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The mainstay of treatment for patients with metastatic pancreatic cancer is chemotherapy, but the development of targeted therapies and immunotherapies heralds a new era in their care. Although actionable alterations are detected infrequently, routine molecular testing should be performed in all patients. The NCCN Guidelines provide the current evidence-based recommendations for maintenance therapy in the metastatic setting. For patients with resectable, borderline resectable, and locally advanced or unresectable tumors, critical questions remain regarding the role of radiation therapy.

A plethora of advancements in the management of locally advanced rectal cancer continue to be developed. Treatment strategies have primarily focused on modifying the current standard paradigm of rectal cancer management—including the complete omission of surgery or radiotherapy, or instead using immunotherapy as first-line treatment in eligible patients. Recommendations for optimal therapeutic strategies, based on a patient’s clinical stage, have been outlined in the NCCN Guidelines for Rectal Cancer.

Treatment of children with neuroblastoma depends on accurate assessment of the risk of relapse. Factors used in risk stratification for patients with neuroblastoma include disease stage, MYCN amplification status, age, tumor histology, presence or absence of segmental chromosome aberrations, and tumor cell ploidy. The goal of treatment for patients with low-risk neuroblastoma is cure with minimal toxicity. However, for those with high-risk neuroblastoma, the treatment approach involves multiple therapeutic modalities, including multi-agent chemotherapy at conventional doses, surgery, high-dose chemotherapy with autologous stem cell rescue, external-beam radiotherapy, a differentiating agent, and immunotherapy. Multidisciplinary collaboration is essential for optimal care.

The standard treatment for limited-stage small cell lung cancer (SCLC) is concurrent chemoradiation, with a small subset of patients that could potentially benefit from surgery. For extensive-stage SCLC, the current standard of care is chemoimmunotherapy with a PD-1/PD-L1 inhibitor. The role of prophylactic cranial irradiation in SCLC is currently under debate, and is being investigated in the ongoing MAVERICK trial. Despite high initial response rates to chemoradiotherapy, relapse is common, and outcomes for these patients remain poor. However, recent advances in understanding the molecular biology of SCLC have led to the identification of potential new targets for treatment, including the combination of temozolomide with PARP inhibitors and DLL3-targeted bispecific T-cell engager therapy, both of which have shown activity in early studies.

The past decade has seen a host of advancements in the management of metastatic urothelial carcinoma. Although efforts to identify novel systemic therapies are still ongoing, immune checkpoint inhibitors have become the preferred treatment option in this patient population. Recommendations for optimal treatment strategies—based on a patient’s eligibility for cisplatin—have been outlined in the NCCN Guidelines for Bladder Cancer in both the first-line and subsequent-line settings.

The systemic therapeutic landscape for cutaneous melanoma continues to evolve, with numerous diverse options currently available. Several clinical trials have resulted in approvals from the FDA and subsequent revisions to the NCCN Guidelines, which reflect the most up-to-date, evidence-based data relating to the evaluation and management of these malignant neoplasms. Combination checkpoint blockades, anti–PD-1 and anti–CTLA-4 monotherapies, and mutation-directed therapies are among the NCCN-recommended approaches across the neoadjuvant, first-line, and later-line settings. Tumor-infiltrating lymphocyte therapy, a recent addition in the later-line setting, may mark a new era in the management of metastatic disease.

Endometrial cancer has moved from being a histologic diagnosis alone to one that also considers the molecular classification of the tumor. Molecular classification is not only feasible but highly recommended because it improves the diagnostic classification and provides prognostic information that may guide treatment. The NCCN Cervical/Uterine Cancers Guidelines recognize the novel approach proposed by FIGO, but has concerns about the 2023 FIGO staging system and therefore does not recommend its use by clinicians. Advances in systemic treatment, particularly the introduction of immunotherapy, has greatly improved outcomes in endometrial cancer, especially for patients with mismatch repair–deficient tumors.

Metastatic hormone receptor–positive, HER2-negative breast cancer treatment is increasingly individualized as more of the tumor landscape is described and targeted therapies are developed. CDK4/6 inhibitors have demonstrated consistency in prolonging progression-free survival across several clinical trials in advanced disease. Research in endocrine therapy highlighted the noninferiority of fulvestrant compared with aromatase inhibitors after disease progression. Studies such as the PEARL and Young-PEARL trials challenged the superiority of chemotherapy over endocrine therapy in certain populations, including premenopausal women. Sequential CDK4/6 inhibitor therapy after disease progression showed potential benefits, though definitive data are lacking. Targeting the PI3 kinase pathway, particularly with capivasertib in patients with pathway alterations, showed significant improvements in progression-free survival. ESR mutations have been identified as a key factor in resistance to endocrine therapy, with elacestrant showing promise in overcoming this challenge. Finally, in early-stage cancer, the question of whether ovarian suppression along with endocrine therapy can show the same results as chemotherapy is being explored, but the answer remains to be seen.

Patients with smoldering myeloma should undergo periodic risk assessment—if they are deemed at high risk for disease progression, clinical trials or lenalidomide with or without dexamethasone should be considered. The initial treatment of newly diagnosed myeloma should be based on the patient’s risk, fitness, and preferences. Induction with a quadruplet regimen, followed by autologous transplantation and maintenance therapy, remains the standard of care, especially for those with high-risk disease. For patients with standard-risk disease not undergoing immediate transplantation, triplet or quadruplet induction followed by maintenance is the standard. Appropriate treatment of relapsed disease depends on response to previous treatment, residual side effects, and comorbidities. T-cell–redirecting therapies and other novel agents have shown activity, even in heavily pretreated patients. Most patients will require multiple lines of therapy over the course of the disease.

The introduction of immune checkpoint inhibitors (ICIs), such as pembrolizumab and nivolumab, has significantly improved overall survival in both the first- and second-line settings for patients with head and neck squamous cell carcinomas. In nasopharyngeal carcinomas, the combination of gemcitabine + cisplatin with PD-1 inhibitors has demonstrated impressive response rates and overall survival benefits. However, the unique immune-related adverse events associated with ICIs require patient counseling. Ongoing clinical trials are exploring novel combinations of ICIs with EGFR monoclonal antibodies, tyrosine kinase inhibitors, and therapeutic vaccines to further improve treatment outcomes. Biomarkers, such as circulating HPV-DNA and actionable molecular alterations (eg, HRAS mutations), may help guide treatment decisions and predict patient responses in the future.