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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.
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 either an aromatase inhibitor or an aromatase inhibitor plus CDK 4/6 inhibitor in the first-line setting for patients with metastatic hormone receptor-positive breast cancer. (See "Treatment approach to metastatic hormone receptor-positive breast cancer: Endocrine therapy", section on 'Fulvestrant'.)
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 breast cancer: Endocrine therapy", section on 'CDK 4/6 inhibitors plus letrozole'.)
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'.)
Surgical margin in breast conserving surgery for ductal carcinoma in situ (October 2016)
For women undergoing breast conserving therapy for ductal carcinoma in situ (DCIS), surgical resection margins have a significant impact on local recurrence, but the optimal margin has been controversial. A meta-analysis found a 2 mm margin was associated with a twofold reduction in local recurrence rates compared with a positive margin, and equivalent recurrence rates compared with wider margins . A multidisciplinary consensus guideline advises that 2 mm be the standard for an adequate margin in DCIS treated with breast conserving surgery followed by whole breast irradiation . Clinical judgment is advised when determining whether patients with a negative but <2 mm margin require re-excision. (See "Breast conserving therapy", section on 'Margins for DCIS'.)
Mammography associated with breast cancer overdiagnosis (October 2016)
A study examining data for women age 40 years and older from the Surveillance, Epidemiology, and End Results (SEER) database calculated size-specific breast cancer case fatality rates prior to and after the widespread adoption of mammography screening . The authors estimated that approximately 80 percent of cancers identified by screening would not have caused clinical symptoms. Moreover, the authors calculated that at least two-thirds of the reduction in mortality associated with large tumors may be attributed to improved cancer treatments rather than screening. While acknowledging that cancer overdiagnosis does occur, and that randomized trials demonstrating benefit of mammography were largely conducted prior to modern therapy and imaging, we continue to suggest breast cancer screening for women ages 50 to 74 years, with individualized decision making for those between the ages of 40 and 50 years, given that the overall burden of evidence suggests benefit to screening. (See "Screening for breast cancer: Evidence for effectiveness and harms", section on 'Overdiagnosis'.)
IVF and risk of breast cancer (July 2016)
The body of evidence suggests that breast cancer risk is not increased after in vitro fertilization (IVF), but is limited by lack of long-term follow-up data. In a recent Dutch cohort study of over 19,000 women treated with IVF between 1983 and 1995 and followed for a median of 21 years, the risk of breast cancer was similar to that in subfertile women not treated with IVF and in the general population, adjusted for parity and age at first birth . These data are reassuring, but difficult to generalize to women undergoing contemporary IVF treatment since IVF drug regimens have changed over time and improved success rates have reduced the number of cycles women are exposed to these regimens. Additionally, only 14 percent of the cohort was age >60 years, so the risk of postmenopausal breast cancer was not well defined. (See "In vitro fertilization", section on 'Breast cancer risk'.)
Duration of adjuvant endocrine therapy for breast cancer (July 2016)
For postmenopausal women receiving adjuvant treatment with an aromatase inhibitor (AI) for hormone-positive breast cancer, the standard duration of treatment has been five years. However, data from the MA17R trial demonstrated that a longer course of treatment improves disease-free survival (DFS) . Among approximately 1900 postmenopausal women who had completed four and a half to six years of therapy with an AI, treatment for an additional five years improved five-year DFS relative to those who received placebo (95 versus 91 percent). There was no difference between the groups in regards to overall survival. Bone-related toxic effects were more frequent among those receiving extended treatment. Based on these results, we now offer an additional five years of treatment to those who have completed five years of AI therapy. However, it is reasonable for women with low risk of recurrence who are concerned about the risks and toxicities of extended treatment to omit extended treatment after a risk-benefit discussion. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)
CANCER SCREENING AND PREVENTION
USPSTF recommendations for skin cancer screening (August 2016)
In July 2016, the United States Preventive Services Task Force (USPSTF) updated its statement on skin cancer screening and concluded that there is insufficient evidence to assess the balance of benefits and harms of screening for skin cancer in asymptomatic adults with a clinical visual skin examination . Although we agree with the USPSTF conclusion, we suggest that persons at higher risk for fatal melanoma (eg, white men 50 years of age and over), individuals with multiple moles or at least a few clinically atypical moles, and individuals with the “red hair phenotype” have a total body skin examination performed by a clinician who has had appropriate training in the identification of melanoma. (See "Screening and early detection of melanoma", section on 'Recommendations of expert groups'.)
USPSTF recommendations for colorectal cancer screening (July 2016)
The United States Preventive Services Task Force (USPSTF) issued new guidelines for colorectal cancer screening in average risk adults . The guidelines make a strong recommendation for screening, starting at age 50 years and continuing to age 75 for most patients, but in a departure from prior recommendations do not give preference for any one of seven screening test strategies over another. Options for screening are shown in a table (table 1). We agree with this screening test strategy based on shared decision making. Incorporating patient personal preferences may increase the likelihood that ongoing screening will occur. (See "Screening for colorectal cancer: Strategies in patients at average risk", section on 'USPSTF guidelines'.)
First-line chemotherapy for advanced esophagogastric cancer (October 2016)
There is no globally accepted first-line chemotherapy regimen for advanced, HER2-negative esophagogastric cancer. A network meta-analysis of 17 different chemotherapy regimens concluded that, based upon efficacy and toxicity, a fluoropyrimidine doublet regimen with oxaliplatin, irinotecan, or a taxane was preferred over a fluoropyrimidine/cisplatin doublet or anthracycline or docetaxel-containing triple therapy . For most patients without a clinical trial option, we suggest a platinum/fluoropyrimidine doublet over triplet therapy. We generally prefer oxaliplatin plus a fluoropyrimidine but still consider a cisplatin/fluoropyrimidine doublet to be a reasonable alternative, given the lack of a phase III trial showing inferior results for a cisplatin versus oxaliplatin-containing regimen. (See "Systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Is there an optimal combination regimen?'.)
Proton pump inhibitors may diminish capecitabine efficacy (October 2016)
Two recent studies suggest that proton pump inhibitors diminish the effectiveness of capecitabine in the treatment of colorectal and gastroesophageal cancer [13,14]. It is hypothesized that higher gastric pH levels may inhibit dissolution and absorption of capecitabine. Patients who are receiving a capecitabine-containing regimen for adjuvant treatment of colon cancer or other malignancies should, when possible, avoid taking concurrent proton pump inhibitors. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Capecitabine'.)
Primary colorectal tumor location and response to cetuximab (September 2016)
Biologic agents with significant antitumor activity in metastatic colorectal cancer (mCRC) include bevacizumab and cetuximab, which is only active for RAS wild-type (RAS-WT) tumors. A major unanswered question has been the relative benefit of adding bevacizumab versus cetuximab to first-line cytotoxic chemotherapy for RAS-WT mCRC. A preliminary report from CALGB 80405, a prospective randomized trial of first-line chemotherapy plus either bevacizumab or cetuximab, suggests the importance of primary tumor location . Among patients with RAS-WT tumors, median survival was significantly better with cetuximab as compared with bevacizumab for those with left-sided primary tumors (36 versus 31 months), but not for right-sided primary tumors (17 versus 24 months). These data support a preference for bevacizumab rather than cetuximab as the biologic agent for initial treatment of mCRC with a right-sided primary tumor, even if RAS-WT. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy'.)
Regorafenib for advanced hepatocellular cancer (July 2016)
Regorafenib is an orally active inhibitor of a variety of kinases implicated in angiogenic and tumor growth-promoting pathways. A benefit for second-line regorafenib was suggested in the phase III RESORCE trial, in which 573 patients with advanced hepatocellular cancer (HCC) and radiologic progression after first-line sorafenib were randomly assigned to regorafenib or placebo . In a preliminary report presented at the 18th World Congress on Gastrointestinal Cancer, regorafenib was associated with a significant prolongation in median overall survival (10.6 versus 7.8 months) and significantly higher rates of objective antitumor response and disease control. Grade 3 or 4 adverse events occurring more often with regorafenib were hypertension, hand-foot skin reaction, fatigue, and diarrhea; 68 percent of patients required regorafenib dose modification for adverse events. While these data are preliminary, and optimal patient selection has not been established, a trial of regorafenib is a reasonable option 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 overall survival. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Regorafenib'.)
Imatinib for advanced GIST with a D842V mutation (June 2016)
The tyrosine kinase inhibitor (TKI) imatinib is an effective first-line treatment for most patients with advanced gastrointestinal stromal tumor (GIST), but clinical response correlates with tumor genotype. Prior studies have suggested that some mutations (particularly the D842V mutation in the platelet-derived growth factor receptor alpha [PDGFRA]) confer absolute refractoriness to imatinib . In contrast, a preliminary report of a retrospective series presented at the 2016 annual American Society of Clinical Oncology (ASCO) meeting noted two partial responses among 16 patients with the D842V mutation who were treated with first-line imatinib, with a median time to tumor progression of eight months . While the response rate appears low, imatinib is less toxic for the majority of patients than are other TKIs, and can be tried prior to other agents. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'PDGFRA D842V mutation'.)
ASCO guidelines for treatment of pancreatic cancer (June 2016)
The American Society of Clinical Oncology (ASCO) has issued Clinical Practice Guidelines for metastatic, locally advanced unresectable, and potentially resectable pancreatic cancer [19-21]. The guidelines all emphasize the importance of assessing symptom burden, psychological status, and social supports as early as possible; aggressive supportive care for symptoms such as pain; early referral to palliative care, if appropriate; the integration of patient preferences, goals of care, performance status, and comorbidity into treatment selection; the importance of multidisciplinary collaboration to formulate treatment and care plans; and the need to provide information on clinical trials to all patients. (See "Chemotherapy for advanced exocrine pancreatic cancer" and "Initial chemotherapy and radiation for nonmetastatic locally advanced unresectable and borderline resectable exocrine pancreatic cancer" and "Treatment for potentially resectable exocrine pancreatic cancer".)
Choice of adjuvant chemotherapy for resected pancreatic cancer (June 2016)
Adjuvant chemotherapy is recommended for all patients with resected pancreatic cancer. The standard approach has been gemcitabine monotherapy or, where available, S-1 alone. The benefit of a two-drug regimen was tested in the ESPAC-4 trial, which randomly assigned 730 patients with resected pancreatic adenocarcinoma to six months of gemcitabine with or without capecitabine . In a preliminary report presented at the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), combination therapy was associated with significantly longer median overall survival (28 versus 25.5 months), and twice as many patients remaining alive at five years (19 versus 9). Severe diarrhea, hand-foot syndrome, and neutropenia were all significantly more common with combined therapy.
For most patients we suggest six months of combination chemotherapy with gemcitabine plus capecitabine rather than gemcitabine monotherapy after resection of pancreatic cancer. However, therapy with gemcitabine or S-1 alone remains a reasonable option, particularly for patients with a borderline performance status or a comorbidity profile that precludes intensive therapy. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Gemcitabine plus capecitabine'.)
68-Ga DOTATATE approved for imaging of neuroendocrine tumors (June 2016)
Most well-differentiated neuroendocrine tumors arising in the gastrointestinal tract, pancreas, bronchus, and other sites express somatostatin receptors, and they can be imaged using radiolabeled somatostatin analogs. Uptake of radiolabeled somatostatin analogs is predictive of a clinical response to somatostatin analogs such as octreotide, and a positive scan can also identify an otherwise occult primary site in patients presenting with metastatic disease. Newer positron-emitting somatostatin analogs such as Gallium 68-Ga DOTATATE (68-Ga DOTATATE) have emerged which, when combined with high-resolution positron emission tomography (PET) scanning, are more sensitive than conventional 111-In pentetreotide imaging (OctreoScan) for detection of small lesions . A kit for preparation of 68-Ga DOTATATE injection as a radioactive diagnostic agent for PET imaging (Netspot) was approved by the US Food and Drug Administration in June 2016 . Due to its greater sensitivity, 68-Ga DOTATATE PET may be preferred over conventional 111-In pentetreotide scanning in certain clinical settings (eg, small volume disease), where available. (See "Neuroendocrine neoplasms of unknown primary site", section on 'Initial workup' and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)
Adjuvant therapy following resection of renal cell carcinoma (October 2016)
In a previous randomized trial, adjuvant therapy with antiangiogenic therapy failed to demonstrate any improvement in either progression-free or overall survival in patients with resected localized renal cell carcinoma. In the S-TRAC trial, sunitinib significantly increased progression-free survival compared with placebo; however, there was no difference in overall survival . Currently, there is no defined role for systemic adjuvant therapy following complete surgical resection of a renal cell carcinoma except in the context of a clinical trial. (See "Overview of the treatment of renal cell carcinoma", section on 'Anti-angiogenic and targeted therapy'.)
Cabozantinib versus sunitinib in metastatic renal cell carcinoma (October 2016)
Cabozantinib has been shown to be superior to everolimus in previously treated metastatic renal cell carcinoma. In the CABOSUN trial, cabozantinib significantly increased progression-free survival compared to sunitinib in previously untreated patients with intermediate or high-risk renal cell carcinoma . Cabozantinib may provide an important option for previously untreated patients with metastatic disease, although it currently is approved only for patients who have received prior antiangiogenic therapy. (See "Anti-angiogenic and molecularly targeted therapy for advanced or metastatic clear-cell renal cell carcinoma", section on 'Cabozantinib versus sunitinib'.)
Initial treatment for localized, low-risk prostate cancer (September 2016)
There are many options for treating men with localized, low-risk prostate cancer. The most extensive data comparing these options come from the Prostate testing for cancer and Treatment (ProtecT) trial, in which 1653 patients with localized, low-risk prostate cancer were randomly assigned to active monitoring of serum PSA, radical prostatectomy, or radiation therapy (RT) [27,28]. At a median follow-up of 10 years, there was no difference in 10-year overall survival, which was approximately 99 percent for all three groups. However, the incidence of metastases was increased in patients randomized to active surveillance (6.3 per 1000 person-years versus 2.4 and 3.0 for those managed with radical prostatectomy or RT). Longer follow-up will be required to know whether the higher incidence of metastatic disease affects cancer-specific mortality, overall mortality, or quality of life. Decisions regarding the choice of treatment continue to be individualized based upon a consideration of patient age, comorbidity, and patient preferences. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'ProtecT trial'.)
Screening for bleomycin-induced lung disease (June 2016)
There has been no consensus as to the utility of serial pulmonary function tests (PFTs, including the diffusing capacity for carbon monoxide [DLCO]) to detect early signs of bleomycin-induced lung disease, and practice is variable. Data reported from the contemporary Danish Testicular Cancer database suggest that a systematic approach to assessing PFTs before and during therapy, with early discontinuation of bleomycin for those with a drop in the DLCO of 25 percent or more, resulted in very low rates of both acute and chronic lung disease, and no adverse effect on oncologic outcomes . We suggest assessment of PFTs, including DLCO, at baseline prior to treatment and at intervals during therapy for most adults receiving a bleomycin-containing chemotherapy regimen for any malignancy. The optimal frequency of testing is not established. We suggest discontinuation of bleomycin if there is a decrease in the DLCO of 25 percent or more, even if asymptomatic. (See "Bleomycin-induced lung injury", section on 'Screening for lung toxicity'.)
Role of cabazitaxel in castration-resistant prostate cancer (June 2016)
Cabazitaxel, a semisynthetic taxane derivative, was developed for its activity in patients with prostate cancer and resistance to docetaxel. Cabazitaxel was initially approved at a dose of 25 mg/m² every three weeks based upon phase III results demonstrating improved overall survival compared with mitoxantrone in patients who had previously progressed on docetaxel. Two subsequent phase III trials of cabazitaxel were presented at the 2016 American Society of Clinical Oncology (ASCO) meeting. In a noninferiority trial, men who had progressed on docetaxel were randomly assigned to cabazitaxel at a dose of either 20 or 25 mg/m² . The lower dose met predefined noninferiority criteria for overall survival and was associated with significantly less toxicity. In a trial in patients with castration-resistant prostate cancer, initial chemotherapy with cabazitaxel did not improve overall survival compared with docetaxel . Cabazitaxel at a dose of 20 mg/m² is now the preferred cytotoxic chemotherapy for patients who have progressed on docetaxel while docetaxel remains the recommended agent for patients who are chemotherapy-naïve. (See "Chemotherapy in castration-resistant prostate cancer", section on 'Dose of cabazitaxel'.)
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'.)
Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer (October 2016)
In a phase III trial, niraparib was compared with placebo in approximately 550 patients with platinum-sensitive, recurrent ovarian cancer, stratified by germline mutation status . Niraparib improved progression-free survival in all patient groups, although over a third experienced severe hematologic toxicity. In the absence of overall survival data, and given significant toxicity, the appropriate timeframe and strategy for further treatment (with niraparib as maintenance therapy, or with chemotherapy upon disease progression) is unclear. Niraparib remains investigational and should not be used outside of a clinical trial. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-sensitive disease", section on 'Niraparib'.)
Safety of opportunistic salpingectomy (August 2016)
Opportunistic salpingectomy is a novel strategy for primary prevention of epithelial fallopian tube, ovarian, and peritoneal cancer in women at average risk for this cancer undergoing pelvic surgery for a benign indication. In the first randomized trial of opportunistic salpingectomy versus no opportunistic salpingectomy in such women, operative complications and anti-müllerian hormone levels (a measure of ovarian reserve) were similar in both groups at three months . This trial provides evidence of the short-term safety of this strategy, but large long-term trials are needed to evaluate efficacy and hormonal sequelae over time. (See "Opportunistic salpingectomy for ovarian, fallopian tubal, and peritoneal carcinoma risk reduction", section on 'Ovarian function'.)
Outcome of myomectomy with morcellation in unsuspected uterine sarcoma (August 2016)
Uterine morcellation and myomectomy in women with unsuspected uterine cancer can potentially spread malignant cells, but few data are available about the frequency of tumor dissemination and prognosis. A retrospective cohort study of 59 women with a postoperative diagnosis of previously unsuspected uterine sarcoma compared outcomes of those who underwent myomectomy with morcellation (n = 30) with those who underwent total hysterectomy (n = 29) . At five years, myomectomy with morcellation was associated with significantly lower overall survival rate (38 versus 43 percent) and a trend toward lower recurrence-free survival (24 versus 46 percent). These data illustrate the potential effects of myomectomy with morcellation in women with uterine sarcoma. (See "Differentiating uterine leiomyomas (fibroids) from uterine sarcomas", section on 'Myomectomy'.)
Role of endometrial sampling in preoperative diagnosis of uterine sarcoma (August 2016)
Uterine sarcoma is a rare and aggressive malignancy, with few reliable methods for preoperative diagnosis. In a recent study including 68 women with leiomyosarcoma who underwent endometrial sampling before surgery, the sensitivity of the test for diagnosis of features of a smooth muscle malignancy was 52 percent (leiomyosarcoma: 35 percent, spindle cell or other features suspicious for malignancy: 16 percent) . There was no significant difference in test performance between office endometrial biopsy and dilation and curettage. We suggest endometrial sampling for women with a uterine mass and signs, symptoms, risk factors, or other findings that raise suspicion of uterine sarcoma or endometrial carcinoma or for women in whom planned surgical treatment includes intraperitoneal morcellation. (See "Differentiating uterine leiomyomas (fibroids) from uterine sarcomas", section on 'Endometrial sampling'.)
Guidelines for vulvar cancer treatment from the NCCN (June 2016)
The National Comprehensive Cancer Network (NCCN) has released guidelines for the first time on the treatment of squamous cell vulvar carcinoma . The guidelines address surgery, chemotherapy, and radiation. Key sections regarding surgical resection include use of a ≥1 cm margin for surgical resection and, for women with positive margins, consideration of nodal status in deciding whether to perform a repeat resection. These guidelines are consistent with established practice in gynecologic oncology. Their publication adds an important tumor site to existing NCCN guidelines on cervical, uterine, and ovarian cancers. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Treatment of positive or narrow margins'.)
Management of vaginal cytology results (May 2016)
Vaginal cancer is a rare disease, and screening with vaginal cytology is advised only for selected women at high risk (eg, prior hysterectomy and history of high-grade cervical intraepithelial neoplasia). The American Society for Colposcopy and Cervical Pathology (ASCCP) has published new guidance regarding the management of vaginal cytology results (algorithm 1) . Indications for vaginal colposcopy were provided and included: high-grade squamous intraepithelial lesion (HSIL), atypical squamous cells cannot exclude high-grade lesion (ASC-H), or atypical glandular cells (AGC); atypical squamous cells of undetermined significance (ASC-US) with human papillomavirus (HPV) 16/18-positive; and follow-up testing for ≥ASC-US or HPV-positive. This is the first guideline to address management of vaginal cytology results. (See "Cervical and vaginal cytology: Interpretation of results (Pap test report)", section on 'Management of results'.)
HEAD AND NECK CANCER
Checkpoint inhibitor immunotherapy in head and neck cancer (November 2016)
The management of advanced squamous cell carcinoma of the head and neck that is refractory to platinum-based chemotherapy is difficult. Clinical trials with antibodies that target the programmed cell death 1 (PD-1) protein have demonstrated important clinical activity [39,40], and both pembrolizumab and nivolumab have now been approved by the US Food and Drug Administration (FDA) in this setting. Anti-PD-1 antibodies are the preferred approach for second-line therapy of metastatic or recurrent squamous cell carcinoma of the head and neck that has progressed after prior platinum-based chemotherapy. (See "Treatment of metastatic and recurrent head and neck cancer", section on 'PD-1 inhibitor immunotherapy'.)
Sequential chemotherapy for locoregionally advanced nasopharyngeal carcinoma (September 2016)
The role of sequential (induction) chemotherapy prior to concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma is uncertain. In a phase III trial organized by the Sun Yat-sen University, induction chemotherapy significantly improved overall survival at three years compared with concurrent chemoradiotherapy alone . These results require confirmation from other ongoing phase III trials before sequential therapy can be considered the standard of care. (See "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Sequential chemotherapy'.)
Chemotherapy for metastatic nasopharyngeal carcinoma (June 2016)
Platinum-containing doublet chemotherapy regimens have been considered standard first-line approach to systemic therapy for metastatic nasopharyngeal carcinoma. However, specific chemotherapy combinations have not previously been compared in randomized trials, and there has not been a preferred regimen. In a phase III trial presented at the 2016 American Society of Clinical Oncology (ASCO) meeting, patients were randomly assigned to gemcitabine plus cisplatin or fluorouracil plus cisplatin . Progression-free survival was longer with the gemcitabine regimen, and a preliminary analysis suggested that it was also associated with prolonged overall survival. Based upon these results, gemcitabine plus cisplatin combination is the preferred regimen for patients with metastatic nasopharyngeal cancer. (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma", section on 'Cytotoxic chemotherapy'.)
MELANOMA AND OTHER SKIN CANCER
Adjuvant ipilimumab for high-risk melanoma (October 2016)
Ipilimumab was previously approved for adjuvant use after resection of lymph node-positive cutaneous melanoma on the basis of increased progression-free survival compared with placebo. Additional follow-up from this randomized trial has confirmed that ipilimumab confers a clinically and statistically significant improvement in overall survival at five years . For patients with stage III melanoma at high risk of recurrence, enrollment in a clinical trial evaluating a programmed cell death protein 1 (PD-1) inhibitor is the preferred approach because pembrolizumab or nivolumab are significantly more effective than single-agent ipilimumab in the metastatic disease setting. If this is not possible, adjuvant ipilimumab using the 10 mg/kg dose schedule is preferred over high-dose interferon alfa for patients with lymph node-positive disease. (See "Adjuvant immunotherapy for melanoma", section on 'Ipilimumab'.)
Thrombotic microangiopathy from interferon (October 2016)
Drug-induced thrombotic microangiopathy (DITMA) has been described with a number of chemotherapeutic, immunosuppressive, and other drugs. Unlike thrombotic thrombocytopenic purpura (TTP), DITMA is not associated with severely reduced ADAMTS13 activity, and the principal treatment is drug discontinuation rather than plasma exchange. A new report has provided strong evidence for interferon as a cause of TMA . Patients receiving interferon who develop signs of a TMA should have the drug discontinued promptly before organ failure develops. (See "Drug-induced thrombotic microangiopathy", section on 'Immunosuppressive agents'.)
MC1R gene variants and risk of melanoma (June 2016)
Variants of the melanocortin-1 receptor (MC1R) gene, a key regulator of skin pigmentation, are associated with the sunlight-sensitive red hair/fair skin phenotype, a known risk factor for melanoma. However, some MC1R variants may carry an increased risk of melanoma independent of phenotypic characteristics and sun exposure. In a case-control study including 991 patients with melanoma and 800 controls, carriers of two or more MC1R variants had an approximately twofold increased risk of melanoma, compared with wild type carriers, after adjusting for age, sex, number of sunburns before age 20, and signs of actinic skin damage . Additional studies are needed to determine the precise role of altered MC1R variants in melanoma tumorigenesis. (See "Risk factors for the development of melanoma", section on 'Genetic background'.)
Checkpoint inhibition immunotherapy of uncertain benefit for uveal melanoma (June 2016)
Checkpoint immunotherapy with antibodies targeting PD-1/PD-L1 and CTLA-4 has represented a major advance in the treatment of advanced cutaneous melanoma. However, patients with uveal melanoma were generally excluded from the phase III trials with these agents. In a retrospective series of 56 patients with metastatic uveal melanoma, only two partial responses were observed in patients treated with pembrolizumab, nivolumab, or atezolizumab . Thus, any potential clinical benefit in patients with metastatic uveal melanoma is much more limited than with cutaneous melanoma, and treatment of these patients should focus on clinical trial participation. (See "Uveal and conjunctival melanomas", section on 'Anti-PD-1 or PD-L1 antibodies'.)
Whole brain radiation therapy and cognitive function in patients with limited number of brain metastases (August 2016)
Deferral of adjunctive whole brain radiation therapy (WBRT) in patients with a limited number of brain metastases who are eligible for surgery or stereotactic radiosurgery (SRS) has become more common over the last several years. This practice is supported by accumulating data from randomized trials showing that, although WBRT improves intracranial disease control, it does not appear to improve overall survival, and it is associated with early and delayed side effects that may worsen quality of life. A randomized trial of SRS plus WBRT versus SRS alone in 213 patients with brain metastases found that cognitive deterioration at three months was more common in patients who received WBRT (92 versus 64 percent), while overall survival was similar . Cognitive testing at 6 and 12 months and quality of life measures also favored SRS alone. Based on these results and other relevant studies, we suggest deferring adjunctive WBRT in most patients with a limited number of brain metastases. Such patients require serial neuroimaging after SRS alone to monitor for the development of new or progressive tumors. (See "Overview of the treatment of brain metastases", section on 'Role of adjunctive WBRT'.)
Radiation plus temozolomide in patients with 1p19q non-co-deleted anaplastic gliomas (July 2016)
Two previous randomized trials in patients with anaplastic oligodendroglial tumors found that postoperative treatment with radiation plus PCV (procarbazine, lomustine, and vincristine) improved survival compared with radiation alone. However, the benefit of PCV was primarily seen in patients whose tumors contained co-deletion of chromosomes 1p and 19q. The CATNON trial enrolled 748 patients with newly diagnosed anaplastic gliomas without 1p19q co-deletion and randomly assigned them to one of four treatment arms: radiation alone, radiation with concurrent temozolomide (TMZ), radiation with concurrent and 12 cycles of adjuvant TMZ, and radiation with 12 cycles of adjuvant TMZ . In an interim analysis with a median follow-up of over two years, patients who were randomized to receive 12 cycles of adjuvant TMZ had improved overall survival compared with those who received radiation without adjuvant TMZ (hazard ratio 0.65). Based on these results, we now recommend radiation plus chemotherapy in all patients with newly diagnosed anaplastic gliomas, rather than just those with 1p19q co-deleted tumors. The choice between PCV and TMZ should be individualized based on molecular characteristics of the tumor and patient preferences. (See "Management of anaplastic oligodendroglial tumors", section on 'CATNON'.)
Radiation plus temozolomide in older adults with glioblastoma (June 2016)
Shorter courses of radiation are increasingly used to treat older adults with glioblastoma, but the safety and efficacy of temozolomide in combination with such regimens have not been well studied. In a multinational phase III trial, 562 adults ≥65 years of age with a good performance status were randomly assigned to receive hypofractionated radiation (40 Gy in 15 fractions) plus concurrent and adjuvant temozolomide or radiation alone . Overall survival was significantly prolonged in patients assigned to combination therapy (9.3 versus 7.6 months), and quality of life outcomes were similar aside from an increase in nausea and constipation related to chemotherapy. The addition of temozolomide was especially beneficial in the subset of patients with O-6-methylguanine-DNA methyltransferase (MGMT) methylated tumors (13.5 versus 7.7 months). (See "Management of glioblastoma in older adults", section on 'Efficacy'.)
PALLIATIVE AND SUPPORTIVE CARE
ASCO recommendations on palliative care in patients with advanced cancer (November 2016)
In response to increasing evidence from randomized trials that early palliative care offers benefits in terms of quality of life, mood, end-of-life care, and possibly even survival, an updated provisional clinical opinion from the American Society of Clinical Oncology (ASCO) now recommends integrating dedicated palliative care services into the care of inpatients and outpatients with advanced cancer early in the disease course, concurrent with active treatment . Essential components of palliative care may include symptom, distress, and functional status management; clarification of treatment goals; assistance with medical decision making; coordination with other care providers; and assessment and support of coping needs. (See "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)
Updated MASCC/ESMO guidelines for nausea and emesis related to cancer treatment (October 2016)
Updated guidelines for prevention and management of cancer therapy-associated nausea and vomiting are available from the Multinational Association of Supportive Care in Cancer and the European Society of Medical Oncology (table 2), the consensus panel also provides guidance on the use of prophylactic antiemetics in patients undergoing radiation therapy. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'Recommendations for specific groups'.)
Olanzapine for prevention of nausea and vomiting induced by highly emetogenic chemotherapy regimens (August 2016)
The antipsychotic olanzapine may be a particularly useful agent for preventing delayed chemotherapy-induced nausea and vomiting, which is often poorly controlled with conventional antiemetics. The effectiveness of adding olanzapine to a standard antiemetic regimen was shown in a trial in which 380 patients receiving highly emetogenic chemotherapy (cisplatin or doxorubicin/cyclophosphamide for breast cancer) were randomly assigned to dexamethasone, an NK1R antagonist, and a 5-HT3 receptor antagonist plus either olanzapine (10 mg daily orally on days 1 through 4) or placebo . The proportion of patients with no chemotherapy-induced nausea (the primary endpoint) was higher with olanzapine both in the first 24 hours after chemotherapy and in the delayed period. Rates of complete response (no emesis and no use of rescue medication) were also higher with olanzapine over a five-day period. Patients receiving olanzapine had more sedation on day 2 (severe in 5 percent), which resolved despite continued olanzapine. On the basis of this trial, we now suggest the addition of olanzapine on days 1 through 4 to standard antiemetic therapy for patients receiving highly emetogenic chemotherapy. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'Olanzapine'.)
SOFT TISSUE AND BONE TUMORS
Olaratumab in combination for advanced soft-tissue sarcoma (November 2016)
Olaratumab is a monoclonal antibody that binds to the platelet-derived growth factor receptor alpha (PDGFRA) and blocks binding of PDGF ligands. In a randomized phase II study comparing doxorubicin with or without olaratumab in previously untreated patients with locally advanced or metastatic soft tissue sarcoma (STS) from a variety of histologic subtypes, initial combination therapy was associated with improved median overall survival (27 versus 15 months) . Grade 3 or 4 neutropenia, mucositis, nausea, vomiting, and diarrhea were all more common with combined therapy. Based upon these results, and consistent with the recent approval of olaratumab in the United States for this indication , we suggest doxorubicin plus olaratumab rather than doxorubicin alone for first-line treatment of patients who cannot be cured with radiation or surgery and who have a type of STS for which anthracyclines represent appropriate chemotherapy. (See "Systemic treatment of metastatic soft tissue sarcoma", section on 'Doxorubicin plus olaratumab'.)
Potential interaction between high-dose methotrexate and levetiracetam (November 2016)
Levetiracetam is sometimes used for prophylaxis and treatment of seizures in patients undergoing high-dose methotrexate (MTX) treatment for brain or other central nervous system (CNS) cancers, including lymphomas. Health Canada has issued a safety review describing a potential interaction between the two drugs, noting 13 reports received by the levetiracetam manufacturer and concluding that concurrent use can lead to significantly elevated levels of MTX and increased risk of toxicity . The labeling is being revised to recommend careful MTX blood level monitoring. Additional details are available from Lexi-Interact, the drug interactions tool included within UpToDate. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Coadministered drugs that may interfere with excretion'.)
Osteosarcoma outcomes in poor responders to induction chemotherapy not improved with intensified postoperative chemotherapy (September 2016)
Responsiveness of an osteosarcoma to induction chemotherapy is a major determinant of clinical outcomes. The benefit of altering postoperative chemotherapy for poor responders was tested in the EURAMOS1 trial, in which 618 patients who had ≥10 percent viable tumor in the resected specimen after standard induction chemotherapy (high-dose methotrexate plus doxorubicin and cisplatin [MAP]) were randomly assigned to postoperative MAP with or without ifosfamide plus etoposide (I/E) . The addition of I/E did not improve event-free survival, the primary endpoint, and it was significantly more toxic. These results do not support the addition of I/E to postoperative MAP chemotherapy in patients with poorly responding osteosarcoma after induction chemotherapy. (See "Chemotherapy and radiation therapy in the management of osteosarcoma", section on 'Addition of ifosfamide-based therapy: The EURAMOS-1 trial'.)
Pembrolizumab for PD-L1 high non-small cell lung cancer (October 2016)
In a phase III trial enrolling 305 patients with treatment-naïve advanced non- small cell lung cancer (NSCLC) lacking a driver mutation and expressing PD-L1 in at least 50 percent of tumor cells, pembrolizumab monotherapy improved progression-free survival, overall survival, and objective response rate compared with standard platinum-doublet chemotherapy . It was also associated with lower treatment-related adverse effects. These data support our recommendation for frontline pembrolizumab in patients with a tumor that has at least 50 percent tumor cell staining for PD-L1 and lacks a driver mutation. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'First-line setting'.)
Revised indications for erlotinib for advanced non-small cell lung cancer (October 2016)
The US Food and Drug Administration (FDA) has revised indications for erlotinib to limit use to patients with advanced non-small cell lung cancer (NSCLC) whose tumors have a driving mutation in the epidermal growth factor receptor (EGFR) . This is based on results of the IUNO trial, in which erlotinib maintenance, compared with placebo, did not improve progression-free or overall survival in over 600 patients with advanced NSCLC that lacked an EGFR mutation and who had no progression after platinum-based chemotherapy. Given these results, we no longer suggest EGFR inhibitors as an option for maintenance or subsequent line therapy for NSCLC with wild-type EGFR. (See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation", section on 'Avoidance of EGFR TK inhibitors'.)
Cardiotoxicity of checkpoint inhibitor immunotherapy (November 2016)
Checkpoint inhibitor immunotherapy for melanoma and other cancers may result in severe or fatal cardiotoxicity, even in the absence of a history of significant cardiac risk factors . High-dose steroids are indicated to treat myositis and other cardiac complications, but symptoms may progress in some cases despite steroids. The early institution of more aggressive immunosuppressive therapy and monitoring should be considered for patients without an immediate response to high-dose steroids. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Cardiotoxicity'.)
Early antiretroviral therapy and cancer risk in HIV-infected patients (October 2016)
Antiretroviral therapy (ART) should be initiated in all HIV-infected individuals to reduce AIDS and non-AIDS related events, regardless of the baseline CD4 count. Further analysis of a randomized trial in which over 4500 HIV-infected participants received ART immediately or delayed ART until the CD4 count was <350 cells/microL demonstrated a reduction in infection-related cancers (ie, those associated with human herpesvirus 8, Epstein-Barr virus, and human papillomavirus) with immediate ART (6 versus 23 cases with delayed ART) . There was also a trend towards fewer noninfection-related malignancies with immediate ART. (See "When to initiate antiretroviral therapy in HIV-infected patients", section on 'HIV-related comorbidities'.)
PD-1 inhibition in patients with autoimmune disease or prior immune-related adverse events (October 2016)
Programmed cell death-1 (PD-1) inhibitors generate an immune response that might aggravate an underlying autoimmune disorder or prior immune-related adverse event. A retrospective study analyzed the results of treatment with pembrolizumab or nivolumab in 119 melanoma patients with these potential risk factors . The study found that these patients can safely receive anti-PD1 therapy without the need for permanent discontinuation of drug therapy in most cases. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Pre-existing autoimmune disorder or prior immune-related toxicity'.)
Nivolumab dose regimen (September 2016)
Nivolumab is an IgG4 monoclonal antagonist antibody to PD-1 that is US Food and Drug Administration (FDA)-approved for the treatment of several types of malignancies. The FDA has modified the approved dose regimen for advanced renal cell carcinoma, melanoma, and non-small cell lung cancer to 240 mg intravenously every two weeks until disease progression or intolerable toxicity . This new dose replaces the previous regimen of 3 mg/kg and is based on population pharmacokinetic analyses demonstrating comparable efficacy and safety in patients with these cancers. For patients with Hodgkin lymphoma, or for those with melanoma being treated concurrently with ipilimumab, the recommended dose of nivolumab remains unchanged (3 mg/kg and 1 mg/kg, respectively). (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Nivolumab' and "Immunotherapy of renal cell carcinoma" and "Immunotherapy of advanced melanoma with immune checkpoint inhibition".)
Pulmonary toxicity of anti-PD-1 and anti-PD-L1 antibodies (September 2016)
Pulmonary toxicity is an uncommon but potentially fatal complication of treatment with checkpoint inhibitor immunotherapy targeting programmed cell death-1 (PD-1) or its ligand (PD-L1). The incidence of pneumonitis was 5 percent in a series of 915 patients treated with one of these agents . All patients had immunotherapy withheld until toxicity resolved, and this was sufficient to reverse toxicity in most patients with grade 1 pneumonitis (table 3). For those with more severe toxicity, corticosteroids were indicated. Five out of 43 patients worsened and died despite therapy, mostly attributed to infectious complications or tumor progression. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Pneumonitis'.)
ASCO policy statement on access to opioids for cancer-related pain (July 2016)
Safe prescribing of opioids requires consideration of the risks associated with drug abuse, misuse, and diversion to the illicit marketplace. With increasing prescription drug abuse and opioid-associated overdose deaths, federal and state governments have taken additional steps to regulate opioids beyond the restrictions imposed by the federal Controlled Substances Act. However, inadequate treatment of cancer-related pain is a real problem, and concerns have been raised that many of these well-intentioned proposals will limit legitimate access to opioids for patients with cancer, and challenge the ability of oncologists and palliative care physicians to provide compassionate care that includes adequate pain relief. In response to these concerns, the American Society of Clinical Oncology (ASCO) has issued a policy statement that emphasizes principles for balancing opioid access with the need to curb misuse and abuse . (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Risk assessment and management for patients receiving opioids'.)
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