What's new in oncology

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.

BREAST CANCER

Improvement in breast cancer mortality from 1975 to 2019 (January 2024)

Improvements in breast cancer screening and treatments are decreasing breast cancer mortality. In a study using four simulation models of breast cancer mortality rates in the United States (US), breast cancer screening and treatment in 2019 were associated with a 58 percent reduction in US breast cancer mortality compared with 1975 [1]. Approximately half of this reduction was due to treatment of early breast cancer, while the rest was divided roughly equally between treatment of metastatic breast cancer and breast cancer screening. We support breast cancer screening for appropriate candidates and incorporate novel, data-driven strategies into our treatment recommendations for breast cancer. (See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer", section on 'Introduction' and "Screening for breast cancer: Strategies and recommendations".)

Omission of radiation in select patients with favorable-risk breast cancer (August 2023, Modified January 2024)

Trials are examining omission of radiation in early, favorable-risk breast cancer.

●In a single-arm trial including 500 females ≥55 years with T1N0, grade 1 or 2, luminal A-breast cancer, breast-conserving surgery and endocrine therapy without radiation were associated with a low incidence of local recurrence at five years (2.3 percent) [2].

●A prospective study found that patients ≥50 years with nontriple negative cT1N0 breast cancer that was unifocal on preoperative MRI and pT1N0 or N1mi at the time of surgery could omit adjuvant radiation and experience a low ipsilateral invasive recurrence rate (1 percent at five years) [3].

We consider omission of adjuvant radiation to be an option in women ≥65 years with clinically node-negative, small (tumor size <3 cm), hormone receptor-positive, HER2-negative breast cancer who are willing to take adjuvant endocrine therapy, but we await further data before omitting radiation in other patients. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Possible omission of RT for select ER-positive, HER2-negative cancers'.)

Regional nodal radiation in early breast cancer (November 2023)

Studies are evaluating the impact of adjuvant regional nodal radiotherapy (RT) in patients with early breast cancer. In a meta-analysis including over 12,000 patients, absolute improvements in breast cancer recurrence and mortality from regional nodal RT in trials from the 1990s through 2000s were greatest for patients at highest risk for recurrence; absolute reductions in 15-year breast cancer mortality were 1 to 2 percent among those with no positive axillary lymph nodes, 2 to 3 percent among those with one to three positive nodes, and 4 to 5 percent for those with four or more positive nodes [4]. However, no benefits were observed in earlier trials of nodal RT. The discrepancy is likely due to refinements in radiation techniques. For patients with node-positive or high-risk node-negative breast cancer, we offer adjuvant regional nodal RT. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Approach'.)

Peritumoral lidocaine injection before incision for breast cancer surgery (September 2023)

In a multicenter, randomized trial of over 1000 patients with early breast cancer undergoing mastectomy or breast-conserving surgery, peritumoral injection of 0.5% lidocaine prior to incision improved five-year disease-free survival (87 versus 83 percent) and five-year overall survival (90 versus 86 percent) [5]. The mechanism is unknown but thought to involve blocking voltage-gated sodium channels and thereby preventing activation of prometastatic pathways. The trial protocol for surgical management of breast cancer deviated from what may be considered standard treatment in many clinical practices, so further validation is necessary; however, peritumoral injection of lidocaine may be a reasonable intervention given its simplicity and minimal cost. (See "Breast-conserving therapy", section on 'Incision'.)

Sacituzumab govitecan in hormone receptor-positive, HER2-negative metastatic breast cancer (August 2023)

Sacituzumab govitecan (SG) is an antibody-drug conjugate that previously showed progression-free survival benefits over clinician's choice of therapy in patients with metastatic, heavily pretreated, hormone receptor (HR)-positive, HER2-negative breast cancer; overall survival results from that randomized trial are now available. Among 543 patients, the overall survival with SG was 14.4 versus 11.2 months with clinician's choice of therapy [6]. SG has regulatory approval in the United States for patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting [7,8]. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Sacituzumab govitecan'.)

Pretreatment staging of locally advanced breast cancer (August 2023)

For patients with locally advanced breast cancer, pretreatment imaging is typically obtained to rule out metastatic disease, but the optimal modality is under investigation. In a randomized trial in 369 patients with stage III or IIb (T3N0, but not T2N1) breast cancer, 23 percent of patients assigned to staging with positron emission tomography-computed tomography (PET-CT) were upstaged to stage IV compared with 11 percent assigned to CT of the chest, abdomen, and pelvis (CT C/A/P) and bone scan [9]. This resulted in changes in treatment strategy, such that fewer patients in the PET-CT group received combined modality therapy (81 versus 89 percent). For patients with stage IIIA or higher disease, regardless of whether symptoms are present, we obtain a whole-body PET-CT for staging, but we consider a bone scan plus CT C/A/P to be a reasonable alternative. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer", section on 'Role of imaging'.)

ENDOCRINE TUMORS

Selpercatinib for RET-mutated medullary thyroid cancer (November 2023)

In an open-label, randomized trial comparing selpercatinib (a selective RET inhibitor) with either cabozantinib or vandetanib (less selective antiangiogenic kinase inhibitors with some RET inhibition) in 291 patients with progressive, locally advanced or metastatic RET-mutated medullary thyroid cancer, median progression-free survival was not reached in the selpercatinib group and was 16.8 months in the active comparator group [10]. The 12-month progression-free survival was better with selpercatinib (87 versus 66 percent with cabozantinib or vandetanib); complete response occurred in 12 and 4 percent, respectively. There were fewer grade ≥3 adverse events in the selpercatinib group, and fewer patients discontinued treatment due to adverse events. These finding support our recommendation for selpercatinib as initial therapy in patients with RET-mutated tumors who meet criteria for systemic treatment. (See "Medullary thyroid cancer: Systemic therapy and immunotherapy", section on 'Selpercatinib'.)

GASTROINTESTINAL CANCER

Model for End-stage Liver Disease (MELD) 3.0 for liver transplantation (October 2023, Modified December 2023)

The Model for End-stage Liver Disease (MELD) score is used to allocate livers for transplantation. Recently, the Organ Procurement and Transplantation Network implemented an updated score, MELD 3.0, for prioritizing liver transplantation candidates who are ages 12 and older [11]. MELD 3.0 includes variables from the original model (ie, serum bilirubin, serum creatinine, and international normalized ratio) in addition to other inputs (ie, serum sodium, patient sex, and serum albumin) and a lower creatinine ceiling. Goals of using MELD 3.0 include reducing overall waitlist mortality and improving access for female liver transplant candidates. (See "Model for End-stage Liver Disease (MELD)", section on 'MELD 3.0'. and "Liver transplantation for hepatocellular carcinoma", section on 'MELD 3.0'.)

Risk of pancreatic cancer in stable intraductal papillary mucinous neoplasms (November 2023)

The optimal duration of pancreatic cancer surveillance in patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) is unclear. In a study of over 3800 such patients without worrisome features (WFs) or high-risk stigmata (HRS), 42 percent had BD-IPMNs that remained stable in size and did not develop WF/HRS for at least five years [12]. Within this group, patients ≥75 years with cysts <30 mm and those ≥65 years with cysts <15 mm had a standardized incidence ratio for pancreatic cancer comparable to the general population and low disease-specific mortality. These data suggest that this subgroup may be able to discontinue pancreatic cancer surveillance; however, further studies are needed to validate these results. (See "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Pathophysiology and clinical manifestations", section on 'Pancreatic malignancy'.)

Sotorasib plus panitumumab for KRAS G12C mutant metastatic colorectal cancer (November 2023)

For patients with treatment-refractory, KRAS G12C mutant metastatic colorectal cancer (mCRC), studies are evaluating sotorasib, an irreversible inhibitor of KRAS G12C. In a phase III trial in 160 patients with treatment-refractory KRAS G12C mutant mCRC, sotorasib 960 mg daily plus panitumumab improved progression-free survival (median 5.6 versus 2.2 months) compared with trifluridine-tipiracil or regorafenib at median follow-up of eight months and was well tolerated [13]. For patients with KRAS G12C mutant mCRC who progress on multiple agents including chemotherapy and vascular endothelial growth factor inhibitors, we consider sotorasib plus panitumumab to an acceptable treatment option. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS-mutated tumors'.)

Gemcitabine plus cisplatin and pembrolizumab for advanced cholangiocarcinoma (November 2023)

Advanced cholangiocarcinoma is an aggressive disease with poor survival outcomes, so there is interest in investigating novel approaches, such as the addition of immunotherapy to chemotherapy. In a placebo-controlled, phase III trial of over 1000 patients with treatment-naïve, locally advanced or metastatic biliary tract cancers, the addition of pembrolizumab to gemcitabine plus cisplatin improved overall survival (median 13 versus 11 months) with an acceptable toxicity profile [14]. Based on these data, pembrolizumab, in combination with gemcitabine plus cisplatin, was approved by the US Food and Drug Administration for the treatment of locally advanced unresectable or metastatic biliary tract cancer [15]. We consider this combination to be an appropriate initial treatment option in fit patients with advanced or metastatic cholangiocarcinoma and no hyperbilirubinemia. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'Gemcitabine plus cisplatin and pembrolizumab'.)

Trastuzumab plus tucatinib for advanced cholangiocarcinoma (November 2023)

For patients with advanced or metastatic human epidermal growth factor 2 (HER2)-positive cholangiocarcinoma who progress on chemotherapy, studies are evaluating tucatinib, an oral, highly selective HER2 inhibitor. In a phase II trial in 30 patients with previously treated HER2-positive cholangiocarcinoma, trastuzumab plus tucatinib was associated with an objective response rate of 47 percent [16]. For patients with advanced or metastatic HER2-positive cholangiocarcinoma who progress on gemcitabine, platinum, and/or fluorouracil-based chemotherapy, trastuzumab plus tucatinib is an acceptable option for later-line therapy. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'HER2-positive tumors'.)

Selecting radiation therapy for total neoadjuvant therapy in locally advanced rectal cancer (October 2023)

For patients with locally advanced rectal cancer (LARC) who are treated with total neoadjuvant therapy (TNT; neoadjuvant chemotherapy and radiation therapy [RT] prior to surgical evaluation), the optimal RT schedule is not established. In extended follow-up of a randomized trial in over 900 patients with LARC, TNT using short-course RT (25 Gray total over 5 fractions) had worse five-year locoregional recurrence rates (10 versus 6 percent) and similar overall survival (82 versus 81 percent) relative to neoadjuvant long-course chemoradiation (CRT; 50.4 to 54 Gray total over 28 to 31 fractions, followed by surgery and adjuvant chemotherapy) [17]. Based on these data, for most patients with LARC selecting between RT schedules for TNT, we suggest long-course CRT rather than short-course RT. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Selection of RT schedule'.)

Sugar-sweetened beverages and risk of liver cancer (September 2023)

There is interest in evaluating the impact of sugar-sweetened beverages (such as regular sodas and fruit drinks) on the risk of developing liver cancer. In an observational study of almost 99,000 postmenopausal females, higher intake of sugar-sweetened beverages (one or more servings per day) was associated with an increased risk of developing liver cancer (hazard ratio 1.85) relative to less frequent consumption (three or less servings per month) [18]. These findings support the importance of limiting or avoiding sugar-sweetened beverages as part of a healthy diet for adults and for cancer prevention. (See "Epidemiology and risk factors for hepatocellular carcinoma", section on 'Dietary factors'.)

FOLFOXIRI plus bevacizumab for metastatic colorectal cancer with isolated liver metastases (September 2023)

In patients with metastatic colorectal cancer (mCRC) and isolated hepatic metastases, studies are investigating the optimal approach to systemic therapy. In a phase III trial in almost 300 patients with unresectable mCRC limited to the liver and a right-sided RAS/BRAF V600E mutant primary tumor, initial therapy with FOLFOXIRI (infusional fluorouracil [FU], leucovorin [LV], oxaliplatin, and irinotecan) plus bevacizumab for up to six months improved progression-free survival relative to FOLFOX (oxaliplatin plus LV and short-term infusional FU) or FOLFIRI (irinotecan plus LV and short-term infusional FU) plus bevacizumab (11 versus 9 months) [19]. Rates of complete local treatment (with either surgery or radiation) of hepatic metastases were also higher (51 versus 37 percent). For patients with RAS/BRAF V600E mutant mCRC and initially unresectable isolated liver disease, we suggest initial systemic therapy with FOLFOXIRI plus bevacizumab. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'RAS/BRAF mutant disease'.)

Divarasib in G12C KRAS-mutant solid tumors (September 2023)

Novel agents are under investigation for G12C KRAS-mutant solid tumors. In a phase I study in 137 patients with advanced KRAS-mutant cancers, among the 60 patients with non-small cell lung cancer, the objective response rate to the covalent KRAS G12C inhibitor divarasib was 53 percent, with a median progression-free survival (PFS) of 13.1 months; among the subgroup of 55 patients with metastatic colorectal cancer, the response rate was 29 percent, with a median PFS of 6 months [20]. Responses were also observed in patients with other solid tumors. Treatment was generally well tolerated, with grade ≥3 events occurring in 12 percent of patients. We await further data and/or regulatory approval prior to use of divarasib in G12C KRAS-mutant solid tumors. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Others' and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS-mutated tumors'.)

GENITOURINARY ONCOLOGY

Novel treatment approaches for metastatic urothelial carcinoma (December 2023)

For patients with metastatic urothelial carcinoma (UC), randomized trials are evaluating treatments that improve upon the efficacy and/or tolerability of platinum-based chemotherapy:

●Among 900 patients with previously untreated locally advanced or metastatic UC eligible for platinum-based chemotherapy, enfortumab vedotin (an antibody-drug conjugate) plus pembrolizumab improved overall survival (median 31 versus 16 months) versus platinum-based chemotherapy with less grade ≥3 toxicity (56 versus 70 percent) [21].

●Among 600 cisplatin-eligible patients with advanced or metastatic UC, the addition of nivolumab to gemcitabine and cisplatin improved overall survival (median 22 versus 19 months) [22].

Based on these data, for patients with metastatic UC, we now offer initial treatment with enfortumab vedotin plus pembrolizumab but consider nivolumab plus gemcitabine and cisplatin to be a reasonable alternative. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Enfortumab vedotin plus pembrolizumab' and "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Nivolumab plus gemcitabine plus cisplatin'.)

Enzalutamide and androgen deprivation therapy in prostate cancer with high-risk biochemical recurrence (November 2023)

Trials are evaluating novel hormonal agents such as enzalutamide in subsets of males with recurrent prostate cancer. In a randomized trial in over 1000 males with high-risk biochemical recurrence, enzalutamide plus androgen deprivation therapy (ADT) improved five-year metastasis-free survival compared with enzalutamide alone (87 versus 80 percent) or ADT alone (87 versus 71 percent) [23]. The five-year overall survival in the combination group was improved compared with ADT alone (92 versus 87 percent). Treatment was discontinued due to adverse events in 21 percent of patients in the combination group, 18 percent in the enzalutamide-alone group, and 10 percent in the leuprolide-alone group. Based on these results, we suggest enzalutamide and ADT as initial treatment for prostate cancer with high-risk biochemical recurrence. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'Second generation nonsteroidal antiandrogens plus ADT'.)

Lenvatinib plus pembrolizumab for advanced non-clear cell renal carcinoma (October 2023)

Advanced non-clear cell renal cell carcinoma (RCC) is rare, and there are limited data on the optimal approach to initial therapy. In a phase II trial in over 150 patients with advanced, systemic, therapy-naïve non-clear cell RCC, objective responses for lenvatinib plus pembrolizumab by histology were 67 percent for those with translocation RCC, 54 percent for those with papillary RCC, 52 percent for those with unclassified RCC, and 28 percent for those with chromophobe RCC [24]. We suggest lenvatinib plus pembrolizumab as initial therapy for patients with translocation RCC, and we consider this combination as one of several appropriate initial options for the other histologies. (See "The treatment of advanced non-clear cell renal carcinoma", section on 'Lenvatinib plus pembrolizumab'.)

Standard versus extended lymphadenectomy for radical cystectomy (August 2023)

The benefit of an extended lymphadenectomy during radical cystectomy is controversial. In a phase III trial, 618 patients with cT2-4a N0-2 bladder cancer underwent radical cystectomy with standard or extended lymphadenectomy and were followed for six years [25]. Although more lymph nodes were removed with extended lymphadenectomy (median 39 versus 25), this did not result in more favorable outcomes as rates of nodal metastasis, disease-free survival, and overall survival were similar. Furthermore, extended lymphadenectomy resulted in a higher rate of severe complications (16 versus 8 percent) and more deaths within 90 days (19 versus 7 patients). Given these results, radical cystectomy should be performed with bilateral standard lymphadenectomy, which includes removal of at least 12 external and internal iliac and obturator nodes. (See "Radical cystectomy", section on 'Lymphadenectomy'.)

Belzutifan for advanced clear cell renal carcinoma (January 2023)

For patients with advanced clear cell renal carcinoma (RCC), studies are evaluating targeted agents such as belzutifan, a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). In a randomized trial in approximately 750 patients with treatment-refractory advanced or metastatic clear cell RCC, belzutifan improved progression-free survival (PFS) over everolimus (18-month PFS 23 versus 9 percent) and was well tolerated [26]. Based on these data, the US Food and Drug Administration approved belzutifan for patients with advanced RCC following treatment with an immune checkpoint inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Belzutifan'.)

GYNECOLOGIC ONCOLOGY

Atezolizumab in metastatic cervical cancer (January 2024)

Trials are evaluating the addition of immunotherapy to chemotherapy as initial systemic treatment for metastatic cervical cancer. In an open-label randomized trial in 410 patients with metastatic or recurrent cervical cancer not amenable to curative treatment, the addition of the checkpoint inhibitor atezolizumab to chemotherapy and bevacizumab improved both median progression-free survival (13.7 versus 10.4 months) and overall survival (32 versus 23 months) [27]. Grade ≥3 events occurred in 79 percent receiving atezolizumab and 75 percent in the control group. Although this approach does not yet have regulatory approval, we consider it to be an appropriate initial treatment in patients with metastatic cervical cancer not amenable to curative treatment. (See "Management of recurrent or metastatic cervical cancer", section on 'Atezolizumab'.)

Mirvetuximab soravtansine in folate receptor alpha-positive ovarian cancer (December 2023)

Mirvetuximab soravtansine (MIRV) is a folate receptor (FR) alpha-directed antibody and microtubule inhibitor conjugate that is being evaluated for platinum-resistant, FR alpha-positive epithelial ovarian cancer (EOC). In a randomized trial of MIRV versus investigator's choice chemotherapy in 453 patients with such cancers, MIRV improved objective response rates (42 versus 16 percent), progression-free survival (5.6 versus 4.0 months), and overall survival (16.5 versus 12.8 months) [28]. Grade ≥3 adverse events were less common in the MIRV group (42 versus 54 percent). Based on these results, MIRV has regulatory approval in the United States for FR alpha-positive, platinum-resistant EOC that has been treated with one to three prior systemic treatment regimens. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'Mirvetuximab soravtansine'.)

Avoidance of PARP inhibitors as maintenance for platinum-sensitive relapsed ovarian cancer (September 2023)

For advanced epithelial ovarian cancer (EOC) with platinum-sensitive relapse, poly(ADP-ribose) polymerase (PARP) inhibitors were previously an option for maintenance therapy, irrespective of the presence of a BRCA mutation. However, this strategy no longer has regulatory approval in the United States for patients with BRCA wildtype cancers due to a lack of survival benefit in this population [29-31]. For patients with BRCA wildtype cancers and platinum-sensitive relapse, we use bevacizumab with platinum-based chemotherapy rather than a PARP inhibitor and continue as maintenance treatment. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'PARP inhibitors no longer used'.)

HEAD AND NECK CANCER

Dysphagia-optimized intensity-modulated radiation therapy (DO-IMRT) in patients with head and neck cancer (October 2023)

Dysphagia-optimized intensity-modulated radiation therapy (DO-IMRT), which reduces the radiation doses to the pharyngeal muscles, is under investigation as a method to decrease treatment-related toxicity in patients with head and neck cancer. In a randomized trial in patients with pharyngeal or hypopharyngeal cancer, DO-IMRT modestly improved swallowing function at 12 months compared with standard IMRT group on a scale of patient-reported outcomes [32]. Additional data, including long-term outcomes, are needed to determine the optimal method of administering IMRT. (See "General principles of radiation therapy for head and neck cancer", section on 'Intensity-modulated RT'.)

Epstein-Barr virus screening strategies for nasopharyngeal carcinoma (September 2023)

Various indicators of Epstein-Barr virus (EBV) infection have been investigated as screening strategies for nasopharyngeal carcinoma (NPC) in endemic areas. In a case-control study in Taiwan, EBV DNA load had both higher sensitivity (93 versus 88 percent) and specificity (98 versus 95 percent) compared with EBV antibodies [33]. A second study used a peptide library of EBV sequences to identify anti-BNLF2b (P85-Ab) as a possible novel serologic biomarker for NPC [34]. In a prospective cohort in almost 25,000 participants in China, including 47 patients with NPC, P85-Ab had better sensitivity and specificity than a standard two-antibody-based screening method. While these results are promising, the optimal screening strategy for NPC is still under investigation. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Screening based on Epstein-Barr virus testing'.)

MELANOMA AND OTHER SKIN CANCER

Tebentafusp and uveal melanoma (November 2023)

In patients with human leukocyte antigen (HLA)-A*02:01-positive metastatic uveal melanoma, a randomized trial previously showed an improvement in overall survival (OS) with tebentafusp compared with clinician's choice of systemic therapy at a median follow-up of 14 months. Now, with longer follow-up of 36 months, improvements in OS persist (three-year OS 27 versus 18 percent; median OS 22 versus 17 months) [35,36]. Improvements were also seen in progression-free survival (median 3.4 versus 2.9 months) and objective response rates (11 versus 5 percent). Adverse events were similar to previous reports. With the longer follow-up of this trial, tebentafusp remains the recommended first-line therapy for patients with HLA-A*02:01-positive metastatic uveal melanoma. (See "Metastatic uveal melanoma", section on 'Tebentafusp'.)

Adjuvant nivolumab in resected Merkel cell carcinoma (July 2023)

Several studies are investigating neoadjuvant and adjuvant therapies in patients with resected Merkel cell carcinoma (MCC). In an open-label, phase II trial, patients with any stage, completely resected MCC were randomly assigned after surgery to one year of adjuvant nivolumab versus surveillance [37]. The disease-free survival rate at 24 months was 84 percent with nivolumab versus 73 percent with observation only. Overall survival results are immature. We await further data prior to incorporating adjuvant nivolumab for MCC into routine clinical practice. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Adjuvant systemic therapy'.)

NEUROONCOLOGY

Intraoperative techniques for glioblastoma resection (December 2023)

Several intraoperative neurosurgical techniques are available to improve the extent of glioblastoma resection while minimizing damage to normal brain, but little comparative data exist. In a multicenter parallel-group trial that included over 300 patients undergoing resection of a newly diagnosed glioblastoma, rates of complete resection were comparable with use of either intraoperative magnetic resonance imaging (iMRI) or 5-aminolevulinic acid (ALA; 81 and 78 percent, respectively) [38]. In both groups, absence of any enhancing tumor postoperatively was associated with improved progression-free and overall survival. These results further support use of adjunctive tools like iMRI and ALA to facilitate maximal safe resection; selection of a specific operative plan is individualized based on neurosurgeon preference, tumor location, and availability of various technologies. (See "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas", section on 'Intraoperative techniques'.)

BRAF/MEK targeted therapy in pediatric low-grade glioma (September 2023)

Targeted therapy is preferred for many children with BRAF V600E-mutant low-grade gliomas who require treatment beyond surgery. In a randomized, open-label, phase 2 trial in 110 such children requiring treatment after surgery for either symptoms or progression, first-line targeted BRAF/MEK inhibition (dabrafenib plus trametinib) improved overall response rate compared with carboplatin plus vincristine chemotherapy (47 versus 11 percent); it also improved median progression-free survival (20.1 versus 7.4 months) and was better tolerated [39]. Overall survival data are not yet mature. Although not compared with radiation therapy, targeted therapy has the advantage of avoiding or at least delaying the long-term neurologic and cognitive consequences of radiation, which are of particular concern in younger patients. (See "Uncommon brain tumors", section on 'Ganglioglioma and gangliocytoma'.)

Prevalence of Lynch syndrome in younger adults with glioblastoma (August 2023)

Mismatch repair (MMR) deficiency and Lynch syndrome are rare among patients with glioma as a whole, but certain patients are at increased risk. In a study that included 1225 adult glioma samples referred to a single neuropathology department, nine gliomas were MMR deficient (0.73 percent), including eight isocitrate dehydrogenase (IDH)-wildtype glioblastomas [40]. In a complementary analysis that included >250 additional IDH-wildtype glioblastomas enriched for young-onset cases, the rate of MMR deficiency was as high as 12.5 percent in patients between 18 and 39 years of age. Based on these data, we suggest tumor testing for MMR deficiency in IDH-wildtype glioblastomas in patients younger than 50 years at diagnosis; all patients with MMR deficiency on somatic (tumor) testing should be offered genetic counseling and germline testing for Lynch syndrome. (See "Risk factors for brain tumors", section on 'Mismatch repair deficiency'.)

Resection versus biopsy of glioblastoma in older adults (August 2023)

The role of surgical resection in older adults with glioblastoma is controversial. In the first completed trial, 101 older adults (≥70 years) with a suspected operable glioblastoma were randomly assigned to either resection or biopsy, followed by radiation therapy (in all patients) and temozolomide (in later years of the trial) [41]. Although overall survival was similar between groups (9.4 versus 9.0 months), progression-free survival and quality-of-life outcomes favored resection. The trial was limited by slow enrollment, and confidence intervals for survival were wide. We continue to suggest maximal safe resection for most older adults with operable tumors who are good surgical candidates. (See "Management of glioblastoma in older adults", section on 'Role of surgery'.)

BRAF/MEK targeted therapy in papillary craniopharyngioma (July 2023)

Nearly all papillary craniopharyngiomas harbor a BRAF V600E mutation, and new data confirm that these tumors are exquisitely sensitive to combined BRAF/MEK inhibition. In a multicenter, single-arm, phase 2 study in 16 patients with biopsy-confirmed BRAF V600E-mutant papillary craniopharyngioma and no prior therapy, treatment with vemurafenib plus cobimetinib led to a partial or complete response in 15 of 16 patients (94 percent) [42]. Among responders, median volumetric tumor reduction from baseline was 91 percent. For most patients with newly diagnosed BRAF-mutant papillary craniopharyngioma, we suggest a trial of BRAF/MEK inhibition before proceeding with definitive radiation therapy or an attempt at maximal resection; treatment decisions after four to six cycles of therapy should be individualized based on tumor response, patient age, comorbidities, and risks of radiation and surgery. (See "Craniopharyngioma", section on 'Targeted therapy for BRAF-mutant tumors'.)

PALLIATIVE AND SUPPORTIVE CARE

Olanzapine for cancer-associated anorexia and cachexia (August 2023)

Studies are evaluating approaches to management of anorexia and cachexia in patients with advanced cancer. In a randomized trial, 124 patients starting chemotherapy for lung, pancreaticobiliary, or stomach cancer were assigned to olanzapine 2.5 mg daily or placebo [43]. More patients in the olanzapine group experienced at least 5 percent weight gain (60 versus 9 percent) and appetite improvement (43 versus 30 percent). Olanzapine was well tolerated. These and earlier data led the American Society of Clinical Oncology to support low-dose olanzapine once daily to improve weight gain and appetite in patients with advanced cancer [44], while recognizing that the majority of data come from patients with lung or gastrointestinal cancer. (See "Management of cancer anorexia/cachexia", section on 'Olanzapine'.)

SOFT TISSUE AND BONE TUMORS

Atezolizumab in alveolar soft parts sarcoma (September 2023)

The prognosis of metastatic alveolar soft parts sarcoma (ASPS) is poor, and trials are investigating immune checkpoint inhibitors as a treatment strategy. In longer follow-up of a previously reported single arm trial in 52 adult and pediatric patients, atezolizumab was associated with a response rate of 37 percent and median progression-free survival of 25 months [45]. There were no grade 4 or 5 events. Atezolizumab is approved by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic ASPS [46], and we consider it to be an acceptable option for such patients with limited, but progressive, extracranial disease. (See "Uncommon sarcoma subtypes", section on 'Limited, progressive disease burden'.)

THORACIC ONCOLOGY

Repotrectinib in advanced ROS1-positive NSCLC (January 2024)

Studies are evaluating novel tyrosine kinase inhibitors (TKIs) in advanced ROS1-positive non-small cell lung cancer (NSCLC). In a study of repotrectinib in 71 patients with such cancers who were naïve to TKIs, the median progression-free survival (PFS) was 36 months and the 18-month overall survival (OS) rate was 88 percent. Among 56 patients with one prior TKI and no chemotherapy, the median PFS was 9 months and OS was 25 months [47]. These data contributed to regulatory approval of repotrectinib in the United States [48]. We consider repotrectinib to be an acceptable initial treatment option for patients with advanced ROS1-positive NSCLC. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 rearrangements'.)

Tarlatamab in small cell lung cancer (December 2023)

Delta-like ligand 3 is overexpressed in approximately 90 percent of small cell lung cancer (SCLC). In a phase II study in 220 patients with a median of two prior treatments for SCLC, tarlatamab, an investigational bispecific T cell engager immunotherapy directed against delta-like ligand 3, was associated with response rates of 32 percent among those receiving 10 mg daily and 40 percent among those receiving 100 mg daily [49]. Overall survival rates at 9 months were 66 and 68 percent, respectively. The most common adverse events were cytokine-release syndrome (mostly grade 1 to 2), decreased appetite, and pyrexia. Tarlatamab is under regulatory review in the United States and is not yet available outside of a clinical trial. (See "Treatment of refractory and relapsed small cell lung cancer", section on 'Other options'.)

Stereotactic body radiation therapy in oligometastatic NSCLC (December 2023)

For patients with oligometastatic non-small cell lung cancer (NSCLC), studies are evaluating whether local treatment of metastatic lesions, when used in conjunction with standard systemic therapy, can improve outcomes. In an open-label trial including patients with either oligometastatic breast or NSCLC, among the 59 patients with lung cancer, the addition of stereotactic body radiation therapy to standard of care systemic treatment improved median progression-free survival (PFS, 10.0 versus 2.2 months) but failed to improve overall survival (OS) [50]. PFS benefit was not observed among breast cancer patients. For patients with NSCLC and one to three metastases, we suggest using both local therapy and systemic therapy, while recognizing the need for larger studies to clarify the effect on OS. (See "Oligometastatic non-small cell lung cancer", section on 'Overall'.)

Pemetrexed-cisplatin as adjuvant chemotherapy for nonsquamous NSCLC (December 2023)

Although platinum-based doublet chemotherapy is a standard adjuvant regimen for resected non-small cell lung cancer (NSCLC), trials are investigating the optimal chemotherapy agent to pair with the platinum agent. In a randomized trial including 783 patients with stage II to IIIA nonsquamous NSCLC, there was a nonsignificant trend in recurrence-free survival favoring pemetrexed-cisplatin compared with vinorelbine-cisplatin (43 versus 38 months) [51]; overall survival rates were comparable. Previous data suggest lower rates of neutropenia with pemetrexed-based therapy. For those receiving adjuvant chemotherapy for resected nonsquamous histology NSCLC, we suggest pemetrexed to partner with the platinum agent. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Cisplatin-based doublets'.)

Osimertinib plus chemotherapy in EGFR-mutant NSCLC (November 2023)

Although the targeted agent osimertinib is standard initial treatment in advanced EGFR-mutated non-small cell lung cancer (NSCLC), trials are evaluating the role of added chemotherapy. In a randomized open-label trial including 557 patients with advanced EGFR-mutated NSCLC, initial treatment with osimertinib plus platinum-pemetrexed chemotherapy improved progression-free survival compared with osimertinib alone (29.4 versus 19.9 month) [52]. At 24 months, overall survival was immature, but there was a nonsignificant trend favoring osimertinib-chemotherapy (hazard ratio 0.9, 95% CI 0.65-1.24). Grade ≥3 adverse events were more common with osimertinib-chemotherapy (64 versus 27 percent). We await longer-term survival data prior to incorporating chemotherapy into the initial treatment strategy for EGFR-mutant NSCLC. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Preferred: Osimertinib, with or without chemotherapy'.)

Pembrolizumab and chemotherapy in advanced pleural mesothelioma (November 2023)

Trials are exploring the role of chemoimmunotherapy in newly diagnosed advanced pleural mesothelioma. In an open-label randomized trial of 440 such patients, the addition of pembrolizumab (up to two years) to six cycles of platinum- and pemetrexed-based chemotherapy improved median overall survival (17.3 versus 16.1 months) and three-year overall survival (25 and 17 percent) but increased the rate of grade 3 or 4 adverse events (27 versus 15 percent) [53]. Given the modest benefit and added toxicity, we continue to suggest other options in advanced pleural mesothelioma (ipilimumab-nivolumab or chemotherapy alone) but consider pembrolizumab plus chemotherapy to be an acceptable alternative. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Pemetrexed, platinum, and pembrolizumab'.)

Selpercatinib in RET fusion-positive advanced NSCLC (October 2023)

Trials are investigating novel targeted therapies in oncogene-addicted advanced non-small cell lung cancer (NSCLC). In a randomized trial among 212 patients with advanced RET fusion-positive NSCLC, the RET inhibitor selpercatinib improved median progression-free survival relative to platinum-based chemotherapy (25 versus 11 months) [54]. Pembrolizumab was used with chemotherapy, per investigator's choice. Selpercatinib also improved time to progression in the central nervous system. However, treatment-related grade ≥3 effects were higher with selpercatinib. For patients with advanced RET fusion-positive NSCLC, we suggest selpercatinib rather than chemotherapy or chemoimmunotherapy, but consider pralsetinib, another RET inhibitor, to be a reasonable alternative. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'RET rearrangements'.)

Amivantamab plus chemotherapy for advanced NSCLC with EGFR exon 20 insertion (October 2023)

Although established treatment strategies exist for advanced lung cancer with common activating epidermal growth factor receptor (EGFR) mutations, less is known about uncommon activating EGFR mutations, such as exon 20 insertion mutations. In a randomized trial in 308 patients with advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions who had not received previous systemic therapy, those assigned to the targeted agent amivantamab plus chemotherapy experienced a longer progression-free survival relative to those assigned to chemotherapy alone (11.4 versus 6.7 months) [55]. The most common adverse effects in the amivantamab group were reversible hematologic toxicities. For patients with advanced NSCLC with an EGFR exon 20 insertion mutation, we suggest amivantamab plus chemotherapy. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'For treatment-naïve disease'.)

Systemic therapy for brain metastases from NSCLC (October 2023)

Trials are evaluating systemic therapy as an initial treatment option for subsets of patients with non-small cell lung cancer (NSCLC) with brain metastases:

●In a single-arm trial of single-agent targeted therapy in 19 patients with KRAS G12C-mutated NSCLC and untreated measurable intracranial disease, adagrasib was associated with an intracranial objective response rate of 42 percent and progression-free survival (PFS) of 5.4 months [56].

●In a single-arm trial of chemoimmunotherapy in 40 patients with advanced nonsquamous NSCLC with asymptomatic brain metastases, atezolizumab plus carboplatin and pemetrexed was associated with an intracranial median PFS of 6.9 months and response rate of 43 percent [57].

We consider either of these options to be reasonable initial systemic strategies in the patient populations in the respective trials; nevertheless, radiation is appropriate in such patients with untreated brain metastases, pending further comparative data between radiation and systemic therapy as an initial treatment strategy. (See "Brain metastases in non-small cell lung cancer", section on 'KRAS G12C'.)

Overall survival with adjuvant atezolizumab in resected non-small cell lung cancer (October 2023)

Longer-term overall survival (OS) data are emerging for adjuvant immune checkpoint inhibitors in resected non-small cell lung cancer (NSCLC). In a previously reported randomized trial in 882 patients with stage II to III NSCLC who had undergone surgery and adjuvant cisplatin-based chemotherapy, adjuvant atezolizumab resulted in OS hazard ratios of 0.95 overall, 0.71 among those with programmed death-ligand 1 (PD-L1) tumor cell (TC) ≥1 percent, and 0.43 among those with PD-L1 TC ≥50 percent [58]. OS results remain immature. Based on results from this trial, atezolizumab is approved by the US Food and Drug administration (FDA) as adjuvant treatment following resection and platinum-based chemotherapy for stage II to III NSCLC whose tumors have PD-L1 TC ≥1 percent, as determined by an FDA-approved test [59]. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Adjuvant immunotherapy'.)

Perioperative checkpoint inhibitors in resectable non-small cell lung cancer (June 2023, Modified October 2023)

Trials are evaluating the role of immune checkpoint inhibitors in resectable non-small cell lung cancer (NSCLC). In a randomized trial in almost 400 patients with resectable stage II to IIIB NSCLC, the addition of neoadjuvant pembrolizumab to cisplatin-based chemotherapy, followed by adjuvant pembrolizumab, improved event-free survival rates (62 versus 41 percent at 24 months) and overall survival (median not reached versus 52 months, hazard ratio 0.72) relative to chemotherapy alone [60,61]. In a separate randomized trial in over 800 patients, the addition of perioperative durvalumab to chemotherapy improved event-free survival rates (63 versus 52 percent at 24 months) [62]. Pembrolizumab has been approval by the US Food and Drug Administration (FDA) in patients with resectable NSCLC ≥4 cm or with node-positive disease, in combination with platinum-based chemotherapy as neoadjuvant treatment, with continuation as a single agent in the adjuvant setting [63]. Perioperative durvalumab does not have FDA approval. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Neoadjuvant/perioperative immunotherapy'.)

Divarasib in G12C KRAS-mutant solid tumors (September 2023)

Novel agents are under investigation for G12C KRAS-mutant solid tumors. In a phase I study in 137 patients with advanced KRAS-mutant cancers, among the 60 patients with non-small cell lung cancer, the objective response rate to the covalent KRAS G12C inhibitor divarasib was 53 percent, with a median progression-free survival (PFS) of 13.1 months; among the subgroup of 55 patients with metastatic colorectal cancer, the response rate was 29 percent, with a median PFS of 6 months [20]. Responses were also observed in patients with other solid tumors. Treatment was generally well tolerated, with grade ≥3 events occurring in 12 percent of patients. We await further data and/or regulatory approval prior to use of divarasib in G12C KRAS-mutant solid tumors. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Others' and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS-mutated tumors'.)

Cemiplimab in advanced non-small cell lung cancer (September 2023)

Trials are reporting long-term outcomes of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC). In a randomized trial among 565 patients with advanced NSCLC with programmed death-ligand 1 (PD-L1) of ≥50 percent, cemiplimab improved overall survival relative to platinum-doublet chemotherapy at 35 months’ follow-up (26 versus 13 months), with fewer grade 3–4 treatment-emergent adverse events (18 versus 40 percent) [64]. Based on results from this trial, cemiplimab has regulatory approval in the United States for use in patients with advanced NSCLC with PD-L1 of ≥50 percent without an EGFR, ROS1, or ALK genetic aberration [65], and we consider it to be an appropriate option in this setting. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Data regarding checkpoint inhibitor monotherapy'.)

Nivolumab with stereotactic body radiation therapy in early or locally-recurrent NSCLC (July 2023)

Although stereotactic body radiation therapy (SBRT) is a standard option for nonsurgical candidates with early-stage non small-cell lung cancer (NSCLC), trials are investigating strategies to decrease recurrences. In a randomized trial, 156 patients with stage IA-IIB NSCLC or isolated parenchymal recurrences (tumor size ≤7 cm) were randomly assigned to SBRT with or without four cycles of nivolumab [66]. At a median follow up of 33 months, the nivolumab-SBRT group had better four-year event-free survival than the SBRT only group (77 versus 53 percent). The rate of grade ≥3 events was 15 percent and 0 percent, respectively. While these results are promising, further data are needed prior to incorporation of immunotherapy with SBRT for early or locally-recurrent NSCLC. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Stereotactic body radiation therapy'.)

MISCELLANEOUS TUMORS

Maintenance eflornithine in high-risk neuroblastoma (January 2024)

For patients with high-risk neuroblastoma (HRNBL), there is interest in investigating novel maintenance therapies such as eflornithine, an ornithine decarboxylase inhibitor. In an externally controlled analysis of almost 100 patients with HRNBL who completed multimodality treatment and maintenance immunotherapy, extended maintenance therapy with eflornithine was associated with improved overall survival (hazard ratio 0.38) [67]. Based on these data, the US Food and Drug Administration approved eflornithine as maintenance therapy in patients with HRNBL who achieve at least a partial response to prior systemic agents and complete maintenance immunotherapy. Since maintenance eflornithine is not standard across all institutions, this agent may be offered on a case-by-case basis. (See "Treatment and prognosis of neuroblastoma", section on 'Eflornithine'.)

Severe hepatopathy in children with Wilms tumor (November 2023)

For children with Wilms tumor who develop severe hepatopathy (SH) due to chemotherapy and/or radiation therapy, there are limited studies on restarting therapy. In an observational study of almost 9000 patients treated for Wilms tumor with chemotherapy, the incidence of SH was less than 1 percent [68]. Among the 71 patients who developed SH, a majority (85 percent) were able to either continue or restart chemotherapy, typically at reduced doses. These data suggest that most patients with Wilms tumor who develop SH during treatment may be able to safely restart chemotherapy. (See "Treatment and prognosis of Wilms tumor", section on 'Late effects'.)

OTHER ONCOLOGY

Updated COVID-19 mRNA vaccine recommendations (September 2023)

The US Food and Drug Administration and Centers for Disease Control and Prevention have updated COVID-19 vaccine authorizations and recommendations [69,70]. Available COVID-19 vaccines have been updated to target Omicron variant XBB.1.5 (Moderna COVID-19 vaccine 2023-2024 formula, Pfizer COVID-19 vaccine 2023-2024 formula, and Novavax 2023-2024 formula); bivalent vaccines are no longer available. An updated 2023-2024 formula vaccine is recommended for all individuals aged six months and older. Immunocompetent individuals five years and older should receive one updated vaccine, regardless of prior vaccination history. For individuals who are four years or younger or have an immunocompromising condition (table 1), the number of recommended updated vaccines depends on their vaccination history. Our approach to COVID-19 vaccination is consistent with these recommendations. (See "COVID-19: Vaccines", section on 'Indications and vaccine selection' and "COVID-19: Vaccines", section on 'Benefits of vaccination'.)

Direct oral anticoagulants for cancer-related venous thromboembolism (August 2023)

In patients with cancer-related venous thromboembolism (VTE), accumulating evidence suggests that direct oral anticoagulants (DOACs) and subcutaneous low molecular weight heparin (LMWH) have similar efficacy and safety. In a recent randomized trial of over 670 patients with cancer-related VTE, there were no significant differences between rates at six months for recurrent VTE (6.1 [DOACs] versus 8.8 percent [LMWH]) and major bleeding (5.2 [DOACs] versus 5.6 percent [LMWH]) [71]. Despite limitations such as lack of blinding, late randomization, and poor adherence rates with LMWH, these data are in keeping with previous evidence and support our suggestion for DOACs rather than LMWH in patients with cancer-associated VTE. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Direct oral anticoagulant mono- or dual therapy'.)