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.
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 have not confirmed this benefit [2-4]. 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 had previously 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 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'.)
CANCER SCREENING AND PREVENTION
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'.)
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'.)
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 [17,18]. 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'.)
Nivolumab immunotherapy for metastatic urothelial carcinoma (February 2017)
Cisplatin-based chemotherapy is the preferred initial treatment for patients with metastatic urothelial carcinoma of the bladder and upper urinary tract; however, most patients eventually relapse. In a large phase II study, nivolumab had clinically significant activity in patients who had failed a cisplatin-based regimen . Based upon these results, nivolumab was approved by the US Food and Drug Administration (FDA) for patients that have progressed during or after previous platinum-based chemotherapy either for metastatic disease or for progressive disease less than 12 months after adjuvant or neoadjuvant chemotherapy. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'Nivolumab'.)
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'.)
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) [25,26]. 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'.)
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 [28,29]. 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'.)
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'.)
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 [32,33], 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'.)
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'.)
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'.)
PALLIATIVE AND SUPPORTIVE CARE
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 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'.)
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 1), 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'.)
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'.)
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'.)
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'.)
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 2). 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'.)
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