TND group), following a median follow-up of 39 months. The 3 year Overall Survival was significantly higher in the Elective Neck Dissection group compared with the Therapeutic Neck Dissection group (80.0% vs. 67.5%, HR=0.63; P=0.01). The three year Disease Free Survival was also significantly higher in the END arm compared with TND (69.5% vs 45.9%, HR=0.45; P<0.001). The authors concluded that Elective Neck Dissection in patients with early stage oral squamous cell carcinoma resulted in 37% reduction in mortality risk as well as significantly high Disease Free Survival rates with a 55% reduction in the risk of disease recurrence. END should therefore be considered a standard treatment option. Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. D’Cruz AK, Vaish R, Kapre N, et al. N Engl J Med 2015; 373:521-529

Nicotinamide Reduces the Incidence of Non-Melanomatous Skin Cancers

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SUMMARY: Skin cancer is the most common of all cancers. Approximately, 3.5 million cases of Basal cell and Squamous cell skin cancer (Non-Melanomatous) are diagnosed in the US each year. Most Non-Melanomatous skin cancers develop on the sun-exposed areas of the skin and Basal cell cancers tend to be slow growing and rarely metastasize, whereas Squamous cell cancers are more likely to grow into deeper layers of skin and metastasize. There has been a 35% increase in the incidence of Non-Melanomatous skin cancers between 2006 and 2012 and there has been a 17% increase in the incidence of Basal cell carcinomas over the past 15 years. Patients with Non-Melanomatous skin cancer are at an increased risk of developing a new primary, including breast and lung cancer in woman and prostate cancer in men. A major risk factor for most skin cancers is exposure to UltraViolet (UV) radiation, which damages the DNA of skin cells and suppresses cutaneous immunity. The main source of UV rays are sunlight, tanning lamps and tanning beds. The 3 main types of UV rays include UVA rays, UVB rays that mainly cause sunburns and UVC rays that do not penetrate through our atmosphere and are not in sunlight. Most indoor tanning beds give off large amounts of UVA rays, which have been found to increase skin cancer risk. It appears that there are no safe UV rays. Nicotinamide is an amide form of Vitamin B3 and unlike Nicotinic acid does not cause vasodilatation and associated side effects. Severe Nicotinamide deficiency causes Pellagra, which is characterized by photosensitive dermatitis, dementia, diarrhea and death. Nicotinamide enhances DNA repair after UV exposure and reduces UV radiation induced immunosuppression and in previously published studies was shown to decrease the formation of Actinic keratoses.

The ONTRAC (Oral Nicotinamide to Reduce Actinic Cancer) trial is a double-blind, phase III Study, in which 386 patients were randomly assigned to receive either Nicotinamide 500 mg PO twice daily (N=193 patients) or placebo (N=193 patients), for a period of 12 months. Enrolled patients had 2 or more histologically confirmed Non-Melanomatous skin cancers during the previous 5 years. The mean age was 66 years and 63% of the enrollees were men. Skin evaluations were performed by Dermatologists every 3 months. The primary endpoint was the number of new Non-Melanomatous skin cancers at 12 months and secondary endpoints included number of Squamous cell carcinomas, Basal cell carcinomas, and Actinic keratoses over the same study period. Over the 12 month study period, it was noted that patients in the placebo group developed an average of 2.4 new Non-Melanomatous skin cancers compared with 1.8 in the Nicotinamide group. This meant a Relative Risk Reduction (RRR) of 0.23 (P= 0.02). With regards to the specific subtypes, there was an average of 1.7 new cases of Basal cell carcinoma for patients who received placebo compared to 1.3 new cases for patients who received Nicotinamide. The Relative Risk Reduction was 0.20 (P=0.1). For Squamous cell carcinomas, there was an average of 0.7 cases for patients in the placebo group compared with 0.5 in the Nicotinamide group. The Relative Risk Reduction was 0.30 (P= 0.05). With regards to Actinic keratosis, there was a Relative Risk Reduction of 11% at 3 months (P=0.01), 14% at 6 months (P<0.001), 20% at 9 months (P<0.0001) and 13% at 12 months (P<0.005).

Based on this data the authors concluded that Nicotinamide, an inexpensive, over-the-counter Vitamin supplement, significantly reduces the incidence of Non-Melanomatous skin cancers by 20-30%, in high risk patients and may be an effective chemopreventive agent for Non-Melanomatous skin cancers. Oral nicotinamide to reduce actinic cancer: A phase 3 double-blind randomized controlled trial. Martin AJ, Chen A, Choy B, et al. J Clin Oncol 33, 2015 (suppl; abstr 9000)

ZOMETA® Administered Every 12 Weeks Is Non-inferior to Every 4 Weeks for Bone Metastases

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SUMMARY: Bones are the third most common site of metastatic disease and approximately 100,000 cases of bone metastasis are reported in the United States each year. Cancers originating in the breast, prostate, lung, thyroid and kidney, are more likely to metastasize to the bone. Bisphosphonates inhibit osteoclast-mediated bone resorption and both oral and IV bisphosphonates reduce the risk of developing Skeletal Related Events (SRE’s) and delay the time to SRE’s in patients with bone metastases. Bisphosphonates can also reduce bone pain and may improve Quality of life. Intravenous bisphosphonates, Pamidronate (AREDIA®) and Zoledronic acid (ZOMETA®) have been approved in the US for the treatment of bone metastases. Amino-bisphosphonate, ZOMETA® has however largely replaced AREDIA®, because of its superior efficacy. Both AREDIA® and ZOMETA® are administered IV every 3 to 4 weeks during the first year, following diagnoses of bone metastases. However, the optimal treatment schedule following this initial phase of treatment has remained unclear. Further, renal toxicity, long bone fractures and OsteoNecrosis of the Jaw (ONJ) have been identified as potential problems with bisphosphonate use.

CALGB 70604 (Alliance), is a randomized phase III study in which the efficacy of ZOMETA® administered every 4 weeks was compared with ZOMETA® administered every 12 weeks, in patients with breast cancer, prostate cancer or multiple myeloma, with bone metastases. In this non-inferiority trial, 1822 patients (Breast = 833, Prostate = 674, Myeloma= 270 and Other= 45) were randomly assigned 1:1, to receive ZOMETA® every 4 weeks or every 12 weeks for 2 years. The primary endpoint was incidence of any Skeletal Related Event (SRE) and secondary endpoints included skeletal morbidity rates, performance status, pain using the Brief Pain Inventory and incidences of ONJ and renal dysfunction. Both treatment groups were well matched. Patients in this trial were stratified by disease and analyses by disease was pre-planned. It was noted that for the primary endpoint, there was no significant difference between the two treatment groups with 29% of patients in both treatment groups experiencing at least one SRE (P=0.79). With regards to secondary endpoints, there were still no significant differences between the two treatment groups, including renal dysfunction and ONJ. The authors pointed out that toxicities such as ONJ and renal dysfunction are more likely to occur after 2 years of treatment.

It was concluded that ZOMETA® administered every 3 months for 2 years is non-inferior to ZOMETA® administered every 4 weeks for 2 years, in patients with breast cancer, prostate cancer and multiple myeloma, with bone metastases. A less frequent dosing of ZOMETA® compared with the standard monthly dosing, may be more convenient for the patients and cost effective. CALGB 70604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dosing of zoledronic acid in metastatic cancer. Himelstein AL, Qin R, Novotny PJ, et al. J Clin Oncol 33, 2015 (suppl; abstr 9501)

Late Breaking Abstract-ASCO 2015 Treating Cancer Based on Genomics Regardless of Tumor Type

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SUMMARY: KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti–PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The treatment paradigm for solid tumors has been rapidly evolving with a better understanding of the Immune checkpoints. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152, PD-1(Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic respons