Tag: General Medical Oncology & Hematology

SUMMARY: The FDA on May 23, 2017, granted accelerated approval to KEYTRUDA® (Pembrolizumab) for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair Deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR ColoRectal cancer that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI colon tumors are sporadic and when sporadic, the DNA MisMatchRepair gene is MLH1. Defective MisMatchRepair can also manifest as a germline mutation occurring in 1 of the 4 MisMatchRepair genes which include MLH1, MSH2, MSH6, PMS2. This produces Lynch Syndrome (Hereditary Nonpolyposis ColoRectal Carcinoma – HNPCC), an autosomal dominant disorder and is the most common form of hereditary colon cancer, accounting for 35% of the MSI colorectal cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increased immunogenicity. These tumors are susceptible to PD-1 blockade and respond to treatment with checkpoint inhibitors such as KEYTRUDA® (N Engl J Med 372:2509-2520, 2015). Other MSH-H and dMMR tumors include, Endometrial and GastroIntestinal tumors and to a lesser extent Breast, Prostate, Bladder and Thyroid tumors.

MSI (Micro Satellite Instability) testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). MLH1 gene is often lost in association with PMS2.

KEYTRUDA® 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. This unique FDA approval was based on data from 149 patients with MSI-H or dMMR tumors (15 cancer types), enrolled across five uncontrolled, multi-cohort, multi-center, single-arm clinical trials. Ninety patients had colorectal cancer and 59 patients were diagnosed with one of 14 other cancer types. KEYTRUDA® was administered at 200 mg IV every 3 weeks or 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity, for a maximum period of 24 months. The median age was 55 years and over a third of the patients were 65 yrs or older. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response. The identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, Polymerase Chain Reaction (PCR) tests for MSI-H status or ImmunoHistoChemistry (IHC) tests for MMR deficiency.

The Objective Response Rate (ORR) with KEYTRUDA® was 39.6% with 7.4% Complete Responses and 32.2% Partial Responses. The ORR was 36% in patients diagnosed with ColoRectal Cancer and 46% in patients with any of the other cancer types. Responses lasted six months or more for 78% of those patients, who responded to KEYTRUDA®.

The most common toxicities included fatigue, rash, pruritus, nausea, diarrhea, decreased appetite, cough and dyspnea. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. The Prescribing Information for KEYTRUDA® includes a “Limitation of Use” stating that the safety and effectiveness of KEYTRUDA® in pediatric patients with MSI-H Central Nervous System cancers have not been established.

This is the first FDA approval of a cancer treatment, based on specific genetic biomarker, rather than location in the body where the tumor originated.

Pembrolizumab for patients with previously treated, mismatch repair-deficient microsatellite instability-high advanced colorectal carcinoma: phase 2 KEYNOTE-164 study. Dung L, Thierry A, Won KT, et al. Ann Oncol (2016) 27 (suppl_2): ii79.

First-line pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient or microsatellite instability–high metastatic colorectal Carcinoma. Luis D, Dung L, Takayuki Y, et al. Annals of Oncology (2016) 27 (2): 1-85. 10.1093/annonc/mdw199

SUMMARY: Cancer in general is a disease of the elderly with two thirds of all cancers and close to three fourths of cancer mortality occurring in individuals 65 years of age or older. Elderly patients are less likely to be offered chemotherapy, as these patients are at an increased risk for chemotherapy related toxicity, compared to their younger counterparts. This may be due to a variety of reasons including decreased bone marrow reserve with aging and an increased risk of chemotherapy-related myelosuppression, inability to endure treatment due to decreased physiologic reserves, as well as impaired clearance of chemotherapy drugs due to decreased renal function. Further, cognitive and hearing impairment along with a poor support system also play an important role in the elderly, not seeking medical care, in a timely manner. Unfortunately, elderly patients are often excluded from participating in clinical trials, which makes it even more difficult to weigh the risks and benefits of chemotherapy in this patient group. Patient Performance Status is often taken into consideration to predict tolerance to chemotherapy as well as outcomes, although it remains unclear if this is a valid predictor of toxicity in elderly patients. Identifying elderly patients who are at risk for developing chemotherapy related toxicity, remains an unmet need.

In this study, researchers developed a predictive model for chemotherapy toxicity, which consisted of 11 questions pertaining to age, tumor type, treatment, lab values and geriatric assessment, using data collected from a prospective longitudinal study of 500 patients, 65 years or older. Based on the answers to the 11 questions, a score for the risk of chemotherapy toxicity was calculated and three risk groups were created – Low (0-5 points), Medium (6-9 points) and High (10-19 points). In this Development cohort, the risk for chemotherapy toxicity correlated with an increasing risk score with 53% of patients experiencing grade 3 or higher chemotherapy toxicity.

The authors then validated the predictive model in an independent cohort of elderly adults (N=250) with a median age of 73 years. It was noted that more than one half of patients in the Validation cohort (58%) experienced grade 3 or more toxicity of whom 34% experienced hematologic toxicity and 55% experienced nonhematologic toxicity. The risk of toxicity increased with increasing risk score (36.7% for low risk cohort, 62.4% for medium risk cohort and 70.2% for high risk cohort; P<0.001). These findings were not statistically different from the Development cohort. Interestingly, there was no association between Karnofsky Performance Status and chemotherapy toxicity (P=0.25).

In elderly patients receiving chemotherapy, this tool is best used to distinguish low and high risk patients but is unable to distinguish moderate and high risk patients. Further, this model was only able to predict grade 3 or more toxicity but not grade 2 toxicity, and this may be equally relevant in elderly patients. Because patients included in this study had solid tumors and did not receive biologics or high-dose chemotherapy, these results apply primarily to patients with solid tumors who receive chemotherapy.

The authors concluded that this prediction model is easy to use in clinical practice and allows Oncology Health Care Providers to help elderly patients make informed decisions and also anticipate potential toxicities in high risk elderly patients and take preventive measures accordingly. Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults with Cancer. Hurria A, Mohile S, Gajra A, et al. J Clin Oncol 2016;34:2366-2371

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. ZOMETA®, a third generation amino-bisphosphonate, has however largely replaced AREDIA® because of its superior efficacy, reducing pain and the incidence of Skeletal Related Events, by 25% to 40%. Both AREDIA® and ZOMETA® are administered IV every 3 to 4 weeks, following diagnoses of bone metastases. However, the optimal treatment schedule has remained unclear. Further, renal toxicity, long bone fractures and OsteoNecrosis of the Jaw (ONJ) have been identified as potential toxicities and the incidence of these toxicities increase with cumulative drug exposure.

The purpose of this study was to determine whether ZOMETA® administered every 12 weeks was non-inferior to ZOMETA® administered every 4 weeks. In this open-label, non-inferiority trial, 1822 patients were enrolled (Breast,N=855, Prostate,N=689 and Myeloma,N=278), and were randomly assigned in a 1:1 ratio to receive ZOMETA® every 4 weeks or every 12 weeks, for 2 years. The median age was 65 yrs and patients had at least one site of bone involvement. The Primary endpoint was incidence of at least one Skeletal Related Event within 2 years (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) after randomization. Secondary endpoints included skeletal morbidity rates (mean number of Skeletal Related Events per year), 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.

In the 795 patients who completed the study at 2 years, 29.5% of patients receiving ZOMETA® every 4 weeks and 28.6% of patients receiving ZOMETA® every 12 weeks experienced at least 1 Skeletal Related Event and this was not significantly different. With regards to Secondary endpoints, there were still no significant differences between the two treatment groups with regards to Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction.

The authors concluded that ZOMETA® administered every 3 months for 2 years is non-inferior to ZOMETA®administered every 4 weeks for 2 years, among 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 also be more convenient for the patients and cost effective. XGEVA®, a RANK ligand (RANKL) inhibitor is also approved in the US for the treatment of bone metastases from solid tumors. A study is underway comparing XGEVA® administered every 4 weeks to every 12 weeks, in patients with metastatic breast and prostate cancer. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases. A Randomized Clinical Trial. Himelstein AL, Foster JC, Khatcheressian JL, et al. JAMA. 2017;317:48-58

SUMMARY: VISTOGARD® (Uridine Triacetate) is presently approved in the US for the emergency treatment of adult and pediatric patients, who had severe or life-threatening toxicities within 4 days of treatment, following an overdose of 5-FluoroUracil (5-FU) or XELODA® (Capecitabine). Toxicities related to 5-FU or XELODA® can be caused by impaired drug clearance, Dihydropyrimidine Dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5-FU. Additionally, 5-FU overdoses resulting in death can occur because of infusion pump errors, dosage miscalculations and accidental or suicidal ingestion of XELODA®. These toxicities can manifest as severe mucositis, cytopenias, central neurotoxicity and acute cardiomyopathy.

VISTOGARD® is a pyrimidine analog and following oral administration is deacetylated by nonspecific esterases, yielding Uridine in the circulation. Uridine is a direct antagonist of 5-FU and competitively inhibits 5-FU from incorporating in normal tissues, thus reducing cell damage and cell death. The authors reported the efficacy of VISTOGARD® in two open-label clinical trials in which patients who presented with a 5-FU/XELODA® overdose (N=142) or patients with early onset of severe toxicities (N=26), were treated. These patients received VISTOGARD® granules 10 grams every 6 hours for 20 doses, starting within 96 hours after the termination of 5-FU/XELODA® therapy. The median age was 58 years. Because there were no antidotes available for 5-FU toxicity at the time of this study, and the use of a placebo was unethical, the outcomes of this study were compared to a historical cohort of patients gathered from all available literature (control group), who overdosed on 5-FU and received only best supportive care. The primary endpoint of these studies was survival at 30 days or until chemotherapy could resume, if prior to 30 days.

Of the 142 overdose patients treated with VISTOGARD®,137 patients (96%) survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity and additionally, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical control cohort, 21 of 25 patients (84%) died. Among the 141 VISTOGARD® treated overdose patients with a diagnosis of cancer, 53 resumed chemotherapy in less than 30 days (median time after 5-FU of 19.6 days), indicating a rapid recovery from toxicity. The most common toxicities in patients receiving VISTOGARD® included, nausea, vomiting and diarrhea.

The authors concluded that VISTOGARD® is a safe and effective antidote for 5-FU overexposure, and can facilitate rapid recovery and resumption of chemotherapy. Patients should take VISTOGARD® as soon as possible after overdose, regardless of symptoms or within 4 days of severe or life threatening toxicity. It should be noted that VISTOGARD® is not recommended for treatment of non-emergency adverse events associated with 5-FU and XELODA®, as this therapy may significantly decrease the efficacy of these chemotherapy agents. Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity. Ma WW, Saif WM, El-Rayes BF, et al. Cancer 2017;123:345-356.

SUMMARY: The FDA on August 10, 2016 approved SUSTOL® (Granisetron) extended- release injection, for use in combination with other antiemetics in adults, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of Moderately Emetogenic Chemotherapy (MEC) or Anthracycline and Cyclophosphamide (AC) combination chemotherapy regimen. Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most common adverse effects of chemotherapy and is experienced by about 80% of patients receiving chemotherapy. Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment, whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on Serotonin (5-hydroxytryptamine-5HT3) and its receptors, with the chemotherapeutic agents stimulating the release of Serotonin from the enterochromaffin cells of the small intestine. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are also located centrally in the Chemoreceptor Trigger Zone of the area Postrema. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems.

Granisetron is a first-generation serotonin-3 (5-HT3) receptor antagonist commonly used to treat CINV, but has a short half-life of approximately 8 hours. SUSTOL® is a novel formulation of 2 % Granisetron and a bioerodible tri(ethylene glycol) polymer, designed to provide slow, controlled hydrolysis, resulting in slow and sustained release of Granisetron, thereby preventing both acute and delayed CINV associated with MEC and Highly Emetogenic Chemotherapy (HEC). With a plasma half-life of 24-34 hours, this novel preparation formulation can maintain therapeutic levels of Granisetron for 5 or more days.

The FDA approval of SUSTOL® was based on the efficacy data from a multicenter double-blind trial which included 733 patients who received MEC or AC combination chemotherapy. Patients were randomized to receive either SUSTOL® 10 mg Subcutaneous injection (N=371) or ALOXI® 0.25 mg IV (N=362). This study was structured to compared SUSTOL® with ALOXI® (Palonosetron), which is also a serotonin-3 (5-HT3) receptor antagonist because, ALOXI® is not approved by the FDA to prevent delayed-onset CINV in patients who receive HEC. The trial was designed to allow for the evaluation of non-inferiority of SUSTOL® to ALOXI® in the acute and delayed phases. Antiemetics were administered 30 minutes before chemotherapy on Day 1. Dexamethasone was also administered IV at 8 or 20 mg on Day 1, depending on the chemotherapy regimen administered and those who received Dexamethasone 20 mg IV, were also given an 8 mg oral dose of the drug twice daily on Days 2, 3, and 4. The mean age was 57 years and 79% the patients were female. Approximately 55% of the patients received MEC regimen and 45% of the patients received AC combination chemotherapy. The most frequently used MEC regimen was Carboplatin and Paclitaxel combination (31%). The primary endpoint of the study was Complete Response (CR), which was defined as no emetic episodes or rescue medication during the acute phase (0-24 hours) and the delayed phase (more than 24 to 120 hours) after chemotherapy administration in cycle 1.

The results demonstrated that SUSTOL® was noninferior to ALOXI® . It was noted that among patients receiving MEC (N=406) the CR rate in the acute phase was 83% in the SUSTOL® group compared with 89% in the ALOXI® group. The CR rates in the delayed phase were 69% and 70% respectively. For those patients who received AC chemotherapy (N=327), the CR rate in the acute phase for the SUSTOL® group was 70% compared with 64% in the ALOXI® group. The CR rates in the delayed phase were 50% and 47% respectively. The safety of the FDA recommended dose of SUSTOL® (10 mg Subcutaneous dose), was evaluated in 924 patients across two double-blind, randomized active-controlled studies and it was noted that SUSTOL® was associated with a higher incidence of injection site reactions and constipation.

The authors concluded that SUSTOL® by virtue of its Biochronomer polymer-based drug delivery technology, represents a novel and convenient alternative to intravenous ALOXI® for the prevention of acute and delayed Chemotherapy Induced Nausea and Vomiting. Randomized phase III trial of APF530 versus palonosetron in the prevention of chemotherapy-induced nausea and vomiting in a subset of patients with breast cancer receiving moderately or highly emetogenic chemotherapy. Boccia R, O’Boyle E, Cooper W. BMC Cancer. 2016;16:166. doi:10.1186/s12885-016-2186-4.

SUMMARY: Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most common adverse effects of chemotherapy and is experienced by about 80% of patients receiving chemotherapy. The development of effective antiemetic agents has facilitated the administration of majority of the chemotherapy agents in an outpatient setting avoiding hospitalization. Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment, whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on Serotonin (5-hydroxytryptamine-5HT3) and its receptors, with the chemotherapeutic agents stimulating the release of Serotonin from the enterochromaffin cells of the small intestine. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are also located centrally in the Chemoreceptor Trigger Zone of the area Postrema. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems.

ZYPREXA® (Olanzapine) is an antipsychotic agent that has been shown to block multiple neurotransmitters including Dopamine at D1, D2, D3, and D4 receptors, Serotonin at 5-HT2, 5-HT3 receptors, as well as Catecholamines at alpha1-adrenergic receptors, Acetylcholine at muscarinic receptors and Histamine at H1 receptors in the central nervous system. By virtue of its mechanism of action, ZYPREXA® might have significant antiemetic properties. Based on its pharmacological properties, this study evaluated the efficacy of ZYPREXA® for the prevention of nausea and vomiting, in patients receiving highly emetogenic chemotherapy.

The authors conducted a randomized, double-blind, phase III trial in which patients receiving ZYPREXA® (N=192) were compared to patients receiving Placebo (N=188). Patients received either ZYPREXA® 10 mg PO or matching Placebo daily, on days 1-4 of chemotherapy cycles. All patients additionally received Dexamethasone, Aprepitant or Fosaprepitant, and a 5-HT3 receptor antagonist. Eligible patients had no previous chemotherapy and were receiving Cisplatin at or more than 70 mg/m2 or Cyclophosphamide and Doxorubicin combination. The primary endpoint was nausea prevention and a Complete Response defined as no emesis and no use of rescue medication, was the secondary endpoint.

It was noted that the proportion of patients with no chemotherapy induced nausea was significantly greater with ZYPREXA® than with placebo in the first 24 hours after chemotherapy (74% versus. 45%, P=0.002), the time interval from 25 to 120 hours after chemotherapy (42% versus 25%, P=0.002) and across the overall 120-hour period (37% versus 22%, P=0.002). The Complete Response Rate was also significantly increased with ZYPREXA® during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Sedation, which is a side effect of ZYPREXA®, was observed on day 2 of treatment, with severe sedation noted in 5% of the patients.

The authors concluded that ZYPREXA® significantly improved nausea prevention, as well as Complete Response rate when compared to placebo, among previously untreated patients receiving highly emetogenic chemotherapy. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. Navari RM, Qin R, Ruddy KJ, et al. N Engl J Med 2016; 375:134-142

SUMMARY: The American Cancer Society estimates that in 2016, 1,685,210 new cancer cases will be diagnosed in the United States and 595,690 cancer deaths are projected. It is a well established fact that physical activity reduces the risk of heart disease and all-cause mortality. Additionally, previously published studies have shown reduced risks for Colon, Breast and Endometrial cancers with physical activity. However, it has remained unclear whether physical activity reduces risk of other cancers, which together constitute approximately 75% of all cancers in the United States.

It has been hypothesized that the link between physical activity and cancer is mediated through both hormonal as well as non-hormonal pathways. Hormonal systems such as sex steroids, insulin and insulin-like growth factors, and adipokines can initiate cancer cell growth. Intervention with physical activity by partly reducing adiposity, decreases the levels of estrone, estradiol and insulin in postmenopausal women. Non-hormonal mechanisms linking physical activity to cancer risk, include inflammation, immune function, oxidative stress, and for colon cancer, a reduction in transit time for waste to pass through the gastrointestinal tract.

The authors in this study examined pooled data from 12 prospective cohort studies involving 1.44 million participants, to find out whether there was an association of leisure-time physical activity with incidence of 26 different cancer types. They also examined whether these associations were evident regardless of body size or smoking history. Leisure-time physical activities were defined as activities done at an individual’s discretion, to improve or maintain fitness or health. This could include walking, running, swimming or other moderate- to vigorous-intensity activities. The median physical activity in this study was equivalent to 150 minutes of moderate-intensity activity every week and comparable to the current recommended minimum physical activity level for the US population. Leisure-time physical activity was assessed by self-reported surveys. The median age was 59 years and median BMI was 26.

Participants were followed for a median of 11 years during which period 187,000 new cases of cancer occurred. The authors noted that leisure-time physical activity was associated with lower risk of 13 of 26 cancer types which included Esophageal adenocarcinoma, Liver, Lung, Kidney, Gastric cardia, Endometrial, Myeloid Leukemia, Myeloma, Colon, Head and Neck, Rectal, Bladder and Breast. The greatest risk reduction was noted for Esophageal adenocarcinoma. These associations were evident regardless of body size or smoking history in most cases.

The authors concluded that leisure-time physical activity not only reduces risk of heart disease and risk of death from all causes, but also lowers risk of many types of cancer, regardless of body size or smoking history. Physical activity should therefore be promoted for population-wide cancer prevention and control. Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. Moore SC, Lee I, Weiderpass E, et al. JAMA Intern Med. 2016;176:816-825.