Author: RR

Intraperitoneal Chemotherapy Superior to IV Chemotherapy in Advanced Ovarian Cancer

RR

SUMMARY: The American Cancer Society estimates that over 21,000 women will be diagnosed with ovarian cancer in the United States for 2015 and over 14,000 will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Intraperitoneal (IP) delivery of antineoplatic drugs ("Belly Bath") for ovarian cancer dates back to the late 1970’s and 1980’s. This strategy for ovarian cancer was based on the fact that the peritoneal cavity is the primary site of spread and failure in most cases of advanced ovarian cancer. IP chemotherapy for ovarian cancer facilitates the exposure of tumors in the peritoneal cavity to 10-20 fold greater concentration of Cisplatin and Carboplatin and 1000 fold greater concentration of Paclitaxel, compared to IV administration, thus allowing continuous and prolonged exposure of the tumor to high drug concentrations, without systemic toxicities. Even though three Intergroup Phase III trials demonstrated the superiority of IP therapy over IV therapy, it has not been widely accepted in the US and abroad. Barriers to IP therapy have included inconvenience, IP catheter related complications, higher toxicities, lack of knowledge regarding patient selection for IP therapy as well as minimum number of cycles of IP therapy to administer and uncertain long term benefit.

The authors in this study retrospectively analyzed data from 876 patients in the two phase III, Gynecologic Oncology Group trials (GOG#114 and GOG#172). The purpose of this study was to determine the long-term survival and associated prognostic factors following IP chemotherapy, in patients with advanced ovarian cancer. In both studies, patients were randomly assigned to IP (combined N=440) or IV (combined N=436) chemotherapy. In GOG#114 trial, the two treatment groups were Paclitaxel at 135 mg/m2 IV followed by Cisplatin 75 mg/m2 IV for 6 cycles or Carboplatin IV for 2 courses followed by Paclitaxel 135 mg/m2 IV dose on day 1 and Cisplatin 100 mg/m2 IP on day 8, for 6 cycles. In GOG#172 trial, the two treatment groups (IV vs IP) were Paclitaxel at 135 mg/m2 IV followed by Cisplatin 75 mg/m2 IV on day 2 for 6 cycles or Cisplatin 100mg/m2 IP on day 2 and Paclitaxel 60 mg/m2 IP on day 8, for 6 cycles. Patients in the IP and IV groups were well balanced for baseline characteristics. At a median follow up of 10.7 years, the median Overall Survival with IP chemotherapy was 61.8 months compared with 51.4 months for IV chemotherapy and IP chemotherapy resulted in a 23% reduction in the risk of death (HR=0.77; P=0.002). IP chemotherapy was also associated with improved survival among those patients with gross residual disease ie.1 cm or less (HR = 0.75; P=0.006). The risk for death decreased by 12% for each cycle of IP chemotherapy that patients completed (HR=0.88; P<0.001). Factors significantly associated with poorer Overall Survival included clear/mucinous vs serous histology (HR=2.79; P <0 .001), gross residual vs no visible disease (HR=1.89; P< 0.001), and fewer vs more cycles of IP chemotherapy (HR=0.88; P<0.001). Younger patients were more likely to complete IP chemotherapy, with probability of completion decreasing by 5% with each additional year of age (P<0.001). The authors concluded that IP chemotherapy was associated with significantly prolonged Overall Survival in women with advanced ovarian cancer, including those with gross residual disease, when compared with IV chemotherapy. This benefit extends beyond 10 years and Overall Survival improved with increasing number of IP chemotherapy cycles administered. Long-Term Survival Advantage and Prognostic Factors Associated With Intraperitoneal Chemotherapy Treatment in Advanced Ovarian Cancer: A Gynecologic Oncology Group Study . Tewari D, Java J, Salani R, et al. JCO published online on March 23, 2015; DOI:10.1200/JCO.2014.55.9898.

Clinical Cancer Advances 2015 Annual Report on Progress Against Cancer From the American Society of Clinical Oncology (PART II)

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SUMMARY: Cancer mortality rates in the United States have declined 20% from their peak of 215 per 100,000 in 1991 to 172 per 100,000 in 2010. Part II  of this Annual Report on Progress Against Cancer explores, ADVANCES IN TREATMENT, ADVANCES IN TUMOR BIOLOGY AND ADVANCES IN PATIENT CARE. Clinical study details for several of these studies can be accessed at www.oncoprescribe.com

ADVANCES IN TREATMENT

COMBINATION THERAPY

Chemotherapy and Radiotherapy significantly improves Survival for Patients with Low-Grade Glioma – Radiotherapy has been the standard first-line treatment for patients with low-grade glioma. In a study involving 251 patients with gliomas which included grade 2 Astrocytoma, Oligoastrocytoma, or Oligodendroglioma, the addition of chemotherapy (PCV regimen – (Procarbazine, Lomustine, and Vincristine) to radiation extended median survival by 5.5 years (13.3 vs 7.8 years, P=0.03; HR=0.59) and also resulted in a longer median Progression Free survival (10.4 vs 4 years, P=0.002; HR=0.50), when compared with radiotherapy alone.

First-Line Chemotherapy Added to Hormone Therapy Improves Survival for Men With Advanced Prostate Cancer – Androgen Deprivation Therapy (ADT) has been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. Chemotherapy is usually considered for patients who progress on hormone therapy. In a pivotal phase III study which included 790 men with metastatic, hormone-sensitive prostate cancer, the addition of TAXOTERE® (Docetaxel) chemotherapy to ADT improved median Overall Survival by 10 months from 42.3 months in the ADT alone group to 52.7 months in the ADT plus TAXOTERE® group (HR=0.63; P<0.0006). The median time to clinical progression was 19.8 months in the ADT alone group vs 32.7 months in the ADT plus TAXOTERE® group (P < 0.0001).

TARGETED THERAPY

Overcoming Resistance to EGFR Targeted Agents in Lung Cancer– TARCEVA® (Erlotinib) and GILOTRIF® (Afatinib) are recommended as first-line treatments for patients harboring Epidermal Growth Factor Receptor (EGFR) gene mutations, which are detected in 15% of Caucasian and 40% of Asian patients with NSCLC. An additional EGFR mutation (T790M) is responsible for resistance to EGFR-targeted therapy and may be detected in about 50% of those harboring EGFR mutations in Non Small Cell Lung Cancer (NSCLC). AZD9291 and CO-1686 are two new agents which have demonstrated a 50-60% response rate in patients with T790M mutation.

New second-line treatment options for ALK-positive NSCLC – XALKORI® (Crizotinib) significantly improves PFS and Response Rates in patients with ALK-positive NSCLC. Approximately one third of these patients are resistant to XALKORI® and this has been attributed to acquired mutation within the ALK tyrosine kinase domain, amplification of the ALK fusion gene, subtherapeutic inhibition of ALK tyrosine kinase or activation of other pathways that can cause abnormal cell proliferation. ZYKADIA® (Ceritinib) resulted in an overall Response Rate (RR) of 58% and median PFS of 7 months in this patient population, with responses seen in untreated CNS lesions as well.

FDA Approves First Treatment for Chemotherapy-Resistant, Advanced Stomach Cancer –  CYRAMZA® (Ramucirumab) an angiogenesis inhibitor was approved for the treatment of advanced stomach cancer or gastroesophageal junction adenocarcinoma that progressed during or after chemotherapy. The approval was based on a phase III trial involving 355 patients in which patients treated with CYRAMZA® (Ramucirumab) had longer survival (5.2 vs 3.8 months, HR = 0.78, P=0.047), when compared to placebo.

Lenvatinib: A New Option for a Difficult-to-Treat Thyroid Cancer –  LENVIMA® (Lenvatinib) a Tyrosine Kinase Inhibitor, was approved for the treatment of patients with locally recurrent or metastatic, progressive, RadioActive Iodine (RAI)-refractory Differentiated Thyroid Cancer (DTC). In a phase III study involving 392 patients with advanced RAI-refractory Differentiated Thyroid Cancer (DTC), the median Progression Free Survival was 18.3 months in the LENVIMA® group and 3.6 months in the placebo group (HR= 0.21; P<0.001). The objective response rate with LENVIMA® was 64.8% versus 1.5% with placebo (P<0.001). Another targeted drug, NEXAVAR® (Sorafenib), was approved for the same patient population in 2013.

IMMUNOTHERAPY

Both antibody and cell-based immunotherapy approaches have taken center stage in cancer immunotherapy. Check point inhibitors such as anti CTLA-4. Anti PD-1 and anti PDL1 antibodies unleash the immune system allowing the T cells to attack the malignant cells.

Adjuvant Immunotherapy For Early Stage Melanoma – YERVOY® (Ipilimumab), an anti CTLA-4 antibody decreased the relative risk of recurrence by 25% (HR=0.75; P=0.0013), when compared with placebo, in patients with high risk, completely resected, stage III melanoma

Immunotherapy in Lung Cancer – OPDIVO® (Nivolumab), a PD-1 targeted monoclonal antibody improved overall survival by 41% (HR=0.59; P=0.00025) when compared to TAXOTERE® (Docetaxel) in a randomized phase III trial in patients with metastatic squamous NSCLC, who had experienced disease progression during or after one prior platinum-based chemotherapy regimen. KEYTRUDA® (Pembrolizumab) another PD-1 antibody demonstrated superior responses in patients with lung cancer when the tumors were PD-L1 positive versus PD-L1 negative (23% vs 9%) suggesting that PD-L1 may be a predictor of response to PD-1 and PD-L1 therapies.

Tumor Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy – In this type of immunotherapy, T cells are collected from the patient’s own blood and are genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CAR’s). These cytotoxic T cells with these chimeric antigen receptors on their surface are now able to recognize a specific antigen on tumor cells. These engineered CAR T-cells (CTL019) which are grown in vitro, are then infused into the patient and they in turn proliferate in the patient’s body, recognize and kill cancer cells expressing that specific antigen. In a small study of patients with relapsed or refractory ALL, treatment with autologous Chimeric Antigen Receptor (CAR) T-cells (CTL019 T-cells) resulted in a 90% remission rate with sustained remissions for up to 2 years and overall survival of 78%.

ADVANCES IN TUMOR BIOLOGY

Genomic Profile Based Therapy – In a recent landmark study, analysis of molecular data from approximately 3,500 patients with 12 different forms of cancer, lead to the identification of 11 major molecular subtypes. It was noted that most malignancies that originated from the same tissue or organ had similar genomic profiles. Treatment in the foreseeable future may be based on genomic profile rather than site of origin of the malignancy.

Blood Test Predicts Resistance to Prostate Cancer Therapy – In patients with metastatic CRPC, the presence of Androgen Receptor Variant AR-V7 rather than a normal androgen receptor, in the circulating tumor cells (CTCs) before, during, and after treatment with either XTANDI® (Enzalutamide) or ZYTIGA® (Abiraterone), conferred resistance to these agents. The Androgen Receptor Variant AR-V7 was detected in roughly 40% of patients treated with XTANDI® and 20% of those treated with ZYTIGA®.

Gut Bacteria and Response to Therapy – Two early studies have demonstrated that Intestinal bacteria may be beneficial in priming and mobilizing immune cells to attack tumors. Further, certain chemotherapeutic agents such as CYTOXAN® (Cyclophosphamide) and ELOXATIN® (Oxaliplatin) were less effective when intestinal bacteria were eradicated with antibiotics.

ADVANCES IN PATIENT CARE

Early Initiation of Palliative Care Improves Patient Well Being – In a study of close to 500 patients with advanced cancer early palliative care improved, quality of life at the end of life, spiritual well-being, symptom severity, and satisfaction with care at 4 months after diagnosis.

Pregnancy After Breast Cancer Treatment – Premature Ovarian Failure (POF) is a common unintended consequence of chemotherapy in premenopausal women. Besides loss of fertility, which can influence treatment decisions in young women, ovarian failure can lead to menopausal symptoms, sexual dysfunction and loss of bone density. Two studies reported a promising new way of preserve fertility. In the POEMS (Prevention of Early Menopause Study) phase III trial, the addition of ZOLADEX® (Goserelin) to chemotherapy decreased the POF to 8% compared to 22% with chemotherapy alone (P=0.04). More women in the ZOLADEX® group achieved at least one pregnancy (21%) compared to 11% in the chemotherapy alone group (P=0.03). In a different study, similar findings were noted with the addition of another hormonal agent, TRELSTAR® (Triptorelin) to chemotherapy.

Masters GA, Krilov L, Bailey HH , et al. Published online before print January 20, 2015, doi: 10.1200/JCO.2014.59.9746

Cancers associated with BRCA1 and BRCA2 mutations other than Breast and Ovarian

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SUMMARY:Approximately 5-10% of all Breast and Ovarian cancers are caused by inherited genetic factors and are typically the result from inherited mutations in either the BRCA1 or BRCA2 gene. BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively. They control cell growth by repairing DNA damage and thus prevent tumor development. Mutations in these genes predispose an individual to develop malignant tumors. The presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing Breast and Ovarian cancer, as high as 85% and 40% respectively. While the association of BRCA1 and BRCA2 mutations with Breast and Ovarian cancer risks is well-established, the potential association of these mutations with other cancers has remained unclear. This study was conducted to evaluate the incidence of cancers other than Breast and Ovarian cancer, in known BRCA1 and BRCA2 mutation carriers. The study population included 1072 patients who had received genetic counseling at the UT MD Anderson Cancer Center between 1997 and 2013 and had a confirmed BRCA1 (N=613) or BRCA2 (N=459) mutation. The authors then compared the cancer incidence of the study population with the United States Cancer Statistics. The expected and observed numbers of cancer cases were calculated at 5 year intervals to take into consideration different age-related incidence rates. Standardized Incidence Ratios (SIRs) for each cancer type was then calculated for the entire sample and for BRCA1 mutation carriers and BRCA2 mutation carriers separately. {Standardized Incidence Ratio (SIR) is used to determine if the occurrence of cancer in a relatively small population is high or low. A SIR of 1 would indicate no increase or decrease, SIR of 1.5 indicates an excess of 50%, SIR of 2 indicates an excess of 100%}. Among the study population, 1177 cancers comprising 30 different cancer types were identified. There was no significant increase in cancers other than Breast and Ovarian cancer in individuals with BRCA1 mutation, but there was a trend of increasing incidence of Melanoma in BRCA1 mutation carriers, compared to general population. Individuals with BRCA2 mutation however had significantly higher incidence of Pancreatic cancer in both men and women (SIR= 21.7; P < 0.001), Prostate cancer in men (SIR= 4.9; P = 0.002) and a trend of increasing incidence of Cervical cancer, compared to general population. The authors concluded that their findings support the NCCN practice guidelines for this patient population which includes screening for male Breast cancer, Prostate cancer and Melanoma, acknowledging that specific screening guidelines for Pancreatic cancer do not exist. Mersch J, Jackson MA, Park M, et al. Cancer 2015; 121:269-275

Clinical Cancer Advances 2015 Annual Report on Progress Against Cancer From the American Society of Clinical Oncology (PART I)

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SUMMARY: Cancer mortality rates in the United States have declined 20% from their peak of 215 per 100,000 in 1991 to 172 per 100,000 in 2010. With more than half a million Americans diagnosed with cancer each year, recent advances in cancer treatment and research has lead to improved survival and better quality of life, with 14.5 million cancer survivors alive in the US today. This Annual Report on Progress Against Cancer explored the clinical advances of the prior year (2014), that made the greatest impact on improving cancer care. This report was developed based on research published in peer-reviewed scientific and medical journals and information presented at major scientific meetings over a one year period between October 2013 to September 2014. A brief summary of this report (Part I) is presented. Part I includes, ADVANCE OF THE YEAR and ADVANCES IN PREVENTION AND SCREENING. Clinical trial details for several of these studies can be accessed at www.oncoprescribe.com

ADVANCE OF THE YEAR – TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA

Chronic Lymphocytic Leukemia (CLL) is the most common form of adult leukemia and is more common in the elderly. Four new therapies associated with fewer toxicities compared with standard therapy, were recently approved for patients with CLL.

Two Effective Treatment Options for Patients with Newly Diagnosed CLL

GAZYVA® (Obinutuzumab) is a fully humanized, third generation, type II, anti-CD20 monoclonal antibody that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. In a phase III trial involving 589 treatment naïve CLL patients, GAZYVA® in combination with LEUKERAN® (Chlorambucil) more than doubled the Progression Free Survival (PFS) from 11.1 months with LEUKERAN® alone to 26.7 months (HR=0.18, P<0.001). The combination of GAZYVA® and LEUKERAN® also prolonged Overall Survival (OS) when compared to LEUKERAN® alone (HR=0.41; P=0.002). This benefit however was not noted with the RITUXAN® plus LEUKERAN® combination. Treatment with GAZYVA® plus LEUKERAN® when compared with RITUXAN® plus LEUKERAN® resulted in a longer PFS (26.7 vs15.2 months; HR=0.39; P<0.001), higher complete response rates (20.7% vs 7.0%) and deeper molecular responses.

ARZERRA® (Ofatumumab), a second generation fully human IgG 1 monoclonal antibody, which targets a different region (different epitope) of the CD20 molecule in combination with LEUKERAN®, was compared with LEUKERAN® alone, as first line treatment in a study involving 447 CLL patients. The median PFS was 22.4 months for patients receiving ARZERRA® in combination with LEUKERAN® compared with 13.1 months for those receiving single agent LEUKERAN® (HR=0.57, P< 0.001). The Objective Response Rate was higher with the combination regimen versus single agent LEUKERAN® (82% vs 69%, P=0.001).

Two New Non-Chemotherapy Alternatives for Relapsed and Treatment-Resistant CLL

IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). IMBRUVICA® was compared to single agent ARZERRA® in a phase III trial involving 391 patients with relapsed CLL. Thirty percent (30%) of the patients had deletion of chromosome 17p. 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.

In a phase III study involving 220 previously treated patients with recurrent CLL, ZYDELIG® (Idelalisib), a highly selective oral inhibitor of the enzyme PhosphoInositide 3-Kinase (PI3K) that specifically blocks the delta isoform of PI3K enzyme and its signaling pathway, was combined with RITUXAN® and compared with placebo given along with RITUXAN®. The median PFS with ZYDELIG® in combination with RITUXAN® was significantly prolonged compared with Placebo and RITUXAN® (10.7 months vs 5.5 months). An improvement in the Overall Survival (OS) was also noted in the ZYDELIG® group compared with patients in the RITUXAN® and placebo group (HR = 0.28; P = 0.018).

ADVANCES IN PREVENTION AND SCREENING

Breast Cancer Prevention

The only two drugs currently approved by the FDA to prevent breast cancer are NOLVADEX® (Tamoxifen) and EVISTA® (Raloxifene). These agents block the estrogen receptors and can be used in both pre and postmenopausal women. NOLVADEX® is however associated with thromboembolic evens as well as endometrial carcinoma. ARIMIDEX® (Anastrozole), an Aromatase Inhibitor (AI), in a randomized, double blind, placebo controlled trial, involving 3864 women at increased risk of breast cancer, reduced this risk of breast cancer by 53% compared to placebo, over a 5-year period (P<0.0001), in post-menopausal women. This benefit with ARIMIDEX® was accomplished without increase in the risk of heart attacks or fractures, compared with placebo. There was however increase in the incidence of joint and muscle pain as well as hot flushes and night sweats. Another AI, AROMASIN® (Exemestane) in a previously published study (MAP.3 trial) significantly reduced the incidence of all breast cancers by 53% and invasive breast cancers by 65%, after a median follow up of 3 years.

Screening for Lung Cancer

The United States Preventive Services Task Force (USPSTF) recommended annual screening for lung cancer with Low Dose Computed Tomography in adult individuals, between ages 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. The use of Low Dose CT (LDCT) scans for 3 years in this high risk, healthy patients, resulted in a 20% reduction in Lung cancer mortality, compared to screening with a chest X-Ray in the NCI-sponsored National Lung Screening Trial (NLST).

Masters GA, Krilov L, Bailey HH, et al. Published online before print January 20, 2015, doi: 10.1200/JCO.2014.59.9746

Goserelin for Ovarian Protection during Adjuvant Chemotherapy for Breast Cancer

RR

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, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 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. Premature Ovarian Failure (POF) is a common unintended consequence of chemotherapy in premenopausal women. Besides of loss of fertility, which can influence treatment decisions in young women, ovarian failure can lead to menopausal symptoms, sexual dysfunction and loss of bone density. POEMS (Prevention of Early Menopause Study) is a randomized phase III trial designed to evaluate whether the addition of LHRH (Luteinizing Hormone-Releasing Hormone) analog Goserelin (ZOLADEX®), which suppresses the production of estrogens, to Cyclophosphamide based chemotherapy, would reduce POF in breast cancer patients, when compared to chemotherapy alone. Premenopausal patients less than 50 years of age, with hormone receptor negative (ER/PR negative ), Stage I-IIIA breast cancer, scheduled to receive chemotherapy, were randomly assigned to receive standard Cyclophosphamide based chemotherapy with or without monthly ZOLADEX® . Patients in the ZOLADEX® group received 3.6 mg SQ starting 1 week prior to the first dose of chemotherapy. The primary endpoint was ovarian failure at two years (defined as amenorrhea for the prior 6 months AND post-menopausal FSH level). Other endpoints included pregnancy and survival rates. The median age of the patients was 38 years and median follow up was 4.1 years. Of the 218 evaluable patients, 135 premenopausal women were evaluable for the primary end point. POF rates were 22% in the chemotherapy alone group and 8% in the ZOLADEX® group (P=0.04). When the definition of POF was more liberal to include EITHER amenorrhea or elevated FSH but not both, POF rates were 45% in the chemotherapy alone group and 20% in the ZOLADEX® group (P=0.006). Among the 218 evaluable patients, more women in the ZOLADEX® group achieved at least one pregnancy (21%) compared to 11% in the chemotherapy alone group (P=0.03). Secondary outcomes also favored the ZOLADEX® group with a Disease free Survival (DFS) rate of 78% in the chemotherapy alone group compared with 89% in the ZOLADEX® group (P=0.04) and Overall Survival (OS) rate of 82% in the chemotherapy alone group compared with 92% in the ZOLADEX® group (P=0.05). The authors concluded that the addition of ZOLADEX® to chemotherapy improved fertility prospects with a lower incidence of Premature Ovarian Failure and more pregnancies. Further, the improved Disease Free Survival and Overall Survival is an important additional perk and prevention of Premature Ovarian Failure with ZOLADEX® may be a consideration not only in premenopausal patients with hormone receptor positive breast cancer but also in other malignancies such as lymphomas, when treated with similar chemotherapeutic agents. Goserelin for Ovarian Protection during Breast-Cancer Adjuvant Chemotherapy. Moore HC, Unger JM, Phillips K, et al. N Engl J Med 2015; 372:923-932

AR-V7 in Circulating Tumor Cells may become a Biomarker for Treatment Selection in Metastatic Castrate Resistant Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men excluding skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 220,800 new cases of prostate cancer will be diagnosed in 2015 and over 27,000 men will die of the disease. Prostate cancer is driven by Androgen Receptor (AR) and its signaling pathways. Initial treatment strategies for patients with metastatic prostate cancer include lowering the levels of circulating androgens with medical or surgical castration or blocking the binding of androgens to the androgen receptor. Upon progression {described as Castrate Resistant Prostate Cancer (CRPC), as these tumors are not androgen independent and continue to rely on Androgen Receptor signaling} two agents are presently available for metastatic CRPC. They include ZYTIGA® (Abiraterone) and XTANDI® (Enzalutamide). Both these agents have been shown to improve survival in metastatic CRPC. ZYTIGA® inhibits CYP 17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® competes with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor, thereby inhibiting AR signaling and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR. About 20-40% of the patients do not respond to these newer agents and even those who respond will invariably develop resistance to these drugs. This again has been attributed to persistent AR signaling by variant forms of Androgen Receptor, generated through somatic mutation or aberrant RNA splicing. Androgen Receptor Variant AR-V7 can be detected in the CTCs (Circulating Tumor Cells). AR-V7 does not have the domain to bind androgens and may be associated with resistance to XTANDI®. Further AR-V7 is constitutively active and can independently activate transcription factors and therefore is not effected by androgen depleting agents including ZYTIGA®. With this background, the authors hypothesized that detection of Androgen Receptor variant AR-V7 in circulating tumor cells from men with metastatic prostate cancer would be associated with resistance to both ZYTIGA® and XTANDI®. In a previously published prospective study, data involving 62 patients showed that detection of AR-V7 in Circulating Tumor Cells (CTCs) in men with mCRPC was indeed associated with primary resistance to both ZYTIGA® and XTANDI®. AR-V7–positive patients had inferior overall survival with both XTANDI® (HR = 6.9; P =0.002) and ZYTIGA® (HR = 12.7; P =0.006). AR-V7 was therefore shown to have a prognostic value for outcomes in mCRPC with ZYTIGA® and XTANDI®. In this present publication, the authors studied to determine if AR-V7-positive patients would retain sensitivity to Taxane chemotherapy. The researchers in this small prospective study enrolled 37 patients with metastatic CRPC who were starting Taxane chemotherapy with Cabazitaxel (JEVTANA®) or Docetaxel (TAXOTERE®). Presence or lack of AR-V7 in circulating tumor cells (CTCs), was determined by the qRT-PCR assay. Of the enrolled patients, 46% had detectable AR-V7 in CTCs. The primary endpoint was associations between AR-V7 status and PSA response rates and secondary endpoints included Progression Free Survival (PFS). They noted that the PSA responses were achieved in both AR-V7- positive and AR-V7-negative men and the difference was non-significant (41% versus 65%, P=0.19). Likewise there was no significant difference in the median PFS in AR-V7-positive and AR-V7-negative men (5.1 versus 6.9 months (HR= 2.65; P=0.11). The researchers then combined the data from their previously published study with 62 patients and they noted that, in AR-V7-positive men, PSA responses were higher in Taxane treated versus ZYTIGA®/XTANDI® treated men (41% versus 0%, P<0.001) and PFS were longer in the Taxane treated men as well (HR for PFS = 0.21, P=0.003). The outcomes however did not differ by treatment type in AR-V7-negative men and were comparable. The authors concluded that detection of AR-V7 in CTCs from men with mCRPC is not associated with primary resistance to Taxane chemotherapy, and such patients may retain sensitivity to Taxanes. In AR-V7-positive men however, Taxanes appear to be more efficacious than ZYTIGA® or XTANDI®. AR-V7 once available commercially, may become a biomarker for treatment selection, in metastatic Castrate Resistant Prostate Cancer. AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration-resistant prostate cancer (mCRPC). Antonarakis ES, Lu C, Chen Y, et al. J Clin Oncol 33, 2015 (suppl 7; abstr 138)

Follicular Lymphoma – Evidence Based Treatment Guidelines

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SUMMARY: The American Cancer Society estimates that about 71,850 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 19,800 individuals will die of this disease. Approximately 20% of all NHLs are Follicular Lymphomas (FL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Advanced stage Follicular lymphomas are not curable and as such prolonging Progression Free Survival (PFS) and Overall Survival (OS) while maintaining quality of life (QoL), has been the goals of treatment intervention. Asymptomatic patients with FL are generally considered candidates for “watch and wait” approach, whereas those with B symptoms (fever, night sweats, and weight loss), painful lymphadenopathy/splenomegaly, organ compromise and cytopenias are generally considered candidates for therapy. Follicular Lymphoma International Prognostic Index (FLIPI) is of prognostic value and is used to help with treatment choices. The Ann Arbor classification divides FL into four stages. Patients with stages I and II have localized disease and those with stages III and IV have advanced disease. The World Health Organization (WHO) further classified FL based on histology into low grade (grades 1 and 2) and high grade (grade 3a) FLs. Grade 3b FL which demonstrates diffuse areas of involvement is designated as Diffuse Large B-cell Lymphoma (DLBCL) and is treated as such.

The authors in this publication following review of literature from 2000-2014, addressed FOUR important questions

What treatment options should be considered for localized FL?

Recommendation 1: The preferred treatment for localized FL is Radiation Therapy (RT).

Recommendation 2: Given the potential for long term toxicities, lower doses of RT (24 to 30 Gy) in 1.5 to 2Gy fractions and smaller field sizes, is recommended.

Recommendation 3: Combined modality treatments may be considered for patients with localized disease if positive outcomes are proven in randomized studies.

Recommendation 4: Observation alone may be a reasonable alternative if the potential toxicity of RT outweighs the potential benefits or if the patient refuses RT.

How should asymptomatic advanced-stage FL be managed?

Recommendation 1: Initiation of Chemotherapy or Immunotherapy should be based on the identification of symptoms as defined by the GELF or BNLI criteria.

Recommendation 2: Chemoimmunotherapy or Chemotherapy alone as early treatment is not recommended in asymptomatic advanced FL, because of the lack of published randomized studies. Observation alone is therefore recommended in patients who do not meet the criteria for treatment with Chemotherapy or Immunotherapy.

Recommendation 3: If ongoing randomized studies show positive outcomes with reduced risk of relapse, early treatment with RITUXAN® (Rituximab) with or without RITUXAN® maintenance in asymptomatic patients may be considered.

What treatment options should be considered for symptomatic advanced-stage FL?

Recommendation 1: Based on the lower response rate with RITUXAN® monotherapy, Chemoimmunotherapy is preferred over RITUXAN® monotherapy , for the first-line treatment of symptomatic advanced stage FL, except when Chemotherapy is contraindicated.

Recommendation 2: RITUXAN® should be added to chemotherapy in the first line treatment of symptomatic advanced-stage FL given the improved Overall Response Rate (ORR) and Progression Free survival (PFS) demonstrated with the addition of RITUXAN® to a number of Chemotherapy combinations.

Recommendation 3: TREANDA® (Bendamustine) and RITUXAN® (BR) is the preferred Chemoimmunotherapy regimen for the first-line treatment of symptomatic advanced-stage FL given the superior efficacy and favorable tolerability of this regimen compared to R-CHOP, confirmed in 2 randomized trials.

In which patients should additional treatment be considered (ie, maintenance, consolidation, SCT)?

Recommendation 1: Maintenance RITUXAN® is recommended after first-line treatment of FL given the improved response with RITUXAN® maintenance versus observation, demonstrated in 2 randomized trials. The optimal frequency and duration of maintenance RITUXAN® is presently unclear.

Recommendation 2: High Dose Therapy (HDT) followed by Autologous Stem Cell Transplantation (ASCT) is not recommended as part of front-line treatment of FL, given the lack of a survival benefit and the potential toxicity of this approach. There also is no evidence to support the use of Radioimmunotherapy (RIT) after first-line treatment of FL.

A Canadian Evidence-Based Guideline for the First-Line Treatment of Follicular Lymphoma: Joint Consensus of the Lymphoma Canada Scientific Advisory Board.  Kuruvilla J, Assouline S, Hodgson D, et al. Clinical Lymphoma Myeloma and Leukemia 2015; 15:59-74

OPDIVO® now Approved for Advanced, Refractory Squamous Non-Small Cell Lung Cancer

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SUMMARY: The U. S. Food and Drug Administration granted approval to Nivolumab (OPDIVO®) for the treatment of patients with metastatic squamous Non-Small Cell Lung Cancer (NSCLC) with progression on or after platinum based chemotherapy. 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 estimates that over 221,200 new cases of lung cancer will be diagnosed in the United States in 2015 and a over 158,000 patients will die of the disease. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non-Small Cell Lung Cancer patients with Squamous cell histology have been a traditionally hard- to-treat patient group. The development a novel immunotherapeutic approaches, with a better understanding of the Immune checkpoints has however changed the treatment paradigm. 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 response. The first Immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® (Ipilimumab), an antibody that blocks Immune checkpoint protein/receptor CTLA- 4, has been shown to prolong overall survival in patients with previously treated, unresectable or metastatic melanoma. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. The approval of OPDIVO® was based on CheckMate-017, an open label, multicenter, multinational randomized phase III trial in which 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum-based chemotherapy regimen were randomized to receive OPDIVO® (Nivolumab) 3 mg/kg IV every 2 weeks (N=135) or TAXOTERE® (Docetaxel) 75 mg/m2 IV every 3 weeks (N=137). The primary endpoint was Overall Survival (OS) and secondary endpoints included Progression Free Survival (PFS) and Objective Response Rate (ORR). This study was stopped early at the protocol pre-specified interim analysis after an independent monitoring panel determined that the primary endpoint of improved Overall Survival (OS) with OPDIVO® had been reached. The median OS was 9.2 months for patients assigned to OPDIVO® and 6 months for those in the TAXOTERE® group (HR=0.59; P=0.00025). This suggested a 41% improvement in the OS with OPDIVO® compared to TAXOTERE®. This FDA approval was further supported by a single arm, multinational, multicenter trial in patients with metastatic squamous NSCLC (N=117) who had progressed after receiving a platinum-based therapy and at least one additional systemic regimen. OPDIVO® in this study, was administered as a single agent at 3mg/kg IV every two weeks until disease progression or treatment discontinuation. The primary endpoint was Objective Response Rate (ORR) and exploratory endpoints were Overall Survival (OS), Progression Free Survival (PFS) and efficacy, based on PD-L1 expression status. With 11 months of minimum follow up, the Objective Response Rate (ORR) was 15% independent of PD-L1 status. The estimated one-year survival rate was 41% and median Overall Survival was 8.2 months. The authors noted that an additional 26% of patients had stable disease for a median duration of 6 months, resulting in a disease control rate (ORR+stable disease) of 41%. The most frequent grade 3-4 adverse events noted in at least 5% of the patients were fatigue, dyspnea and musculoskeletal pain. OPDIVO® will now be a new treatment option, with survival advantage, for patients with advanced relapsed and refractory metastatic squamous NSCLC. Phase II study of nivolumab (Anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer. Ramalingam SS, Mazieres J, Planchard D, et al. Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; Chicago, IL. LBA#3462

OPDIVO® (Nivolumab)

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The FDA on March 4, 2015 granted approval to OPDIVO® for the treatment of patients with metastatic Squamous Non-Small Cell Lung Cancer (NSCLC) with progression on or after platinum-based chemotherapy. OPDIVO® was previously approved in December, 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following YERVOY® (Ipilimumab) and if BRAF V600 mutation positive, a BRAF inhibitor. OPDIVO® is a product of Bristol-Myers Squibb Company.

Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer American Society of Clinical Oncology Clinical Practice Guideline Update 2014

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SUMMARY: The American Society of Clinical Oncology (ASCO) recently provided an update on recommendations, for the prophylaxis and treatment of Venous ThromboEmbolism (VTE) in patients with cancer, following a systematic review of 53 publications. They are as follows-

VTE prophylaxis in hospitalized patients

Majority of the hospitalized patients with active malignancy should receive VTE prophylaxis in the absence of contraindications. However there are no definitive data for VTE prophylaxis in patients admitted for short chemotherapy infusions, minor procedures or those undergoing stem-cell or bone marrow transplantation.

VTE prophylaxis in ambulatory patients

Routine VTE prophylaxis is not recommended although prophylaxis with low molecular-weight heparin can be considered in select group of outpatients with solid tumors who are receiving chemotherapy, after discussing the risk/benefits of such intervention. Patients with Myeloma receiving THALOMID® (Thalidomide) or REVLIMID® (Lenalidomide) should receive VTE prophylaxis with either aspirin or low molecular-weight heparin.

VTE prophylaxis in patients undergoing surgery

All cancer patients undergoing major surgical procedures should be considered for VTE prophylaxis with heparin unless there is a bleeding risk. This should be commenced preoperatively and can be complemented with mechanical methods to improve efficacy. This should be continued for at least 7-10 days and for up to 4 weeks postoperatively, in those undergoing major abdominal or pelvic surgery with restricted mobility, obesity, history of VTE or additional risk factors. Decision to consider prophylaxis, for patients undergoing low risk surgery, should be made on an individual basis.

Choice of Anticoagulation for cancer patients with VTE

For cancer patients who have a creatinine clearance of more than 30 ml/min and have newly diagnosed VTE , low molecular-weight heparin is preferred over unfractionated heparin for the initial 5 to 10 days. Low molecular-weight heparin, due to its superiority, is preferred over vitamin K antagonists for long term anticoagulation (6 months). Select cancer patients with metastatic disease or those receiving chemotherapy may be considered for anticoagulation with low molecular-weight heparin or vitamin K antagonists beyond the initial 6 months. A vena cava filter is indicated only for patients with contraindications to anticoagulant therapy and may be considered for those who progress despite optimal anticoagulation with low molecular-weight heparin. Patients with CNS malignancies and VTE should be anticoagulated like any other patient with VTE, monitoring closely for bleeding. Incidental VTE’s should be treated like symptomatic VTE. Decision to treat splanchnic or visceral vein thrombi diagnosed incidentally should be considered on an individual basis. The new novel oral anticoagulants are presently not recommended for prophylaxis or treatment of VTE in patients with cancer because of limited data.

Anticoagulation and survival benefit in patients without VTE

Cancer patients without VTE should not receive anticoagulants to improve survival, as there are no data to support this recommendation.

Monitoring and patient counseling

Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should educate patients about the signs and symptoms of VTE.

Predicting VTE in cancer patients using Risk Score

The risk score model for VTE in cancer patients was developed and validated in multiple studies. The risk of VTE can be significantly reduced amongst these high risk patients by thromboprophylaxis.

Lyman GH, Bohlke K, Khorana AA, et al. J Clin Oncol 2015; 33:654-656