NCCN Continuing Education

Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit^™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-24-008-H01-P

PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until July 10, 2025. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/94855; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.

Release date: July 10, 2024; Expiration date: July 10, 2025

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Overview

Cutaneous melanoma remains a global public health challenge, with an estimated 510,000 new cases and 96,000 deaths by 2040, a 50% estimated increase from 2020.¹ In 2024, approximately 100,640 patients will be diagnosed with and 8,290 patients will die of melanoma in the United States.² Melanoma mortality rates have declined in non-Hispanic white populations since 2014, following the advent of effective immunotherapies and targeted therapies for individuals with advanced disease.^2–5 Importantly, US Hispanic and Black individuals have worse survival outcomes in cutaneous melanoma than other groups, indicating potential persistent racial and ethnic inequities in melanoma diagnosis, access to care, and treatment.^2,6–8

Melanoma risk factors include male sex, age >50 years, phenotypic (eg, tendency to sunburn and/or numerous or atypical nevi), and genetic predisposition (eg, germline mutations), as well as personal or family history of melanoma and environmental factors (eg, excessive exposure to UV radiation in people with lighter skin tones).^2,9–16 Melanoma occurs most often in non-Hispanic white individuals with lighter skin, but it can occur in people with darker skin tones (especially in acral sites—palms, soles, fingernails, and toenails), in any racial and ethnic group, and in areas of the body without substantial sun exposure. As with nearly all malignancies, the outcome of cutaneous melanoma is dependent upon the stage at presentation; earlier detection is associated with improved survival.¹⁷

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous Melanoma (termed Melanoma: Cutaneous) provide multidisciplinary recommendations for the management of all stages or recurrence of melanoma, including surgical, systemic (neoadjuvant and adjuvant), and radiation therapy (RT) options. In addition to the latest updates to the neoadjuvant systemic therapies added throughout the guidelines, the panel created a new section for the principles of neoadjuvant therapy to serve as a resource for physicians.

Neoadjuvant Systemic Therapy Options for Cutaneous Melanoma

In the setting of a suspicious melanocytic neoplasm, complete/excisional skin biopsy is recommended when feasible. This will optimize histopathologic microstaging of the melanoma to assess Breslow thickness presence of ulceration, microsatellites, and dermal mitotic rate, the latter not included in staging but with significant prognostic impact. Once cutaneous melanoma is confirmed, wider excision is performed (with peripheral surgical margins based on Breslow thickness), along with pathologic staging of the regional lymph nodes (in appropriate cases) via sentinel lymph node biopsy, the status of which remains a key prognostic factor in medical decision-making and patient outcomes. The last 15 years have been groundbreaking regarding more effective systemic treatment of metastatic melanoma, with the advent of immune checkpoint inhibitors and targeted therapy (BRAF/MEK inhibitors).^18–26 More recent studies, which are summarized in this article, have focused on the use of immune checkpoint blockade–based and targeted therapies in the neoadjuvant setting (before surgical resection) to improve outcomes for patients with resectable high-risk stage III nodal and resectable stage IV disease.

A major question in melanoma management is whether treatment with immune checkpoint blockade before surgery induces an enhanced antitumor immune response and improved clinical outcomes. Patients with stage III resectable melanoma are potential candidates for this neoadjuvant approach because they have poor outcomes when treated with surgery alone and are thus typically offered systemic adjuvant therapy following surgical resection of bulky lymph nodes and/or in-transit disease.²⁷ RT may also be considered to the nodal basin in selected patients at high risk for nodal recurrence based on the location, size, number of involved nodes, and presence of gross and/or histologic extracapsular extension, although the benefits of reduced lymph node field recurrence with RT must be weighed against potential toxicities, such as lymphedema.

Response to PD-1 blockade requires the presence of preexisting antitumor T cells in contact with cancer cells.²⁸ In the adjuvant setting, resecting the bulk of the tumor (along with the tumor-infiltrating lymphocytes in the surgical specimen) may remove many of the potential antitumor T cells that would proliferate after PD-1 blockade. Neoadjuvant therapy posits that administration of anti–PD-1 therapy before surgery could induce an immune response from a larger population of tumor-infiltrating T cells. Inhibiting PD-1 immune checkpoints before surgery would then induce a systemic immune response at local and distant sites, leaving behind larger numbers of antitumor T cells. This was the central hypothesis for seminal neoadjuvant S1801 trial—that neoadjuvant PD-1 blockade could activate more antitumor T cells and improve clinical outcomes compared with administration of the same drug delivered postoperatively.²⁹

The clinical, pathologic, and radiographic response to the initial round of neoadjuvant immunotherapy could potentially guide postoperative adjuvant therapy selection, with duration and extent depending on the degree of pathologic response in the postneoadjuvant surgical specimen.^28,30 Other potential advantages to neoadjuvant therapy include an earlier start of systemic therapy and elimination of unnecessary surgery (eg, in patients with rapid development of metastatic disease), although counterbalanced against the potential drawbacks of delays in surgery and/or introduction of immune toxicity prior to surgery.

In this update of the NCCN Guidelines for Cutaneous Melanoma, the panel discussed neoadjuvant systemic therapies with proven efficacy for predominantly resectable stage III melanoma based on prospective trial data. These neoadjuvant regimens include recommended preferred regimens of pembrolizumab monotherapy, “flip dose” nivolumab, 3 mg/kg and ipilimumab, 1 mg/kg; other recommended regimens: nivolumab, nivolumab, and relatlimab; and those that are useful in certain circumstances: dabrafenib/trametinib and talimogene laherparepvec (T-VEC), the latter for in-transit metastasis. These regimens were added as recommendations in the setting of resectable stage III (clinically positive nodes), stage III (clinically satellite/in-transit metastasis), local satellite/in-transit and/or nodal recurrence (Figures 1–4). Given the strength of the trial data, neoadjuvant therapy for clinically positive nodes/nodal recurrence is generally preferred over the previous standard approach of therapeutic lymph node dissection (TLND), followed by adjuvant systemic treatment.

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ME-6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma: Cutaneous, Version 2.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0036

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ME-7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma: Cutaneous, Version 2.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0036

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ME-14. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma: Cutaneous, Version 2.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0036

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ME-16. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma: Cutaneous, Version 2.2024.

Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.0036

Pembrolizumab

Pembrolizumab is a monoclonal antibody that selectively binds to PD-1 and blocks the interaction with its ligand, PD-L1. In the randomized phase II SWOG 1801 study, 313 patients with resectable stage IIIB–IVC melanoma were provided with 3 doses of neoadjuvant pembrolizumab (200 mg every 3 weeks) followed by adjuvant pembrolizumab (15 additional doses) versus adjuvant pembrolizumab alone (18 doses) and both groups received surgical excision.²⁹ At a median follow-up of 14.7 months, the neoadjuvant arm (n=154) was associated with an improved event-free survival rate of 72% (95% CI, 64%–80%) compared with 49% (95% CI, 41%–59%) in the adjuvant-only arm at 2 years.

Treatment-related adverse events (TRAEs) of grade ≥3 severity were experienced in 12% of patients in the neoadjuvant arm compared with 14% of patients in the adjuvant arm. Based on the level of evidence of this data and a previously published phase Ib clinical trial with 5-year follow-up,^31,32 the panel made the following recommendations: pembrolizumab was included as an NCCN category 2A, preferred regimen, given as a neoadjuvant therapy for resectable stage III (clinically positive nodes), stage III (clinically satellite/in-transit), local satellite/in-transit recurrence, and nodal recurrence, followed by surgery and adjuvant systemic therapy.

Nivolumab/Ipilimumab

The interaction between the negative regulator CTLA-4 with its 2 distinct ligands CD80 and CD86 is selectively blocked by ipilimumab, a monoclonal antibody that binds to CTLA-4. The following trials investigated nivolumab, an anti–PD-1 antibody, alone or in combination with ipilimumab to treat cutaneous melanoma in the neoadjuvant setting.

In the OpACIN study, 20 patients with palpable stage III melanoma were randomized to receive nivolumab 1 mg/kg and ipilimumab 3 mg/kg as 4 courses after surgery (adjuvant arm) or 2 courses before surgery and 2 courses postsurgery (neoadjuvant arm).³³ Neoadjuvant therapy was achievable with all patients; however, 90% (n=9) of patients in each arm experienced ≥1 grade 3–4 adverse events (AEs). Pathologic responses were achieved in 78% (n=7) of patients treated in the neoadjuvant arm and none of these patients experienced relapse with a median follow-up of 25.6 months. At a median follow-up of 69 months, 1 in 7 patients with a pathologic response to neoadjuvant therapy had disease recurrence.³⁴ These trials showed that a significant percentage of patients could achieve pathologic response with a nivolumab/ipilimumab neoadjuvant treatment; however, toxicity was a limiting factor to the widespread implementation of this combination therapy, and the panel found this dosing schedule unsuitable for this setting.

OpACIN-neo was a multicentre, open-label, phase II, randomized, controlled trial designed to evaluate alternative dosing for nivolumab and ipilimumab to improve toxicity while retaining the efficacy of this regimen.^34–36 The eligible patients were adults (age ≥18 years) who had resectable stage III melanoma involving lymph nodes only and measurable disease. The study was divided into 3 neoadjuvant dosing schedules: (1) group A (n=30): 2 cycles of nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks intravenously; (2) group B (n=30): 2 cycles of nivolumab 3 mg/kg + ipilimumab 1 mg/kg (also referred to as a “flip-dose” regimen) every 3 weeks intravenously; or (3) group C (n=26): 2 cycles of ipilimumab 3 mg/kg every 3 weeks directly followed by 2 cycles of nivolumab 3 mg/kg every 2 weeks intravenously.

Within 12 weeks, grade 3–4 immune-related AEs (irAEs) were observed in 40% (n=12) of group A, 20% (n=6) of group B, and 50% (n=13) of group C.³⁵ The difference in grade 3–4 toxicity between groups B and A was –20% (95% CI, –46% to 6%; P=.158) indicating a likely considerable decrease in toxicity for nivolumab 3 mg/kg and ipilimumab 1 mg/kg. A radiologic objective response was observed in 63% (n=19; 95% CI, 44% to 80%) of patients in group A, 57% (n=17; 95% CI, 37% to 75%) of group B, and 35% (n=9; 95% CI, 17% to 56%) of group C. Additionally, pathologic responses occurred in 80% (n=24; 95% CI, 61% to 92%) of group A, 77% (n=23; 95% CI, 58% to 90%) of group B, and 65% (n=17; 95% CI, 44% to 83%) of group C. With comparable radiologic objective response and pathologic responses along with a reduced toxicity in group B, this regimen of nivolumab 3 mg/kg + ipilimumab 1 mg/kg for 2 doses showed promise for a broader clinical application. After a median follow-up of 47 months, the estimated 3-year relapse-free survival (RFS) and overall survival (OS) rates were 82% and 92%, respectively.³⁴ Interestingly, the estimated 3-year RFS rate was 95% for patients with a pathologic response and 37% for those without a pathologic response (P<.001).

PRADO was an extension of the OpACIN-neo trial that altered adjuvant therapy and surgical planning based on pathologic response rate (pRR) to neoadjuvant treatment.^37,38 Patients (n=99) with clinical stage IIIB–D received neoadjuvant nivolumab (3 mg/kg) + ipilimumab (1 mg/kg) for 2 doses. Prior to systemic therapy, a marker was placed in an index lymph node, which was resected after 2 doses to assess pathologic response. The pRR was 72% (n=71; 95% CI, 62%–80%), and of the 61% (n=60; 96% CI, 50%–70%) of patients who achieved major pathologic response (MPR; ≥90% of tumor cell death identified), TLND and adjuvant therapy were withheld from 59 patients, reducing their surgical morbidity. Those with a pathologic partial response (pPR) underwent TLND only while patients with pathologic nonresponse (pNR) underwent TLND and adjuvant systemic therapy.

Within the first 12 weeks, grade 3–4 toxicity was observed in 22 (22%; 95% CI, 14%–32%) patients. The 24-month RFS and distant metastasis–free survival rates were 93% (95% CI, 87% to >99%) and 98% (95% CI, 94% to >99%) in patients with MPR, both rates were 64% (95% CI, 41%–99%) in patients with pPR, and were 71% (95% CI, 55%–94%) and 76% (95% CI, 60%–97%) in patients with pNR, respectively. Optimal adjuvant therapy was not clear but could include anti–PD-1 monotherapy or observation for MPR. Alternatively, anti–PD-1 or dabrafenib/trametinib and/or lymph node basin RT can be used for those lacking MPR. A randomized study is ongoing to assess the approach of index lymph node resection (with omission of TLND) in patients with MPR.

Based on the level of evidence of this data, the nivolumab 3 mg/kg + ipilimumab 1 mg/kg combination therapy was included as an NCCN category 2A, preferred regimen, neoadjuvant systemic treatment option (followed by surgery and adjuvant treatment) for resectable stage III (clinically positive nodes), stage III (clinically satellite/in-transit), local satellite/in-transit recurrence, and nodal recurrence.

Nivolumab Monotherapy

A randomized noncomparative trial investigated nivolumab monotherapy versus a nivolumab/ipilimumab combination in the neoadjuvant setting for patients with high-risk resectable melanoma.³⁹ Eligible patients with predominantly stage IIIB–C melanoma were enrolled in the trial (n=23) and given nivolumab 3 mg/kg intravenously every 14 days for up to 4 doses in the monotherapy arm (n=12) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg intravenously every 21 days for up to 3 doses in the combination arm (n=13). The combination arm achieved a high response rate (overall response rate [ORR], 73%; pathologic complete response [pCR], 45%); however, this was associated with significant toxicity (73% grade 3 TRAEs). The monotherapy arm yielded modest response rates (ORR, 25%; pCR, 25%) and lower toxicity (8% grade 3 TRAEs). Median follow-up was 15.0 months (range, 5.8–22.6 months) in the monotherapy arm and 15.6 months (range, 5.8–24.4 months) in the combination arm. These data led to the addition of nivolumab monotherapy in the NCCN Guidelines. Nivolumab was included as an NCCN category 2A, other recommended regimen, neoadjuvant therapy option (followed by surgery and adjuvant treatment) for resectable stage III (clinically positive nodes), stage III (clinically satellite/in-transit), local satellite/in-transit recurrence, and nodal recurrence. The designation of other recommended regimen was designated by the panel due to the limited response rate and small cohort size.

Nivolumab and Relatlimab-rmbw

Relatlimab is a monoclonal antibody that targets the immune checkpoint Lymphocyte-Activation Gene-3 (LAG-3) to inhibit binding with ligands such as major histocompatibility complex class II (MHC-II). Other studies have demonstrated that the combination of nivolumab and relatlimab in patients with unresectable melanoma led to an improved progression-free survival over nivolumab alone; however, toxicity was more frequent and severe in the combination treatment.²⁵ Amaria et al⁴⁰ conducted a multi-institutional single-arm phase II study to investigate relatlimab and nivolumab in the neoadjuvant setting for patients with resectable clinical stage IIIB–D or oligometastatic stage IV melanoma and no prior immunotherapy exposure. Eligible patients (n=30) received 2 doses of nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks followed by surgical resection and 10 doses of adjuvant combination therapy to complete 46 weeks of treatment.

Among eligible patients, there was a 57% pCR rate, 70% pRR, 57% radiographic response rate, and no grade 3–4 irAEs. The RFS rate at 1 and 2 years was 100% and 92%, respectively, for patients with pathologic response, whereas nonresponders only achieved 88% and 55% (P=.005). Based on these data, the nivolumab/relatlimab combination was included as an NCCN category 2A, other recommended regimen, neoadjuvant systemic therapy option (followed by surgery and adjuvant treatment) for resectable stage III (clinically positive nodes), stage III (clinically satellite/in-transit), local satellite/in-transit recurrence, and nodal recurrence.

Dabrafenib/Trametinib if BRAF V600 Mutation–Positive

Dabrafenib, a highly specific inhibitor of the BRAF V600–mutant kinase, and trametinib, a selective allosteric MEK inhibitor, are a combination targeted therapy for patients with a BRAF V600 mutation. In a single-center, open-label, randomized phase II trial at the University of Texas MD Anderson Cancer Center, 21 adult patients were included with confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAF V600–mutated melanoma and ECOG performance status 0–1.⁴¹ A total of 14 patients were assigned to neoadjuvant plus adjuvant dabrafenib and trametinib systemic therapy (neoadjuvant group) and 7 patients were assigned to up-front surgery and consideration for adjuvant therapy (adjuvant group).

The neoadjuvant group received 8 weeks of dabrafenib 150 mg twice daily and trametinib 2 mg once daily followed by surgery. This was followed by up to 44 weeks of adjuvant dabrafenib and trametinib starting 1 week after surgery for a cumulative 52 weeks of treatment. Significantly more patients in the neoadjuvant group (10/14; 71%) were alive without disease progression after a median follow-up of 18.6 months (IQR, 14.6–23.1 months) than those in the adjuvant group (0/7; 0%). The median event-free survival was 19.7 months (95% CI, 16.2 months–not estimable) versus 2.9 months (95% CI, 1.7 months–not estimable), respectively, with a hazard ratio (HR) of 0.016 (95% CI, 0.00012–0.14; P<.0001). The most common AEs in the neoadjuvant group were grade 1–2 toxicities, including chills (n=12; 92%), headache (n=12; 92%), and pyrexia (n=10; 77%), and 2 (15%) patients reported grade 3 diarrhea; no grade 4 events or treatment-related deaths occurred.

NeoCombi was a single-arm, open-label, single-center, phase II study conducted at the Melanoma Institute Australia (Sydney, NSW, Australia).⁴² Eligible patients included adults with histologically confirmed resectable stage IIIB–C BRAF V600 mutation–positive melanoma with ECOG performance status 0–1. The study enrolled 35 eligible patients who received neoadjuvant dabrafenib + trametinib and underwent resection. Patients received dabrafenib 150 mg twice daily + trametinib 2 mg once daily for 52 weeks (12 weeks of neoadjuvant therapy before complete resection and 40 weeks of adjuvant therapy). Median follow-up for these patients was 27 months (IQR, 21–36 months).

Overall, 30 (86%) patients achieved a response at resection: complete response in 16 (46%; 95% CI, 29%–63%) and partial response in 14 (40%; 95% CI, 24%–58%). Additionally, stable disease was achieved by 5 patients (14%; 95% CI, 5%–30%) and no patients experienced disease progression. Pathologic response was achieved by all patients (n=35) after resection and evaluation, with 17 (49%; 95% CI, 31%–66%) experiencing a pCR. Serious TRAEs occurred in 6 (17%) patients and grade 3–4 AEs in 10 (29%) patients, and no treatment-related deaths were reported.

The NCCN Guidelines recommend the use of dabrafenib/trametinib combination targeted therapy as a category 2A, useful in certain circumstances, neoadjuvant therapy systemic option for resectable stage III (clinically positive nodes), stage III (clinically satellite/in-transit), local satellite/in-transit recurrence, and nodal recurrence, followed by surgery and adjuvant treatment. Although anti–PD-1–based options are preferred, if immunotherapy is contraindicated, dabrafenib and trametinib could be considered for a short course (4–12 weeks) of preoperative therapy. The panel recommendations also indicate that other BRAF/MEK inhibitor combinations (vemurafenib/cobimetinib or encorafenib/binimetinib) can be considered in the event of unacceptable toxicities to dabrafenib/trametinib or based on side effect profiles. However, in contrast with immunotherapy, neoadjuvant therapy has not been studied in comparison with adjuvant dabrafenib and trametinib.

Talimogene Laherparepvec

Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1–based intralesional oncolytic immunotherapy. A randomized open-label, phase II trial was conducted in 150 patients with resectable stage IIIB–IVM1a melanoma who received either T-VEC followed by surgery (arm 1, n=76) or surgery alone (arm 2, n=74).⁴³ Neoadjuvant T-VEC was associated with improved RFS at 2 years with 29.5% for arm 1 and 16.5% for arm 2 (overall HR, 0.75; 80% CI, 0.58–0.96). The OS at 2 years was 88.9% for arm 1 and 77.4% for arm 2 (overall HR, 0.49; 80% CI, 0.30–0.79). Even at 3 years the RFS and OS differences between arms persisted. In arm 1, 17.1% experienced a pCR and AEs were consistent with previous reports for T-VEC. Based on modest efficacy for lymph node disease and little effect in distant metastatic disease, this approach is only recommended for certain patients with satellite/in-transit disease. The NCCN Guidelines include recommendations for T-VEC in the neoadjuvant setting as a category 2A, initial treatment option for resectable stage III (clinical satellite/in-transit) and local satellite/in-transit recurrence melanoma, followed by clinical assessment with or without imaging to determine the treatment response or disease progression.

Conclusions

The treatment landscape of advanced melanoma continues to evolve. Questions regarding current neoadjuvant approaches remain that require further prospective investigation, such as appropriate duration of neoadjuvant systemic therapy before resection, extent of subsequent surgery, how pathologic response (especially pCR or MPR) to neoadjuvant therapy impacts postoperative use of adjuvant therapy, and which neoadjuvant regimens are associated with the highest response rates and best survival outcomes. Large phase III studies could provide supporting data for recommendations in other settings, such as bulky, resectable stage II cutaneous melanoma or resectable stage IV metastatic melanoma, the latter often extrapolating data from the stage III setting. Studies have also revealed prognostic factors such as MPR and pCR that can alter the approach to subsequent treatments for patients with advanced melanoma, pending further examination. These NCCN Guidelines Insights discuss the latest clinical data regarding neoadjuvant systemic therapies from which the panel provided the above recommendations. For a complete list of updates, see Version 2.2024 of the NCCN Guidelines for Cutaneous Melanoma, available at NCCN.org.

NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise indicated.

NCCN CATEGORIES OF PREFERENCE

Preferred intervention: Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.

Other recommended intervention: Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.

Useful in certain circumstances: Other interventions that may be used for selected patient populations (defined with recommendation).

All recommendations are considered appropriate.

Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.

The NCCN Guidelines® Insights highlight important changes in the NCCN Guidelines® recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding the content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.