NCCN Guidelines® Insights: Squamous Cell Skin Cancer, Version 1.2022

Featured Updates to the NCCN Guidelines

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  • 1 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 2 Duke Cancer Institute;
  • | 3 Stanford Cancer Institute;
  • | 4 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 5 City of Hope National Medical Center;
  • | 6 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 7 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 8 Moffitt Cancer Center;
  • | 9 UCLA Jonsson Comprehensive Cancer Center;
  • | 10 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 11 Fred & Pamela Buffett Cancer Center;
  • | 12 Huntsman Cancer Institute at the University of Utah;
  • | 13 Fox Chase Cancer Center;
  • | 14 Mayo Clinic Cancer Center;
  • | 15 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 16 University of Michigan Rogel Cancer Center;
  • | 17 Memorial Sloan Kettering Cancer Center;
  • | 18 O’Neal Comprehensive Cancer Center at UAB;
  • | 19 Abramson Cancer Center at the University of Pennsylvania;
  • | 20 University of Colorado Cancer Center;
  • | 21 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 22 UC San Diego Moores Cancer Center;
  • | 23 St. Jude Children’s Research Hospital/University of Tennessee Health Science Center;
  • | 24 Roswell Park Cancer Institute;
  • | 25 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 26 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 27 Vanderbilt-Ingram Cancer Center;
  • | 28 The University of Texas MD Anderson Cancer Center;
  • | 29 University of Wisconsin Carbone Cancer Center; and
  • | 30 National Comprehensive Cancer Network.

The NCCN Guidelines for Squamous Cell Skin Cancer provide recommendations for diagnostic workup, clinical stage, and treatment options for patients with cutaneous squamous cell carcinoma. The NCCN panel meets annually to discuss updates to the guidelines based on comments from panel members and the Institutional Review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new surgical recommendation terminology (peripheral and deep en face margin assessment), as well as recent updates on topical prophylaxis, immunotherapy for regional and metastatic disease, and radiation therapy.

NCCN: Continuing Education

Target Audience: This activity 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.

Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-20-015-H01-P

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/90982; 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 e-mail education@nccn.org.

Release date: December 10, 2021; Expiration date: December 10, 2022

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Squamous Cell Skin Cancer

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Squamous Cell Skin Cancer

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:

Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Individuals Who Provided Content Development and/or Authorship Assistance:

Chrysalyne D. Schmults, MD, MS, Panel Chair, has disclosed receiving grant/research support from Castle Biosciences, Regeneron, and Sanofi.

Beth McCullough, RN, BS, CMSRN, Guidelines Layout Specialist, NCCN, has disclosed no relevant financial relationships.

Mary A. Dwyer, MS, CGC, Director, Guidelines Operations, NCCN, has disclosed no relevant financial relationships.

Mai Q. Nguyen, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed no relevant financial relationships.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to https://www.nccn.org/guidelines/guidelines-panels-and-disclosure

This activity is supported by educational grants from Agios Pharmaceuticals; AstraZeneca; Clovis Oncology, Inc.; Daiichi Sankyo; Eisai; Epizyme Inc.; Novartis; and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. This activity is supported by an independent medical education grant from Bristol-Myers Squibb, and Regeneron Pharmaceuticals, Inc. and Sanofi Genzyme. This activity is supported by an independent medical educational grant from Mylan Inc. This activity is supported by a medical education grant from Karyopharm Therapeutics. This activity is supported by an independent educational grant from AbbVie.

Overview

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer.13 Numerous population-based studies have demonstrated that the incidence of CSCC is rising rapidly.1,46 Some studies show that CSCC incidence rates are increasing more rapidly than basal cell carcinoma, reducing the difference in incidence between these skin cancers.2,3,7 Although rarely metastatic, CSCC can produce substantial local destruction along with disfigurement and may involve extensive areas of soft tissue, cartilage, and bone. Patients with CSCCs generally have a good prognosis, with a 5-year survival rate of ≥90%.1,8,9

Peripheral and Deep En Face Margin Assessment

A major update in the 2022 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Squamous Cell Skin Cancer is a change of the term “complete circumferential peripheral and deep margin assessment (CCPDMA)” to “peripheral and deep en face margin assessment (PDEMA).” This change is made across all 4 NCCN Guidelines for Non-Melanoma Skin Cancer. With this change, the panel hopes to achieve broader recognition of the term by pathologists and Mohs surgeons, who are ultimately responsible for the processing of excised specimens.

The discussion was prompted by comments from the Institutional Review (IR), as well as general concern from current panel members, about a lack of understanding of the term CCPDMA term among treating physicians and pathologists around the country. The term CCPDMA was initially developed to avoid jargons that are unique to any particular specialty. It was thought that CCPDMA would enforce consistency across treatment modalities and encapsulate accurately what needs to be achieved. However, after an extensive discussion, the panel agreed that the term CCPDMA introduces significant variation in the interpretation of “complete margin assessment.” Many pathologists, according to panel members, will cut vertical sections across the deep margin instead of en face or horizontal deep sections, as desired by PDEMA. Thus, the panel decided the term PDEMA has greater clarity in specifying what is meant by total margin evaluation. However, some concern remains about the lack of consensus regarding the meaning of the term “en face” among physicians from the rest of the world.

It must be reiterated that the NCCN panel strongly recommends PDEMA as the preferred surgical technique for high-risk CSCC. The 2 methods to achieve PDEMA are Mohs and Tubingen, which use rapid frozen sections and paraffin-embedded sections, respectively. It has been established in earlier versions of the guidelines that PDEMA is the preferred excision method for NCCN-designated very-high-risk CSCC because it allows intraoperative analysis of 100% of the excision margin and is associated with low recurrence rates. High-risk features, as outlined in the NCCN Guidelines, include size ≥4 cm (any location), poor differentiation, desmoplastic CSCC, >6 mm in thickness or invasion beyond subcutaneous fat, perineural involvement (PNI) with tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm, and lymphatic or vascular involvement.

An extensive meta-analysis of studies with long-term follow-up (≥5 years) reported local recurrence rates of 3.1% for primary CSCCs and 10% for recurrences treated with Mohs.10 Results from this meta-analysis found that cure rates for Mohs depended on tumor diameter (<2 vs ≥2 cm: 98.1% vs 74.8%) and differentiation (well vs poorly differentiated: 97.0% vs 67.4%). For each of these subgroups, cure rates for Mohs were higher than for treatment with non-Mohs modalities.10 Retrospective and prospective observational studies of localized primary CSCCs treated with Mohs reported local recurrence rates of 1.2% to 4.1% and rates of metastases between 0% and 6.3%.1121 Compared with primary tumors, rates of local recurrence or metastasis after Mohs are higher for recurrent tumors (previously treated with a non-Mohs modality).13,22 For recurrent CSCCs treated with Mohs, subsequent local recurrences occurred in 5.9% to 7.7% of cases; metastasis in 0% to 10%.1117 Other risk factors associated with recurrence after Mohs include larger subclinical extension and more Mohs stages required for clearance.13 CSCC with PNI is associated with elevated rates of recurrence (6.8%–32.3%) in studies that occasionally include basal cell carcinoma as well as treatment with radiation therapy (RT).2328 Risk factors associated with metastasis after Mohs include size >2 cm, Clark level (metastatic CSCC are more likely to be deeper, Clark level III–V), poor differentiation, location in areas of prior radiation, small tumor nests and infiltrative tumor strands, single-cell infiltration, PNI, and acantholysis.22

Excision with PDEMA using permanent section analysis or intraoperative frozen section analysis is acceptable as an alternative to Mohs provided that it includes a complete assessment of all deep and peripheral margins (for more information, see the full version of these guidelines at NCCN.org). The descriptive term PDEMA underscores the panel’s belief that complete histologic assessment of the entire marginal surface is the key to optimal tumor removal for NCCN-designated very-high-risk tumors.

Standard Excision With Incomplete Margin Assessment

As noted earlier, excision with PDEMA is the preferred surgical technique for very-high-risk CSCC. However, if standard excision with incomplete margin assessment (vertical sections) is used for treatment of a very-high-risk tumor due to unavailability of PDEMA, wider surgical margins than those recommended for low-risk lesions must be taken. Reconstruction should be delayed until clear margins have been reported, and increased recurrence rates should be expected. For the 2022 update, the IR suggested that there might need to be more guidance regarding margin sizes for very-high-risk tumors. However, the panel maintained their stance that due to the wide variability of clinical characteristics that may define a very-high-risk tumor, it is not feasible to recommend a defined margin for standard excision of very-high-risk CSCC. Keen awareness of the subclinical extension of CSCC is advised when selecting a treatment modality with incomplete margin assessment for a very-high-risk tumor. These margins may need to be modified based on tumor- or patient-specific factors.

The NCCN panel also considered a review of the literature regarding margin recommendations for high-risk CSCCs and a discussion of this topic. According to Brodland and Zitelli,29 for CSCCs in high-risk locations (scalp, ears, eyelids, nose, lips) or with other high-risk features (histologic grade ≥2, invasion of subcutaneous tissue), lesions with a diameter <1 cm, 1 to 1.9 cm, and ≥2 cm would require margins of at least 4 mm, 6 mm, and 9 mm, respectively. Results from other retrospective analyses of CSCCs removed with Mohs further support that larger excision margins are needed to consistently achieve clear margins as tumor diameter increases and when other risk factors are present (eg, poor differentiation, high-risk location, PNI).13,17,30,31 Compared with primary tumors, recurrent tumors have larger subclinical extension and require more Mohs stages for complete removal.13,31 Currently, the European Dermatology Forum recommends standard excisions with 6- to 10-mm peripheral clinical margins for high-risk CSCCs based on criteria defined by Stratigos et al.32,33 The British Association of Dermatologists recommend at least 6-mm peripheral clinical margins for high-risk CSCC tumors and ≥10 mm margins for very-high-risk tumors (refer to Keohane et al34 for risk stratification). The United Kingdom National Multidisciplinary Guidelines also concur with a minimum of 6-mm clinical margins for high-risk CSCC as defined by Newlands et al.35 Thus, there seems to be consensus among the European guidelines, which should provide additional points of guidance for treating physicians. However, the NCCN panel, at this point in time, does not recommend a defined margin for standard excision of high-risk CSCC due to lack of data regarding optimal margins for various risk profiles.

Management of Patients at High Risk of Developing Multiple CSCCs

Treatment of Precancers

Actinic keratoses are a premalignant skin condition that should be treated at first development, particularly in patients with diffuse actinic keratosis/field cancerization, because these patients are at high risk of developing multiple primary CSCCs. Cryotherapy has been used to treat actinic keratosis for many decades, despite lack of prospective randomized trials comparing it with nontreatment. In more recent years, large prospective randomized trials in patients with actinic keratoses (n>100) have shown that each of the following therapies provides better complete clearance rates compared with placebo: topical 5-FU ± calcipotriol,3641 topical imiquimod,4245 topical tirbanibulin,46 and photodynamic therapy.4754

In this update of the NCCN Guidelines, the panel voted to include a preference for 5-FU based on data from a randomized trial testing 4 treatment approaches for actinic keratosis. In this study, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received 5-FU (74.7%; 95% CI, 66.8%–81.0%) than among those who received imiquimod (53.9%; 95% CI, 45.4%–61.6%), MAL-PDT (37.7%; 95% CI, 30.0%–45.3%), or ingenol mebutate (28.9%; 95% CI, 21.8%–36.3%).55 Additionally, the hazard ratio for treatment failure was significantly higher with imiquimod (2.03; 95% CI, 1.36%–3.04%), MAL-PDT (2.73; 95% CI, 1.87%–3.99%), and ingenol mebutate (3.33; 95% CI, 2.29%–4.85%) than with 5-FU (P≤.001 for all).55 The panel emphasized that the longest duration for CSCC prophylaxis has been demonstrated with the combination of 5-FU and calcipotriol. As a follow-up to the original study by Cunningham et al,41 it was recently demonstrated that more participants who received topical calcipotriol + 5-FU for actinic keratosis remained disease-free over the >1,500-day period (P=.0765) compared with those receiving petroleum jelly–based skin product + 5-FU.56 Moreover, significantly fewer participants in the test cohort developed CSCC on the treated face and scalp within 3 years (2/30 [7%] vs 11/40 [28%] in the control group; hazard ratio, 0.215; 95% CI, 0.048–0.972; P=.032).56

In this version of the NCCN Guidelines, the panel voted to include topical tirbanibulin for the treatment of actinic keratosis. In recently published results from 2 identically designed double-blind phase III trials, patients received either tirbanibulin or vehicle (placebo) ointment for the treatment of actinic keratoses on the face or scalp. In both trials, complete clearance by day 57 occurred in significantly more patients in the tirbanibulin group compared with the vehicle group (trial 1: 44% vs 5% [95% CI, 32–47; P<.001]; trial 2: 54% vs 13% [95% CI, 33–51; P<.001]).46 Besides adding topical tirbanibulin, the panel removed topical ingenol mebutate because it was taken off the market pending further review of its association with higher skin cancer occurrence.

Prevention in High-Risk Patients

Treatment of precancerous lesions at first development can help prevent the development of subsequent invasive tumors, but prophylactic treatment may be needed for patients who have a history of multiple lesions and/or extensive diffuse actinic keratosis/field cancerization. Oral synthetic retinoids (eg, acitretin, isotretinoin) have been tested in prospective studies in patients at high risk for multiple actinic keratoses or CSCCs, including transplant recipients,5762 patients with xeroderma pigmentosa,63 or those with psoriasis and PUVA (psoralen + UVA) exposure.64 By comparison with placebo or with CSCC incident rates during treatment-free periods, data from these studies support that oral synthetic retinoids significantly reduce the incidence of new CSCCs.5861,63,64 Because of the inconsistency of data demonstrating acitretin efficacy, the panel decided to include a recently published review to further support the recommendation of acitretin for high-risk patients.65 It was calculated across 4 independently published articles that acitretin led to a 54% reduction in CSCC (mean, 0.57 per patient per year) and 56% reduction in keratinocyte carcinomas (mean, 0.68 per patient per year).65 Despite its efficacy, it was postulated that the drug is still underused due to its relatively high cost, the need for frequent laboratory studies, adverse effects, and rebound after cessation of efficacious therapy.65

Systemic Therapy for Squamous Cell Skin Cancer

A wide variety of cytotoxic therapies have been tested in patients with regional or distant metastatic CSCC. Those most commonly used are cisplatin, carboplatin, and 5-FU, either as monotherapy or combination regimens.6676 For the 2022 update, the panel voted to include carboplatin ± paclitaxel under options useful in certain circumstances for use with RT. A prospective study by Suntharalingam et al77 demonstrated that among patients with head and neck mucosal SCC, weekly carboplatin and paclitaxel given concurrently with definitive once-daily external-beam RT was well tolerated with a complete response (CR) at the primary site of 82%. The total (primary site and neck) CR was 75% and the 3-year overall survival was 48%. Two recent albeit retrospective studies confirmed the efficacy of this regimen. Vlacich et al78 reported that the 30-year locoregional control rate with intensity-modulated RT and concurrent carboplatin + paclitaxel was 83.2%, with disease-free survival and overall survival rates of 78.8% and 76.5%, respectively. Maring et al79 reported a recurrence rate of 30% for patients treated with RT plus carboplatin + paclitaxel, compared with 38% of those treated with RT + cisplatin (P=.6). Event-free survival and overall survival were reported to be 30 and 28 months, respectively, for the RT plus carboplatin + paclitaxel group, versus 37 and 35 months, respectively, for the RT + cisplatin group. However, significantly higher grade 3/4 acute toxicity was observed for the cisplatin group (P=.002). Even though all 3 studies reported treatment completion by most participants (>90%), Agulnik et al80 deemed the regimen infeasible due to a high occurrence of adverse events. Nevertheless, their study enrolled a very small number of participants (n=6) and therefore the results should be considered with caution. It should be noted that these studies were conducted in patients with head and neck mucosal SCC; data were extrapolated to CSCC.

In addition to several trials testing new approaches to treating locally advanced unresectable or metastatic CSCC with targeted agents,8184 immune checkpoint inhibitors have been tested in this setting85,86 (ClinicalTrials.gov identifiers: NCT02721732, NCT02760498, NCT02978625, NCT03108131), In the Version 2.2021 update of the NCCN Guidelines, the panel modified their recommendations for pembrolizumab and cemiplimab-rwlc. Both immune checkpoint inhibitors are now recommended for locally advanced, recurrent, or metastatic disease if curative RT or surgery is not feasible. Recent published data reported an objective response rate (ORR) of 44% to 54%, a CR of 0% to 13%, and a partial response (PR) of 31% to 50% to cemiplimab-rwlc in patients with locally advanced, recurrent, or metastatic CSCC.8790 Data from the phase II KEYNOTE-629 trial, which included patients with locally advanced, recurrent, or metastatic CSCC, reported an ORR of 34% to 50%, a CR of 4% to 17%, and a PR of 25% to 33% for patients treated with pembrolizumab.91,92 Preliminary data and the clinical experience of NCCN panel members suggest that other anti–PD-1 inhibitors may also be effective in this setting.

RT for Squamous Cell Skin Cancer

Although surgery is the mainstay of local treatment for CSCC, patient preference and other factors may lead to the choice of RT as primary therapy for local disease without lymph node involvement. A large meta-analysis reported 5-year recurrence risks of 6.7% and 10% after RT of primary and recurrent CSCC, respectively.10 Subsequent retrospective analyses on smaller samples of patients with primary CSCCs treated with first-line RT (37–233 patients) have reported a large range of recurrence rates—from 2.8% to 30%, with higher rates for patients with locally advanced disease (size >2 cm or deeply invasive).9398 The risk of recurrence appears to increase with increasing lesion size and T stage.96,98,99 A few small studies (n<20) have reported that for CSCCs that were previously treated and recurred, treatment with RT results in recurrence in 16.7% of cases.95,98

In this update of the NCCN Guidelines, the panel removed their recommendation that RT is usually reserved for patients aged >60 years because of concerns about long-term sequelae in younger patients. It was generally agreed among panel members that age is not the primary consideration for RT and that patients aged <60 years can receive RT for multiple reasons, including personal preferences. Additionally, there was concern from the IR that the statement regarding insufficient long-term efficacy and safety data for the routine use of radioisotope or electronic surface brachytherapy was inaccurate. The panel revised this statement to say “isotope-based brachytherapy can be an effective treatment for certain sites of disease, particularly on the head and neck” and maintained their stance that “there are insufficient long-term efficacy and safety data to support the routine use of electronic surface brachytherapy.” The revision in the isotope-based brachytherapy recommendation is based on results from multiple studies acknowledging the efficacy of this technique.100106 Of note, a retrospective multicentric analysis of 1,676 carcinomas of the skin of the nose and nasal vestibule yielded a local control rate of 93% with a minimum follow-up of 2 years. It was determined in this study that local control depended on tumor size (diameter <2 cm: 96%; diameter 2–3.9 cm: 88%; diameter ≥4 cm: 81%) and tumor site (external surface of the nose: 94%; vestibule: 75%).105 Thus, isotope-based brachytherapy can be considered for appropriate patients with CSCC.

Summary

For the NCCN Guidelines for Squamous Cell Skin Cancer, Version 1.2022, the panel spent a substantial amount of time deliberating and finalizing the new terminology “PDEMA: peripheral and deep en face margin assessment,” which is now used in all 4 NCCN Guidelines for Non-melanoma Skin Cancer. The change is deemed important for broader understanding and application of desirable surgical and histologic techniques, which will ideally reduce disease recurrence. New data from recent clinical trials and current news were also discussed extensively, and are now reflected in the updated recommendations for CSCC prophylaxis (5-FU and 5-FU plus calcipotriol, topical tirbanibulin, and the removal of topical ingenol mebutate) and regional disease treatment (carboplatin ± paclitaxel in combination with RT, cemiplimab-rwlc, and pembrolizumab). Some recommendations for RT were also revised, with the removal of the 60-year age cutoff for RT and the updated language for isotope-based brachytherapy. The panel hopes these recommendations will be incorporated into professional practice, with the ultimate goal of improving outcomes for patients with squamous cell skin cancer.

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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 noted.

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

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (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 the 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 their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2021.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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