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

Ovarian function suppression for premenopausal patients with high risk hormone receptor positive, HER2-negative breast cancer (March 2023)

Premenopausal patients with high-risk hormone receptor-positive, HER2-negative breast cancer are often treated with ovarian function suppression (OFS) plus either an aromatase inhibitor (AI) or tamoxifen, but few data exist regarding the long-term benefits of OFS. At twelve years of follow-up of a randomized trial in premenopausal patients with hormone receptor-positive breast cancer, 85 percent of whom had HER2-negative disease, tamoxifen alone had a lower rate of disease-free survival (72 percent) relative to both tamoxifen plus OFS (76 percent) and exemestane plus OFS (79 percent) [1]. Overall survival rates were 87 percent with tamoxifen alone, 89 percent with tamoxifen plus OFS, and 89 percent with exemestane plus OFS. Given the toxicities associated with OFS, and the greater likelihood of benefit for those with high-risk features, we reserve its use for patients at high risk for recurrence from hormone receptor-positive, HER2-negative breast cancer (eg, those ≤35 years of age or with risk factors for which chemotherapy is indicated). (See "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer", section on 'Rationale for OFS'.)

Long-term data with paclitaxel-trastuzumab in small, node-negative, HER2-positive breast cancers (March 2023)

In patients with small, node-negative, HER2-positive breast cancers, studies of the deintensified adjuvant chemotherapy regimen paclitaxel-trastuzumab have suggested good outcomes, but long-term data have been limited. In a phase II study that enrolled 410 patients with node-negative tumors <3 cm, adjuvant treatment with weekly paclitaxel for 12 weeks plus trastuzumab for 1 year was associated with a 10-year disease-free survival of 91 percent and overall survival of 94 percent [2]. Although paclitaxel-trastuzumab has never been compared directly with more intensive regimens, we typically suggest it for patients with small, node-negative, HER2-positive tumors, given the excellent outcomes that have been observed with this regimen in this population. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Node-negative tumors <2 cm'.)

Radiation in select older women with early hormone receptor-positive, HER2-negative breast cancer (March 2023)

Older patients with early hormone receptor-positive, HER2-negative breast cancers receiving adjuvant endocrine therapy may be candidates for omission of adjuvant radiation therapy (RT) after breast-conserving surgery (BCS); however, long-term data with this strategy are limited. Now, with follow-up of 9.1 years of a randomized trial in 1300 women age ≥65 years with node-negative breast cancers <3 cm treated with BCS, the 10-year rate of local breast cancer recurrence was lower in women assigned to RT than the no-RT group (0.9 versus 9.5 percent) [3]. However, there were no statistically significant differences in overall survival or distant metastases between the two groups. Although omission of radiation may be a reasonable option for women ≥65 years with node-negative, hormone receptor-positive, HER2-negative breast cancers <3 cm for whom endocrine therapy is planned, referral to a radiation oncologist for discussion of the risks and benefits is appropriate; some such women may opt for RT in order to reduce the risk of locoregional recurrence. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Omission of RT for older women with ER-positive breast cancer'.)

Tucatinib in advanced HER2-positive breast cancer with brain metastases (March 2023)

Newer anti-HER2-directed tyrosine kinase inhibitors such as tucatinib are being used for patients with advanced, HER2-positive breast cancer, but data in those with brain metastases are emerging. In an updated analysis of the HER2CLIMB trial, which included patients with heavily pretreated HER2-positive metastatic breast cancer, the addition of tucatinib to capecitabine and trastuzumab improved median overall survival among patients with brain metastases (22 versus 13 months), including in the subset with active brain metastases (21 versus 12 months) [4]. For patients with advanced HER2-positive breast cancer, we consider the tucatinib, capecitabine, and trastuzumab combination to be an effective subsequent-line systemic treatment option, including for those with brain metastases. (See "Brain metastases in breast cancer", section on 'Tucatinib, capecitabine, and trastuzumab'.)

Elacestrant in ESR1-mutated advanced hormone receptor-positive, HER2-negative breast cancer (February 2023)

Elacestrant is an oral selective estrogen receptor down-regulator that now has regulatory approval in the United States for use in postmenopausal women and men with Elacestrant is an oral selective estrogen receptor down-regulator that now has regulatory approval in the United States for use in postmenopausal women and men with -mutated advanced hormone receptor-positive, HER2-negative breast cancer that has progressed on at least one line of prior endocrine therapy [5]. Given previously demonstrated progression-free survival benefits over fulvestrant in this setting, as well as the ease of oral administration, we now suggest its use for such patients. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'ESR1 mutation-positive'.)

Long-term risks and benefits of tamoxifen prevention for breast cancer (February 2023)

Tamoxifen is used as a preventative strategy in patients at high risk of breast cancer, but the long-term effects are less well understood. A modeling study suggested that the lifetime absolute risk reduction associated with a five-year course of tamoxifen plus radiographic screening was 95 invasive breast cancers and 42 breast cancer deaths per 1000 high-risk women [6]. However, tamoxifen was associated with 11 more cases of endometrial cancer per 1000 women. Given the balance of risks and benefits, we continue to offer tamoxifen as a chemoprevention strategy for patients at high risk of breast cancer. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Benefits relative to placebo'.)

Imaging after mastectomy for early breast cancer survivors (February 2023)

Patients who have undergone mastectomy for early breast cancer often inquire about subsequent imaging surveillance. In a meta-analysis of 16 studies in patients with prior breast cancer who underwent mastectomy (with or without reconstruction), cancer detection rates with mammography, ultrasound, and magnetic resonance imaging were each <1 percent [7]. The majority of cancers detected on imaging were also detected on physical examination. Given the small benefit and the risk of false positives, we limit post-mastectomy imaging studies to patients who have findings on history or physical examination that suggest local breast cancer recurrence. Surveillance on the contralateral breast should continue. (See "Approach to the patient following treatment for breast cancer", section on 'Breast MRI'.)

Number of doses of zoledronic acid for adjuvant treatment of breast cancer (February 2023)

Trials have investigated zoledronic acid in a range of schedules for the adjuvant treatment of breast cancer. In a randomized trial (ABCSG-12), disease-free and overall survival were similar among patients who received ≤6 zoledronic acid infusions compared with those who received ≥7 zoledronic acid infusions [8]. When using zoledronic acid for adjuvant treatment of breast cancer, we commonly administer 4 mg every six months for three years (six doses), although 4 mg every three months for two years is also considered an acceptable option. (See "Use of osteoclast inhibitors in early breast cancer", section on 'Dosing and duration'.)

Fam-trastuzumab deruxtecan in breast cancer brain metastases (January 2023)

Treatment for patients with breast cancer brain metastases (BMs) typically includes a local approach (ie, surgery or radiation), and few data exist regarding systemic therapy alone. In a study including 13 patients with advanced HER2-positive breast cancer and either asymptomatic untreated BMs or progressive BMs after local therapy, the antibody-drug conjugate fam-trastuzumab deruxtecan was associated with an intracranial response rate of 46 percent [9]. Data on durability of response were not yet mature for this subgroup. Although limited, these data add to accumulating evidence supporting fam-trastuzumab deruxtecan in patients whose BMs have progressed despite prior local therapy; however, the number of patients with newly diagnosed BMs treated with fam-trastuzumab deruxtecan in lieu of radiotherapy is very small, and further data are required before this strategy is employed in routine clinical practice. (See "Brain metastases in breast cancer", section on 'Fam-trastuzumab deruxtecan'.)

Ribociclib plus endocrine therapy in aggressive hormone receptor-positive, HER2-negative metastatic breast cancer (January 2023)

For hormone receptor-positive, HER2-negative metastatic breast cancer, initial treatment often consists of endocrine therapy plus a cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i), but chemotherapy has been favored for extensive visceral metastases. Now, in a trial in 222 premenopausal patients with aggressive, hormone receptor-positive, HER2-negative breast cancer (half of whom had visceral crises), initial treatment with endocrine therapy plus ribociclib improved progression-free survival relative to combination chemotherapy (24 versus 12 months), with better tolerability [10]. Time to tumor response was 4.9 versus 3.2 months, respectively. For patients with hormone receptor-positive, HER2-negative metastatic breast cancer, including those with extensive visceral metastases, we typically suggest endocrine therapy plus a CDK 4/6i, although chemotherapy is an appropriate alternative. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Choosing between endocrine therapy and chemotherapy'.)

Low-dose tamoxifen as prevention against breast cancer (December 2022)

Although a course of tamoxifen 20 mg daily for five years is often offered as prevention to patients at high risk for breast cancer, lower dose and duration has been investigated. In longer-term follow up (>9 years) of a trial enrolling 500 women with intraepithelial neoplasia, patients who were randomly assigned to three years of tamoxifen at 5 mg daily had fewer neoplastic events than those assigned to placebo (hazard ratio 0.58) [11]. Although we continue to suggest tamoxifen 20 mg daily for five years as chemoprevention against breast cancer, given more data and longer follow-up, 5 mg daily is a reasonable alternative. Given that 5 mg pills are not commercially available, using 10 mg on alternate days is reasonable due to tamoxifen's long half-life. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Dose and duration'.)

Limitations in fulvestrant plus palbociclib as a subsequent-line treatment in advanced breast cancer (December 2022)

For metastatic hormone receptor-positive, HER2-negative breast cancer, the combination of an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) is often used as initial therapy; trials are investigating the use of fulvestrant plus a CDK 4/6i as a next-line option. One trial found that, among patients who develop a resistance blood ESR1 mutation on an AI plus a CDK 4/6i, a switch to fulvestrant/palbociclib improved progression-free survival (PFS) over continuation of therapy; the effect on overall survival was uncertain [12]. A separate trial in patients with progression on an AI plus a CDK 4/6i found no improvement in PFS with palbociclib plus fulvestrant versus fulvestrant alone [13]. We await further prospective data prior to using fulvestrant plus a CDK 4/6i after progression on an AI plus a CDK 4/6i in metastatic hormone receptor-positive breast cancer. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'ESR1 wild-type'.)

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer (December 2022)

For patients with HER2-positive metastatic breast cancer, antibody-drug conjugates are available after progression on trastuzumab and a taxane, but the optimal sequence has been unclear. In the phase III Destiny-Breast03 trial among 524 patients with HER2-positive metastatic breast cancer with progression on a trastuzumab- and taxane-containing regimen, trastuzumab deruxtecan (T-DXd) improved overall survival compared with trastuzumab emtansine (T-DM1; hazard ratio 0.64) [14]. Grade ≥3 adverse events occurred in 56 percent on T-DXd and 52 percent on T-DM1. Interstitial lung disease occurred in 15 and 3 percent, respectively. Based on results of this trial, for patients with HER2-positive metastatic breast cancer that is progressive on a taxane and trastuzumab, we suggest T-DXd as next-line therapy rather than T-DM1. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Rationale for T-DXd over T-DM1'.)

Acupuncture in aromatase inhibitor-induced joint pain (December 2022)

For patients with breast cancer who experience aromatase inhibitor (AI)-related joint pain, a randomized trial previously demonstrated short-term improvements with acupuncture over sham acupuncture and waitlist control. Now, with longer follow-up, patients assigned to 12 weeks of acupuncture experienced a median improvement of approximately one point on a pain scale of 0 to 10 at 52 weeks compared with the other groups [15]. We consider acupuncture to be a useful adjunctive or alternative option to pharmacologic strategies in patients with breast cancer who experience AI-induced joint pain. (See "Managing the side effects of tamoxifen and aromatase inhibitors", section on 'Musculoskeletal pains and stiffness'.)

Adjuvant olaparib in high-risk, early HER2-negative breast cancer (November 2022)

For BRCA carriers with high-risk, early HER2-negative breast cancer, adjuvant treatment with the poly(ADP-ribose) polymerase inhibitor olaparib previously demonstrated progression-free survival benefits in the OlympiA trial. Now, with longer follow-up of 3.5 years, adjuvant olaparib also demonstrated an overall survival (OS) benefit (4-year OS 90 versus 86 percent) [16]. Based on these data, for BRCA carriers with early, HER2-negative breast cancer meeting high risk criteria from the OlympiA trial (table 1), we suggest adjuvant olaparib orally twice daily for one year. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'BRCA carriers with high-risk disease'.)

Risk of second primary cancers in male breast cancer survivors (November 2022)

The risks for second primary cancers among male breast cancer survivors is being evaluated. In one study that included data from over 10,000 male breast cancer survivors, the standardized incidence ratio (SIR) of a second primary cancer, relative to healthy male controls, was 1.3; specifically, there were increased risks of colorectal (SIR 1.3), pancreatic (SIR 1.6), and thyroid (SIR 5.6) cancer [17]. Male breast cancer survivors should engage in cancer screening according to age, family history, and genetic risk factors, if present. (See "Breast cancer in men", section on 'Post-treatment surveillance'.)

Breast implant-associated cancer (October 2022)

Breast implant-associated malignancies are rare, with most concern related to breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The US Food and Drug Administration and the American Society of Plastic Surgery have recently focused on breast implant-associated squamous cell cancer (BIA-SCC), which can also occur in the capsule surrounding the implant [18]. Clinical features of BIA-SCC that differ from BIA-ALCL include its longer average time to onset after implantation, more aggressive behavior, and higher mortality. BIA-SCC is also associated with either smooth or textured implants, whereas BIA-ALCL is predominantly associated with textured implants. When treating patients who have late-onset peri-implant changes, seroma, or mass, it is essential to consider the possibility of BIA-SCC in addition to BIA-ALCL. (See "Implant-based breast reconstruction and augmentation", section on 'Squamous cell carcinoma'.)

CANCER SURVIVORSHIP

Cisplatin-related ototoxicity in testicular cancer survivors (February 2023)

Testicular cancer survivors treated with cisplatin are at risk for ototoxicity such as hearing loss and tinnitus, but studies of their impact on physical and mental health were previously limited. In an observational study of almost 250 testicular cancer survivors treated with cisplatin-based chemotherapy, those with hearing loss and tinnitus were more likely to report cognitive dysfunction, depression, fatigue, and worsened overall health [19]. For testicular cancer survivors treated with cisplatin-based chemotherapy, we continue to routinely screen for hearing loss and tinnitus and refer for formal audiometry testing in those with reported symptoms. (See "Approach to the care of long-term testicular cancer survivors", section on 'Ototoxicity'.)

GASTROINTESTINAL CANCER

Increasing frequency of early-onset colorectal cancer (March 2023)

Early-onset colorectal cancer (CRC) is being more frequently diagnosed in the United States. In an observational study from the American Cancer Society, the proportion of new CRC cases among adults under the age of 55 years increased from 11 to 20 percent between 1995 and 2019 [20]. These findings are mostly driven by the increasing rate of left-sided CRC and rectal cancers in this population. Further studies are needed to understand the cause of this pattern, and public awareness of CRC screening and associated symptoms are necessary. (See "Colorectal cancer: Epidemiology, risk factors, and protective factors", section on 'Age and early onset colorectal cancer'.)

Trifluridine-tipiracil plus bevacizumab for metastatic colorectal cancer (March 2023)

For patients with treatment-refractory metastatic colorectal cancer (mCRC), there is interest in investigating novel treatment options. In a phase III trial (SUNLIGHT) of almost 500 patients with mCRC who progressed on one to two lines of systemic therapy, the addition of bevacizumab to trifluridine-tipiracil improved median progression-free survival (6 versus 2 months) and overall survival (11 versus 8 months), with a manageable toxicity profile [21]. For patients who progress on multiple lines of therapy including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF agent, and anti-EGFR therapy (if RAS wild-type), we consider the combination of trifluridine-tipiracil plus bevacizumab to be one of several acceptable treatment options. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Trifluridine-tipiracil with or without bevacizumab'.)

Perioperative chemotherapy for locally advanced colon cancer (March 2023)

Most patients with localized colon cancer are treated with upfront surgery, but neoadjuvant chemotherapy may be appropriate in selected patients with locally advanced disease. In a phase III trial (FOxTROT) of over 1000 patients with imaging-predicted, T3-4N0-2 primary colon cancer, perioperative oxaliplatin-based chemotherapy reduced the rates of residual/recurrent disease at two years (17 versus 22 percent) and reduced serious surgical complications compared with surgery followed by adjuvant chemotherapy [22]. While neoadjuvant chemotherapy may be appropriate for select patients with locally advanced colon cancer (eg, those with potentially compromised surgical margins or medically inoperable tumors), further studies are necessary and clinical trial enrollment is encouraged. (See "Overview of the management of primary colon cancer", section on 'Neoadjuvant therapy'.)

Pembrolizumab for advanced hepatocellular carcinoma (February 2023)

Pembrolizumab has regulatory approval in the United States for patients with advanced hepatocellular carcinoma (HCC) refractory to tyrosine kinase inhibitors such as sorafenib and lenvatinib, but has not previously demonstrated an overall survival (OS) benefit. In a placebo-controlled phase III trial (KEYNOTE-394) of over 400 patients with advanced, treatment-refractory HCC from Asia, pembrolizumab improved OS (median 15 versus 13 months) [23]. For patients with advanced HCC and no more than Child's Class Pugh A disease who have progressed on sorafenib or lenvatinib, we continue to consider pembrolizumab to be an acceptable option. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Pembrolizumab'.)

Tucatinib plus trastuzumab for HER2-positive metastatic colorectal cancer (January 2023)

For patients with HER2-positive metastatic colorectal cancer (CRC), there is interest in investigating novel therapies such as tucatinib, a selective inhibitor of HER2 and HER3. In a phase II trial of over 80 patients with HER2-positive, RAS wild-type, chemotherapy-refractory metastatic CRC, the combination of tucatinib plus trastuzumab demonstrated an objective response rate of 38 percent [24]. Based on these data, the US Food and Drug Administration granted accelerated approval for tucatinib in combination with trastuzumab in adult patients with RAS wild-type, HER2-positive unresectable or metastatic CRC that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and we consider this to be an appropriate option for this population. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors'.)

Perioperative versus adjuvant gemcitabine and nabpaclitaxel for resectable pancreatic cancer (January 2023)

For patients with resectable pancreatic adenocarcinoma, clinical trials are evaluating the role of neoadjuvant versus adjuvant chemotherapy. In a randomized phase II trial (NEONAX) in over 100 patients with resectable pancreatic cancer, 6 months of perioperative (two cycles of neoadjuvant and four cycles of adjuvant) gemcitabine plus nabpaclitaxel was compared with 6 months of adjuvant treatment with the same chemotherapy [25]. Median disease-free survival was 12 versus 6 months for perioperative versus adjuvant treatment, and median overall survival was 26 versus 17 months, respectively, but these differences were not statistically significant. For patients with potentially resectable pancreatic cancer, we consider either 6 months of perioperative systemic chemotherapy or adjuvant chemotherapy to be appropriate strategies. If perioperative chemotherapy is chosen, gemcitabine plus nabpaclitaxel is an appropriate option for the adjuvant component of treatment. (See "Treatment for potentially resectable exocrine pancreatic cancer", section on 'Induction chemotherapy alone'.)

ASCO guideline on management of metastatic colorectal cancer (November 2022)

A 2022 guideline on management of metastatic colorectal cancer is available from the American Society of Clinical Oncology (ASCO) [26]. The key recommendations include offering first-line pembrolizumab rather than cytotoxic chemotherapy to patients with deficient mismatch repair; a preference for an agent targeting the epidermal growth factor receptor rather than antiangiogenic therapy if a biologic agent is chosen for first-line therapy of RAS/BRAF wild type, left-sided primary tumors; a triplet rather than doublet chemotherapy backbone for first-line therapy of selected patients with shared decision-making; a recommendation for cytoreductive surgery plus systemic chemotherapy for selected patients with isolated peritoneal metastases; and stereotactic body radiotherapy following systemic chemotherapy for patients with oligometastatic liver metastases who are not considered appropriate for resection. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors' and "Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer", section on 'Overt peritoneal carcinomatosis' and "Nonsurgical local treatment strategies for colorectal cancer liver metastases", section on 'Tumor ablation plus systemic chemotherapy'.)

Peptide receptor radioligand therapy versus sunitinib for progressive pancreatic neuroendocrine tumors (September 2022)

Therapeutic options for progressive unresectable somatostatin receptor-expressing pancreatic neuroendocrine tumors include molecularly targeted agents such as sunitinib or peptide receptor radioligand therapy (PRRT) using radiolabeled somatostatin analogs (eg, Lutetium-177 [¹⁷⁷Lu] dotatate). In a randomized trial directly comparing 177Lu dotatate versus sunitinib in 84 patients with no prior cytotoxic or molecularly targeted therapy or PRRT, 12-month progression-free survival was twofold higher with 177Lu dotatate, and the toxicity profile was more favorable [27]. While there remains no clear consensus on optimal sequencing of therapy, the higher rates of antitumor activity and better tolerability observed with 177Lu dotatate makes this a preferable initial option rather than molecularly targeted therapy in appropriate patients, particularly those who are symptomatic from their disease. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Efficacy versus other treatments'.)

GENITOURINARY ONCOLOGY

Lenvatinib plus pembrolizumab for advanced clear cell renal carcinoma (March 2023)

The combination of lenvatinib plus pembrolizumab is approved for the treatment of advanced renal cell carcinoma (RCC), but long-term overall survival (OS) data were previously limited. In extended follow-up of a phase III trial of over 1000 patients with treatment-naïve advanced clear cell RCC, at median follow-up of approximately 34 months, lenvatinib plus pembrolizumab improved three-year OS relative to sunitinib (66 versus 62 percent) [28]. For patients with advanced clear cell RCC, lenvatinib plus pembrolizumab continues to be one of our preferred initial treatment options. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Lenvatinib plus pembrolizumab'.)

Nadofaragene firadenovec for Bacillus Calmette-Guerin-unresponsive non-muscle invasive bladder cancer (March 2023)

For patients with Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC), there is interest in new treatments such as nadofaragene firadenovec, a recombinant adenovirus vector. In a nonrandomized trial in patients with BCG-unresponsive NMIBC, among 103 patients with carcinoma in situ (CIS), 53 percent experienced a complete response within three months of treatment with nadofaragene firadenovec [29,30]. Based on these data, the US Food and Drug Administration approved nadofaragene firadenovec for the treatment of high-risk BCG-unresponsive NMIBC with CIS (with or without papillary tumors). Although we typically suggest radical cystectomy in such patients, we consider nadofaragene firadenovec to be one acceptable alternative for those who are ineligible for or decline radical cystectomy. (See "Management of recurrent or persistent non-muscle invasive bladder cancer", section on 'Nadofaragene firadenovec'.)

Management of localized, low-risk prostate cancer (March 2023)

Long-term data from trials investigating active monitoring, surgery, and radiation for localized prostate cancer are emerging. At 15 years of follow-up of a randomized trial in over 1600 men with localized prostate cancer, most of whom had low-risk disease, metastases were more frequent among those assigned to active monitoring compared with surgery or radiation (9.4 versus 4.7 and 5.0 percent, respectively); however, the rates of prostate cancer mortality were low in all groups (3.1, 2.2, and 2.9 percent, respectively), and differences were not statistically significant [31]. For most individuals with localized, low-risk prostate cancer, definitive therapy (radical prostatectomy, brachytherapy, or external beam radiation) or active surveillance are all appropriate options. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'ProtecT trial'.)

Rucaparib in metastatic, BRCA-associated, castration-resistant prostate cancer (March 2023)

Trials are exploring the use of poly(ADP-ribose) polymerase inhibitors in metastatic, castration-resistant prostate cancer (CRPC) with certain genetic alterations. In a randomized trial, patients with CRPC with a BRCA1, BRCA2, or ATM alteration who had disease progression on a second-generation androgen-receptor pathway inhibitor (ARPI) were assigned to rucaparib or a physician's choice control [32]. In the BRCA subgroup, the median duration of imaging-based, progression-free survival was longer with rucaparib than control (11.2 months versus 6.4 months). The most frequent adverse events with rucaparib were fatigue and nausea. For males with metastatic In the BRCA subgroup, the median duration of imaging-based, progression-free survival was longer with rucaparib than control (11.2 months versus 6.4 months). The most frequent adverse events with rucaparib were fatigue and nausea. For males with metastatic associated CRPC, we consider rucaparib to be an appropriate option after treatment with an ARPI and a taxane. (See "Management of advanced prostate cancer with germline or somatic homologous recombination repair deficiency", section on 'Rucaparib'.)

Sequencing of androgen-deprivation therapy with radiation in nonmetastatic prostate cancer (February 2023)

The optimal sequencing of short-term androgen deprivation therapy (ADT) when delivered with radiotherapy (RT) for prostate cancer is undefined. In an analysis of patient-level data from 12 randomized trials in patients receiving RT for localized disease, neoadjuvant/concurrent and concurrent/adjuvant ADT relative to RT were associated with mostly similar disease outcomes among patients receiving whole-pelvis RT [33]. However, among patients receiving prostate-only RT, concurrent/adjuvant ADT was associated with improved overall survival (hazard ratio 0.69) and other disease outcomes relative to neoadjuvant/concurrent ADT. Despite these results, we continue to initiate ADT prior to RT in patients receiving both treatments for localized prostate cancer, given prior data as well as the opportunity to maximally cytoreduce prior to RT; however, we consider concurrent initiation to also be acceptable. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Sequencing and duration'.)

Chemoradiation with fluorouracil and mitomycin for muscle-invasive bladder cancer (February 2023)

For patients with muscle-invasive bladder cancer (MIBC), chemoradiation (CRT) with fluorouracil (FU) plus mitomycin is an established treatment option, but data for long-term outcomes were previously limited. In extended follow-up of a phase III trial of almost 400 patients with MIBC, the addition of FU/mitomycin to radiation therapy continued to improve locoregional disease control (five-year locoregional recurrence-free rate of 63 versus 49 percent) and reduce the rate of cystectomy (14 versus 22 percent) [34]. For patients with MIBC treated with CRT for bladder preservation, we consider FU/mitomycin to be one of several acceptable concurrent chemotherapy regimens. (See "Bladder preservation treatment options for muscle-invasive urothelial bladder cancer", section on 'Chemoradiation versus radiation monotherapy'.)

Lack of survival benefit for atezolizumab as initial therapy in advanced urothelial carcinoma (January 2023)

Atezolizumab, a programmed cell death ligand-1 (PD-L1) inhibitor, was previously approved by the US Food and Drug Administration (FDA) for patients with advanced or metastatic urothelial carcinoma (mUC) in patients ineligible for any platinum-based chemotherapy and in those with PD-L1 positive cancers ineligible for cisplatin-based chemotherapy. However, in a randomized phase III trial of over 1000 patients with treatment-naïve mUC, the addition of atezolizumab to platinum-based chemotherapy failed to improve overall survival [35]. Based on these data, the FDA withdrew regulatory approval for atezolizumab for the above indications, and we no longer use it as initial therapy for patients with platinum-ineligible mUC [36]. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'Other agents'.)

GYNECOLOGIC ONCOLOGY

Letrozole and abemaciclib in estrogen receptor-positive recurrent endometrial cancer (January 2023)

For patients with metastatic endometrial cancer, chemotherapy and immunotherapy are often used as initial lines of treatment, but there is interest in endocrine-based therapy as an alternative. In a phase II study in 30 patients with recurrent estrogen receptor (ER)-positive endometrial cancer, the combination of an aromatase inhibitor and cyclin dependent kinase (CDK) 4/6 inhibitor (letrozole and abemaciclib, respectively) was associated with a response rate of 30 percent and median progression-free survival of 9.1 months [37]. For patients with metastatic ER-positive endometrial cancer, we consider an aromatase inhibitor plus a CDK 4/6 inhibitor to be an acceptable alternative to chemotherapy- and immunotherapy-based strategies, particularly for those with minimally symptomatic or indolent disease. (See "Treatment of metastatic endometrial cancer", section on 'Endocrine therapy, for ER-positive cancers'.)

Avoidance of niraparib and rucaparib maintenance in platinum-sensitive, relapsed, BRCA wildtype ovarian cancer (December 2022)

In randomized trials, niraparib and rucaparib previously showed progression-free survival benefits as maintenance therapy in platinum-sensitive, relapsed ovarian cancer, irrespective of the presence of either a BRCA mutation or homologous recombination deficiency (HRD). However, in longer follow up, there was a lack of overall survival benefit in patients with BRCA wildtype, platinum-sensitive recurrent breast cancer, leading to removal of regulatory approval by the US Food and Drug Administration for this indication [38,39]. This change does not affect approval of niraparib as maintenance after first-line treatment. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'PARP inhibitors'.)

Rucaparib maintenance in newly diagnosed ovarian cancer (December 2022)

For newly diagnosed advanced ovarian cancer with response to platinum-based chemotherapy, maintenance with the poly(ADP-ribose) polymerase (PARP) inhibitor niraparib improves progression-free survival (PFS), but trials are evaluating other PARP inhibitors. In a trial in 538 patients with newly diagnosed stage III to IV, high-grade ovarian cancer undergoing surgical cytoreduction and responding to platinum-doublet chemotherapy, rucaparib maintenance improved PFS relative to placebo (20 versus 9.2 months) [40]. PFS benefits were observed both in homologous repair deficient (HRD) tumors and those lacking HRD, although benefits were lesser in this group. We await regulatory approval prior to using rucaparib maintenance in newly diagnosed ovarian cancer. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer", section on 'Efficacy'.)

Mirvetuximab soravtansine in platinum-resistant epithelial ovarian cancer (November 2022)

Mirvetuximab soravtansine is a folate receptor alpha-directed antibody and microtubule inhibitor conjugate that has regulatory approval in the United States for folate receptor-alpha positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) that has previously been treated with one to three prior systemic treatment regimens [41]. In an earlier randomized trial in patients with platinum-resistant EOC, the agent resulted in a nonsignificant trend towards better progression-free survival compared with investigator's choice chemotherapy in those with folate receptor-alpha high tumors (hazard ratio 0.69), with better tolerability. We consider mirvetuximab soravtansine to be an appropriate later-line option in platinum-resistant EOC. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'Other agents'.)

Doxorubicin and trabectedin as first-line therapy for advanced leiomyosarcoma (October 2022)

The combination of doxorubicin plus trabectedin holds promise in metastatic leiomyosarcoma (LMS). In a randomized trial including 150 patients with metastatic leiomyosarcoma of uterine or nonuterine soft tissue sarcoma origin, progression-free survival was longer in patients assigned to doxorubicin plus trabectedin followed by trabectedin versus doxorubicin alone (12.2 versus 6.2 months, adjusted hazard ratio 0.41) [42]. Improvements were noted in both the nonuterine and uterine subgroups. The most common grade ≥3 adverse events with and without trabectedin were neutropenia (80 versus 13 percent), anemia (31 versus 5 percent), thrombocytopenia (47 versus 0 percent), and febrile neutropenia (28 versus 9 percent). We consider doxorubicin plus trabectedin followed by trabectedin to be an acceptable option for the initial treatment of fit patients with advanced LMS. (See "Treatment and prognosis of uterine leiomyosarcoma", section on 'In combination with trabectedin'.)

HEAD AND NECK CANCER

Reirradiation schedules for locally recurrent nasopharyngeal carcinoma (March 2023)

For patients with locally recurrent nasopharyngeal carcinoma (NPC), reirradiation using standard fractionation schedules poses therapeutic challenges, including a significant risk of late radiation (RT)-related complications. In an open-label randomized trial of almost 200 patients with locally recurrent, unresectable NPC, intensity-modulated RT (IMRT) using a hyperfractionated schedule (65 Gy in 54 fractions, given twice daily) improved three-year overall survival (75 versus 55 percent) and reduced grade ≥3 toxicities (34 versus 57 percent) compared with standard fractionation (60 Gy in 27 fractions, given daily) [43]. Based on these data, for patients with locally recurrent unresectable NPC who are candidates for reirradiation, we administer IMRT using a hyperfractionated schedule rather than standard fractionation. (See "Treatment of recurrent and metastatic nasopharyngeal carcinoma", section on 'Reirradiation'.)

Targeted therapies for metastatic salivary gland tumors (February 2023)

The treatment of metastatic salivary gland tumors (SGTs) is evolving, and updated guidelines from the National Comprehensive Cancer Network include more targeted treatment options, which are available for clinical use [44]. For patients with HER2-positive metastatic nonsecretory SGTs, we offer trastuzumab plus pertuzumab as initial therapy to those who wish to avoid or have contraindications to chemotherapy; we consider fam-trastuzumab deruxtecan to be one acceptable treatment option for those who progress on trastuzumab-based therapy. For patients with a metastatic BRAF V600E mutated SGT of any histology and no other actionable molecular alterations, we suggest initial therapy with dabrafenib and trametinib rather than chemotherapy or other systemic agents as this combination is well tolerated and results in robust, prolonged responses. (See "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease", section on 'HER2 overexpression' and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease", section on 'BRAF V600E mutant tumors'.)

MELANOMA AND OTHER SKIN CANCER

Nivolumab for pediatric patients with advanced melanoma (March 2023)

In pediatric patients with advanced melanoma, there are limited data to guide systemic treatment options. In February 2023, the US Food and Drug Administration (FDA) granted regulatory approval for nivolumab in pediatric patients (age 12 years and older) for the following indications [45]: unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab, and advanced or metastatic melanoma that has been completely resected, as adjuvant therapy for one year. These approvals are based on trials of these regimens in adult patients and pharmacokinetic studies in pediatric patients that demonstrate similar exposure to nivolumab as that reported in adults. We agree with use of nivolumab in children with these indications. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Adjuvant nivolumab' and "Overview of the management of advanced cutaneous melanoma", section on 'Pediatric and adolescent patients'.)

Nivolumab for advanced cutaneous squamous cell carcinoma (March 2023)

Studies are investigating immune checkpoint inhibitors for advanced cutaneous squamous cell carcinoma (cSCC). In a phase II trial of over 20 patients with metastatic and/or locally advanced cSCC treated with nivolumab, the objective response rate was 58 percent [46]. Median progression-free and overall survival were 13 and 21 months, respectively. Nivolumab was also well tolerated even in older adults. Based on these data, we consider nivolumab to be one of several acceptable treatment options for patients with metastatic or locally advanced cSCC not amenable to treatment with surgery or radiation therapy. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Nivolumab'.)

Nivolumab-relatlimab for immunotherapy-refractory metastatic melanoma (February 2023)

For patients with metastatic melanoma who progress on nivolumab plus ipilimumab, there is interest in novel agents such as relatlimab, a lymphocyte activation gene-3 (LAG-3) inhibitor. In an early phase trial (RELATIVITY-020), among a subgroup of over 300 patients with metastatic melanoma treated with a programmed cell death-1 (PD-1) or PD-1 ligand-1 (PD-L1) inhibitor (with or without ipilimumab), the objective response rate for nivolumab-relatlimab was 12 percent, and six-month progression-free survival was 29 percent [47]. For patients with metastatic melanoma who progress on nivolumab plus ipilimumab, we consider nivolumab-relatlimab to be one of several acceptable treatment options. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Prior treatment with nivolumab plus ipilimumab'.)

Tumor-infiltrating lymphocytes in advanced melanoma (January 2023)

For patients with metastatic melanoma who progress on immune checkpoint inhibitors, effective treatment options are limited, and there is interest in developing novel therapies. In a randomized trial in almost 200 patients with advanced unresectable or metastatic cutaneous melanoma (a majority of whom had progressed on a programmed cell death-1 [PD-1] inhibitor), personalized adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) improved progression-free survival over single-agent ipilimumab (median 7.2 versus 3.1 months) [48]. While these data are promising, the use of TILs remains investigational, and we await regulatory approval prior to incorporating this approach into routine clinical practice. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'What is the role of tumor-infiltrating lymphocytes?'.)

Adjuvant nivolumab for high-risk node-negative melanoma (December 2022)

In patients with resected, high-risk node-negative (stage IIB and IIC) cutaneous melanoma, one year of adjuvant pembrolizumab reduces recurrence risk, but studies are evaluating other immune checkpoint inhibitors. In an open-label phase III trial (CheckMate-76K) of almost 800 patients with resected stage IIB and IIC melanoma, one year of adjuvant nivolumab improved one-year recurrence-free survival over placebo (89 versus 79 percent) and was well tolerated [49]. Based on these data, for patients with high-risk node-negative (stage IIB and IIC) cutaneous melanoma, we suggest one year of adjuvant immunotherapy with either pembrolizumab or nivolumab. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Adjuvant nivolumab'.)

Nivolumab plus ipilimumab for advanced Merkel cell carcinoma (November 2022)

There are limited effective treatment options for patients with metastatic Merkel cell carcinoma (MCC) who progress on single-agent immunotherapy. In a phase II study in patients with advanced or metastatic MCC, in a subset of 12 patients with disease refractory to single-agent immunotherapy, nivolumab plus ipilimumab demonstrated objective and complete response rate of 42 and 25 percent, respectively [50]. Based on these data, we suggest combination immunotherapy with nivolumab plus ipilimumab rather than chemotherapy for patients with metastatic MCC who progress on single-agent immunotherapy. (See "Treatment of recurrent and metastatic Merkel cell carcinoma", section on 'Nivolumab plus ipilimumab'.)

Neoadjuvant pembrolizumab for high-risk, node-positive melanoma (November 2022)

For patients with high-risk node-positive (Stage IIIB, IIIC, IIID) melanoma, neoadjuvant immunotherapy was effective in phase I and II trials, but randomized studies comparing this approach with adjuvant immunotherapy, the standard of care, were previously lacking. In a phase III trial of over 300 patients with resectable macroscopic stage IIIB-IV melanoma, neoadjuvant pembrolizumab improved two-year event-free survival (72 versus 49 percent) compared with primary surgical resection followed by adjuvant pembrolizumab [51]. Overall survival data are not mature. Based on these data, for patients with high-risk node-positive (stage IIIB, IIIC, IIID) melanoma and macroscopic disease that is resectable, we suggest initial therapy with neoadjuvant pembrolizumab rather than primary surgery. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Macroscopic disease'.)

Adjuvant nivolumab plus ipilimumab for metastatic melanoma (November 2022)

For patients with metastatic melanoma who have undergone definitive treatment of all sites of disease, adjuvant nivolumab plus ipilimumab improves recurrence-free survival (RFS), but data on overall survival (OS) were previously unavailable. In final results of a randomized phase II trial (IMMUNED) of approximately 170 patients with metastatic melanoma and no evidence of disease after local therapy, adjuvant nivolumab plus ipilimumab improved four-year OS compared with placebo (84 versus 63 percent) [52]. The combination also improved RFS when compared with placebo (64 versus 15 percent) and nivolumab monotherapy (64 versus 31 percent). Based on these data, in patients with metastatic melanoma who have undergone definitive treatment, we continue to suggest adjuvant nivolumab plus ipilimumab for four doses followed by maintenance nivolumab to complete one year of therapy rather than surveillance alone. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Adjuvant nivolumab plus ipilimumab'.)

Adjuvant pembrolizumab for resected cutaneous melanoma (November 2022)

Adjuvant pembrolizumab has regulatory approval for patients with resected, high-risk, node-negative (Stage IIB and IIC) cutaneous melanoma, but long-term follow-up outcomes are limited. In extended follow-up of a phase III trial of almost 1000 patients with resected Stage IIB and IIC disease, pembrolizumab improved distant metastasis-free survival (88 versus 82 percent) and recurrence-free survival (81 versus 73 percent) at two years [53]. Based on these data, we continue to suggest the use of adjuvant pembrolizumab for patients with Stage IIB and IIC melanoma after complete resection. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Adjuvant pembrolizumab'.)

NEUROONCOLOGY

Reirradiation in patients with recurrent glioblastoma (March 2023)

Small studies in patients with recurrent high-grade gliomas have suggested that repeat radiation using modern high-precision techniques is feasible in selected patients, but its effect on survival has been unclear. In a phase II multicenter randomized trial of bevacizumab with or without repeat radiation (35 Gy in 10 fractions) in 182 patients with recurrent glioblastoma, bevacizumab plus reirradiation improved median progression-free survival compared with bevacizumab alone (7.1 versus 3.8 months), but median overall survival was similar between groups (10.1 versus 9.7 months) [54]. The trial population was heterogeneous, and quality-of-life outcomes were not available. Further studies are needed to determine which patients with recurrent glioblastoma are most likely to benefit from reirradiation. (See "Management of recurrent high-grade gliomas", section on 'External beam delivery techniques'.)

Direct oral anticoagulants for treatment of venous thromboembolism in patients with brain tumors (January 2023)

Accumulating evidence in patients with brain tumors suggests that direct oral anticoagulants (DOACs) are associated with a lower risk of intracranial hemorrhage (ICH) than other forms of anticoagulation. In a recent observational study of 121 patients with glioblastoma and venous thromboembolism (VTE) who were treated with a DOAC or low molecular weight (LMW) heparin, the six-month incidence of clinically relevant ICH was lower with DOACs than LMW heparin (0 versus 24 percent), while rates of recurrent VTE were similar (0 versus 4 percent) [55]. Based on these and other data, we favor DOACs as a safer and more convenient option in patients with primary and metastatic brain tumors who are selected to receive anticoagulation for VTE. We generally avoid anticoagulation in patients with intratumoral hemorrhage within the past four weeks or a remote history of a clinically significant ICH. (See "Treatment and prevention of venous thromboembolism in patients with brain tumors", section on 'Direct oral anticoagulants'.)

Role of pneumocystis pneumonia prophylaxis with temozolomide (December 2022)

Patients with glioblastoma treated with daily temozolomide can develop pneumocystis pneumonia as a result of selective lymphopenia, but rates are not well characterized and use of antimicrobial prophylaxis in the neuro-oncology community is variable.

●In a population-based study that included more than 5000 Canadian patients with gliomas treated with temozolomide chemoradiotherapy, the incidence of pneumocystis pneumonia within one year of treatment was low (0.74 percent) and there were few infection-related deaths [56].

●In a related case-control study, the absolute risk reduction associated with prophylaxis was low (estimated number needed to treat to prevent one infection = 288), while the risk of grade 3/4 neutropenia was elevated (number needed to harm = 34) [57].

We suggest pneumocystis prophylaxis during chemoradiation in patients with glioblastoma who have additional risk factors for opportunistic infection (eg, glucocorticoid use, lymphopenia); in others, risks of prophylaxis may outweigh benefits. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'Pneumocystis prophylaxis'.)

Guideline on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors (October 2022)

A new multinational guideline is available on the diagnosis and treatment of rare glial and neuronal tumors in children and adults [58]. Over 20 tumors are included in the guideline, corresponding to the 2021 update of the World Health Organization classification of central nervous system tumors. Surgery is the cornerstone of management for nearly all of these tumors, and radiation therapy is used selectively in the adjuvant and recurrent/refractory setting. Relevant molecular markers and targeted therapies are also reviewed. (See "Uncommon brain tumors", section on 'Circumscribed astrocytic gliomas'.)

Proton craniospinal irradiation in patients with solid tumor leptomeningeal disease (October 2022)

For patients with leptomeningeal disease (LMD) from solid tumors, craniospinal irradiation (CSI) with photons is typically not appropriate due to high risk of toxicity and low likelihood of meaningful benefit. However, proton CSI has an improved toxicity profile compared with photon CSI, and there has been renewed interest in its role. In a randomized phase II trial of proton CSI versus involved field radiation in 63 patients with LMD from either breast cancer or non-small cell lung cancer, proton CSI improved both median central nervous system progression-free survival (7.5 versus 2.3 months) and overall survival (9.9 versus 7.5 months) compared with involved field radiation, with no difference in the rate of serious adverse effects [59]. Although more data are needed, where available, proton CSI is an option in selected patients with LMD who have adequate functional status and controlled systemic disease. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Proton craniospinal radiation'.)

PALLIATIVE AND SUPPORTIVE CARE

Comprehensive geriatric assessment in older patients with cancer (February 2023)

Comprehensive geriatric assessment for patients with cancer has been shown to improve patient satisfaction with overall care and decrease chemotherapy toxicity. However, in a recent randomized trial in 350 older adults with cancer, patients assigned to geriatric assessment experienced similar patient-reported quality of life, functional status, and severe toxicities as usual oncologic care [60]. The COVID-19 pandemic may have affected the intervention and outcomes of this trial; moreover, there were methodologic differences with prior studies. Given these considerations and the multiple prior randomized trials showing benefit, we continue to incorporate comprehensive geriatric assessment into cancer care for older adults. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Supporting evidence'.)

Limited role for glucocorticoids in cancer-related fatigue (February 2023)

Patients with advanced cancer often experience fatigue related to both their disease and its treatments. In a meta-analysis of three randomized trials in 165 patients with advanced cancer-related fatigue, one week of dexamethasone resulted in a small improvement in symptoms versus placebo, but this difference did not reach statistical significance [61]. Given limited supporting evidence and known adverse events with glucocorticoids, we reserve their use in the treatment of cancer-related fatigue for patients who are in the terminal phase of advanced cancer. (See "Cancer-related fatigue: Treatment", section on 'Glucocorticoids'.)

Joint guideline on integrative medicine for pain management in oncology (February 2023)

A joint guideline is available from the American Society of Clinical Oncology (ASCO) and the Society for Integrative Oncology (SIO) that provides evidence-based recommendations on integrative medicine for pain management in oncology patients [62]. The evidence quality was judged low to intermediate for most interventions, and most recommendations were weak or moderate. The recommendations are summarized in the table (table 2) and outlined in the algorithm (algorithm 1); specific recommendations sorted by type of pain and stratified according to the quality of evidence and strength of the recommendation are outlined in the table (table 3). (See "Rehabilitative and integrative therapies for pain in patients with cancer", section on 'Clinical practice guidelines'.)

Lack of benefit of CBD oil for relief of symptoms in advanced cancer (December 2022)

Cannabidiol (CBD) is a naturally occurring molecule without psychoactive properties that can be procured by patients from legal marijuana dispensaries, online companies, or street suppliers. Although CBD oil is used by patients for a variety of conditions, there are few data on the risks and benefits in patients with cancer. A single phase II randomized trial of CBD oil for relief of symptoms in advanced cancer concluded that, compared with placebo, CBD oil did not add value to the reduction in symptom distress (including pain, nausea, vomiting, appetite loss, depression, or anxiety) provided by specialist palliative care [63]. Use of CBD oil cannot be recommended for symptom management in advanced cancer. (See "Management of poorly controlled or breakthrough chemotherapy-induced nausea and vomiting in adults", section on 'CBD oil' and "Management of cancer anorexia/cachexia", section on 'Cannabis and cannabinoids' and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)", section on 'Choosing an agent for a therapeutic trial'.)

Eflapegrastim for chemotherapy-induced neutropenia (September 2022)

The US Food and Drug Administration has approved eflapegrastim, a novel long-acting formulation of granulocyte colony stimulating factor (G-CSF), to decrease the incidence of infection in adult patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia [64]. Approval was based on two separate trials of patients with early-stage breast cancer treated with docetaxel plus cyclophosphamide and randomized to eflapegrastim or pegfilgrastim. Efficacy was comparable, but despite the lower G-CSF dose with eflapegrastim, the incidence of adverse events (ie, bone pain, injection site reactions) was not lower in either trial. Given the available data, these two medications appear clinically similar, and agent selection may depend largely on institutional formulary and insurance constraints. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Eflapegrastim'.)

SOFT TISSUE AND BONE TUMORS

Atezolizumab for advanced alveolar soft part sarcoma (January 2023)

For patients with metastatic alveolar soft part sarcoma (ASPS), treatment options are limited and there is interest in investigating novel therapies. In a phase II trial (Study ML39345) in almost 50 adult and pediatric patients with unresectable or metastatic ASPS, atezolizumab demonstrated an objective response rate of 24 percent and was well tolerated [65]. For patients with unresectable or metastatic ASPS who have limited but progressive extracranial disease burden, we suggest single-agent immunotherapy rather than surveillance, and we consider atezolizumab to be one appropriate treatment option. (See "Uncommon sarcoma subtypes", section on 'Limited, progressive disease burden'.)

Chemotherapy for localized Ewing sarcoma (December 2022)

For patients with localized Ewing sarcoma (ES), vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide plus etoposide (VDC/IE) is used in the United States as neoadjuvant therapy, while vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) is used in Europe. In a randomized phase III trial (EE2012) of over 600 patients with ES, initial treatment with VDC/IE improved overall survival over VIDE (three-year overall survival 82 versus 75 percent), reduced rates of grade ≥3 febrile neutropenia (58 versus 74 percent), and shortened treatment duration by two months [66]. Based on these data, for patients with localized ES, we recommend initial chemotherapy with VDC/IE rather than VIDE. (See "Treatment of Ewing sarcoma", section on 'Selection of therapy'.)

Pimitespib for advanced gastrointestinal stromal tumors (October 2022)

For patients with advanced gastrointestinal stromal tumors (GIST) who have progressed on multiple tyrosine kinase inhibitors, there is interest in novel targeted agents. In a phase III trial in almost 90 patients with advanced GIST refractory to imatinib, sunitinib, and regorafenib, the heat-shock protein 90 inhibitor pimitespib improved median progression-free survival (2.8 versus 1.4 months) compared with placebo, as well as cross-over-adjusted median overall survival (14 versus 8 months) [67]. For patients with advanced GIST refractory to imatinib, sunitinib, and regorafenib, pimitespib is an acceptable treatment option, but is available only in Japan. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Pimitespib'.)

THORACIC ONCOLOGY

Sotorasib in KRAS G12C-mutated advanced NSCLC (March 2023)

Multiple agents targeting the KRAS G12C mutation in non-small cell lung cancer (NSCLC) have emerged, including sotorasib. In an open-label, randomized controlled trial, among 345 patients with KRAS G12C-mutated advanced NSCLC who experienced progression on platinum-based chemotherapy and a programmed cell death-1 (PD-1) or PD-1 ligand-1 (PD-L1) inhibitor, those assigned to sotorasib had a better progression-free survival (PFS) compared with the docetaxel group (median PFS 5.6 versus 4.5 months), with fewer serious treatment-related adverse events (11 versus 23 percent) [68]. Overall survival was similar between the two groups. For patients with advanced NSCLC with a KRAS G12C mutation that has progressed on a prior line of therapy, we suggest sotorasib rather than further chemotherapy; the targeted agent adagrasib is also a reasonable option. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Sotorasib'.)

Sublobar versus lobar resection in small, peripheral NSCLC (February 2023)

Among patients with small, peripheral non-small cell lung cancer (NSCLC), previous data suggested improved survival with sublobar relative to lobar resection. By contrast, in a recent randomized trial in nearly 700 patients with peripheral NSCLC with a tumor of ≤2 cm and pathologically confirmed node-negative disease, sublobar resection resulted in a similar overall survival compared with lobar resection (80 versus 79 percent) [69]. Five-year disease-free survival was also similar (63.6 versus 64.1 percent). Given that the sum of data suggests at least equivalent and possibly improved survival, we continue to suggest sublobar resections in patients with small, peripheral NSCLC, when technically feasible. This approach should be limited to primary tumors ≤2 cm located in the outer one-third of the lung parenchyma, with lobar nodes that are uninvolved on frozen section. (See "Management of stage I and stage II non-small cell lung cancer", section on 'Small peripheral tumors'.)

Adjuvant pembrolizumab in resected NSCLC (December 2022)

Although adjuvant atezolizumab is used in select cases of resected non-small cell lung cancer (NSCLC), trials are examining other immune checkpoint inhibitors in this setting. In the PEARLS/KEYNOTE-091 trial, among almost 1200 patients with completely resected stage IB (T ≥4 cm) to IIIA NSCLC, adjuvant pembrolizumab improved disease-free survival relative to placebo in the overall group (54 versus 42 months; hazard ratio [HR] 0.76), with a nonsignificant trend toward improvement in those with tumor programmed cell death ligand 1 (PD-L1) ≥50 percent (median not reached in either arm; HR 0.82) [70]. Overall survival results were immature at a median follow up of 36 months. We await further data and regulatory approval prior to routine use of adjuvant pembrolizumab in resected NSCLC. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Adjuvant immunotherapy'.)

Immune checkpoint inhibitor combinations plus chemotherapy in advanced NSCLC (November 2022)

The addition of immune checkpoint inhibitors to chemotherapy improves survival in advanced non-small cell lung cancer (NSCLC), with new combinations being investigated. In preliminary results of Study 16113, among 466 patients randomly assigned to chemotherapy with or without cemiplimab, the cemiplimab group experienced an improvement in median overall survival (22 versus 13 months), with low rates of serious adverse events [71]. Similarly, in the POSEIDON trial, the addition of tremelimumab plus durvalumab to chemotherapy improved median survival (15 versus 11 months), with acceptable rates of grade ≥3 toxicity [72]. These results have led to US Food and Drug Administration approvals of combinations of cemiplimab as well as tremelimumab/durvalumab with chemotherapy in advanced NSCLC lacking certain driver mutations. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Cemiplimab plus chemotherapy'.)

Serplulimab in extensive-stage small cell lung cancer (October 2022)

In extensive-stage small cell lung cancer (ES-SCLC), the addition of either atezolizumab or durvalumab to platinum-based induction chemotherapy has improved survival; trials are exploring the use of other checkpoint inhibitors. In a randomized trial including 585 patients with treatment-naïve, extensive-stage SCLC, the addition of serplulimab to chemotherapy improved overall survival (15.4 versus 10.9 months), with modestly higher incidence of grade ≥3 adverse events (33 versus 28 percent) [73]. We await regulatory approval prior to incorporating serplulimab into treatment for ES-SCLC. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Other combinations'.)

MISCELLANEOUS TUMORS

Preoperative chemotherapy in bilateral Wilms tumor (November 2022)

Studies are investigating the strategy of preoperative chemotherapy followed by kidney parenchymal-sparing resection for patients with bilateral Wilms tumor. In long-term follow-up of a single arm, prospective study in almost 200 patients with bilateral Wilms tumor, this strategy was associated with a four-year overall survival rate of 95 percent [74]. It was greater for those with low-risk disease, intermediate-risk disease, and blastemal-type tumors than for those with high-risk diffuse anaplasia (>90 versus 72 percent). Fewer than 3 percent of patients required bilateral nephrectomy. For patients with bilateral Wilms tumor, we continue to suggest preoperative chemotherapy followed by kidney parenchymal-sparing resection rather than more extensive bilateral kidney resection. (See "Treatment and prognosis of Wilms tumor", section on 'Bilateral kidney involvement'.)

Tissue-agnostic approval of selpercatinib for RET fusion-positive solid tumors (November 2022)

Selpercatinib has received a tissue-agnostic, accelerated approval from the US Food and Drug Administration for treatment of adult patients with locally advanced or metastatic solid tumors and a rearranged during transfection (RET) gene fusion with disease progression on or following prior systemic treatment or those who have no satisfactory alternative treatment options. Approval was based on the phase 1/2 LIBRETTO-001 basket trial of 41 patients with a variety of solid tumors containing an RET fusion gene, in which the objective response rate was 44 percent and median duration of response was 24.5 months [75]. The most common grade 3 or worse treatment-emergent adverse events were hypertension and elevated serum transaminases. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RET fusion-positive tumors' and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease".)

Sodium thiosulfate to reduce cisplatin ototoxicity in children with nonmetastatic solid tumors (September 2022)

Sodium thiosulfate (STS) has been approved by the US Food and Drug Administration to decrease the risk of cisplatin-related ototoxicity in pediatric patients aged 1 month or older with a localized, nonmetastatic solid malignancy [76]. Approval was based on two randomized trials, the Children's Oncology Group ACCL0431 trial and the SIOPEL-6 trial, which both demonstrated a lower incidence of ototoxicity among children treated with STS in the setting of hepatoblastoma or a solid tumor including germ cell cancer, medulloblastoma, neuroblastoma, or osteosarcoma. Given ongoing concerns about possible inferior oncologic outcomes, the approval was not extended to individuals with a metastatic solid tumor. The approved dose is based on actual body weight, as outlined in the US prescribing information [77]. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Strategies'.)

OTHER ONCOLOGY

Timing of systemic treatments and stereotactic body radiation therapy for metastatic disease (March 2023)

Although metastases-directed stereotactic body radiation therapy (SBRT) is generally tolerable, there are limited data regarding potential interactions between radiation and systemic therapy. An expert guideline based on systematic review suggested holding most immunotherapy and targeted agents on the day of SBRT, although consensus was reached that pertuzumab and trastuzumab may be administered on the day of SBRT [78]. Our practice is generally consistent; we hold most systemic treatments on the days of SBRT, and consider the type of and urgency for systemic therapy, location of SBRT, and the patient's tolerance of the procedure and the systemic therapy when deciding when to resume. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

Convalescent plasma in patients with cancer and COVID-19 (February 2023)

The optimal treatment of COVID-19 in patients with cancer continues to evolve. In a randomized trial of over 100 hospitalized patients with severe COVID-19, including almost 60 patients with cancer, the addition of convalescent/vaccinated plasma to standard of care (SOC) did not improve outcomes in the overall population. However, among patients with cancer (most with hematologic malignancies), this approach resulted in a faster median time to improvement (13 versus 31 days) and improved survival (89 versus 57 percent at 60 days) relative to SOC alone [79]. The trial was small, heterogeneous, and included few patients with solid tumors. As such, we continue to treat patients with cancer who have been hospitalized with COVID-19 with other standard COVID-19 strategies (algorithm 2) and consider convalescent plasma as an additional treatment strategy for patients with hematologic malignancies and severe symptoms. (See "COVID-19: Considerations in patients with cancer", section on 'Management of COVID-19'.)

Medication-related osteonecrosis of the jaw in patients with cancer (January 2023)

Antiresorptive therapy controls bone pain and reduces skeletal-related events in patients with bone metastases. A 2022 position paper from the American Association of Oral Maxillofacial Surgeons defines medication-related osteonecrosis of the jaw (MRONJ) as a complication of antiresorptive therapy, used either alone or in combination with immune modulators or antiangiogenic agents [80]. Nevertheless, the guideline advises that MRONJ is uncommon, and that oncology patients should receive antiresorptive agents if indicated, even if they are at risk of developing MRONJ or had MRONJ in the past. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Osteoclast inhibitors'.)

No role for statin therapy in preventing anthracycline cardiotoxicity (December 2022)

Cardiac toxicity caused by anthracycline-based chemotherapy is a major complication of cancer treatment, and there is an unmet need to identify therapies that attenuate this toxicity. In a recent trial that included nearly 300 patients who were treated with doxorubicin for either lymphoma or breast cancer and who had normal left ventricular ejection fraction (LVEF), patients randomly assigned to statin therapy or to placebo had similar decreases in LVEF after 24 months [81]. The trial used the gold standard of cardiovascular magnetic resonance imaging to quantify LVEF but was limited by missing LVEF values in more than one-third of participants. These findings do not support a role for statin therapy in preventing anthracycline-induced left ventricular systolic dysfunction; our approach to mitigating anthracycline cardiotoxicity includes limiting the cumulative dose of anthracycline and monitoring for early signs of toxicity with echocardiography. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Primary prevention with cardiovascular drugs'.)