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

Surgical axilla evaluation for clinically node-negative breast cancer (May 2024)

Patients with clinically node-negative breast cancer typically undergo sentinel lymph node biopsy (SLNB). If ≤2 SLNs are positive and whole breast radiation is planned, completion of axillary lymph node dissection (ALND) is not required. The recent SENOMAC trial randomly assigned 2540 patients with T1 to T3 breast cancer and one or two SLNs containing macrometastasis (>2 mm) to either completion or omission of ALND [1]. Most patients in both groups received radiation including nodal target volumes. Recurrence-free survival was similar for both groups at 47 months median follow-up. Based on these and prior results, we recommend omitting completion of ALND in patients with clinically node-negative, T1, T2, or T3 breast cancer who are undergoing breast-conserving surgery or mastectomy with SLNB, have fewer than three SLNs containing metastasis, and plan to undergo postsurgical radiation. (See "Overview of sentinel lymph node biopsy in breast cancer", section on 'One or two sentinel node metastases'.)

Use of axillary ultrasound to guide omission of sentinel node biopsy in early breast cancer (April 2024)

Approaches to treatment de-escalation for early breast cancer are under investigation. In a randomized trial that included nearly 1500 females with stage I (<2 cm) breast cancer and negative axillary ultrasound, those assigned to sentinel lymph node biopsy (SLNB) versus no axillary surgery at the time of primary breast surgery experienced similar rates of axillary recurrence, as well as disease-free and overall survival [2]. Omitting surgical axillary staging did not impact the selection of adjuvant treatment, although the study population was dominated by patients with low-risk cancers (93 percent with estrogen receptor-positive, HER2-negative disease). Despite these results, we continue to obtain SLNB in most patients with a clinically negative axilla (by examination and imaging), given that it can influence adjuvant treatment selection and administration, particularly for younger patients. (See "Overview of management of the regional lymph nodes in breast cancer", section on 'Can ultrasound identify patients who can omit sentinel node biopsy?'.)

Breast cancer-specific mortality in male breast cancer (April 2024)

Studies are evaluating prognosis of male breast cancer. In a cohort study including 2836 men with early, hormone receptor-positive breast cancer, the 20-year risk of breast cancer-specific mortality was 12 percent for stage I disease, 26 percent for stage II disease, and 46 percent for stage III disease [3]. There was an increase in late recurrences as nodal involvement increased, such that a bimodal distribution was present for those with N3 and stage III disease peaking at 4 and 11 years. Higher stage, grade, and age were all associated with higher risks. These estimates are helpful in counseling males with early, hormone receptor-positive breast cancer. (See "Breast cancer in men", section on 'Prognosis'.)

Tumor-infiltrating lymphocytes in triple-negative breast cancer (April 2024)

Studies are evaluating the prognostic significance of tumor-infiltrating lymphocytes (TIL) in early breast cancer. In a retrospective study including nearly 2000 patients with early triple negative breast cancer (TNBC) treated with locoregional therapy only, each 10 percent higher TIL increment was associated with improvements in overall survival (HR 0.88), after adjusting for other prognostic variables [4]. However, multiagent chemotherapy is typically administered for patients with early stage TNBC; further study is required to know whether TILs may be used to identify patients as candidates for less intensive treatment. (See "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Tumor infiltrating lymphocytes'.)

Ribociclib in hormone receptor-positive, HER2-negative early breast cancer (April 2024)

For patients with high-risk early hormone receptor (HR)-positive, HER2-negative breast cancer, trials are evaluating the addition of adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitors. In a randomized trial in 5101 patients with high-risk stage IIA to III disease (table 1), the addition of ribociclib to adjuvant endocrine therapy improved invasive disease-free survival at three years (90 versus 87 percent) and decreased distant recurrences (4.7 versus 6.7 percent) [5]. Overall survival is immature. Although these data are promising, we await long-term data and/or regulatory approval prior to using ribociclib in the adjuvant setting for high-risk HR-positive, HER2-negative disease. Select patients are candidates for adjuvant abemaciclib, a different CDK 4/6 inhibitor. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'CDK 4/6 inhibitors for select patients with high-risk disease'.)

Neoadjuvant therapy in HER2-positive breast cancer (April 2024)

Trials are investigating whether select patients receiving neoadjuvant therapy for HER2-positive breast cancer may receive anti-HER2 directed therapy alone, without chemotherapy. In a randomized phase 2 trial including 356 patients with clinical stage I to IIIA HER2-positive cancer, patients were assigned to treatment with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP; group A) versus trastuzumab and pertuzumab, with or without endocrine therapy, depending on hormone receptor status (group B) [6]. After two treatment cycles, patients in group B who were positron emission tomography (PET) responders continued with their assigned treatment for six cycles, while PET nonresponders were switched to receive six cycles of TCHP. At a median follow-up of 43 months, no statistically significant differences in event-free or overall survival were observed between groups A and B. Longer follow-up and a larger trial are required, however, prior to routine omission of chemotherapy in the neoadjuvant setting for HER2-positive breast cancer. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'HER2-targeted therapy without chemotherapy'.)

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 [7]. 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".)

GASTROINTESTINAL CANCER

Lack of overall survival benefit for primary tumor resection in metastatic colorectal cancer (April 2024)

For patients with unresectable metastatic colorectal cancer (CRC) and an asymptomatic primary tumor, randomized trials are evaluating the benefits of upfront primary tumor resection. In a combined analysis of two multicenter, randomized clinical trials in almost 400 such patients, primary tumor resection prior to initial systemic therapy failed to improve overall survival compared with immediate systemic therapy (median 17 versus 19 months, hazard ratio 0.94) [8]. Based on these data and the potential risks of surgery, we recommend against upfront primary tumor resection for patients with unresectable metastatic CRC and an asymptomatic primary tumor. (See "Locoregional methods for management of metastatic colorectal cancer", section on 'Unresectable metastatic disease'.)

Nivolumab plus chemotherapy for metastatic gastric and gastroesophageal adenocarcinoma (April 2024)

For patients with previously untreated advanced or metastatic gastric or gastroesophageal (GEJ) adenocarcinoma, the combination of nivolumab and chemotherapy is an established treatment option, but long-term overall survival (OS) data are limited. In continued follow-up of a randomized trial in over 1500 such patients, the addition of nivolumab to fluorouracil and oxaliplatin-based chemotherapy improved three-year OS rates (17 versus 10 percent), with benefits mainly driven by those with combined positive score (CPS) ≥5 (21 versus 10 percent) [9]. We continue to offer nivolumab plus chemotherapy as an initial treatment option in patients with gastric and GEJ adenocarcinomas and CPS ≥5. (See "Initial systemic therapy for metastatic esophageal and gastric cancer", section on 'CPS of 10 or more'.)

Tislelizumab for treatment-refractory metastatic esophageal squamous cell carcinoma (March 2024)

For patients with treatment-refractory metastatic esophageal squamous cell carcinoma (SCC), studies are evaluating the efficacy of immune checkpoint inhibitors (ICIs). In a randomized trial in over 500 patients with advanced or metastatic esophageal SCC who progressed on initial platinum-based chemotherapy, tislelizumab, a programmed cell death 1 (PD-1) inhibitor, improved overall survival relative to paclitaxel, docetaxel, or irinotecan (median 8.6 versus 6.3 months), with less toxicity [10]. Based on these data, tislelizumab was approved by the US Food and Drug Administration for the treatment of adult patients with unresectable or metastatic esophageal SCC after prior systemic chemotherapy that did not include a PD-1 or programmed cell death ligand 1 (PD-L1) inhibitor [11], and we also consider it to be an acceptable option in this population. (See "Second- and later-line systemic therapy for metastatic gastric and esophageal cancer", section on 'Tislelizumab'.)

Nonoperative management of rectal cancer after total neoadjuvant therapy (March 2024)

For patients with locoregionally advanced rectal cancer (LARC), studies are evaluating surveillance alone (ie, nonoperative management) for those who achieve a complete clinical response (cCR) to neoadjuvant therapy (NAT). In a phase II trial in over 300 patients with LARC treated with NAT (chemotherapy and chemoradiation), those with a cCR were offered surveillance, whereas those with an incomplete response were offered total mesorectal excision (TME) [12]. In extended follow-up, patients on surveillance who underwent surgery after tumor regrowth had similar five-year disease-free survival as those who had immediate TME (64 percent each). In patients with LARC treated with NAT, surveillance at a center of excellence for rectal cancer continues to be an appropriate alternative to surgery. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Benefits and risks'.)

Nivolumab plus ipilimumab for mismatch repair deficient metastatic colorectal cancer (February 2024)

For patients with metastatic colorectal cancer (mCRC) that is mismatch repair deficient (dMMR) with high levels of microsatellite instability (MSI-H), there is interest in evaluating immune checkpoint inhibitors. In a randomized trial in approximately 300 patients with treatment-naïve dMMR/MSI-H mCRC, nivolumab plus ipilimumab improved progression-free survival over chemotherapy (two-year progression-free survival of 72 versus 14 percent), with less toxicity [13]. For patients with dMMR/MSI-H mCRC, we now recommend initial therapy with nivolumab plus ipilimumab. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Nivolumab plus ipilimumab'.)

GENITOURINARY ONCOLOGY

Nogapendekin alfa inbakicept for BCG-unresponsive non-muscle invasive bladder cancer (May 2024)

For patients with Bacillus Calmette-Guerin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC), studies are evaluating novel therapies such as nogapendekin alfa inbakicept (NAI), an interleukin 15 superagonist antibody cytokine fusion protein. In an open-label trial in over 150 patients with BCG-unresponsive NMIBC, among the subgroup of 82 patients with carcinoma in situ (CIS), intravesical NAI plus BCG demonstrated a complete response rate of 71 percent and two-year overall survival (OS) of 94 percent [14]. Among the 72 patients with papillary disease only, two-year OS was 92 percent. Based on these data, the US Food and Drug Administration approved intravesical NAI in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors [11]. (See "Treatment of recurrent or persistent non-muscle invasive urothelial carcinoma of the bladder", section on 'Nogapendekin alfa inbakicept'.)

Adjuvant pembrolizumab for high-risk, muscle-invasive bladder cancer (April 2024)

Studies are evaluating adjuvant immunotherapy in patients with locally advanced urothelial carcinoma (UC) found to have high-risk (ie, muscle-invasive or node-positive) disease at radical cystectomy. In a randomized trial of over 700 patients with high-risk UC after radical cystectomy who received neoadjuvant cisplatin-based chemotherapy or were ineligible for adjuvant cisplatin-based chemotherapy, one year of adjuvant pembrolizumab improved median disease-free survival over observation (29 versus 14 months) with an acceptable toxicity profile [15]. We consider adjuvant pembrolizumab to be an appropriate option for patients with advanced UC and high-risk disease after radical cystectomy, particularly those who are ineligible for cisplatin. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder", section on 'Adjuvant pembrolizumab'.)

Overall survival with adjuvant pembrolizumab in localized renal cell carcinoma (February 2024, Modified April 2024)

In patients with localized clear cell renal cell carcinoma (RCC) treated with nephrectomy, adjuvant immunotherapy is an established treatment option, but long-term data on overall survival (OS) were previously limited. In extended follow-up of a randomized trial in approximately 1000 patients with clear cell RCC treated with nephrectomy, one year of adjuvant pembrolizumab improved four-year OS compared with placebo (91 versus 86 percent) [16]. For patients with clear cell RCC at intermediate-high or high risk of disease recurrence following nephrectomy, we recommend adjuvant pembrolizumab. (See "Overview of the treatment of renal cell carcinoma", section on 'Approach to adjuvant therapy'.)

Adjuvant chemotherapy for upper tract urothelial carcinoma (March 2024)

For patients with urothelial carcinoma of the upper urinary tract (UTUC) and high-risk features (ie, muscle invasive and/or node-positive disease), adjuvant platinum-based chemotherapy improves disease-free survival (DFS), but data for overall survival (OS) were not previously reported. In extended follow-up of a phase III trial of over 260 patients with high-risk UTUC treated with radical nephroureterectomy, the addition of adjuvant gemcitabine plus platinum-based chemotherapy improved five-year OS (66 versus 57 percent) and continued to improve five-year DFS (62 versus 45 percent) with an acceptable toxicity profile [17]. In patients with high-risk UTUC treated with nephroureterectomy, we recommend the use of adjuvant gemcitabine and platinum-based chemotherapy. (See "Malignancies of the renal pelvis and ureter", section on 'Adjuvant platinum-based chemotherapy'.)

Overall survival with neoadjuvant chemotherapy in localized muscle-invasive bladder cancer (January 2024)

For patients with localized muscle-invasive bladder cancer (MIBC), dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) and gemcitabine plus cisplatin (GC) are used as neoadjuvant regimens prior to radical cystectomy, but data on overall survival (OS) are limited. In a randomized trial in almost 500 patients with localized MIBC, ddMVAC improved five-year OS relative to GC among those treated with neoadjuvant chemotherapy alone (66 versus 57 percent), with a nonsignificant trend toward improvement among those receiving both neoadjuvant and adjuvant treatment (64 versus 56 percent); however toxicity was higher [18]. For most patients with localized MIBC receiving neoadjuvant chemotherapy, we consider both ddMVAC and GC to be appropriate options. (See "Neoadjuvant therapy for localized muscle-invasive urothelial carcinoma of the bladder", section on 'Selection of therapy'.)

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 [19]. 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 for advanced and metastatic clear cell renal carcinoma", section on 'Belzutifan'.)

GYNECOLOGIC ONCOLOGY

Updated vulvar carcinoma staging system (May 2024)

An updated version of the American Joint Committee on Cancer tumor, node, metastasis staging for vulvar carcinoma has been published (table 2) [20]. This version is now in alignment with the 2021 International Federation of Gynecology and Obstetrics vulvar carcinoma staging system. Both systems are used worldwide to stage patients with squamous and basal cell carcinomas, adenocarcinomas, and carcinomas arising from the Bartholin gland. (See "Squamous cell carcinoma of the vulva: Staging and surgical treatment", section on 'Staging system'.)

Types of hysterectomy in patients with stage IB1 cervical cancer (March 2024)

Patients with stage IB1 cervical cancer (ie, >5 mm depth of stromal invasion and ≤2 cm in greatest dimension) are typically treated with radical hysterectomy; however, less extensive surgery is being evaluated. In a randomized trial including over 640 patients with stage IB1 cervical cancer, radical hysterectomy and simple hysterectomy plus lymph node assessment resulted in similar rates of recurrence at three years (2.2 and 2.5 percent, respectively) [21]. Although the study has limitations, including a short follow-up period, simple hysterectomy with lymph node assessment may be an acceptable alternative to radical hysterectomy in patients with IB1 cervical cancer. (See "Management of early-stage cervical cancer", section on 'Type of surgery'.)

Pembrolizumab with chemoradiation in locally advanced cervical cancer (March 2024)

Trials are investigating the use of immune checkpoint inhibitors in locally advanced cervical cancer. In a randomized trial among 598 patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III to IVA cervical cancer, the addition of pembrolizumab to weekly cisplatin and radiation (external beam followed by brachytherapy) improved 12-month progression-free survival (81 versus 70 percent) [22,23]. Overall survival data are not mature. Pembrolizumab now has regulatory approval in the United States in combination with chemoradiotherapy for patients with FIGO 2014 stage III to IVA cervical cancer. This includes patients who, irrespective of lymph node involvement, have tumor invasion of the lower vagina (with or without extension onto pelvic sidewall), hydronephrosis/nonfunctioning kidney, or spread to adjacent pelvic organs. (See "Management of locally advanced cervical cancer", section on 'Incorporation of pembrolizumab for select patients with more advanced disease'.)

Increasing incidence of cervical and uterine corpus cancer in the United States (February 2024)

In January 2024, the American Cancer Society published their annual report of cancer statistics in the United States [24]. Notable trends in regard to gynecologic cancers include a 1.7 percent increase in the annual incidence of cervical cancer from 2012 to 2019 in individuals aged 30 to 44 years, after decades of decline. Cancer of the uterine corpus (all ages) continued to increase by approximately 1 percent annually and was the only cancer in the report in which survival decreased. These and other data emphasize the continued importance of both early detection and prevention (eg, for cervical cancer: human papillomavirus vaccination and screening for precursor lesions; for endometrial cancer: achieving and maintaining a normal body mass index). (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Incidence and mortality' and "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Epidemiology' and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Prognosis'.)

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) [25]. 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) [26]. 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'.)

HEAD AND NECK CANCER

Toripalimab plus gemcitabine and cisplatin in metastatic nasopharyngeal carcinoma (December 2023)

In patients with metastatic nasopharyngeal carcinoma (NPC), the addition of immunotherapy to chemotherapy has been promising in early phase trials. In a placebo-controlled trial in 289 patients with recurrent of metastatic NPC, the addition of the novel checkpoint inhibitor toripalimab to gemcitabine and cisplatin improved median progression-free survival (21 versus 8 months) and overall survival (not reached versus 34 months, hazard ratio 0.63) [27]. Grade ≥3 treatment-related toxicities were similar between the two groups (90 percent). Based on these data, the US Food and Drug Administration approved toripalimab in combination with gemcitabine and cisplatin in patients with metastatic NPC, and we suggest its use as the initial treatment strategy for such patients. (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma", section on 'Rationale for addition of immunotherapy'.)

MELANOMA AND OTHER SKIN CANCER

Tumor-infiltrating lymphocyte therapy in metastatic melanoma (March 2024)

Tumor-infiltrating lymphocyte (TIL) therapy is an autologous infusion of T cells that are produced and expanded ex vivo from a tumor specimen obtained via metastasectomy. Treatment includes nonmyeloablative chemotherapy prior to TIL therapy and interleukin 2 after TIL infusion. The US Food and Drug Administration recently approved the use of TIL therapy in patients with unresectable or metastatic melanoma after progression on a programmed cell death-1 (PD-1) inhibitor and a BRAF inhibitor (if BRAF V600 mutation positive) [28]. Earlier data comparing TIL therapy to ipilimumab in this population demonstrated improved progression-free survival. We now offer TIL to such patients if they have an excellent performance status. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Tumor-infiltrating lymphocytes'.)

NEUROONCOLOGY

Tovorafenib in BRAF-altered pediatric low-grade gliomas (May 2024)

Tovorafenib is a first-in-class oral type II RAF inhibitor recently approved by the US Food and Drug Administration for treatment of relapsed or refractory pediatric low-grade glioma (LGG) harboring a BRAF V600E mutation or BRAF fusion or rearrangement [29]. In a phase II trial among 69 such patients (50 percent with optic pathway glioma), response rates ranged from 51 to 67 percent depending on response criteria, with a median duration of response of 14 to 17 months [30]. Tovorafenib is now one of several targeted therapy options for children with recurrent/progressive BRAF-altered LGG; ongoing phase III trials are investigating these agents in the upfront setting versus chemotherapy. (See "Optic pathway glioma", section on 'Role of MAPK pathway inhibition'.)

ONC201 in H3 H27M-mutant diffuse midline glioma (May 2024)

Diffuse midline gliomas (DMGs) are highly aggressive tumors with a poor prognosis despite radiation therapy, and no standard systemic therapies exist. Among DMGs with a histone 3 (H3) K27M mutation, the investigational therapy ONC201 (dordaviprone) has shown promising activity. In a summary of 50 patients with recurrent H3 K27M-mutant DMG treated with ONC201 on one of four clinical trials (46 adults, 4 children), the overall response rate was 20 percent with a median duration of response of 11.2 months [31]. The drug was well tolerated. Based on these results, an international, randomized, placebo-controlled phase III trial is underway in patients with newly diagnosed H3 K27M-mutant diffuse gliomas (excluding pontine and spinal tumors) [32]. (See "Diffuse intrinsic pontine glioma", section on 'Investigational therapies'.)

Intraoperative techniques for glioblastoma resection (December 2023, Modified April 2024)

Two recent trials in patients with glioma illustrate the utility of intraoperative neurosurgical techniques to improve extent of resection while minimizing damage to normal brain.

●In a multicenter parallel-group trial that included 314 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) [33]. In both groups, absence of any enhancing tumor postoperatively was associated with improved progression-free and overall survival.

●In a randomized trial of iMRI versus conventional neuronavigation in 321 patients with new low- or high-grade glioma, iMRI improved progression-free survival, and there was a nonsignificant trend towards improved overall survival in patients with high-grade glioma [34].

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'.)

Chimeric antigen receptor T cell therapies in glioblastoma (March 2024)

Genetically manipulated immunologic therapies are under investigation in patients with recurrent glioblastoma. Several groups have demonstrated that chimeric antigen receptor T (CAR-T) cells targeted against glioblastoma surface antigens can be delivered systemically or intraventricularly to achieve on-target T cell trafficking and radiographic tumor responses [35-37]. In the largest study in 65 patients with recurrent high-grade glioma, CAR-T cells targeting interleukin-13 receptor alpha 2 were delivered intratumorally and/or intraventricularly at escalating doses; administration was safe, and several partial or complete responses were observed [36]. Tumor responses generally have not been durable, however, and clinical trials are ongoing. (See "Management of recurrent high-grade gliomas", section on 'Immunotherapy'.)

PALLIATIVE AND SUPPORTIVE CARE

Mirtazapine in patients with cancer-related anorexia (April 2024)

Patients with advanced cancer are at risk for cancer-related anorexia and weight loss; studies are evaluating strategies to manage these issues. In a randomized trial in 86 patients with advanced non-small cell lung cancer, mirtazapine improved mean daily energy intake by 379 kcal versus placebo and reduced the proportion of patients with sarcopenia (57 versus 83 percent), although appetite scores were not higher [38]. Despite these results, previous data are inconsistent. As such, we prefer other strategies including dietary counseling and olanzapine for cancer-related anorexia. (See "Management of cancer anorexia/cachexia", section on 'Mirtazapine'.)

SOFT TISSUE AND BONE TUMORS

T-cell therapy for sarcoma (April 2024)

T-cell therapy is a novel strategy under investigation in a variety of cancers. T-cells are harvested, engineered to target an antigen presented by a specific human leukocyte antigen (HLA) subtype, and reinfused after lymphodepleting chemotherapy. In a phase II study in HLA-A*02-positive patients with previously treated MAGE-A4 expressing synovial or myxoid-round cell liposarcoma, the T-cell therapy afamitresgene autoleucel (afami-cel) was associated with a response rate of 37 percent [39]. Cytokine release syndrome occurred in 71 percent of patients. Although these results are promising, we await further data or regulatory approval prior to routine use of afami-cel in sarcoma. (See "Second and later lines of therapy for metastatic soft tissue sarcoma", section on 'T-cell therapy'.)

THORACIC ONCOLOGY

Perioperative toripalimab or nivolumab with chemotherapy in NSCLC (February 2024, Modified May 2024)

Randomized trials are evaluating the role of perioperative immune checkpoint inhibitors in resectable non-small cell lung cancer (NSCLC).

●Among patients with stage III NSCLC, the addition of toripalimab to perioperative chemotherapy improved event-free survival (EFS; hazard ratio [HR] 0.40), with a trend toward improved overall survival (HR 0.62) [40]. Grade ≥3 events occurred in 63 versus 54 percent, with and without toripalimab.

●Among patients with stage IIA to IIIB NSCLC, the incorporation of perioperative nivolumab with neoadjuvant chemotherapy improved 18-month EFS (70 versus 50 percent, HR 0.58) [41]. Grade ≥3 events occurred in 33 and 25 percent, respectively.

Overall survival in both trials was immature. We await longer-term data and/or regulatory approval prior to use of perioperative toripalimab or nivolumab in resectable NSCLC. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Neoadjuvant/perioperative immunotherapy'.)

Adjuvant alectinib in ALK-positive NSCLC (April 2024)

Trials are investigating targeted agents in the adjuvant setting for non-small cell lung cancer (NSCLC). An open-label, randomized trial included 257 patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA according to the 7th edition Cancer Staging Manual (table 3) [42]. Patients assigned to two years of adjuvant alectinib versus four cycles of platinum-based chemotherapy had better two-year disease-free survival (DFS; 94 versus 64 percent) and central nervous system DFS (hazard ratio 0.22), with lower toxicities. For patients with resected, ALK-positive NSCLC that is at least 4 cm or node positive, we offer adjuvant alectinib, irrespective of whether adjuvant chemotherapy was administered. We use the same risk stratification in ALK-positive cancers as in ALK-negative cancers to decide whether patients should also receive adjuvant chemotherapy. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'ALK-positive cancers'.)

Treatment for EGFR-positive NSCLC after progression on a targeted agent (April 2024)

Trials are investigating the optimal treatment strategy for patients with epidermal growth factor receptor (EGFR) positive advanced non-small cell lung cancer (NSCLC) that has progressed on a tyrosine kinase inhibitor (TKI).

●In a randomized trial in 657 patients with progression on osimertinib, median progression-free survival (PFS) was longer with the combination of the bispecific EGFR-MET antibody amivantamab plus chemotherapy versus chemotherapy alone (6.3 versus 4.2 months) [43]. At the first interim overall survival analysis, the hazard ratio for death favored the amivantamab-chemotherapy group but was not statistically significant.

●Other recently reported trials have examined the benefit of adding an immune checkpoint inhibitor (with or without bevacizumab) to chemotherapy after progression on a TKI, with mixed results in regard to PFS [44,45].

Based on available data, for patients with EGFR-positive advanced NSCLC progressive on osimertinib and without histologic transformation, we suggest the addition of amivantamab to platinum-based chemotherapy; chemotherapy, with or without an immune checkpoint inhibitor, is an acceptable alternative. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'No histologic transformation'.)

Osimertinib and chemotherapy in EGFR-mutated NSCLC with brain metastases (March 2024)

Trials are investigating systemic treatment options for those with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with central nervous system (CNS) disease. In a randomized trial, among the 222 patients with baseline CNS disease from EGFR-mutated NSCLC, osimertinib plus chemotherapy resulted in a 24-month CNS progression-free survival of 74 percent versus 54 percent with chemotherapy alone, but the difference was not statistically significant (hazard ratio 0.58, 95% CI 0.33-1.01) [46]. Results in the overall study population (with and without CNS disease) also favored combination therapy, with a trend towards improved overall survival [47]. For patients with EGFR-mutated NSCLC and brain metastases, we now suggest osimertinib and chemotherapy, but consider osimertinib alone a reasonable alternative. (See "Brain metastases in non-small cell lung cancer", section on 'Osimertinib with chemotherapy'.)

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 [48]. These data contributed to regulatory approval of repotrectinib in the United States [49]. 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 [50]. 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 approved by the US FDA for patients with extensive stage SCLC with disease progression on or after platinum-based chemotherapy. (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) [51]. 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 overall survival. (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) [52]; 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) [47]. 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 'Initial therapy for common mutations'.)

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) [53]. 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".)

OTHER ONCOLOGY

Pemivibart for prevention of COVID-19 in selected immunocompromised patients (April 2024)

Monoclonal antibodies have been used as adjunctive pre-exposure prophylaxis to reduce the risk of COVID-19 in individuals expected to have suboptimal response to vaccination, although emergence of variants that escape neutralization limit their utility. In March 2024 in the United States, the novel monoclonal antibody pemivibart received emergency use authorization (EUA) to prevent COVID-19 in individuals age 12 years or older (weighing at least 40 kg) who have moderate-to-severe immunocompromising conditions (table 4) [54]. Pemivibart is active against JN.1, the dominant SARS-CoV-2 variant. We suggest pemivibart in individuals at the highest risk for vaccine nonresponse (eg, those with hematologic malignancy or recent history of transplantation) as long as it remains active against the main circulating variants. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Limited role for monoclonal antibodies in selected patients'.)