Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.
Adjuvant trastuzumab in early HER2-positive breast cancer (February 2017)
In the Herceptin Adjuvant (HERA) trial, over 5000 women with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer who had completed adjuvant chemotherapy were randomly assigned to observation or to the addition of trastuzumab for one or two years [1-4]. In the final report of this study, at a median of 11 years of follow-up, one year of trastuzumab improved disease-free and overall survival relative to observation . There were no further improvements with extension to two years of trastuzumab, but the incidence of cardiotoxicity was higher. These results support our approach of administering adjuvant trastuzumab for one year to those with HER2-positive early breast cancer. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Treatment duration'.)
Duration of adjuvant endocrine therapy for breast cancer (July 2016, Modified February 2017)
For postmenopausal women receiving adjuvant treatment with an aromatase inhibitor (AI) for hormone-positive breast cancer, the minimum duration of treatment is five years. While data from the MA17R trial demonstrated that extending the duration from 5 to 10 years improved recurrence-free survival , preliminary results from the NSABP-B42, DATA, and IDEAL trials, reported at the San Antonio Breast Cancer Symposium, have not confirmed this benefit [6-8]. No study has demonstrated a benefit in overall survival with extended adjuvant AI therapy, and bone-related toxic effects are more frequent among those receiving extended treatment. While variations in methodology likely account for the differences in recurrence-free survival between the studies, the magnitude of any potential benefit is likely to be greatest for those at highest risk for recurrence. While we previously had recommended an extended course of AI adjuvant therapy for most postmenopausal women with nonmetastatic hormone-positive disease, based on the new data, we now suggest offering extended adjuvant aromatase inhibitor therapy to those with high-risk disease (eg, node-positive or ≥T3 disease). (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)
Fulvestrant in hormone receptor-positive, HER2-negative breast cancer (November 2016)
Results from the phase III FALCON trial, which included 462 women with metastatic estrogen receptor (ER)-positive breast cancer who had not received prior hormone therapy, demonstrated improved progression-free survival with fulvestrant over anastrazole (16.6 versus 13.8 months) . Quality of life outcomes were similar between the two groups. These data support our approach of using fulvestrant as an alternative to an aromatase inhibitor in the first-line setting for patients with metastatic hormone receptor-positive breast cancer. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy", section on 'Fulvestrant with or without an AI'.)
CDK 4/6 inhibitors plus letrozole in hormone receptor-positive, HER2-negative breast cancer (November 2016)
The addition of cyclin-dependent kinase (CDK) 4/6 inhibitors to aromatase inhibition improves outcomes in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer.
●In a phase III study of 700 postmenopausal women with recurrent or metastatic, hormone receptor-positive, HER2-negative breast cancer receiving first-line letrozole, the addition of the CDK 4/6 inhibitor ribociclib improved progression-free survival . Ribociclib was associated with higher rates of grade 3 or 4 adverse events (eg, neutropenia, leukopenia, and elevated transaminases), though over 90 percent of patients were able to complete therapy.
●In a phase III study of over 600 postmenopausal women with metastatic, hormone receptor-positive, HER2-negative breast cancer, the combination of palbociclib and letrozole demonstrated improved progression-free survival and objective response rate compared with letrozole alone . Rates of neutropenia, fatigue, and diarrhea were higher with the combination.
Given improved disease outcomes but higher rates of toxicities, we offer the combination of CDK 4/6 inhibitors plus letrozole to patients with higher burdens of disease who are able to accept the increased risks of this treatment. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy", section on 'Aromatase inhibitors plus CDK 4/6 inhibitors'.)
Obesity as a risk factor for cardiotoxicity from anthracycline and trastuzumab-based regimens (November 2016)
Among patients receiving anthracyclines or sequential treatment with anthracyclines and trastuzumab for breast cancer, being obese or overweight increases the risk of developing cardiotoxicity . Obesity or being overweight are factors favoring a nonanthracycline-based regimen, but should be balanced with other disease and patient risk factors in the selection of an appropriate adjuvant treatment regimen. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Risk factors' and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Choice of chemotherapy'.)
CANCER SCREENING AND PREVENTION
Risk of colon cancer in patients with diverticulitis (April 2017)
The utility of routine colonoscopy after acute diverticulitis is debated. An analysis of data from a Danish registry showed that patients hospitalized for diverticulitis were twice as likely to develop colon cancer over the 18-year study period as those without diverticulitis, and over 50 percent of colon cancers were diagnosed within one year of diagnosis of diverticulitis . This study underscores the importance of endoscopic surveillance in patients with diverticular disease and supports our recommendation for performing a colonoscopy after the complete resolution of an episode of acute diverticulitis in patients who have not had a colonoscopy within a year. (See "Acute colonic diverticulitis: Medical management", section on 'Colonoscopy for all patients'.)
Vitamin D and prevention of cancer (April 2017)
In a trial comparing the effect of vitamin D and calcium supplementation with placebo on the incidence of cancer in over 2000 postmenopausal women, there was no difference between groups in the incidence of cancer at four years . An analysis by cancer site showed no difference in the incidence of breast cancer between the two groups; there were too few cancers at other sites to analyze. Although several study limitations may have contributed to the absence of an effect, including enrollment of patients with a relatively high baseline vitamin D level and permission to take vitamin D supplements (up to 800 international units daily) outside of the intervention, vitamin D supplementation for the prevention of cancer is not warranted. (See "Vitamin D and extraskeletal health", section on 'Cancer'.)
Flexible sigmoidoscopy and colorectal cancer screening in older women (January 2017)
Flexible sigmoidoscopy is one of several screening modalities recommended by the US Preventive Services Task Force for colorectal cancer (CRC) screening. However, sigmoidoscopy is less effective at detecting lesions in the right side of the colon (beyond the 60 cm reach of the sigmoidoscope) than the left side, and right-sided lesions are more common in older women. A study that pooled results from three randomized trials (nearly 300,000 individuals) comparing screening by sigmoidoscopy with no screening found that the incidence of CRC at 10 to 12 years was decreased in men but, in women, only in those younger than 60 years . Current screening recommendations do not indicate gender-based preferences for screening options, but these findings call into question the effectiveness of flexible sigmoidoscopy as a screening modality for women over age 60 years. (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Evidence of effectiveness' and "Screening for colorectal cancer: Strategies in patients at average risk", section on 'Comparison of tests'.)
Fecal immunochemical testing for colorectal cancer screening (January 2017)
Multiple test strategies are available for screening in people with average risk for colorectal cancer (CRC). Annual stool testing for occult blood using a guaiac reagent (gFOBT) has been widely implemented and is one of the screening strategies endorsed by the US Preventive Services Task Force. Fecal immunochemical testing (FIT) is another option and has the potential advantages of better test performance (improved sensitivity for CRC and advanced adenomas) and better patient adherence (one stool sample, no diet restrictions) compared with gFOBT. The US Multi-Society Task Force has published consensus guidelines recommending FIT over gFOBT when occult blood stool testing is elected for CRC screening . (See "Tests for screening for colorectal cancer: Stool tests, radiologic imaging and endoscopy", section on 'Immunochemical tests for fecal blood' and "Screening for colorectal cancer: Strategies in patients at average risk", section on 'Comparison of tests'.)
Effectiveness of screening colonoscopy in older adults (January 2017)
The effectiveness of screening for colorectal cancer (CRC) in older adults is uncertain. Randomized trials of screening colonoscopy have not been completed, and trials currently underway do not include adults 75 years and older. A study of Medicare beneficiaries found that undergoing colonoscopy believed to be for screening modestly decreased the risk of CRC (2.2 versus 2.6 percent in the no-screening group) over an eight-year period for those aged 70 to 74 years, with a smaller, but statistically non-significant, decrease in risk (2.8 versus 3.0 percent in the no-screening group) for those 75 to 79 years . Adverse events following colonoscopy occurred in less than 1 percent. The decision whether to recommend screening for a patient at any age, but especially those over 75 years of age, should depend upon the patient's health status, anticipated life expectancy, risk for colorectal cancer (CRC), and personal values. (See "Screening for colorectal cancer: Strategies in patients at average risk", section on 'Screening in older adults'.)
Laparoscopic versus open surgery for rectal cancer (May 2017)
Transabdominal rectal cancer surgery can be performed via open, laparoscopic, or robotic approaches. In a systematic review and meta-analysis of 14 randomized trials, laparoscopic surgery resulted in a higher rate of noncomplete total mesorectal excision than open surgery (13 versus 10 percent) . Other technical outcomes were not different. Long-term data are needed to determine whether the higher rate of noncomplete total mesorectal excision will result in worse survival. In the absence of these data, the best surgical approach needs to be determined individually by tumor and patient characteristics, as well as surgeon experience. (See "Rectal cancer: Surgical principles", section on 'Laparoscopic versus open approach'.)
Regorafenib for second-line treatment of advanced hepatocellular cancer (April 2017)
In a randomized trial, regorafenib was shown to provide benefit as a second-line agent for patients with advanced hepatocellular cancer (HCC) and Child-Pugh A liver function who progressed after receiving sorafenib . Compared with placebo, regorafenib significantly improved median overall survival, and the main toxicities were hypertension, hand-foot skin reaction, fatigue, and diarrhea. Largely based upon these data, in April 2017, the US Food and Drug Administration expanded the indications for regorafenib to include patients with HCC previously treated with sorafenib. While optimal patient selection has not been established, a trial of regorafenib is reasonable for patients progressing after first-line sorafenib who maintain a good performance status and adequate liver function, and who are willing to trade treatment-related morbidity for the possibility of a small gain in survival. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Regorafenib'.)
Guideline on use of molecular markers in colorectal cancer (April 2017)
The prognostic value of a wide variety of potentially clinically applicable molecular markers has been extensively studied in colorectal cancer (CRC). An updated multisociety United States guideline recommends testing for DNA mismatch repair protein (MMR) status to identify patients at high risk for Lynch syndrome, expanded or extended RAS testing for patients being considered for therapy targeting the epidermal growth factor receptor (EGFR), and BRAF V600 mutational analysis for deficient MMR tumors with loss of MLH1 expression to evaluate for Lynch syndrome risk . They also concluded that there was insufficient evidence to use BRAF mutational status as a predictive molecular biomarker for response to anti-EGFR therapies. However, this is a controversial area. UpToDate recommends not using EGFR inhibitors in patients with a tumoral BRAF V600E mutation. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Molecular factors'.)
ASCO guideline update for adjuvant chemotherapy in pancreatic cancer (April 2017)
A focused clinical practice guideline update for potentially curable pancreatic cancer has been issued by the American Society of Clinical Oncology (ASCO) . For most patients, six months of adjuvant chemotherapy using a doublet regimen of capecitabine plus gemcitabine is preferred over gemcitabine alone, in the absence of concerns for toxicity or tolerance. Treatment should be initiated within eight weeks of resection, assuming complete surgical recovery. This guideline update supports our prior recommendation for doublet therapy. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Choice of therapy'.)
Open versus laparoscopic resection for stage II or III colon cancer (March 2017)
In a trial involving over 1000 patients with stage II or III colon cancer, colon resection performed with complete mesocolic excision and central vascular ligation resulted in equally excellent five-year survivals (over 90 percent) whether surgery was performed open or laparoscopically . Thus, surgeons treating colon cancer have a choice of techniques, but must follow strict oncologic principles, including complete mesocolic excision, to ensure optimal outcomes. (See "Surgical resection of primary colon cancer", section on 'Regional lymphadenectomy'.)
Telotristat for refractory carcinoid syndrome diarrhea (March 2017)
Telotristat inhibits the production of serotonin by carcinoid tumors and reduces the frequency of carcinoid syndrome diarrhea. The randomized TELESTAR trial compared two doses of oral telotristat (250 mg and 500 mg, each taken three times daily) against placebo in 135 patients who had uncontrolled symptoms from carcinoid syndrome despite treatment with a somatostatin analog . Treatment with telotristat at either dose was associated with a reduction in bowel movement frequency compared with placebo, and the drug was well tolerated. Based upon these results, telotristat has been approved in the United States, in combination with somatostatin analog therapy, for the treatment of adults with diarrhea related to carcinoid syndrome that is inadequately controlled by somatostatin analog therapy alone . The recommended dose is 250 mg three times daily . (See "Treatment of the carcinoid syndrome", section on 'Telotristat'.)
Assessing response to chemoradiotherapy in anal cancer (February 2017)
An analysis of data from the ACT II trial supports the view that anal squamous cell cancers (SCCs) continue to regress for up to 26 weeks after the completion of chemoradiotherapy and that the decision to pursue surgery for persisting disease is best deferred until then . The complete clinical response (cCR) rate increased over time, and 72 percent of those not in a cCR at 11 weeks achieved it at 26 weeks. Furthermore, the greatest separation in long-term outcomes between responders and nonresponders occurred when the assessment was delayed until 26 weeks. Based upon these results, we agree with updated guidelines from the National Comprehensive Cancer Network recommending that patients can be watched for up to six months following completion of chemoradiotherapy as long as there is no progressive disease during this period of follow-up. (See "Clinical features, staging, and treatment of anal cancer", section on 'Assessing the response to primary chemoradiotherapy'.)
HER2-targeted therapy in advanced gastroesophageal adenocarcinoma (November 2016)
An expert panel convened by the College of American Pathologists (CAP), American Society of Clinical Pathology (ASCP) and American Society of Clinical Oncology (ASCO) has provided an evidence-based joint guideline on HER2 testing and clinical decision-making in advanced gastroesophageal adenocarcinomas :
●All patients who have documented advanced gastroesophageal adenocarcinoma and who are considered good candidates for trastuzumab should have their tumor tissue tested for HER2 overexpression and/or amplification prior to trastuzumab treatment.
●Because of intratumoral heterogeneity, a minimum of five biopsy specimens, and optimally six to eight, should be obtained to avoid false negative results. Laboratories/pathologists should perform immunohistochemical staining (IHC) first, with in situ hybridization (ISH) reserved for an IHC result of 2+ (equivocal).
●Patients with HER2-positive tumors (IHC 3+ or ISH+) should be offered trastuzumab-containing combination chemotherapy as initial treatment. There is no evidence to support continuation of trastuzumab or other HER2-directed therapy beyond progression in patients initially treated with trastuzumab. (See "Systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Assessment of HER2 status and selection of candidates for trastuzumab'.)
Adjuvant versus early salvage radiation therapy in prostate cancer (May 2017)
The optimal management of men with pathologic T3 disease and an undetectable prostate-specific antigen (PSA) following radical prostatectomy is uncertain. There are no completed randomized trials comparing adjuvant radiation therapy (RT) with salvage RT when a biochemical relapse is first detected. A retrospective study found that observation with early salvage RT for a rising serum PSA was as effective as adjuvant RT in terms of metastasis-free and overall survival at eight years follow-up . For men with pathologic T3 disease and negative or minimally positive surgical margins following radical prostatectomy and with an undetectable serum PSA, either adjuvant RT or early salvage RT (if there is a rise in serum PSA) are reasonable options. (See "Prostate cancer: Pathologic stage T3 disease or positive surgical margins following radical prostatectomy", section on 'Adjuvant RT versus early salvage RT'.)
Checkpoint inhibition immunotherapy for advanced urothelial carcinoma (April 2017, Modified May 2017)
The role of checkpoint inhibition immunotherapy for patients with advanced urothelial carcinoma is expanding. Pembrolizumab, an agent targeting the programmed cell death-1 (PD-1) protein, has been shown to prolong survival in patients who relapse and is approved in the US for this indication. Based upon expanded phase I or phase II studies, four other anti-PD-1 or anti-PD-L1 checkpoint inhibitors (atezolizumab, nivolumab, durvalumab, avelumab) have also been approved by the US Food and Drug Administration (FDA) for patients who progressed during or within 12 months after cisplatin-based chemotherapy.
In a multicenter, single-arm phase II study, atezolizumab was used as first-line therapy in patients who were not eligible for treatment with a cisplatin-based regimen . In this study, the objective response rate was 23 percent, and the majority of those patients continued to respond at the time of analysis. Based upon these results, the FDA approved atezolizumab as initial therapy for patients who are not candidates for a cisplatin-based chemotherapy regimen. We suggest using atezolizumab, nivolumab, durvalumab, or avelumab for patients who have relapsed after initial treatment with a cisplatin regimen, and using atezolizumab as initial therapy for patients who are unable to undergo treatment with cisplatin. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'Immunotherapy'.)
Quality of life in men with localized prostate cancer (March 2017)
Radical prostatectomy, external beam radiation therapy, brachytherapy, and active surveillance all are important options for the treatment of low-risk, clinically localized prostate cancer. Two large prospective studies using validated instruments provide important additional insights into the impact on quality of life for each of these treatment modalities [30,31]. The choice of therapeutic approach depends upon an informed patient decision incorporating knowledge about the potential advantages and disadvantages associated with each approach along with personal preferences (table 1 and table 2 and table 3). (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'Quality of life'.)
Hypofractionated radiation therapy for prostate cancer (March 2017)
Historically, conventional schedules for external beam radiation therapy (RT) for localized prostate cancer have used daily doses given for seven to eight weeks. In the randomized PROFIT trial, a hypofractionated RT schedule (a larger dose per fraction given over four weeks) was noninferior in terms of both efficacy and toxicity to a conventional schedule, confirming results from three other phase III trials . For patients in whom costs and convenience are important considerations, hypofractionated RT is an appropriate alternative to a conventional schedule. (See "External beam radiation therapy for localized prostate cancer", section on 'Hypofractionation'.)
Adjuvant chemotherapy for urothelial carcinoma of the upper urinary tract (January 2017)
Patients with locally advanced urothelial carcinoma of the upper urinary tract and those with positive lymph nodes following nephroureterectomy are at high risk for recurrence and death. A retrospective analysis of data from the National Cancer Database found that those receiving adjuvant chemotherapy had a significantly prolonged overall survival . In the absence of randomized trials, we suggest adjuvant chemotherapy for these patients if they are fit for chemotherapy. (See "Malignancies of the renal pelvis and ureter", section on 'Adjuvant chemotherapy'.)
Chemotherapy for mediastinal nonseminomatous germ cell tumors (January 2017)
Cisplatin-based chemotherapy is the primary treatment for patients with mediastinal nonseminomatous germ cell tumors (NSGCTs). However, many patients require subsequent surgical resection of a residual thoracic mass. In a retrospective analysis, the combination of bleomycin, etoposide, and cisplatin (BEP) was associated with significantly more severe pulmonary toxicity and treatment-related deaths than the combination of etoposide, ifosfamide, and cisplatin (VIP) . In the absence of randomized trials, we recommend VIP rather than BEP for the initial chemotherapy of mediastinal NSGCTs. (See "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum", section on 'Systemic chemotherapy'.)
Survival with laparoscopic staging for early endometrial carcinoma (May 2017)
The second largest randomized trial of total laparoscopic hysterectomy versus total abdominal hysterectomy for treatment of apparent stage I endometrial carcinoma reported similar disease-free survival at 4.5 years and overall survival for the two techniques . Based on these and previous data, laparoscopic hysterectomy appears to be a reasonable approach for initial management of women with apparent stage I endometrial cancer and may be preferable to open surgery because of lower perioperative morbidity. (See "Endometrial carcinoma: Pretreatment evaluation, staging, and surgical treatment", section on 'Laparoscopy'.)
Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer (March 2017)
In a phase III trial, enrolling approximately 550 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have responded to platinum-based chemotherapy, niraparib maintenance improved progression-free survival relative to placebo, although over a third experienced severe hematologic toxicity . Based on these results, the US Food and Drug Administration (FDA) has approved niraparib for the maintenance treatment of such patients . However, overall survival data are still immature and niraparib has not been compared with bevacizumab, which is better studied in the maintenance setting. Pending further data, we reserve use of niraparib maintenance for patients with relapsed ovarian cancer who are not candidates for bevacizumab and who are in a complete or partial response to platinum-based chemotherapy. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-sensitive disease".)
Hysterectomy-corrected cervical cancer mortality rates and racial variation (February 2017)
Cervical cancer incidence and mortality rates are known to vary across racial groups in the United States but can be underestimated if data are not adjusted for prior hysterectomy. In a population-based study that corrected for the prevalence of hysterectomy, cervical cancer mortality in black women was more than twice that of white women from 2000 to 2012 (10.1 versus 4.7 per 100,000) . These data add to the body of evidence showing a racial disparity in cervical cancer mortality and support the need for research to identify and overcome the factors that account for this disparity. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Incidence and mortality'.)
Rucaparib in BRCA mutation-associated advanced ovarian cancer (January 2017)
Poly-ADP ribose polymerase (PARP) inhibitors have activity against BRCA mutation-associated epithelial ovarian cancer. The PARP inhibitor rucaparib is now approved by the US Food and Drug Administration for BRCA mutation-associated advanced ovarian cancer that has been treated with two or more lines of chemotherapy, based on response rates of over 50 percent in such cancers [39,40]. We now offer rucaparib as an option in this setting. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease", section on 'Patients with a BRCA mutation'.)
Risk of preterm delivery following loop electrosurgical excision procedure (LEEP) (November 2016)
Studies have consistently found an increased risk for preterm delivery in pregnancies conceived after cold knife conization, but data are mixed regarding the risk with laser conization and loop electrosurgical excision procedure (LEEP). In the largest study of pregnancy outcomes after treatment for cervical intraepithelial neoplasia (CIN), a Norwegian registry study of almost 10,000 births confirmed that prior treatment for CIN was associated with an increased risk of preterm birth compared with no prior treatment . The strongest associations were for cold knife and laser conization, but a small increase in risk was also observed for LEEP. Women with CIN 2,3 who plan future childbearing should be counseled about the risks and benefits of both treatment and observation. (See "Cervical intraepithelial neoplasia: Reproductive effects of treatment", section on 'Risks of individual treatment methods'.)
MELANOMA AND OTHER SKIN CANCER
Avelumab immunotherapy for metastatic Merkel cell carcinoma (March 2017)
Chemotherapy historically has been the standard approach to treating advanced Merkel cell carcinoma (MCC). Avelumab, a monoclonal antibody that blocks the PD-1 ligand (PD-L1), was approved by the US Food and Drug Administration based on a phase II study demonstrating a 32 percent response rate (23 percent partial and 9 percent complete), relatively durable remissions (six-month progression-free survival 40 percent), and a favorable side effect profile [42,43]. Based upon these results, avelumab is our preferred treatment for patients with metastatic MCC. (See "Staging and treatment of Merkel cell carcinoma", section on 'Avelumab'.)
Targeted therapy for advanced melanoma with an NRAS mutation (March 2017)
Binimetinib, an inhibitor of MEK, is able to block the MAPK pathway in patients with advanced melanoma and an NRAS driver mutation. In a phase III trial in this patient population, binimetinib significantly prolonged progression-free survival compared with chemotherapy in patients who had progressed during or after immunotherapy . Binimetinib is not currently approved for use outside of a clinical trial setting. (See "Molecularly targeted therapy for metastatic melanoma", section on 'NRAS-mutated tumors'.)
Retreatment with BRAF and MEK inhibition in advanced melanoma (March 2017)
Targeted therapy with a combination of BRAF and MEK inhibition is an important treatment option for tumors that contain a driver mutation in BRAF. However, most patients eventually develop progressive disease. Results from a prospective phase II study provide evidence that retreatment with the combination of a BRAF and MEK inhibitor may be of value in patients who have acquired resistance to both mitogen-activated protein kinase (MAPK)-targeted therapy and immune checkpoint inhibitors . (See "Molecularly targeted therapy for metastatic melanoma", section on 'Retreatment'.)
PALLIATIVE AND SUPPORTIVE CARE
US REMS requirements eliminated for use of epoetin and darbepoetin (April 2017)
The US Food and Drug Administration (FDA) instituted a Risk Evaluation and Mitigation Strategy (REMS) program in 2010 for the use of erythropoiesis stimulating agents (ESAs) in patients receiving myelosuppressive chemotherapy for cancer, which required hospitals and physicians to enroll, complete training, and provide written documentation of the discussion of risk with patients prior to instituting ESAs. In 2017, the FDA determined that full implementation of the REMS had had minimal impact on ESA utilization beyond the changes observed after the Medicare restriction of coverage for ESAs and multiple other FDA regulatory actions. The FDA concluded that the REMS was no longer necessary and the REMS requirements were eliminated for these ESA products in patients receiving myelosuppressive chemotherapy for cancer . (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'APPRISE: the FDA Risk Evaluation and Mitigation Strategy program'.)
Concurrent benzodiazepines in opioid-using patients and overdose risk (April 2017)
Benzodiazepines can potentiate the respiratory depressant effects of opioid medication, and concurrent use may be a factor in the rising rate of opioid overdose. In an analysis of a large sample of patients prescribed an opioid, the proportion who concurrently received a benzodiazepine nearly doubled over 12 years . Concurrent use of both medications was associated with an increased risk of opioid overdose compared with patients receiving only the opioid. Avoiding this medication combination may prevent some overdoses. (See "Prevention of lethal opioid overdose in the community", section on 'Risk factors'.)
Naldemedine for opioid-induced constipation (March 2017)
The benefit of naldemedine, an oral peripherally acting opioid receptor antagonist, for opioid-induced constipation (OIC) was shown in two identically designed 12-week phase III randomized trials conducted in patients with noncancer chronic pain and OIC . In a preliminary report, naldemedine, compared with placebo, decreased constipation and was well tolerated with no signs or symptoms of opioid withdrawal or decrease in opioid analgesic efficacy. Naldemedine has been approved in the United States for OIC in adult patients with chronic noncancer pain . However, efficacy has also been shown for treatment of OIC in cancer patients , and naldemedine can be used off label in this population. The European Medicines Agency has approved naldemedine for treatment of OIC without restriction to noncancer pain . (See "Cancer pain management with opioids: Prevention and management of side effects", section on 'Other oral agents'.)
Scalp hypothermia to prevent chemotherapy-induced alopecia (March 2017)
Two prospective studies have evaluated the efficacy of two different automated scalp cooling devices in women with early stage breast cancer [52,53]:
●In an interim analysis of a randomized trial comparing the Paxman Scalp Cooling device and no scalp hypothermia for women with breast cancer receiving adjuvant chemotherapy (one-third anthracycline-based, the remainder taxane-based), one-half of the hypothermia group had limited hair loss (to less than 50 percent, not requiring a wig) compared with none in the control group . Adverse events were all grade 1 and 2, including primarily headache and feeling cold. The success rate was higher with taxane-containing regimens.
●In a multicenter prospective cohort study, 101 patients receiving non-anthracycline taxane-based chemotherapy and who used the DigniCap Scalp Cooling device were compared with 16 concurrently treated controls who did not use the device . Two-thirds of the intervention group, compared with none of the control group, had limited hair loss (to less than 50 percent) one month after the end of chemotherapy. At a median follow-up of 2.5 years, no patient developed scalp metastases.
These results confirm prior studies on the efficacy and safety of scalp hypothermia to reduce chemotherapy-induced alopecia. One of these devices (DigniCap) is FDA-cleared for this use in the United States. (See "Chemotherapy-induced alopecia", section on 'Efficacy and safety'.)
Early initiation of palliative care and survival (February 2017)
When initiated early in the disease course, palliative care improves clinical and quality of care outcomes; randomized trials in patients with cancer or advanced lung disease also report a survival advantage, although more diverse palliative care populations have not been studied. A meta-analysis of seven randomized trials involving 2184 patients concluded that there was no association between early initiation of palliative care and overall survival . Previous reports of a possible survival advantage may have reflected bias in patient selection; only one of the seven trials was rated as having a low risk of bias. (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)
Palliative care during hematopoietic cell transplantation (February 2017)
For patients with serious life-threatening illness, comprehensive palliative care can be successfully integrated with disease-modifying treatment. The benefits of delivering palliative care alongside potentially curative treatment were shown in a randomized trial of inpatient palliative care consultation versus usual transplant care in 160 adults with hematologic malignancies undergoing autologous or allogeneic hematopoietic cell transplantation . At two weeks posttransplant, the increase in depression, anxiety, and overall symptom burden was less in the intervention group, and the decrease in quality of life (QOL) was also smaller. Depression and QOL benefits persisted at three months. (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)
Antipsychotics for delirium in terminally ill patients (January 2017)
The benefit of antipsychotics for management of delirium in terminally ill patients has been called into question by a randomized trial in which 247 inpatients of a hospice or palliative care service with mild to moderately severe delirium were assigned to oral risperidone, haloperidol, or placebo every 12 hours for 72 hours . All patients received individualized supportive care. Patients who received antipsychotics had more severe delirium, worse delirium-associated distress scores, more use of midazolam, more extrapyramidal effects, and worse short-term survival. In our view, this study does not justify abandoning the use of antipsychotics for severely agitated delirious patients but points to the importance of reversing precipitating causes, providing best supportive care for symptomatic distress associated with delirium, and the need for additional research on the use of antipsychotics. (See "Overview of managing common non-pain symptoms in palliative care", section on 'Treatment'.)
Dosing interval for zoledronic acid in patients with bone metastases (January 2017)
For patients with bone metastases from a solid tumor, the approved dose and schedule of administration for zoledronic acid to reduce the frequency of skeletal-related events (SREs) is 4 mg every three to four weeks. Less frequent dosing is supported by data from CALGB (Alliance) trial 70604, which randomly assigned 1822 patients with bone metastases from breast or prostate cancer or multiple myeloma to the same dose of zoledronic acid every 4 or every 12 weeks for two years, starting with the first dose. There was no difference in the proportion of patients who developed at least one SRE (29.5 versus 28.6 percent) . There are now sufficient data in breast and castration-resistant prostate cancer to support dosing of zoledronic acid every 12 rather than every 4 weeks, and we suggest this approach for most patients. We still prefer every-four-week dosing, at least initially, for patients who have extensive or highly symptomatic bone metastases. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Dosing interval'.)
Alectinib in crizotinib-naive ALK-positive NSCLC (May 2017)
For patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) without central nervous system (CNS) involvement, crizotinib is typically administered as frontline therapy. In a phase III trial of over 200 crizotinib-naive patients with advanced ALK-positive NSCLC for up to two years, alectinib, a second generation ALK inhibitor, improved progression-free survival (PFS) compared with crizotinib (PFS not reached versus 10.2 months), with fewer toxicities . However, overall survival results are immature. While we prefer alectinib as initial therapy for those with ALK-positive NSCLC and CNS involvement, we continue to suggest frontline crizotinib for others with advanced ALK-positive NSCLC, pending further data. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Alectinib'.)
Pembrolizumab approved with chemotherapy in treatment-naïve nonsquamous NSCLC (May 2017)
The anti-programmed death-1 (PD-1) antibody pembrolizumab has been approved by the US Food and Drug Administration (FDA) in combination with carboplatin and pemetrexed for treatment-naïve patients with advanced, nonsquamous non-small cell lung cancer (NSCLC). In a randomized phase II trial of 123 such patients, the addition of pembrolizumab to carboplatin and pemetrexed improved objective response rate (55 versus 29 percent, respectively) and progression-free survival (13 versus 6 months, respectively) relative to chemotherapy alone . Although we continue to prefer pembrolizumab monotherapy for those with ≥50 percent tumor cell staining for PD-L1, and targeted agents for those with EGFR or ALK genetic alterations, we now offer the combination of carboplatin, pemetrexed, and pembrolizumab as one frontline treatment option for other patients with nonsquamous NSCLC. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Pembrolizumab'.)
Ceritinib in ALK-positive non-small cell lung cancer (January 2017)
For patients with anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC), inhibition of ALK is the preferred frontline approach. A randomized trial compared ceritinib, an ALK inhibitor, with pemetrexed and a platinum agent in such patients and found improved progression-free survival (17 versus 8 months) and, for those with brain metastasis, a higher intracranial objective response rate (73 versus 27 percent) . Although we use ceritinib only for patients with ALK-positive NSCLC who are intolerant of or who have progressed on the ALK inhibitor crizotinib, these data support further study of ceritinib in the frontline setting. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Ceritinib'.)
Screening interval for lung cancer (January 2017)
The optimal strategy for screening high-risk individuals for lung cancer is the subject of active study. In new results from the NELSON trial, in which almost 16,000 current or former smokers were randomly assigned to low-dose computed tomography (LDCT)-based screening versus observation only, extending the screening interval from 1 to 2.5 years reduced the proportion of cancers detected at an early stage . These data support our approach to screen annually with LDCT when screening patients who are at high risk for lung cancer. (See "Screening for lung cancer", section on 'Other trials'.)
Atezolizumab in advanced non-small cell lung cancer (December 2016)
Novel immunotherapies are playing an increasing role in the treatment of non-small cell lung cancer (NSCLC), particularly in patients who have progressed on chemotherapy. In a phase III trial enrolling approximately 1200 patients who had progressed on platinum-based chemotherapy, those randomly assigned to the PD-L1 antibody atezolizumab compared with docetaxel experienced an improvement in median overall survival (13.8 versus 9.6 months) with fewer side effects, regardless of PD-L1 expression or histology . These data support our approach of offering patients who have progressed on prior chemotherapy (and targeted therapy, for those with EGFR or ALK genetic alterations) salvage treatment with immunotherapy. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Following platinum-based chemotherapy'.)
Osimertinib versus chemotherapy in T790M, EGFR-positive NSCLC (December 2016)
In a randomized trial of over 400 patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) who had progressed on frontline EGFR inhibitors and demonstrated a T790M resistance mutation, osimertinib improved progression-free survival (10.1 versus 4.4 months) and objective response rate (71 versus 31 percent) relative to a platinum-based chemotherapy combination . Osimertinib also resulted in fewer ≥ grade 3 toxicities (23 versus 47 percent). These data support our approach of using osimertinib in patients with EGFR-mutant NSCLC with T790M-mediated resistance to EGFR inhibitors. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Management of acquired resistance'.)
Types of cancers associated with obesity (April 2017)
Excess weight is associated with an increased risk of developing and dying from cancer, but the number and types of cancers are inconsistent across studies. In a review of 204 meta-analyses that investigated the association between indices of adiposity and developing 36 primary cancers and their subtypes, associations were identified for esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract, pancreas, breast (in women who had never taken hormones), endometrium, ovary, and kidney . (See "Obesity in adults: Health consequences", section on 'Cancer'.)
Decline in secondary malignancies among childhood cancer survivors (March 2017)
In addition to recurrences of primary malignancies, cancer survivors are at a higher risk for secondary malignancies as a result of their cancer treatments. In a study of over 23,000 survivors of childhood cancer, 6.9 percent of survivors experienced neoplasms, most commonly breast or thyroid cancer, over a mean follow-up of 20.5 years . The frequency of subsequent malignancies decreased by decade of diagnosis (2.1, 1.7 and 1.3 percent for the 1970s, 1980s and 1990s, respectively). This decline may be related to a decrease in the proportion of individuals receiving radiation and the median radiation dose administered over time. (See "Overview of cancer survivorship care for primary care and oncology providers".)
2017 revision of the AJCC/UICC TNM classification (December 2016)
The tumor (T), node (N), metastasis (M) staging classification from the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) was extensively revised in the 8th edition of the AJCC Cancer Staging Manual in November 2016 . Implementation of the new staging tables in the United States has been delayed until January 2018 to allow for the updating of protocols, guidelines, and software . However, AJCC recommends that clinicians use the latest scientific information provided in the 8th edition for patient care, and UpToDate is including the 2017 TNM classification tables for all sites in addition to those of the 7th edition (2010), which remain in effect until January 2018. Outside of the United States, the UICC has implemented the 8th edition changes as of January 1, 2017. (See "Tumor node metastasis (TNM) staging system and other prognostic factors in cutaneous melanoma" and "Tumor, Node, Metastasis (TNM) staging classification for breast cancer" and "Tumor, node, metastasis (TNM) staging system for non-small cell lung cancer" and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)
Type 1 diabetes mellitus and anti-PD-1 immunotherapy (December 2016)
Checkpoint inhibitor immunotherapy with an anti-programmed cell death 1 (PD-1) receptor antibody, often in conjunction with ipilimumab, has resulted in the acute onset of type 1 diabetes mellitus in rare cases. This may be manifested by severe hyperglycemia or diabetic ketoacidosis . These patients have remained insulin-dependent for diabetic control following management of their acute episode. Blood glucose is typically monitored weekly during the first 12 weeks of therapy with the combination of nivolumab plus ipilimumab. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Type 1 diabetes mellitus'.)
- Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659.
- Cameron D, Piccart-Gebhart MJ, Gelber RD. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017.
- Gianni L, Dafni U, Gelber RD, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236.
- Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013; 382:1021.
- Goss PE, Ingle JN, Pritchard KI, et al. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med 2016; 375:209.
- jan-Heijnen VC, Van Hellemond IE, Peer PG, et al. First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer. San Antonio Breast Cancer Symposium 2016; S1-03.
- Mamounas EP, Bandos H, Lembersky BC, Geyer CE. A randomized, double-blinded, placebo-controlled clinical trial to evaluate extended adjuvant endocrine therapy (5 years of letrozole) in postmenopausal women with hormone-receptor positive breast cancer who have completed previous adjuvant endocrine therapy: Initial results of NRG oncology/NSABP B-42. San Antonio Breast Cancer Symposium 2016; S1-05.
- Blok EJ, van de Velde CJH, Meershoek-Klein Kranenbarg EM, et al. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006-05). San Antonio Breast Cancer Symposium 2016; S1-04.
- Robertson JF, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet 2016; 388:2997.
- Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 2016; 375:1738.
- Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016; 375:1925.
- Guenancia C, Lefebvre A, Cardinale D, et al. Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis. J Clin Oncol 2016; 34:3157.
- Mortensen LQ, Burcharth J, Andresen K, et al. An 18-Year Nationwide Cohort Study on The Association Between Diverticulitis and Colon Cancer. Ann Surg 2017; 265:954.
- Lappe J, Watson P, Travers-Gustafson D, et al. Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial. JAMA 2017; 317:1234.
- Holme Ø, Schoen RE, Senore C, et al. Effectiveness of flexible sigmoidoscopy screening in men and women and different age groups: pooled analysis of randomised trials. BMJ 2017; 356:i6673.
- Robertson DJ, Lee JK, Boland CR, et al. Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastrointest Endosc 2017; 85:2.
- García-Albéniz X, Hsu J, Bretthauer M, Hernán MA. Effectiveness of Screening Colonoscopy to Prevent Colorectal Cancer Among Medicare Beneficiaries Aged 70 to 79 Years: A Prospective Observational Study. Ann Intern Med 2017; 166:18.
- Martínez-Pérez A, Carra MC, Brunetti F, de'Angelis N. Pathologic Outcomes of Laparoscopic vs Open Mesorectal Excision for Rectal Cancer: A Systematic Review and Meta-analysis. JAMA Surg 2017; 152:e165665.
- Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 389:56.
- Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017; 35:1453.
- Khorana AA, Mangu PB, Berlin J, et al. Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017; :JCO2017724948.
- Kitano S, Inomata M, Mizusawa J, et al. Survival outcomes following laparoscopic versus open D3 dissection for stage II or III colon cancer (JCOG0404): a phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol 2017; 2:261.
- Kulke MH, Hörsch D, Caplin ME, et al. Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome. J Clin Oncol 2017; 35:14.
- https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm544035.htm (Accessed on March 03, 2017).
- http://www.xermelo.com/Media/Default/pdfs/Product_Info_telotristat_etiprate.pdf (Accessed on March 03, 2017).
- Glynne-Jones R, Sebag-Montefiore D, Meadows HM, et al.. Best time to assess complete clinical response. Lancet Oncol 2017.
- Bartley AN, Washington MK, Ventura CB, et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2016; 140:1345.
- Fossati N, Karnes RJ, Boorjian SA, et al. Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series. Eur Urol 2017; 71:886.
- Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389:67.
- Barocas DA, Alvarez J, Resnick MJ, et al. Association between radiation therapy, surgery, or observation for localized prostate cancer and patient-reported outcomes after 3 years. JAMA 2017; 317:1127.
- Chen RC, Basak R, Meyer AM, et al. Association Between Choice of Radical Prostatectomy, External Beam Radiotherapy, Brachytherapy, or Active Surveillance and Patient-Reported Quality of Life Among Men With Localized Prostate Cancer. JAMA 2017; 317:1141.
- Catton CN, Lukka H, Gu CS, et al. Randomized Trial of a Hypofractionated Radiation Regimen for the Treatment of Localized Prostate Cancer. J Clin Oncol 2017; :JCO2016717397.
- Seisen T, Krasnow RE, Bellmunt J, et al. Effectiveness of Adjuvant Chemotherapy After Radical Nephroureterectomy for Locally Advanced and/or Positive Regional Lymph Node Upper Tract Urothelial Carcinoma. J Clin Oncol 2017; 35:852.
- Ranganath P, Kesler KA, Einhorn LH. Perioperative Morbidity and Mortality Associated With Bleomycin in Primary Mediastinal Nonseminomatous Germ Cell Tumor. J Clin Oncol 2016; 34:4445.
- Janda M, Gebski V, Davies LC, et al. Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free Survival Among Women With Stage I Endometrial Cancer: A Randomized Clinical Trial. JAMA 2017; 317:1224.
- Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016; 375:2154.
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf (Accessed on March 29, 2017).
- Beavis AL, Gravitt PE, Rositch AF. Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer 2017; 123:1044.
- http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm533891.htm (Accessed on January 05, 2017).
- Kristeleit RS, Shapira-Frommer R, Oaknin A, et al. Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high-grade ovarian carcinoma (HGOC) and a BRCA mutation (BRCAmut): Analysis of pooled data from Study 10 (parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2). ESMO 2016; 856O.
- Bjørge T, Skare GB, Bjørge L, et al. Adverse Pregnancy Outcomes After Treatment for Cervical Intraepithelial Neoplasia. Obstet Gynecol 2016; 128:1265.
- Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016; 17:1374.
- http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf (Accessed on March 25, 2017).
- Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017; 18:435.
- Schreuer M, Jansen Y, Planken S, et al. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAF(V600)-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol 2017; 18:464.
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103951s5375lbl.pdf (Accessed on April 18, 2017).
- Sun EC, Dixit A, Humphreys K, et al. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ 2017; 356:j760.
- Hale ME, Wild J, Reddy J, et al. Efficacy and Safety of Naldemedine for the treatment of opioid-induced constipation in subjects with chronic non-cancer pain receiving opioid therapy: results from two Phase 3 clinical trials (abstract 598). Data presented at the 2016 Digestive Disease Week, San Diego, CA, May 21, 2016. Abstract available online at http://www.gastrojournal.org/article/S0016-5085(16)30515-7/pdf (Accessed on March 30, 2017).
- https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/208854Orig1s000ltr.pdf (Accessed on March 30, 2017).
- Katakami N, Oda K, Tauchi K, et al. Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients With Cancer. J Clin Oncol 2017; :JCO2016708453.
- http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-001893-PIP01-15/pip_001533.jsp&mid=WC0b01ac058001d129 (Accessed on March 30, 2017).
- Nangia J, Wang T, Osborne C, et al. Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial. JAMA 2017; 317:596.
- Rugo HS, Klein P, Melin SA, et al. Association Between Use of a Scalp Cooling Device and Alopecia After Chemotherapy for Breast Cancer. JAMA 2017; 317:606.
- Kavalieratos D, Corbelli J, Zhang D, et al. Association Between Palliative Care and Patient and Caregiver Outcomes: A Systematic Review and Meta-analysis. JAMA 2016; 316:2104.
- El-Jawahri A, LeBlanc T, VanDusen H, et al. Effect of Inpatient Palliative Care on Quality of Life 2 Weeks After Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial. JAMA 2016; 316:2094.
- Agar MR, Lawlor PG, Quinn S, et al. Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial. JAMA Intern Med 2017; 177:34.
- Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 2017; 317:48.
- Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017.
- Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016; 17:1497.
- De Castro Jr G, Tan DS, Crino L, et al. First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4). WCLC 2016; PL03.07.
- Yousaf-Khan U, van der Aalst C, de Jong PA, et al. Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval. Thorax 2017; 72:48.
- Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017; 389:255.
- Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 2017; 376:629.
- Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ 2017; 356:j477.
- Turcotte LM, Liu Q, Yasui Y, et al. Temporal Trends in Treatment and Subsequent Neoplasm Risk Among 5-Year Survivors of Childhood Cancer, 1970-2015. JAMA 2017; 317:814.
- AJCC Cancer Staging Manual, 8th, Amin MB. (Ed), American Joint Committee on Cancer, Chicago 2017.
- https://cancerstaging.org/About/news/Pages/Implementation-of-AJCC-8th-Edition-Cancer-Staging-System.aspx (Accessed on December 15, 2016).
- Okamoto M, Okamoto M, Gotoh K, et al. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig 2016; 7:915.