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.
Updated guideline on bone-modifying agents for metastatic breast cancer (October 2017)
In conjunction with Cancer Care Ontario, the American Society of Clinical Oncology has issued a focused guideline update on the role of bone-modifying agents (BMAs) in metastatic breast cancer . Evidence is not sufficient to support the choice of one BMA over another; options for zoledronic acid now include every-12-week dosing as an alternative to monthly treatment, and BMAs should not be used alone for management of bone pain, given their modest analgesic benefit. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Dosing interval' and "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Overview of the approach to osteoclast inhibition'.)
Long-term outcomes of women with breast cancer and sentinel node metastasis (October 2017)
The American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial established the safety of omitting routine axillary lymph node dissection (ALND) in women with early-stage breast cancer, no palpable axillary adenopathy, and one or two metastatic sentinel lymph nodes. Now, extended follow-up to about 10 years continues to show that both overall survival and disease-free survival after sentinel lymph node dissection (SLND) alone are noninferior to ALND . These results support Z0011's early conclusion that women undergoing breast conserving surgery and SLND do not require routine ALND. (See "Overview of sentinel lymph node biopsy in breast cancer", section on 'One or two sentinel node metastases'.)
Abemaciclib for hormone receptor-positive, HER2-negative advanced breast cancer (September 2017)
Abemaciclib is the third CDK 4/6 inhibitor to become available for use in women with hormone receptor-positive, HER2-negative advanced breast cancer. In a phase III trial, abemaciclib plus fulvestrant improved progression-free survival compared with fulvestrant alone , and in a nonrandomized phase II study abemaciclib showed single agent activity in patients with progression following chemotherapy . Based upon these results, abemaciclib was approved by the US Food and Drug Administration in combination with fulvestrant for women with progressive disease after prior endocrine therapy and for use as a single agent for women with progressive disease after endocrine therapy and chemotherapy. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy", section on 'Abemaciclib'.)
Adjuvant partial breast irradiation for lower risk, early-stage breast cancer (August 2017)
Partial breast irradiation (PBI) refers to the use of limited, focused radiation as a more convenient alternative to conventional whole breast radiation therapy (WBRT) after breast-conserving surgery for early-stage breast cancer. In a randomized trial, over 2000 women ≥50 years of age who had undergone breast-conserving surgery for lower risk, early-stage breast cancer were randomly assigned to 40 Gy WBRT (control); 36 Gy WBRT and 40 Gy PBI (reduced-dose group); or 40 Gy PBI (partial-breast group) . Five-year local relapse rates were similar for all groups. For women who are ≥50 years of age with hormone receptor-positive, node-negative tumors ≤3 cm, PBI is a reasonable alternative to WBRT. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Efficacy'.)
Nonanthracycline-based adjuvant therapy for low-risk, HER2-negative breast cancer (August 2017)
Anthracyclines are commonly used in the adjuvant management of early-stage breast cancer but have associated cardiac risks. In a joint analysis of the Anthracyclines in Early Breast Cancer (ABC) Trials, among over 4000 women with early-stage human epidermal growth factor receptor (HER2)-negative breast cancer, the nonanthracycline regimen docetaxel and cyclophosphamide (TC) was inferior to an anthracycline, cyclophosphamide, and taxane-based regimen in regards to four-year invasive-free survival (88 versus 91 percent) for the overall group . However, in subgroup analysis, anthracyclines did not meaningfully improve outcomes relative to nonanthracycline-based therapy in women with lower-risk disease. For women who have indications for chemotherapy, we offer TC as adjuvant treatment for those with lower-risk HER2-negative tumors (eg, those with node-negative, hormone receptor-positive breast cancer or node-negative, triple-negative breast cancer <1 cm). (See "Adjuvant chemotherapy for HER2-negative breast cancer", section on 'Acceptable alternatives to anthracycline-based treatment'.)
Bisphosphonates not protective against breast cancer in postmenopausal women (August 2017)
Although some studies have suggested a protective effect of bisphosphonates against breast cancer, others, including a large observational cohort of over 64,000 postmenopausal women followed for approximately seven years , have not. Studies may be confounded by the frequent use of bisphosphonates to treat osteoporosis, and women with osteoporosis are more likely to have a lower estrogen environment and therefore a lower baseline risk of breast cancer regardless of bisphosphonate exposure. (See "Factors that modify breast cancer risk in women", section on 'Bisphosphonates'.)
Risks of breast and ovarian cancer among BRCA mutation carriers (June 2017)
In a prospective cohort study of over 9800 female BRCA mutation carriers, cumulative rates of breast and ovarian cancer until age 80 years were 72 and 44 percent for BRCA1 carriers and 69 and 17 percent for BRCA2 carriers, respectively . In addition to educating women regarding their genetic risk factors, we also counsel women on how other risk modifiers, including reproductive history, use of hormonal therapy, and oophorectomy status, may impact their lifetime cancer risks. (See "Prevalence of BRCA1 and BRCA2 mutations and associated cancer risks", section on 'Breast and ovarian cancer' and "Prevalence of BRCA1 and BRCA2 mutations and associated cancer risks", section on 'Nongenetic cancer risk modifiers'.)
Olaparib in BRCA-associated, HER2-negative breast cancer (June 2017)
The role of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in metastatic breast cancer is being investigated. In the phase III OlympiAD trial, over 300 patients with metastatic HER2-negative, BRCA-associated breast cancer with disease progression despite chemotherapy were randomly assigned to the PARP inhibitor olaparib or to chemotherapy . Progression-free survival (PFS) was longer for the PARP group (7.0 versus 4.2 months), with fewer toxicities. Overall survival data are not yet mature. In the setting of evolving data, some UpToDate contributors offer olaparib to those with metastatic HER2-negative, BRCA-associated breast cancer that has progressed on previous therapies, while others await further survival data prior to suggesting this therapy. (See "Systemic treatment for metastatic breast cancer: General principles", section on 'Special considerations for BRCA carriers'.)
Nonanthracycline-based regimens in the neoadjuvant treatment of HER2-positive breast cancer (June 2017)
Although efficacy of anthracycline or nonanthracycline-based regimens is similar in the adjuvant setting for patients with local HER2-positive breast cancer, data in the neoadjuvant setting are limited. In a phase III trial of over 400 patients with stage II to III HER2-positive breast cancer randomly assigned to nonanthracycline- or anthracycline-based neoadjuvant chemotherapy with concurrent pertuzumab and trastuzumab, the rates of pathologic complete response rate (pCR) did not differ between the arms (67 versus 68 percent, respectively) . Rates of febrile neutropenia and decline in left ventricular ejection fraction were higher among those receiving anthracyclines. These data support our approach of offering nonanthracycline-based chemotherapy, together with HER2-directed therapy, to women receiving neoadjuvant treatment for HER2-positive breast cancer. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Nonanthracycline-based treatment'.)
Adjuvant pertuzumab for HER2-positive breast cancer (June 2017)
While pertuzumab has shown benefit in the neoadjuvant setting for high-risk HER2-positive breast cancer, its role in the adjuvant setting is just now emerging. In the phase III APHINITY trial, over 4800 patients with HER2-positive breast cancer who were treated with adjuvant chemotherapy and trastuzumab were randomly assigned to pertuzumab (concurrent with trastuzumab) or placebo . At a median follow-up of approximately 45 months, patients receiving pertuzumab had higher three-year invasive disease-free survival rates (94 versus 93 percent), with the greatest benefit for those with node-positive disease. Given this trial, we now suggest the addition of adjuvant pertuzumab for women with node-positive disease or larger, node-negative tumors (>2 cm). However, some patients may reasonably choose against additional treatment, given the added toxicities of pertuzumab and lack of demonstrated overall survival benefit. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Addition of pertuzumab for high-risk disease'.)
Adjuvant capecitabine for residual HER2-negative breast cancer after neoadjuvant chemotherapy (June 2017)
In a randomized trial of approximately 900 patients with HER2-negative breast cancer and residual disease after neoadjuvant chemotherapy, patients in the adjuvant capecitabine group, compared with placebo, had higher rates of five-year disease-free survival (74 versus 68 percent) and overall survival (89 versus 84 percent) . Subgroup analyses suggested that these findings were driven primarily by outcomes in patients with triple-negative disease. Toxicities were higher in patients receiving capecitabine, including diarrhea, neutropenia, and hand-foot syndrome. Given these results, we now suggest capecitabine for patients with residual HER2-negative breast cancer after neoadjuvant therapy, though observation is also acceptable, given the increased toxicities associated with adjuvant capecitabine. (See "Adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)
Radiation for nonmetastastic breast cancer and cardiovascular risk (June 2017)
Many women treated for nonmetastatic breast cancer receive radiation therapy after surgical resection. In a meta-analysis of 39 studies involving almost 1.2 million patients with breast cancer, the risk of coronary artery disease and cardiac death was somewhat increased (relative risk 1.3 and 1.38, respectively) for those who received radiotherapy relative to those who did not . However, absolute risks for these complications were low (76 and 126 cases, respectively, per 100,000 person-years). For appropriately selected patients, adjuvant radiation remains a safe and effective treatment for nonmetastatic breast cancer. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies", section on 'Meta-analyses and randomized trials'.)
CANCER SCREENING AND PREVENTION
IUD use impacts cervical cancer incidence (November 2017)
Prior studies have suggested that intrauterine devices (IUDs), one of the most reliable forms of long-acting reversible contraception, are associated with a reduction in cervical cancer. Now, a meta-analysis including 16 studies reported that the incidence of cervical cancer was reduced by about one-third in IUD users compared with nonusers . This protective effect is particularly important for women at higher risk of cervical cancer, such as those who have not received the human papillomavirus vaccine or who do not have access to cervical cancer screening. It is not known if the type of device influences the reduction in cervical cancer risk. (See "Intrauterine contraception: Devices, candidates, and selection", section on 'Benefits'.)
Evaluation for occult cancer in unprovoked venous thromboembolism (August 2017)
Whether patients with a diagnosis of unprovoked venous embolism (VTE) should be evaluated for occult cancer with an extensive or more limited strategy is controversial. In a meta-analysis of 10 prospective studies (over 2000 patients with unprovoked VTE), the prevalence of cancer at one year was 5 percent . Extensive screening, performed in nearly 60 percent of patients, detected more cancer initially than limited evaluation, but the difference was not significant at one year. The effect on long-term mortality is unknown. Until the benefits of extensive evaluation strategies are proven, we suggest evaluating patients with a single episode of unprovoked VTE using a limited strategy (clinical examination, routine laboratory studies, chest radiography, and age-appropriate screening) for the detection of occult cancer. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'First episode of uncomplicated unprovoked VTE'.)
Whole-body MRI in Li Fraumeni syndrome (August 2017)
The high risk of new malignancies in individuals with Li Fraumeni syndrome (LFS) has led to the evaluation of whole-body MRI (WB-MRI) as a surveillance tool. A meta-analysis of the multicenter experience with this modality found that WB-MRI identified previously undiagnosed malignancies in 7 percent of individuals, most of whom were amenable to definitive treatment . However, 30 percent of individuals had a false-positive result that required further evaluation. Longitudinal studies are required to further define the role of WB-MRI in LFS. (See "Li-Fraumeni syndrome", section on 'Cancer surveillance strategy'.)
Vaginal dehydroepiandrosterone for genitourinary symptoms in postmenopausal cancer survivors (October 2017)
Treatment of genitourinary syndrome of menopause (GSM) in survivors of estrogen-sensitive malignancies is challenging because vaginal estrogen may be contraindicated. In a randomized trial comparing two doses of vaginal dehydroepiandrosterone (DHEA) with a nonhormonal vaginal moisturizer in postmenopausal cancer survivors (primarily breast cancer), all three groups reported similar improvement in dyspareunia and vaginal dryness symptoms at 12 weeks, but only the higher dose DHEA group reported significant improvement in sexual function over baseline on a validated sexual health measure . Vaginal DHEA holds promise as a GSM treatment for breast cancer survivors, but safety concerns remain because it increases serum estrogen levels. (See "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)", section on 'Women with breast cancer'.)
Nomogram to estimate survival in advanced pancreatic cancer (November 2017)
Second-line therapy may improve survival in advanced pancreatic cancer (APC), although the best way to predict which patients will benefit is not established. An analysis of data from 462 consecutive patients with APC treated at a single institution identified nine factors (age, smoking status, liver metastases, performance status, pain, jaundice, ascites, duration of first-line chemotherapy, and second-line treatment regimen) that independently influenced survival and were used to develop a prognostic model which discriminated three groups . Benefit from second-line chemotherapy was higher in the better prognostic groups. The model is the basis for a nomogram to estimate individual survival probabilities following first-line chemotherapy for APC, which may assist in clinical decision making. (See "Chemotherapy for advanced exocrine pancreatic cancer", section on 'Second-line therapy'.)
Nivolumab for second-line treatment of advanced hepatocellular carcinoma (October 2017)
Nivolumab is a fully human monoclonal antibody that targets the programmed cell death-1 receptor, restoring T-cell immune activity directed against the tumor cell. In the Checkmate 040 trial, nivolumab was administered to 255 patients with advanced hepatocellular cancer (HCC) and Child Pugh A or B cirrhosis whose disease had either progressed on sorafenib or who refused or were intolerant of the drug . An objective antitumor response was found in 49 patients (19 percent), including a complete response in six patients. Durable benefit was observed both in sorafenib-naïve and sorafenib-experienced patients . Most adverse events were mild and transient. In September 2017, the US Food and Drug Administration expanded nivolumab indications to include treatment of HCC in patients who have been previously treated with sorafenib . While regorafenib was also approved for this patient group in April 2017, we now suggest treatment with nivolumab given the potential for a higher objective response rate (including some complete responders) and a more favorable side effect profile compared with regorafenib. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Checkpoint inhibitor immunotherapy'.)
Anti-EGFR therapy and primary tumor location in metastatic colorectal cancer (October 2017)
Accumulating data suggest that the site of the primary tumor influences the effectiveness of first-line treatments for metastatic colorectal cancer (mCRC) that target the epidermal growth factor receptor (EGFR). In a meta-analysis of trials comparing anti-EGFR with anti-vascular endothelial growth factor (VEGF) agents when added to standard first-line chemotherapy, patients with RAS wild-type (wt) mCRC and a left-sided primary tumor had longer survival with anti-EGFR treatment, while there was a trend toward longer survival in patients with right-sided tumors who received bevacizumab . Given these data, when a biologic agent is chosen as a component of first-line therapy, we suggest treatment with an anti-EGFR antibody rather than bevacizumab for patients with RAS/BRAF wt mCRC and a left-sided primary tumor. For most patients with RAS/BRAF wt mCRC and a right-sided primary tumor, we suggest bevacizumab rather than an anti-EGFR antibody in conjunction with first-line chemotherapy, although anti-EGFR agents could be used for later lines of therapy. (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Anti-EGFR agent versus bevacizumab with first-line chemotherapy'.)
Expanded indications for PD-1 inhibitors in advanced gastric cancer (September 2017)
Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death 1 protein (PD-1), a key receptor in a pathway by which cancers evade immune surveillance. The efficacy of pembrolizumab in previously treated gastric and esophagogastric junction (EGJ) adenocarcinomas was shown in a cohort of 259 patients included in the KEYNOTE-059 trial, which showed a higher response rate in patients whose tumors overexpressed the ligand for PD-1 (PD-L1) . Previously, pembrolizumab had been approved for treatment of refractory advanced tumors, including gastric/EGJ adenocarcinomas, that had high levels of microsatellite instability or deficient mismatch repair proteins. In September 2017, based largely upon the results of the KEYNOTE-059 study, pembrolizumab approval was extended to include patients with PD-L1-overexpressing gastric and EGJ adenocarcinomas who had received two or more lines of chemotherapy, and, if appropriate, HER2-targeted therapy . In Japan, a second PD-1 inhibitor, nivolumab, has been approved for any unresectable advanced or recurrent gastric cancer that has progressed after conventional chemotherapy. (See "Systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'PD-1 and PD-L1 inhibitors'.)
Selective internal radiotherapy not effective for chemotherapy-naïve hepatic predominant metastatic colorectal cancer (August 2017)
Early trials suggested that combined hepatic arterial injection of radioactive isotope-tagged resin microspheres (selective internal radiotherapy, SIRT) improved outcomes over either hepatic intraarterial chemotherapy or intravenous fluoropyrimidines alone in patients with hepatic predominant metastatic colorectal cancer (mCRC). However, in a combined analysis of three parallel phase III trials of chemotherapy-naïve patients receiving oxaliplatin-containing chemotherapy, the addition of SIRT did not improve median overall or progression-free survival, or the chance of subsequent liver resection, and it was more toxic than chemotherapy alone . We recommend against the addition of SIRT to modern oxaliplatin-containing chemotherapy in patients with chemotherapy-naïve mCRC. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases", section on 'SIRT plus systemic chemotherapy'.)
Nivolumab approval extended to mismatch repair-deficient metastatic colorectal cancer (August 2017)
Immunotherapy with checkpoint inhibitors, such as pembrolizumab, that block the programmed death receptor-1 (PD-1) benefits patients with metastatic colorectal cancer (mCRC) whose tumors are deficient in mismatch repair (dMMR). The benefit of nivolumab, a different PD-1 blocking antibody, was evaluated in a trial that reported an objective response in 23 of 74 patients treated with nivolumab alone, with response persisting at least 12 months in eight patients . Largely based upon these data, in August 2017, the US Food and Drug Administration (FDA) extended the approval of nivolumab to dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan . (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Immune checkpoint inhibitors and mismatch repair deficient tumors'.)
Single test for detecting multiple RAS mutations in colorectal cancer (July 2017)
All patients with metastatic colorectal cancer (mCRC) who are candidates for therapy targeting the epidermal growth factor receptor (EGFR) should have their tumor tested for multiple mutations in both KRAS and NRAS (termed "extended RAS testing") . Such testing has been performed sequentially as individual tests. Anti-EGFR monoclonal antibody therapy should be restricted to patients whose tumors lack RAS mutations. A new next generation sequencing test, the PRAXIS Extended RAS Panel, detects the presence of 56 specific mutations in KRAS and NRAS in tumor tissue and provides more expeditious results to inform therapy decisions for patients with mCRC. The test was approved by the US Food and Drug administration in July 2017 . (See "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations", section on 'Extended RAS testing'.)
Routine lateral lymph node dissection for low rectal cancer (July 2017)
In patients with rectal cancer, total mesorectal excision (TME) is standard procedure, but lateral lymph node dissection is not routinely performed, especially when nodes are clinically negative. In a large Japanese trial of patients with stage II/III rectal cancer below the peritoneal reflection and clinically negative lateral nodes randomly assigned to TME with or without lateral node dissection, the five-year relapse-free survival rate was similar for both groups, but the local recurrence rate was higher without lateral lymph node dissection, and most recurrences occurred in the lateral compartment . This trial affirmed that routine lateral node dissection is warranted in Japan due to the high prevalence of lateral node involvement. In the United States, TME alone may be sufficient given the widespread use of neoadjuvant therapy (not offered in this trial). Therapeutic lateral node dissection can be offered to select patients with clinically positive lateral nodes. (See "Rectal cancer: Surgical principles", section on 'Routine lateral or extended lymphadenectomy'.)
Adjuvant capecitabine for biliary cancer (July 2017)
The benefit of adjuvant therapy for resected cholangiocarcinoma is debated. In the phase III BILCAP trial, 447 patients with completely resected cholangiocarcinoma or gallbladder cancer were randomly assigned to 24 weeks of oral capecitabine or placebo . In a preliminary report, the improvement in median overall survival with capecitabine was potentially clinically meaningful although not statistically significant. We continue to suggest chemoradiotherapy in addition to chemotherapy rather than chemotherapy alone for patients with completely resected node-positive or margin-positive disease; for those not receiving chemoradiotherapy, chemotherapy alone is an option. (See "Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis", section on 'Chemotherapy'.)
Neoadjuvant FLOT versus an epirubicin-based triplet for gastric cancer (July 2017)
The best chemotherapy regimen for perioperative (neoadjuvant plus adjuvant) treatment in gastric cancer has not been established, and practice is variable. The FLOT4-AIO trial compared the FLOT regimen (docetaxel plus oxaliplatin, leucovorin and short-term infusional fluorouracil [FU]) versus epirubicin plus cisplatin and either infusional FU (ECF) or capecitabine (ECX) in over 700 patients with potentially resectable gastric or gastroesophageal junction cancer . In a preliminary report, FLOT was associated with better survival, a higher pathologic complete response rate, a greater number of patients receiving the full course of adjuvant therapy, and a generally more favorable side effect profile. For most patients, we suggest FLOT rather than ECF or ECX when neoadjuvant chemotherapy is indicated. (See "Adjuvant and neoadjuvant treatment of gastric cancer".)
Updated ESMO guidelines for rectal cancer (July 2017)
The European Society for Medical Oncology (ESMO) has updated their guidelines for treatment of rectal cancer . Among the many changes from the 2013 guidelines, they suggest a selective approach to postoperative chemoradiotherapy in patients with resected stage II and III disease (table 1), recommending it only for patients with certain high-risk features identified at the time of surgery (table 2). The guidelines also suggest that neoadjuvant chemoradiotherapy be reserved for transmural (T3) tumors with >5 mm of extramural invasion; for other cases, initial surgery is preferred. (See "Adjuvant therapy for resected rectal adenocarcinoma", section on 'Indications'.)
Duration of adjuvant oxaliplatin for stage III colon cancer (July 2017)
Six months of oxaliplatin-based chemotherapy has been standard adjuvant treatment for stage III colon cancer, but associated neuropathy has prompted interest in shorter treatment. In preliminary results from a pooled analysis of over 12,000 patients with stage III colon cancer from six trials comparing three versus six months of treatment, there was less neuropathy, and the absolute decrement in three-year disease-free survival (DFS) with three months of treatment was very small (<1 percent) . Noninferiority for shorter treatment was supported for earlier substages of disease (T1-3, N1) but not T4 or N2 disease (table 1). These data are preliminary, and overall survival results are not mature. In the interim, we continue to suggest six months of oxaliplatin-based therapy for high-risk disease (T4, N2), but it seems reasonable to limit adjuvant therapy to three months in patients with low-risk disease (T1-3, N1). Patients with low-risk disease who place a high value on minimizing the risk of a disease recurrence may still choose six months of therapy, with oxaliplatin doses adjusted based upon neurotoxicity. Patients with higher-risk disease who place a higher value on avoiding neurotoxicity may choose three months of therapy if they are willing to accept a small potential detriment in DFS. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Duration of therapy'.)
Lenvatinib for advanced hepatocellular cancer (July 2017)
The benefits of first-line sorafenib for advanced hepatocellular cancer (HCC) are modest. A randomized noninferiority trial (the REFLECT study) compared lenvatinib versus sorafenib in over 900 patients with unresectable HCC and no prior systemic therapy . In a preliminary report presented at the 2017 annual meeting of the American Society of Clinical Oncology (ASCO), lenvatinib was noninferior in terms of median overall survival, and both the objective response rate and time to tumor progression were significantly better. Rates of grade 3 or 4 hypertension were higher with lenvatinib, while hand-foot skin reaction was more frequent with sorafenib. Lenvatinib represents a reasonable first-line treatment alternative to sorafenib, especially for patients who cannot tolerate sorafenib. (See "Systemic treatment for advanced hepatocellular carcinoma".)
Pembrolizumab for advanced colorectal cancer and other refractory solid tumors with deficient DNA mismatch repair (May 2017)
In a small study comparing pembrolizumab administration in patients with mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) or with MMR proficient (pMMR) mCRC, the objective response rate and disease control rate were 50 and 89 percent, respectively, for patients with dMMR mCRC and 0 and 16 percent for the pMMR group [36-38]. Largely based upon these data, the US Food and Drug Administration granted accelerated approval to pembrolizumab for the treatment of patients with advanced microsatellite instability-high (MSI-H) or dMMR mCRC that has progressed following conventional chemotherapy . The approval of pembrolizumab also extended to a variety of other advanced solid tumors (including endometrial, other gastrointestinal, breast, prostate, bladder, and thyroid) that were MSI-H or dMMR, had progressed following prior treatment, and for which there were no satisfactory alternative treatment options. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Immune checkpoint inhibitors and mismatch repair deficient tumors' and see "Treatment of recurrent or metastatic endometrial cancer", section on 'Immune checkpoint inhibitors'.
No incremental benefit from robotically assisted radical nephrectomy (October 2017)
Radical nephrectomy is increasingly performed with robotic assistance, despite a lack of evidence of incremental benefit. In a study including over 23,000 patients in a United States database who underwent radical nephrectomy, robotic radical nephrectomy was associated with longer operative time and higher hospital costs than the conventional laparoscopic approach, without lowering the rate of overall or major complications . We suggest conventional laparoscopic surgery for radical nephrectomy; however, robotic assistance may have a role in partial nephrectomy. (See "Definitive surgical management of renal cell carcinoma", section on 'Radical nephrectomy'.)
Nivolumab plus ipilimumab for advanced intermediate/poor-risk renal cell carcinoma (September 2017)
Antiangiogenic agents such as sunitinib are currently used as initial treatment for patients with advanced renal cell carcinoma (RCC). A phase III trial evaluated initial treatment with a combination of the checkpoint inhibitors nivolumab and ipilimumab in such patients. In an initial report of this trial, the checkpoint inhibitor combination, compared with sunitinib, increased the objective response rate and progression-free survival in previously untreated intermediate/poor-risk patients, particularly in those whose tumors had high PD-L1 expression . The combination of nivolumab plus ipilimumab is not approved for use in advanced RCC; additional follow-up, including the impact on overall survival, will be required to define the role of this combination. (See "Immunotherapy of renal cell carcinoma", section on 'Nivolumab plus ipilimumab'.)
PIVOT trial of surgery versus observation in localized prostate cancer (July 2017)
The PIVOT trial randomly assigned men with localized prostate cancer to radical prostatectomy or observation . After a median follow-up of 12.7 years, the difference in the overall risk of death (61 and 67 percent for surgery and observation, respectively) was not statistically significant; only 9 percent of all deaths were due to prostate cancer. Additional treatment for prostate cancer was eventually required in 34 percent of those managed with radical prostatectomy and 60 percent of those managed with observation. Both erectile dysfunction and urinary incontinence were more frequent with radical prostatectomy. (See "Radical prostatectomy for localized prostate cancer", section on 'Survival impact of radical prostatectomy'.)
Abiraterone/prednisone plus ADT for prostate cancer (June 2017)
Abiraterone blocks the conversion of steroid precursors to androgenic steroids within prostate cancer cells, thus providing the rationale for combining ADT with abiraterone. Two large trials demonstrated that the combination of abiraterone plus androgen deprivation therapy (ADT) prolongs overall survival, compared with ADT alone, in patients with castration-sensitive disease [43,44]. For men with high-risk advanced or metastatic prostate cancer, we recommend that ADT be combined with abiraterone or with docetaxel, as either combination prolongs overall survival compared with ADT monotherapy. The choice of regimen should include a discussion with the patient of the potential toxicities associated with each agent. (See "Initial systemic therapy for castration-sensitive prostate cancer", section on 'ADT plus abiraterone'.)
Adjuvant therapy and resected renal cell carcinoma (June 2017)
The role of adjuvant therapy following complete resection of renal cell carcinoma (RCC) has been unclear, with conflicting results from two previous trials using sunitinib and sorafenib. In an initial report from the PROTECT trial in patients with completely resected RCC, there was no difference in disease-free survival comparing adjuvant pazopanib with placebo . Except for patients enrolled in a formal clinical trial, there is no current role for adjuvant therapy with vascular endothelial growth factor (VEGF) pathway inhibitors in patients with resected RCC. (See "Overview of the treatment of renal cell carcinoma", section on 'Antiangiogenic and targeted therapy'.)
Immunotherapy plus targeted therapy for metastatic renal cell carcinoma (June 2017)
Checkpoint inhibitor immunotherapy targeting programmed cell death 1 (PD-1) or PD ligand 1 (PD-L1) has demonstrated improved overall survival in metastatic cancer from multiple primary sites, including second-line therapy of metastatic renal cell carcinoma (RCC). Efforts to improve further the results of checkpoint inhibition immunotherapy are looking at various combination approaches. Two phase I/II studies presented at the 2017 American Society of Clinical Oncology meeting reported promising activity for the combinations of atezolizumab plus bevacizumab and avelumab plus axitinib [46-48]. Phase III clinical trials are in progress with both of these regimens for the initial treatment of metastatic RCC. (See "Immunotherapy of renal cell carcinoma", section on 'Combined antiangiogenic plus checkpoint inhibitor therapy'.)
Oral contraceptives and ovarian cancer risk (June 2017)
Use of oral estrogen-progestin contraceptives is associated with a reduction in risk of ovarian cancer. In the largest and longest duration study of oral contraceptive use, the Royal College of General Practitioners’ Oral Contraception Study followed over 46,000 women for up to 44 years and found that ever-use of oral contraceptives was associated with a 33 percent reduction in ovarian cancer risk . This finding supports previous data and our recommendation for use of oral contraceptives in women who desire ovarian cancer risk reduction who have not undergone risk reduction surgery and who are not trying to conceive. (See "Risk-reducing bilateral salpingo-oophorectomy in women at high risk of epithelial ovarian and fallopian tubal cancer" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Epidemiology and risk factors", section on 'Oral contraceptives'.)
Sentinel lymph node biopsy in endometrial cancer (May 2017)
Sentinel lymph node biopsy for staging endometrial carcinoma is increasingly performed instead of selective or extended nodal dissection. In the largest multicenter prospective study of the procedure in over 300 women with clinical stage I endometrial carcinoma, successful mapping of at least one sentinel lymph node was achieved in 86 percent and the sensitivity of the sentinel lymph node was 97 percent . Nevertheless, we believe further study is needed before sentinel lymph node biopsy is established as a reasonable alternative to full pelvic lymphadenectomy in endometrial carcinoma. (See "Endometrial carcinoma: Pretreatment evaluation, staging, and surgical treatment".)
Pembrolizumab as a second-line option in metastatic or recurrent cervical cancer (November 2017)
Metastatic or recurrent squamous cell cervical cancer has a poor prognosis. First-line treatment includes chemotherapy with bevacizumab, an antiangiogenic agent. There are few data to guide second-line therapy. Pembrolizumab, a programmed cell death 1 (PD-1) immune checkpoint inhibitor, was evaluated in a prospective phase Ib study in women with PD-L1-positive tumor cells and disease progression after first-line therapy for metastatic or recurrent cervical cancer. The overall response rate was 17 percent (4 of 24 patients) and median duration of response was 5.4 months . While potentially promising, we await data from further studies before using pembrolizumab for this indication. Pembrolizumab has been approved for use in a variety of other advanced solid tumors (including endometrial, gastrointestinal, breast, prostate, bladder, and thyroid) that show deficiency in DNA mismatch repair, have progressed following prior treatment, and for which alternative treatment options are not available. (See "Management of recurrent or metastatic cervical cancer", section on 'Second-line therapy'.)
Bevacizumab and chemotherapy benefit confirmed in metastatic cervical cancer (October 2017)
Metastatic, persistent, or recurrent squamous cell cervical carcinoma has a poor prognosis, but survival has shown stepwise improvement with treatment with chemotherapy and, most recently, the angiogenesis inhibitor bevacizumab. The final results of the GOG 240 trial confirmed the 2012 interim results . The combination of bevacizumab and chemotherapy resulted in longer overall survival (16.8 versus 13.3 months) and progression-free survival (8.2 versus 6.0 months) than chemotherapy alone. Severe hypertension was more frequent in the bevacizumab group. The final results of this study further support our recommendation to treat women with recurrent or metastatic cervical cancer (who are not surgical candidates) with bevacizumab combined with chemotherapy. (See "Management of recurrent or metastatic cervical cancer", section on 'Chemotherapy plus bevacizumab as first-line treatment'.)
PARP inhibitor maintenance therapy in platinum-sensitive, recurrent ovarian cancer (March 2017, Modified September 2017)
Inhibitors of poly-ADP ribose polymerase (PARP) are being actively evaluated as maintenance therapy in platinum-sensitive relapsed ovarian cancer. In phase III trials of women with recurrent ovarian cancer who achieved a response to their most recent platinum-based treatment, the PARP inhibitors niraparib, olaparib, and rucaparib have each demonstrated progression-free survival benefits as maintenance therapy compared with placebo [53-56]. These data have led to approvals by the US Food and Drug Administration of both niraparib and olaparib in this setting [57,58]. However, overall survival data for PARP inhibitors as maintenance therapy are immature, and these agents have not been compared with bevacizumab, which is better established in the maintenance setting. Pending further data, we reserve use of PARP inhibition as maintenance therapy for patients with relapsed ovarian cancer who are not candidates for bevacizumab and who are in a complete or partial response to platinum-based chemotherapy. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-sensitive disease".)
Adjuvant chemoradiation for high-risk resected endometrial cancer (August 2017)
Optimal adjuvant management of high-risk resected endometrial cancer remains unclear. In the phase III GOG-258 trial, over 700 patients with high-risk resected endometrial cancer were randomly assigned to adjuvant chemoradiation versus chemotherapy alone . Although there was no difference in relapse-free survival between the groups, there were fewer lower vaginal, lower pelvic, and paraortic recurrences with the addition of radiation. Rates of severe toxicities were similar between the arms. Given these data, we offer adjuvant chemoradiation to those with resected endometrial cancer with risk factors for local relapse (eg, extensive lymph node involvement or deep invasion). (See "Adjuvant treatment of high-risk endometrial cancers".)
Risks of breast and ovarian cancer among BRCA mutation carriers (June 2017)
In a prospective cohort study of over 9800 female BRCA mutation carriers, cumulative rates of breast and ovarian cancer until age 80 years were 72 and 44 percent for BRCA1 carriers and 69 and 17 percent for BRCA2 carriers, respectively . In addition to educating women regarding their genetic risk factors, we also counsel women on how other risk modifiers, including reproductive history, use of hormonal therapy, and oophorectomy status, may impact their lifetime cancer risks. (See "Prevalence of BRCA1 and BRCA2 mutations and associated cancer risks", section on 'Breast and ovarian cancer' and "Prevalence of BRCA1 and BRCA2 mutations and associated cancer risks", section on 'Nongenetic cancer risk modifiers'.)
Laparoscopic interval debulking after neoadjuvant chemotherapy for ovarian cancer (May 2017)
Women with stage IIIC or IV ovarian cancer and unresectable disease may be candidates for neoadjuvant chemotherapy (NACT) followed by interval debulking, typically performed with laparotomy. Results of a large retrospective study suggest that laparoscopy could be a minimally invasive option for such debulking. Compared with laparotomy, laparoscopy was associated with similar three-year overall survival rates (47.5 versus 52.6 percent), similar suboptimal debulking rates (20.0 versus 22.6 percent), a shorter hospital stay by one day, and similar 30-day readmission rates . Further study is needed to evaluate whether short-term morbidity is reduced with use of laparoscopy. (See "Cancer of the ovary, fallopian tube, and peritoneum: Staging and initial surgical management", section on 'Role of laparoscopy'.)
HEAD AND NECK CANCER
Plasma EBV DNA screening in populations at high risk for nasopharyngeal carcinoma (August 2017)
Epstein-Barr virus (EBV) infection is an important etiologic risk factor for nasopharyngeal carcinoma (NPC) in regions where NPC is endemic. In a large cohort study, screening a healthy high-risk population for EBV DNA had a high sensitivity and specificity for the detection of early-stage NPC and was associated with a favorable progression-free survival (97 percent) at three years for newly diagnosed cases . While EBV-specific serologic screening has had limited specificity for nasopharyngeal carcinoma in other studies, analysis of plasma EBV DNA appears to have superior screening characteristics for screening an at-risk population for NPC in high-risk populations. EBV DNA screening can detect the cancer at an early stage with improved treatment outcomes compared with an unscreened population. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Screening based on EBV virus testing'.)
Hyperfractionation for definitive radiation therapy of head and neck cancer (August 2017)
Standard radiation therapy (RT) for definitive treatment of head and neck cancer is administered as a single daily dose, five days per week for seven weeks, but alternative schedules may improve outcomes in selected settings. In the MARCH meta-analysis, hyperfractionation without concurrent chemotherapy improved overall survival at 5 and 10 years, compared with once-a-day treatment . However, hyperfractionation has not been shown to improve survival in conjunction with concurrent chemotherapy. The relative benefits of hyperfractionation when given without concurrent chemotherapy need to be balanced against the increased cost and inconvenience associated with this approach. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations", section on 'MARCH meta-analysis'.)
Sequential induction chemotherapy and chemoradiotherapy for locally advanced head and neck cancer (August 2017)
The outcome of sequential therapy (induction chemotherapy followed by concurrent chemoradiotherapy) has yielded conflicting results in multiple clinical trials. An Italian phase III trial demonstrated improved overall survival with sequential therapy compared with concurrent chemoradiotherapy alone . Sequential therapy may offer advantages over concurrent chemoradiotherapy alone in select situations. Choice of therapy should be an individual clinician/patient decision, but generally, sequential therapy is reserved for healthy patients at high risk for both distant and locoregional recurrence. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Induction plus concurrent chemotherapy versus concurrent chemotherapy alone'.)
MELANOMA AND OTHER SKIN CANCER
Ipilimumab plus T-VEC in unresectable advanced melanoma (October 2017)
Talimogene laherparepvec (T-VEC) is an attenuated oncolytic herpes simplex virus that contains the granulocyte macrophage colony stimulating factor gene. T-VEC is injected directly into tumor to induce both a local and systemic immune response. In a randomized phase II trial in patients with advanced melanoma, objective response rates were higher for the combination of T-VEC plus ipilimumab compared with ipilimumab alone (39 versus 18 percent) and the incidence of serious adverse events was roughly comparable . Additional study and longer follow-up will be required to determine the role of T-VEC in combination with checkpoint inhibitors. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Checkpoint inhibition plus intralesional T-VEC'.)
Adjuvant therapy of cutaneous melanoma (September 2017)
Patients at high risk for recurrence after definitive surgical resection of cutaneous melanoma are candidates for adjuvant therapy. In a phase III trial, nivolumab increased relapse-free survival compared with ipilimumab . In another phase III trial, dabrafenib plus trametinib increased relapse-free and overall survival compared with placebo in patients with a BRAF V600 mutation . Neither regimen is currently approved in the adjuvant setting, but enrollment of high-risk patients in formal clinical trials should be considered whenever feasible. (See "Adjuvant therapy for cutaneous melanoma", section on 'Staging, tumor characteristics, and prognosis'.)
Nivolumab plus ipilimumab for advanced melanoma (September 2017)
The CheckMate 067 trial in previously untreated patients with advanced melanoma demonstrated improved progression-free survival and objective response rates for both the combination of nivolumab plus ipilimumab and for nivolumab alone, compared with ipilimumab alone. Results of this trial have now been updated with a minimum follow-up of three years and confirm the superiority of nivolumab plus ipilimumab versus ipilimumab alone in terms of overall survival, objective response rate, and progression-free survival . The combination of nivolumab plus ipilimumab is the preferred immunotherapy treatment for previously untreated patients with advanced melanoma. (See "Immunotherapy of advanced melanoma with immune checkpoint inhibition", section on 'Ipilimumab plus nivolumab'.)
Systemic therapy for melanoma brain metastases (June 2017)
Patients with central nervous system involvement from melanoma historically have had a very poor prognosis. Preliminary reports from two phase II studies suggest that the combination of nivolumab plus ipilimumab has important clinical activity against intracranial metastases [68,69]. Antitumor activity has also been observed with targeted therapy for patients whose melanoma has a BRAF V600 mutation. A multidisciplinary approach that considers all available treatment modalities is essential for the proper treatment of the patient with melanoma brain metastases. (See "Management of brain metastases in melanoma", section on 'Nivolumab plus ipilimumab'.)
Management of a positive sentinel lymph node biopsy in patients with cutaneous melanoma (June 2017)
Historically, completion dissection of all involved nodal basins was considered the standard treatment approach for patients with cutaneous melanoma and a positive sentinel lymph node biopsy (SLNB). In the phase III Multicenter Selective Lymphadenectomy Trial II (MSLT II), patients with a positive SLNB were randomly assigned to either completion lymph node dissection or observation that included ultrasound evaluation of the appropriate lymph node basins at each follow-up visit . Melanoma-specific survival at three years was the same for both groups, although the incidence of recurrence in regional lymph nodes was higher in patients managed with observation and ultrasound surveillance. The incidence of lymphedema was higher in patients who underwent immediate lymph node dissection. For patients with a positive SLNB, we suggest clinical observation coupled with ultrasound surveillance of the positive nodal basin. Completion lymph node dissection is indicated if, in the absence of distant metastases, there is evidence of regional lymph node recurrence. (See "Evaluation and treatment of regional lymph nodes in melanoma", section on 'Multicenter Selective Lymphadenectomy Trial II'.)
Duration of postradiation temozolomide in glioblastoma (July 2017)
Postradiation monthly temozolomide is a standard component of initial therapy for glioblastoma, but the number of cycles has been subject to variation, with some centers treating beyond six cycles for patients with stable disease. In a retrospective study of over 600 patients with glioblastoma enrolled in four randomized trials who were free of progression after six cycles of adjuvant temozolomide, receipt of more than six cycles was associated with a slight improvement in progression-free survival but no difference in overall survival . Since extended adjuvant therapy exposes patients to ongoing treatment-related toxicities, these results support our practice of stopping adjuvant therapy after six cycles of monthly temozolomide. (See "Initial postoperative therapy for glioblastoma and anaplastic astrocytoma", section on 'Treatment duration'.)
Postoperative stereotactic radiosurgery for resected brain metastases (July 2017)
Two randomized trials lend further support to the use of postoperative stereotactic radiosurgery (SRS) rather than whole brain radiation therapy (WBRT) or observation after resection of a single brain metastasis. In one trial, patients treated with single-fraction SRS to the surgical cavity had improved neurocognitive function and similar overall survival compared with those treated with WBRT . In the second trial, single-fraction SRS decreased rates of local recurrence compared with observation, especially for tumors smaller than 2.5 cm preoperatively . Larger tumors may be better suited for multiple-fraction SRS, which allows for a higher dose of radiation to be delivered to the surgical cavity. (See "Overview of the treatment of brain metastases", section on 'Postoperative radiation'.)
PALLIATIVE AND SUPPORTIVE CARE
Thalidomide for delayed nausea and vomiting after highly emetogenic chemotherapy (November 2017)
Neurokinin-1 receptor (NK1R) antagonists prevent delayed emesis from highly emetogenic chemotherapy (HEC), but are not available worldwide. In a randomized trial in patients receiving HEC, thalidomide (100 mg twice daily on days 1 to 5) was compared with placebo; all patients received palonosetron on day 1 and dexamethasone on days 2 through 4 . Patients receiving thalidomide had better control of acute and delayed nausea and vomiting but higher rates of sedation, dizziness, constipation, and dry mouth. An NK1R antagonist is preferred for patients receiving HEC, but the combination of thalidomide plus palonosetron and dexamethasone is an option for prevention of delayed emesis in patients who lack access to NK1R antagonists. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'Thalidomide'.)
Lorazepam plus haloperidol for persistent agitated delirium (September 2017)
Haloperidol is standard therapy for the symptomatic management of agitated delirium in medically ill patients. In a randomized trial, 90 patients with advanced cancer who were admitted to an acute palliative care unit and had persistent agitated delirium despite scheduled haloperidol were assigned to receive a single intravenous dose of lorazepam or placebo . The lorazepam group had lower RASS (Richmond Agitation-Sedation Scale) scores at eight hours, required less rescue neuroleptics, were perceived to be more comfortable by blinded caregivers and nurses, and had similar survival to the placebo group (68 versus 73 hours). For palliative care patients with persistent agitated delirium despite the use of haloperidol, we suggest a single dose of intravenous lorazepam rather than haloperidol alone. (See "Palliative care: The last hours and days of life", section on 'Delirium'.)
Misuse of prescribed opioids (September 2017)
Misuse of prescribed opioid drugs is a major source of escalating rates of opioid use disorder and opioid overdose in the United States. The 2015 National Survey on Drug Use and Health estimated that among the 92 million US adults prescribed opioid drugs in the prior year, almost 13 percent reported prescription opioid misuse, and 2 percent reported having a prescription opioid use disorder . Misuse reported by study subjects included taking higher or more frequent doses than prescribed and buying or using opioids prescribed to someone else. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Misuse'.)
Single fraction radiation therapy for epidural spinal cord compression (June 2017)
The optimal dose and schedule of external beam radiation therapy (EBRT) for treatment of epidural spinal cord compression (ESCC) is debated. In a preliminary report of the SCORAD III trial that compared single dose (8 Gy) versus multifraction EBRT (40 Gy in 20 fractions) in patients with spinal cord or cauda equina compression related to prostate, lung, breast, or gastrointestinal cancer and who were not appropriate surgical candidates, outcomes (median overall survival, treatment-related toxicity, bowel function and quality of life, need for retreatment) were similar for both radiation schedules . For most patients who have metastases from solid tumors and an estimated life expectancy of three months or less, we suggest a single EBRT fraction of 8 Gy. A more protracted course of RT may provide better long-term local control for selected patients (eg, those with myeloma or lymphoma, or a prolonged natural history, oligometastatic disease, slow progression of motor deficits, or who are receiving EBRT after surgical decompression). (See "Treatment and prognosis of neoplastic epidural spinal cord compression, including cauda equina syndrome", section on 'Dose and schedule'.)
Safe storage of prescription opioids (May 2017)
Although safe storage of prescription opioid medications (eg, locked cabinet) is recommended, it infrequently occurs. In a United States nationally representative survey of over 1000 adults with prescription opioid use in the past 12 months, only 9 percent reported safe storage of their medications . In further analysis of those adults with children younger than 18 years of age in the household, safe storage was reported in less than one-third of households with young children and 12 percent of households with children older than six years of age . These results support the need for anticipatory guidance by health care providers, emphasizing opioid safe storage and how it may limit opioid misuse and overdose, especially in households with children and adolescents. Further research should focus on developing and implementing effective means of secure storage in households. (See "Opioid intoxication in children and adolescents", section on 'Safe storage'.)
Osimertinib in EGFR mutated advanced non-small cell lung cancer (September 2017)
First-generation tyrosine kinase inhibitors (TKIs) have been the standard front-line treatment for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). In preliminary results from the phase III FLAURA trial in these patients, osimertinib, a third-generation EGFR TKI, prolonged progression-free survival compared with either gefitinib or erlotinib . We now prefer osimertinib as the front-line option for advanced EGFR-mutant NSCLC, although earlier-generation EGFR TKIs are acceptable alternatives. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Osimertinib in the front-line setting'.)
Duration of nivolumab treatment in advanced NSCLC (September 2017)
The optimal duration of therapy for immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) is unknown. In preliminary results of CheckMate-153, over 200 patients with advanced NSCLC who had been treated with the anti-PD-1 antibody nivolumab for one year without progression were randomly assigned to continue treatment or to discontinue, with the possibility of resuming upon disease progression . Those continuing treatment experienced improvement in progression-free survival and a nonsignificant trend towards improved overall survival relative to those treated for one year. For patients treated with an immune checkpoint inhibitor, we suggest continued treatment until progression or unacceptable toxicity occurs. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Duration of treatment'.)
Postoperative surveillance for nonmetastatic NSCLC (September 2017)
Although surveillance for patients who have been treated for nonmetastatic lung cancer typically includes computed tomography (CT) scans, there are no data from randomized trials supporting this strategy. In preliminary results of a trial in which 1775 patients with early or locally advanced non-small cell lung cancer (NSCLC) were randomly assigned to postoperative surveillance with either clinical examination and chest x-ray or these measures plus CT scans, median overall survival was 8.2 versus 10.3 years, respectively, a difference that was not statistically significant . Given the limited median follow-up in this study and pending longer follow-up, we continue to include CT scans as part of our surveillance strategy. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Approach'.)
Durvalumab in NSCLC (September 2017)
Despite administration of chemoradiotherapy, the prognosis for unresectable stage III non-small cell lung cancer (NSCLC) remains poor. In a phase III trial, over 700 patients with stage III NSCLC without progression after at least two cycles of platinum-based chemoradiotherapy were randomly assigned to the programmed death ligand 1 (PD-L1) antibody durvalumab or to placebo . Durvalumab increased the median progression-free survival (16.8 versus 5.6 months), with comparable rates of severe adverse events. Overall survival results are immature. Although these results are promising, we await further data or approval by regulatory agencies prior to routine incorporation of durvalumab in the management of stage III NSCLC. (See "Management of stage III non-small cell lung cancer", section on 'Immunotherapy'.)
Ceritinib in ROS1 translocated NSCLC (August 2017)
First-line therapy for ROS1 translocated non-small cell lung cancer (NSCLC), which comprises 1 to 2 percent of NSCLCs, has been the first generation tyrosine kinase inhibitor crizotinib. In a phase II trial including 28 patients with advanced ROS1 translocated NSCLC, the objective response rate with the second generation tyrosine kinase inhibitor ceritinib was over 60 percent . Among those who had progressed on crizotinib, the median progression-free survival on ceritinib was over nine months. However, given that ceritinib has not been compared with crizotinib in the frontline setting for those with ROS1 translocations, and only limited data exist in the setting of crizotinib progression, further study is required prior to routine clinical use of ceritinib for ROS1-driven NSCLCs. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 translocation'.)
Twice-daily versus once-daily concurrent chemoradiotherapy for LS-SCLC (August 2017)
In the CONVERT trial, almost 550 patients receiving concurrent chemoradiotherapy for limited stage small cell lung cancer (LS-SCLC) were randomly assigned to receive radiation either twice daily (45 Gy in 30 fractions) or once daily (66 Gy in 33 fractions) . Twice-daily treatment resulted in a nonsignificant trend towards improved median overall survival (30 versus 25 months). Although neutropenia was more frequent with twice-daily treatment, severe esophagitis and pneumonitis were similar between the groups. Given these data, we suggest twice-daily administration of concurrent chemoradiotherapy to a total of 45 Gy but recognize once-daily treatment to a total of 60 to 70 Gy as an acceptable alternative. (See "Limited stage small cell lung cancer: Initial management", section on 'Accelerated hyperfractionation'.)
No benefit with nivolumab as frontline treatment for advanced NSCLC (June 2017)
Immunotherapy using programmed death receptor 1 (PD-1) antibodies is an area of active investigation in non-small cell lung cancer (NSCLC). In a phase III trial of over 400 treatment-naïve NSCLC patients with at least 5 percent programmed death receptor-ligand 1 (PD-L1) expression, nivolumab did not improve progression-free or overall survival compared with platinum-doublet chemotherapy . Further research is needed to identify patients who might benefit from frontline nivolumab. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'First-line setting'.)
Revised follow-up for a solitary pulmonary nodule (June 2017)
Fleischner Society guidelines have been updated to reflect the accumulating data on the malignancy risk of incidental pulmonary nodules and growth rates of lung cancer . Important changes include guidance on identifying benign nodules with minimal follow-up imaging. For patients with a solid or subsolid (ground glass or part-solid) solitary pulmonary nodule measuring <6 mm, follow-up computed tomography (CT) is optional, but no longer required. A solitary pulmonary nodule that is solid and unchanged on serial CT over a two-year period, or subsolid and unchanged over a five-year period, is likely benign and does not need further diagnostic evaluation. Recommendations in UpToDate have been revised to reflect these new guidelines. (See "Diagnostic evaluation and management of the solitary pulmonary nodule", section on 'Management strategy' and "Diagnostic evaluation and management of the solitary pulmonary nodule", section on 'Solid nodules ≤8 mm'.)
Adjuvant EGFR inhibition in EGFR-mutated NSCLC (June 2017)
Chemotherapy has been used as standard adjuvant systemic treatment for non-small cell lung cancer (NSCLC), regardless of the presence of a driver mutation. However, in preliminary results of a phase III trial of over 200 patients with stage II to IIIA epidermal growth factor receptor (EGFR)-mutated NSCLC, median disease-free survival was longer (20 versus 18 months) and severe adverse events were less frequent for those randomly assigned to 24 months of adjuvant gefitinib compared with those assigned to chemotherapy . We await overall survival data before routine incorporation of adjuvant EGFR inhibition into clinical practice. (See "Adjuvant systemic therapy in resectable non-small cell lung cancer", section on 'Molecularly targeted agents'.)
Next-generation ALK-inhibitors in crizotinib-naive ALK-positive NSCLC (June 2017)
For patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), crizotinib has been administered as frontline therapy. However, newer agents have shown promising efficacy in advanced ALK-positive NSCLC:
●In a global trial of 303 patients randomly assigned to frontline crizotinib versus the next-generation inhibitor alectinib (ALEX), those receiving alectinib experienced a longer progression-free survival (PFS, not reached versus 11.1 months), with fewer toxicities, at a median follow-up of approximately 18 months . These results are consistent with an earlier Japanese trial .
●In a phase III trial of 376 patients comparing ceritinib, another next-generation ALK inhibitor, with pemetrexed and a platinum agent, ceritinib improved progression-free survival (17 versus 8 months) . Ceritinib has not been compared with crizotinib in the frontline setting.
For patients with newly diagnosed, ALK-positive NSCLC, we now recommend frontline therapy with alectinib. For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
Pembrolizumab approved with chemotherapy in treatment-naïve nonsquamous NSCLC (May 2017)
The anti-programmed death-1 (PD-1) antibody pembrolizumab has been approved by the US Food and Drug Administration (FDA) in combination with carboplatin and pemetrexed for treatment-naïve patients with advanced, nonsquamous non-small cell lung cancer (NSCLC). In a randomized phase II trial of 123 such patients, the addition of pembrolizumab to carboplatin and pemetrexed improved objective response rate (55 versus 29 percent, respectively) and progression-free survival (13 versus 6 months, respectively) relative to chemotherapy alone . Although we continue to prefer pembrolizumab monotherapy for those with ≥50 percent tumor cell staining for PD-L1, and targeted agents for those with EGFR or ALK genetic alterations, we now offer the combination of carboplatin, pemetrexed, and pembrolizumab as one frontline treatment option for other patients with nonsquamous NSCLC. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Pembrolizumab'.)
Brigatinib in crizotinib-refractory ALK-positive NSCLC (May 2017)
While the first generation anaplastic lymphoma kinase (ALK) inhibitor crizotinib is highly active in patients with ALK-positive non-small cell lung cancer (NSCLC), almost all patients develop resistance to the drug. In a phase II study of 222 patients with crizotinib-refractory, ALK-positive NSCLC receiving the next generation ALK inhibitor brigatinib, progression-free survival was 9.2 and 12.9 months, respectively, among those receiving a lower and higher dose of the agent . Although it has been associated with early pulmonary toxicity in approximately 9 percent of cases, brigatinib is now approved by the US Food and Drug Administration (FDA) for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib . We consider brigatinib or another next generation ALK inhibitor, ceritinib or alectinib, to be appropriate therapy in this setting. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Brigatinib'.)
No added benefit from MEK inhibitor in KRAS-mutant NSCLC (May 2017)
Although KRAS-mutant lung cancer is the largest genomically defined subset of non-small cell lung cancer (NSCLC), there are no established targeted therapies for its treatment. In a phase III trial of over 500 patients with advanced KRAS-mutant NSCLC, the addition of selumetinib, a mitogen-activated protein kinase (MEK) inhibitor, to docetaxel failed to improve progression-free survival, overall survival, or response rate relative to docetaxel alone . We continue to treat patients with advanced KRAS-mutant NSCLC in the same manner as those with unknown or untargetable mutation status. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Targeted therapy under investigation'.)
Incidence of endocrinopathies with checkpoint inhibitor immunotherapy (October 2017)
Immunotherapy of cancer with checkpoint inhibitors is associated with multiple immune-related adverse events, including hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, and type 1 diabetes. In a systematic review of 38 randomized trials, thyroid dysfunction was the most common endocrinopathy . The combination of nivolumab plus ipilimumab was associated with the highest incidence of hypothyroidism, while monotherapy with a PD-1 inhibitor (nivolumab, pembrolizumab) had the lowest incidence. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Endocrinopathies'.)
Risk of Stevens-Johnson syndrome in cancer patients (September 2017)
Patients with active malignancy, and in particular those with hematologic cancers, have an increased risk of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), a severe mucocutaneous reaction most commonly triggered by medications. An analysis of data from a large cohort of over 100,000 cancer patients found that the average annual incidence rate of SJS/TEN was approximately 30 to 60 times higher than in the general population . Whether the increased risk is due to the malignancy itself, the frequent immunocompromised state of cancer patients, or the increased exposure of these patients to potentially causative medications remains uncertain. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Malignancy'.)
New ASCO guideline aims to improve communication skills (September 2017)
The way in which serious news is conveyed can substantially influence the emotional response to the news, beliefs and attitudes toward the medical staff, and how patients view their future. While there are no consistent findings from randomized interventional studies that show better patient outcomes after modifying communication skills to deliver serious news, a number of studies have shown that clinician communication skills can be improved by training. A 2017 guideline from the American Society of Clinical Oncology (ASCO) recommends communication skills training for oncologists and presents best practices for core communication skills when clinicians are communicating with patients and their loved ones about goals of care, prognosis, treatment options, and end of life care (table 3) . (See "Discussing serious news", section on 'Can communication skills be taught and learned?'.)
Fertility preservation with cryopreserved ovarian tissue transplantation (July 2017)
For women at risk of ovarian failure due to planned gonadotoxic therapy and who desire fertility preservation, increasing evidence supports use of ovarian tissue cryopreservation followed by autotransplantation (OTT) after completion of therapy. In a 2017 meta-analysis, endocrine function was restored for at least four months after OTT in over 60 percent of women . OTT was associated with similar live birth rates as conventional frozen embryo transfer, and over 60 percent of women who conceived after an orthotopic transplant conceived naturally. (See "Fertility preservation in patients undergoing gonadotoxic treatment or gonadal resection", section on 'Outcomes'.)
Proton pump inhibitors may decrease absorption of capecitabine (July 2017)
Elevated gastric pH levels associated with use of proton pump inhibitors may alter dissolution and absorption of capecitabine and impair its efficacy. A secondary analysis of a large phase III study comparing capecitabine plus oxaliplatin with or without lapatinib for the treatment of advanced gastroesophageal cancer showed lower overall survival in patients who received concomitant proton pump inhibitors; a similar finding has been reported in patients receiving adjuvant capecitabine for colon cancer . Patients who are receiving a capecitabine-containing regimen for any cancer should probably not take proton pump inhibitors concurrently. (See "Systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Oral fluoropyrimidines' and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Capecitabine'.)
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