Definitive and Postoperative Radiation Therapy for Basal and … Care and... · 2020-01-22 · 6...

Practical Radiation Oncology (2019)

Definitive and Postoperative Radiation Therapy for Basal and Squamous Cell

Cancers of the Skin: An ASTRO Clinical

Practice Guideline

Anna Likhacheva, MD, MPH,a* Musaddiq Awan, MD,b Christopher A. Barker, MD,c Ajay Bhatnagar, MD,d Lisa Bradfield,e Mary Sue Brady,

MD,f Ivan Buzurovic, PhD,g Jessica L. Geiger, MD,h Upendra

Parvathaneni, MBBS,i Sandra Zaky, MD,j and Phillip M. Devlin, MD,k

a. Sutter Medical Center, Sacramento, CA, Department of Radiation Oncology and Task Force Vice Chair b. Medical College of Wisconsin, Milwaukee, WI, Department of Radiation Oncology c. Memorial Sloan Kettering Cancer Center, New York, NY, Department of Radiation Oncology d. Alliance Oncology, Casa Grande, AZ, Department of Radiation Oncology e. American Society for Radiation Oncology, Arlington, VA f. Memorial Sloan Kettering Cancer Center, New York, NY, Department of Surgery g. Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, Department of Radiation Oncology h. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, Department of Hematology and Medical

Oncology i. University of Washington, Seattle, WA, Department of Radiation Oncology j. Stanford University, Stanford, CA, Department of Radiation Oncology and Guideline Subcommittee

Representative k. Dana-Farber/Brigham and Women’s Cancer Center, Boston, MA, Department of Radiation Oncology

and Task Force Chair

* Corresponding author: Anna Likhacheva, MD, MPH; [email protected].

mailto:[email protected]

2 ASTRO Radiation for Basal and Squamous Cell Cancers Guideline Practical Radiation Oncology

Task Force Members’ Disclosure Statements

Before initiating work on this guideline, all task force members completed disclosure statements and

disclosures are published within this report. Where potential conflicts were detected, remedial measures to

address them were taken.

Musaddiq Awan: Elekta (honoraria – new disclosure added after final consensus voting); Christopher Barker:

Alpha Tau Medical (travel expenses [ended]), Elsevier (honoraria [ended]), Amgen, Elekta, UCSF, and Merck

(research), NCCN (honoraria, travel expenses [ended]), Regeneron (advisory board [ended]), University of

Florida and University of Rochester (honoraria[ended]); Ajay Bhatnagar: Arizona Radiological Society (ACR

State Chapter President), Cancer Treatment Services International (stock), Icad (consultant and research);

Phillip Devlin (Chair): Massachusetts Medical Society (Finance and Audit Committee); Sirtex (honoraria, travel

expenses, advisory board [ended]); Jessica Geiger (American Society of Clinical Oncology representative):

Regeneron (research, advisory board [new disclosures added after final consensus voting]), Genentech/Roche

(research); Anna Likhacheva (Vice Chair): Reflexion (spouse employment), Russian Society of Clinical Oncology

(travel expenses); and Mary Sue Brady (Society of Surgical Oncology representative), Ivan Buzurovic,

Upendra Parvathaneni, and Sandra Zaky reported no disclosures.

Disclaimer and Adherence — American Society for Radiation Oncology guidelines present scientific, health,

and safety information and may reflect scientific or medical opinion. They are available to ASTRO members

and the public for educational and informational purposes only. Commercial use of any content in this

guideline without the prior written consent of ASTRO is strictly prohibited.

Adherence to this guideline does not ensure successful treatment in every situation. This guideline

should not be deemed inclusive of all proper methods of care or exclusive of other methods reasonably

directed to obtaining the same results. The physician must make the ultimate judgment regarding therapy

considering all circumstances presented by the patient. ASTRO assumes no liability for the information,

conclusions, and findings contained in its guidelines. This guideline cannot be assumed to apply to the use of

these interventions performed in the context of clinical trials. This guideline is based on information available

at the time the task force conducted its research and discussions on this topic. There may be new

developments that are not reflected in this guideline and that may, over time, be a basis for ASTRO to revisit

and update the guideline.


Table of Contents

Preamble .................................................................................................................................................... 4

1. Introduction............................................................................................................................................ 6

2. Methods ................................................................................................................................................. 6

2.1. Task Force Composition ................................................................................................................................ 6

2.2. Document Review and Approval .................................................................................................................. 6

2.3. Evidence Review ........................................................................................................................................... 6

2.4. Scope of the Guideline .................................................................................................................................. 7

3. Key Questions and Recommendations ..................................................................................................... 9

3.1. Key Question 1: Indications for definitive RT ................................................................................................ 9

3.2. Key Question 2: Indications for postoperative radiation therapy .............................................................. 10

3.3. Key Question 3: Indications for RT for treating regional nodes and regional disease management ......... 13

3.4. Key Question 4: Radiation techniques and dose-fractionation schedules for primary site management . 15

3.5. Key Question 5: Use of chemotherapy, biologic, and immunotherapy agents before, during or after RT 20

4. Conclusion/Future Directions .................................................................................................................21

5. Acknowledgements ................................................................................................................................22

Figure 1. PRISMA Diagram .........................................................................................................................22

Appendix 1. Peer Reviewers and Disclosures ..............................................................................................23

Appendix 2. Abbreviations .........................................................................................................................24

Appendix 3. Literature Search Strategies ....................................................................................................25

References ................................................................................................................................................30


Preamble

As the leading organization in radiation oncology, the American Society for Radiation Oncology (ASTRO) is dedicated to improving quality of care and patient outcomes. A cornerstone of this goal is the development and dissemination of clinical practice guidelines based on systematic methods to evaluate and classify evidence, combined with a focus on patient-centric care and shared decision-making. ASTRO develops and publishes guidelines without commercial support, and members volunteer their time. Disclosure Policy — ASTRO has detailed policies and procedures related to disclosure and management of industry relationships to avoid actual, potential, or perceived conflicts of interest. All task force members are required to disclose industry relationships and personal interests, beginning 12 months before initiation of the writing effort. Disclosures go through a rigorous review process with final approval by ASTRO’s Conflict of Interest Review Committee. For the purposes of full transparency, task force members’ comprehensive disclosure information is included in this publication. The complete disclosure policy for Formal Papers is available online. Selection of Task Force Members — The Guideline Subcommittee strives to avoid bias by selecting a multidisciplinary group of experts with variation in geographic region, gender, ethnicity, race, practice setting, and areas of expertise. Representatives from organizations and professional societies with related interests and expertise are also invited to serve on the task force. Methodology — The task force uses evidence-based methodologies to develop guideline recommendations in accordance with the National Academy of Medicine (formerly Institute of Medicine) standards. The evidence identified from key questions (KQs) is assessed using the Population, Intervention, Comparator, Outcome, Timing, Setting (PICOTS) framework. A systematic review of the KQs is completed, which includes creation of evidence tables, that summarize the evidence base task force members use to formulate recommendations. Table 1 describes ASTRO’s recommendation grading system. Consensus Development — Consensus is evaluated using a modified Delphi approach. Task force members confidentially indicate their level of agreement on each recommendation based on a 5-point Likert scale, from “strongly agree” to “strongly disagree”. A prespecified threshold of ≥75% (≥90% for expert opinion recommendations) of raters that select “strongly agree” or “agree” indicates consensus is achieved. Recommendation(s) that do not meet this threshold are removed or revised. Recommendations edited in response to task force or reviewer comments are resurveyed before submission of the document for approval. Annual Evaluation and Updates — Guidelines are evaluated annually beginning 2 years after publication for new potentially practice-changing studies that could result in a guideline update. In addition, the Guideline Subcommittee will commission a replacement or reaffirmation within 5-years of publication.

http://www.astro.org/About-ASTRO/Governance/COI-Policies/Policy-on-COI-Review-for-ASTRO-Formal-Papers


Table 1. ASTRO recommendation grading classification system

ASTRO’s recommendations are based on evaluation of multiple factors including the QoE, individual study quality, and panel consensus, all of which inform the strength of recommendation. QoE is based on the body of evidence available for a particular key question and includes consideration of number of studies, study design, adequacy of sample sizes, consistency of findings across studies, and generalizability of samples, settings, and treatments.

Strength of Recommendation

Definition Overall QoE

Grade Recommendation

Wording

Strong

• Benefits clearly outweigh risks and burden, or risks and burden clearly outweigh benefits.

• All or almost all informed people would make the recommended choice.

Any (usually high,

moderate, or expert opinion)

“Recommend/ Should”

Conditional

• Benefits are finely balanced with risks and burden or appreciable uncertainty exists about the magnitude of benefits and risks.

• Most informed people would choose the recommended course of action, but a substantial number would not.

• A shared decision-making approach regarding patient values and preferences is particularly important.

Any (usually moderate,

low, or expert opinion)

“Conditionally Recommend”

Overall QoE Grade Type/Quality of Study Evidence Interpretation

High • 2 or more well-conducted and highly-generalizable

RCTs or meta-analyses of such trials.

The true effect is very likely to lie close to the estimate of the effect based on the body of

evidence.

Moderate

• 1 well-conducted and highly-generalizable RCT or a meta-analysis of such trials OR

• 2 or more RCTs with some weaknesses of procedure or generalizability OR

• 2 or more strong observational studies with consistent findings.

The true effect is likely to be close to the estimate of the effect based on the body of

evidence, but it is possible that it is substantially different.

Low

• 1 RCT with some weaknesses of procedure or generalizability OR

• 1 or more RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes OR

• 2 or more observational studies with inconsistent findings, small sample sizes, or other problems that potentially confound interpretation of data.

The true effect may be substantially different from the estimate of the effect. There is a risk

that future research may significantly alter the estimate of the effect size or the

interpretation of the results.

Expert Opinion*

• Consensus of the panel based on clinical judgement and experience, due to absence of evidence or limitations in evidence.

Strong consensus (≥90%) of the panel guides the recommendation despite insufficient

evidence to discern the true magnitude and direction of the net effect. Further research

may better inform the topic.

Abbreviations: ASTRO = American Society for Radiation Oncology; QoE = quality of evidence; RCTs = randomized controlled trials. *A lower quality of evidence, including expert opinion, does not imply that the recommendation is conditional. Many important clinical questions addressed in guidelines do not lend themselves to clinical trials but there still may be consensus that the benefits of a treatment or diagnostic test clearly outweigh its risks and burden.


1. Introduction

Skin cancer is the most prevalent cancer type in the United States with an incidence rate of over 5

million cases annually.1 Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) account for

over 95% of all skin cancer diagnoses. A variety of treatment options are available and include surgical

excision, cryotherapy, radiation therapy (RT), and topical agents. Although surgical excision is considered to be

the primary treatment approach for curative treatment of BCC and cSCC, RT can play an integral role in both

the definitive and adjuvant settings.

The role of RT for BCC and cSCC has been poorly defined owing to lack of high-quality evidence. To the

best of our knowledge, no evidence-based clinical practice guidelines, endorsed by a large professional

organization currently exist to provide direction on the use of RT for these malignancies. In view of the lack of

consensus on this subject, ASTRO commissioned a task force to formulate evidence-based recommendations

for the use of definitive and postoperative RT in patients with BCC and cSCC.

2. Methods

2.1. Task Force Composition

The task force consisted of a multidisciplinary team of radiation, medical, and surgical oncologists,

dermatopathologists, a radiation oncology resident, a medical physicist, and a dermatologist. This guideline

was developed in collaboration with the American Society of Clinical Oncology and the Society of Surgical

Oncology, who provided representatives and peer reviewers.

2.2. Document Review and Approval

The guideline was reviewed by 17 official peer reviewers (see Appendix 1 for the reviewer’s disclosure

information) and revised accordingly. The modified guideline was posted on the ASTRO website for public

comment in April 2019. The final guideline was approved by the ASTRO Board of Directors and endorsed by the

American Association of Physicists in Medicine, American College of Radiology, American Head and Neck

Society, and the Society of Surgical Oncology.

2.3. Evidence Review

A systematic literature review of human subject studies indexed in MEDLINE (through PubMed) was

conducted. The inclusion criteria required research to involve adults (≥18 years of age) with a diagnosis of

nonmetastatic invasive BCC and cSCC, to be published in English, from May 1988 through June 2018 and RT to

be delivered with curative intent. The literature search excluded preclinical and dosimetric studies, as well as

publications addressing re-irradiation or palliation. KQ1 studies were limited to those with ≥100 patients, KQs

2 to 4 used ≥50 patients and KQ5 reduced the patient number to ≥15 since minimal evidence exists on

chemotherapy, biologic, and immunotherapy agents. See Appendix 2 for the list of abbreviations, Appendix 3

for the detailed search protocol and Figure 1 for the Preferred Reporting Items for Systematic Reviews and


Meta-Analyses (PRISMA) diagram showing the number of articles screened, excluded and included in the

evidence review.

Both Medical Subject Heading (MeSH) terms and key search terms for all KQs included: skin

neoplasms[Mesh]; basal cell; squamous cell; neoplasms, basal cell[Mesh]; neoplasms, squamous cell[Mesh];

dose fractionation[Mesh]; radiotherapy[Mesh]; radiation; and radiotherapy. Additional terms specific to the

KQs and hand searches supplemented the electronic search.

A general conclusion from this search is that there are limited, well-conducted modern randomized

trials to underpin clinical paradigms for treatment of patients with cSCC and BCC with radiation treatment. The

task force had to rely on synthesis of retrospective study results and expert opinion, which is reflected in the

low-to-moderate quality of evidence designation for the majority of the recommendations. The online data

supplement includes evidence tables that summarize the data used by the task force to formulate

recommendations. References selected and published in this document are representative and not all-

inclusive. The outcomes of interest are listed in Table 2.

2.4. Scope of the Guideline

This guideline covers only the subjects specified in the KQs (Table 2). The guideline refers to the most

current staging system for BCC and cSCC which is the eighth edition of the TNM (tumor, node, metastasis)

staging system published by the American Joint Committee on Cancer2 (Table 3). It should be noted that in

contrast to the seventh edition, the eighth edition for skin carcinomas is limited to cancers located on the head

and neck. The recommendations herein address management of primary sites of the head and neck, trunks,

and limbs. Outside the scope of this guideline are several related topics, including RT and systemic therapy in

the setting of metastatic BCC and cSCC, dermatopathologic aspects of skin cancer diagnosis, nuances of

surgical management and the technical details of radiation delivery for skin cancer. Additionally, this guideline

does not pertain to the management of mucosal head and neck squamous cell carcinoma, vulvar, penile, or

perianal skin carcinoma.

Table 2. KQs in Population, Intervention, Comparator, Outcome (PICO) format

KQ Population Intervention Comparator Outcomes

(Same for all KQs)

1 What are the appropriate indications for definitive RT for BCC and cSCC? • Cancer control

• Disease-free survival

• Local and regional recurrence risk

• Toxicity

• Quality of life

Patients with BCC and/or cSCC Definitive RT Other definitive

therapies

2 What are the appropriate indications for PORT after surgery for BCC and cSCC?

Patients with BCC and/or cSCC that underwent surgical resection and are considered for postoperative RT

RT to primary site, nodal regions, or nerve tracks

No RT

3 What are the appropriate indications for RT for treating regional nodes? What dose and fractionation should be used for management of regional disease?

Patients with BCC and/or cSCC who have:

• primary tumor features with high risk of regional lymph node recurrence

• regional lymph node features with high risk of recurrence after therapeutic lymphadenectomy

RT No RT

https://doi.org/10.1016/j.prro.2019.10.014



4 What are the preferred dose-fractionation schedules and radiation techniques for the management of the primary site in BCC and cSCC?

Patients with BCC and/or cSCC considered for brachytherapy, superficial, orthovoltage, or megavoltage RT in the definitive or postoperative setting

Comparing different RTs, radiation techniques and fractionation schemes

N/A

5 When is it appropriate to use chemotherapy, biologic, and immunotherapy agents before, during, or after RT in the treatment of BCC or cSCC?

Patients with BCC and/or cSCC for whom addition of systemic therapy to RT may be clinically advantageous

Chemotherapy, biologic therapy, immunotherapy

Absence of chemotherapy, biologic therapy, immunotherapy

Abbreviations: 3-D = 3-dimensional; BCC = basal cell carcinoma; cSCC = cutaneous squamous cell carcinoma; N/A = not applicable; and RT = radiation therapy.

Table 3. AJCC Cancer Staging - Cutaneous Carcinoma of the Head and Neck, Clinical Staging, 8th Edition*

T category Clinical N category

(same as clinical N category for p16-neg oropharynx ca) Tis Carcinoma in situ N1 Single ipsilateral lymph node, ≤3 cm and ENE (−)

T1 Tumor ≤2 cm in greatest dimension N2a Single ipsilateral lymph node, >3 cm but not >6 cm and

ENE (−)

T2 Tumor >2 cm and ≤4 cm in greatest

dimension N2b Multiple ipsilateral lymph node, none >6 cm and ENE (−)

T3 Tumor >4 cm in greatest dimension and/or

perineural invasion and/or deep invasion†

and/or minor bone erosion

N2c Bilateral or contralateral lymph nodes, none >6 cm and

ENE (−)

N3a Metastasis in a lymph node >6 cm in greatest dimension

and ENE (−)

N3b Clinically overt ENE (+)

M category

T4a Tumor with gross cortical bone/marrow

invasion

M0 No distant metastases

M1 Metastasis to ≥1 distant organ

T4b Tumor with skull base invasion and/or skull

base foramen involvement

Abbreviations: AJCC = American Joint Committee on Cancer; and ENE = extranodal extension. * Applies only to cutaneous squamous cell carcinomas and all other nonmelanoma skin carcinomas of the head and neck (except Merkel cell carcinoma). † Deep invasion is defined as invasion beyond the subcutaneous fat or >6 mm (as measured from the granular layer of adjacent normal epidermis to the base of the tumor); perineural invasion for T3 classification is defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring ≥0.1 mm in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression. Adapted with permission from AJCC, eighth edition.2


3. Key Questions and Recommendations

3.1. Key Question 1: Indications for definitive RT (Table 4)

See online data supplement for the evidence supporting the recommendations for KQ1.

What are the appropriate indications for definitive RT for BCC and cSCC?

Table 4. Recommendations for definitive RT

KQ1 Recommendations Strength of

Recommendation Quality of

Evidence (Refs)

1. In patients with BCC and cSCC who cannot undergo or decline

surgical resection, definitive RT is recommended as a curative

treatment modality.

Strong Moderate

3-8

2. In patients with BCC and cSCC in anatomical locations where

surgery can compromise function or cosmesis, definitive RT is

conditionally recommended as a curative treatment modality.

Conditional Moderate

9-11

3. Definitive RT for BCC and cSCC is conditionally not

recommended in patients with genetic diseases predisposing to

heightened radiosensitivity.

Conditional Expert Opinion

Abbreviations: BCC = basal cell carcinoma; cSCC = cutaneous squamous cell carcinoma; KQ = key question; RT = radiation therapy.

RT is an effective therapy for durable local control of BCC and cSCC characterized by an appealing

combination of therapeutic efficacy and functional and cosmetic preservation. These features make definitive

RT an attractive alternative to surgery in a number of clinical scenarios, but strict recommendations regarding

the comparative effectiveness of the 2 approaches is stymied by the absence of prospective randomized trials

comparing different local therapies including surgery, RT, and other local ablative treatments. A single

randomized study initiated in 1982 compared surgery and RT for treatment of early stage BCC of the face.3 The

relevance of this study to current practice is limited as the techniques used predated modern volumetric 3-

dimensional (3-D) planning RT and micrographic surgical techniques. It concluded that surgery led to slightly

higher local control and better cosmetic results, but it is notable that the 4-year actuarial failure rate in the RT

arm was only 7.5%, suggesting that RT is a highly effective alternative to surgery if surgical options are limited.3

Given the noninvasive nature of RT, physician- and patient-reported cosmetic outcome has been an important

secondary endpoint in most studies.7,12-14

In contrast to randomized data, there is ample retrospective and single-arm prospective evidence

characterizing outcomes for skin carcinomas after treatment with modern RT. When reviewing this evidence, it

should be noted that some patients on these studies had locally advanced and regional nodal disease and

would not have been candidates for Mohs resection. Definitive RT, even despite selection bias, is consistently

associated with high local control rates.6,7,15-17 A meta-analysis of 9729 patients with BCC and cSCC over 21

studies since 1986 confirmed excellent control with RT.18 The investigators observed that the median 1-year

local recurrence rate was 2% and the 5-year local recurrence rate was 14% when combining all fractionation

regimens. Also notable is the fact that this meta-analysis found that the rate of “good” or “better” cosmesis in

the 21 studies to be 80%.18 A 2018 meta-analysis (published after our evidence inclusion date) analyzed 40



randomized and 5 nonrandomized studies of various available interventions for primary cutaneous BCC. It

concluded that recurrence rates were similar for excision (3.8%), Mohs surgery (3.8%), and external-beam

radiation (3.5%).19

This body of evidence underpins the guidance that definitive radiation may be considered as a curative

option when surgery can compromise function or cosmesis in an anatomically sensitive area. Good functional

outcomes are especially relevant for commonly sun-exposed area of the face (eg, ears, nose, lips, eyelids).

Careful selection among the various RT techniques can further enhance cosmetic and functional sparing. For

example, orthovoltage beam or brachytherapy techniques are well-suited for especially sensitive ocular

anatomy associated with medial canthus or eyelid lesions.10,11,20 Surgical deformity of the nose and lips can

lead to poor cosmesis and compromised function lending these sites to be particularly suitable for treatment

with definitive RT.9-11,21,22 Specialized radiation techniques (eg, surface and interstitial brachytherapy), have

additional capacity to deliver definitive RT doses to achieve tumor eradication while minimizing normal tissue

exposure.11,23

Retrospective studies have found that SCC portends a worse local control and disease survival than

BCC when single modality treatment is utilized.24 An observation that BCC is a more radiosensitive entity is

supported by a prospective randomized trial in which dose de-escalation resulted in lower local control rates

for cSCC, but not BCC.5,16,22,25 Furthermore, emerging evidence suggests that patients with cSCC and high-risk

features (ie, poor differentiation, recurrent disease, perineural spread, immunosuppressed state) or locally

advanced disease are particularly vulnerable to worse outcomes, and that multimodality therapy – including

combinations of surgery, radiation, and/or chemotherapy – may confer better disease control than RT or

surgery alone.26-29 A multidisciplinary cancer care team with an emphasis on shared decision-making is

beneficial for this population.

RT, like all cancer interventions, carries risks. For RT this includes acute dermatitis, dryness, permanent

local alopecia, telangiectasias and – in rare cases – secondary malignancy.30 Two important principles for RT

treatment are that (1) histologic confirmation is required prior to initiation of treatment and (2) overall life

expectancy should be considered and discussed with younger patients, for whom a larger lifetime risk of

developing secondary malignancy in the treatment field is expected. The use of definitive RT is discouraged for

the treatment of cSCC or BCC in patients with genetic conditions predisposing them to heightened

radiosensitivity, such as ataxia telangiectasia, nevoid basal cell carcinoma syndrome (Gorlin syndrome), or Li-

Fraumeni syndrome. Poorly controlled connective tissue disorders are a relative contraindication to treatment.

Although concrete clinical evidence against the use of RT in this setting is lacking, and single case reports on

feasibility of RT do exist, the task force agreed that available surgical and systemic options should be

exhausted before RT is offered to patients with heightened radiosensitivity.31,32

3.2. Key Question 2: Indications for postoperative radiation therapy (Table 5)


What are the appropriate indications for postoperative radiation therapy (PORT) for BCC and cSCC?



Table 5. Recommendations for PORT



Evidence (Refs)

Both BCC and cSCC

1. PORT is recommended for gross perineural spread that is

clinically or radiologically apparent. Strong Moderate

29,33-36

cSCC

2. PORT is recommended for patients with cSCC having close or

positive margins that cannot be corrected with further surgery

(secondary to morbidity or adverse cosmetic outcome).

Strong Low

37

3. PORT is recommended for patients with cSCC in the setting of

recurrence after a prior margin-negative resection. Strong

Moderate 38-43

4. In patients with cSCC, PORT is recommended for T3 and T4

tumors.* Strong

Moderate 44-46

5. In patients with cSCC, PORT is recommended for desmoplastic†

or infiltrative tumors in the setting of chronic

immunosuppression.

Strong Moderate

44,46

BCC

6. PORT is conditionally recommended in patients with BCC with

close or positive margins that cannot be corrected with further

surgery (secondary to morbidity or adverse cosmetic

outcome).

Conditional Low 8,24

7. PORT is conditionally recommended in patients with BCC in the

setting of recurrence after a prior margin-negative resection. Conditional

Low 8,24,47,48

8. PORT is conditionally recommended in patients with BCC with

locally advanced or neglected tumors involving bone or

infiltrating into muscle.

Conditional Low 8,24,45

Abbreviations: BCC = basal cell carcinoma; cSCC = cutaneous squamous cell carcinoma; KQ = key question; PORT = postoperative radiation therapy; RT = radiation therapy.

* American Joint Committee on Cancer staging table, eighth edition.2 † The presence of desmoplasia on light microscopy is defined as fine branches of tumor cells at the periphery and a surrounding stromal reaction. All cSCC in which at least one-third of the representative tumor specimen meet these criteria is classified as desmoplastic cSCC. One study reported findings that perineural or perivascular invasion were always associated with desmoplasia.46

Because RT is effective in the definitive treatment of patients with BCC and cSCC as monotherapy, it is

rational to use PORT in patients at high risk for recurrence following surgical resection. Hence, the use of RT in

the postoperative setting is widely felt to be justified for poor prognostic features that have been established

by a few prospective and multiple retrospective studies.8,24,29,33-38,44-49 It should be noted that prior to radiation

treatment planning, clinicians need to ascertain all appropriate tumor resection information including the final

Clark level, depth of invasion, nerve involvement and margin status when available.

Cutaneous SCC is a much more aggressive entity than BCC with a far greater risk for regional and nodal

spread. Thus, the task force recommends more wide-ranging utilization of PORT in the cSCC population. This

recommendation is likewise reflected in attaching a conditional qualification to the recommendation to offer


PORT for BCC.24,29,50 PORT should be considered in patients with cSCC when the tumor is recurrent, after a

margin negative resection, large (≥4 cm), deeply invasive (>6 mm) or has extensive microscopic perineural

invasion (PNI) or clinically apparent nerve involvement.29,33-36 Immunosuppressed patients with

desmoplastic/infiltrative subtype of cSCC are at high risk for cancer specific mortality.44,46,50 PORT should also

be considered in patients with BCC or cSCC eroding into bone or involving the skull base neural foramina as

these scenarios are generally not salvageable if they recur.51 44,46,50 For the majority of well demarcated BCC

and small (<2 cm) cSCC, a surgical margin of 4 mm around the clinical borders of the tumor are considered

adequate. However, tumors that are larger, moderately-to-poorly differentiated, invading subcutaneous

tissue, and located in high-risk areas (eg, scalp, ears, nose, lips, eyelids) require at least a 6 mm margin.52,53

These recommendations refer to conventional surgical excision. Following Mohs excision, narrower margins

may be adequate although assessing tumor characteristics after Mohs-assisted excisions may be challenging.

Because depth of invasion cannot be accurately measured on horizontally-sectioned tissue and PNI may be

reported as present or absent without a nerve diameter measurement, it is imperative that the Mohs

intraoperative tumor histology and findings be reconciled with the preoperative tumor histology to obtain a

complete pathologic assessment of the tumor.

It is notable that most studies establishing risk factors for local recurrence for BCC and cSCC are limited

to patients with skin carcinomas of the head and neck.8,29,33-37,48,50 Treatment of the trunk and limb skin cancer

thus requires further extrapolation from an already scant literature base. Conversely, the cosmetic and

functional implications relevant to the head and neck anatomic location are less relevant in the treatment of

tumors arising on the trunk and extremities. In patients whose tumors arise on the trunk or extremities,

reresection of recurrent tumors is likely to be less challenging than in patients with tumors of the head and

neck, where salvage therapy for recurrence may be more morbid and less effective.29

Though PNI is a well-known predictor of local recurrence of BCC and cSCC, the criterion defining

significant PNI varies across the literature. For example, extensive microscopic PNI has been defined by Sapir et

al as involvement of >2 nerves.35 This study reported that the recurrence free survival in nerve pathways (94%

vs 24%, P=0.01) and disease-free survival (73% vs 40%, P=0.05) were significantly higher in patients who

received PORT for microscopic extensive disease than in those who did not receive PORT. It also found that

there was no benefit from PORT in patients who had focal microscopic PNI involving 1 to 2 nerves.36 However,

it should be noted that while their definitions of focal and extensive microscopic PNI are simple and

reproducible, they are not widely accepted and require validation.

Compared to microscopically detected focal PNI, RT target volumes for gross perineural spread

(clinically or radiologically detectable) and extensive PNI (involving >2 nerves) are typically more generous and

often electively include the nerve pathway proximal to the skull base ganglion.51,54 For head and neck cSCCs

(and rarely for BCCs) with gross perineural spread, the trigeminal and facial nerve pathways are the most

important cranial nerve pathways to consider inclusion in the radiation treatment volume. Familiarity with the

anatomical pathways of these nerves to their ganglia in the Meckel’s cave and the geniculate ganglion near the

internal auditory meatus is required to contour the elective target volumes. Additionally, the

intercommunicating pathways between the cranial nerves (V3 and VII via auriculo temporal nerve and V2 and

VII via the vidian nerve and greater superficial petrosal nerve) should be considered for inclusion in the

treatment volume while balancing the risk of additional treatment related morbidity.51

The task force believes that the dose for treating gross perineural spread that is detectable on imaging

(preferably magnetic resonance imaging) should be equivalent to definitive doses as outlined in KQ4 and

preferably be delivered using conventional fractionation. Optimal dose and fractionation for elective


treatment of subclinical disease along the potential nerve pathways is less clearly defined, but giving a high

priority to radiation tolerance of adjacent critical structures is encouraged.51

3.3. Key Question 3: Indications for RT for treating regional nodes and regional disease management (Table 6)


What are the appropriate indications for RT for treating regional nodes? What dose and fractionation should

be used for management of regional disease?

Table 6. Recommendations for RT for treating regional nodes and regional disease management


Recommendation

Quality of

Evidence (Refs)

1. For patients with cSCC or BCC that metastasized to clinically

apparent regional lymph nodes, therapeutic lymphadenectomy

followed by adjuvant RT is recommended, with the exception of

patients that have a single, small (<3 cm) cervical lymph node

harboring carcinoma, without extracapsular extension.

Strong Moderate

40,50,55-70

2. For patients with cSCC or BCC that metastasized to clinically

apparent regional lymph nodes, definitive RT is only

recommended for patients who are medically inoperable or

surgically unresectable.

Strong Moderate

28,60-62,65,67-69

3. For patients with cSCC at high risk of regional nodal metastasis,

imaging and sentinel lymph node biopsy are conditionally

recommended to guide the need for and target of lymph node

basin RT.

Implementation Remark:

Close clinical follow-up of the lymph node basin is important for

patients in whom sentinel lymph node biopsy is unlikely to be

accurate due to: (1) an extensive initial primary resection

and/or reconstruction or (2) tumor location in the head and

neck area.

Conditional Expert Opinion

46

4. For patients with cSCC at high risk of regional nodal metastasis

(thickness >6 mm), elective lymph node basin RT is conditionally

recommended only for those undergoing RT to the primary site

with overlap of the adjacent nodal basin.

Conditional Low

24,28,44,46,71-82

5. For patients with BCC or cSCC undergoing adjuvant RT after

therapeutic lymphadenectomy, a dose of 6000–6600 cGy

(conventional fractionation [180–200 cGy/fx]) is recommended.

Strong Moderate

28,64,83-85

6. For patients with cSCC undergoing elective RT in the absence of

a lymphadenectomy, a dose of 5000–5400 cGy (conventional

fractionation [180–200 cGy/fx]) is recommended.

Strong Moderate

28,64,83-85



Abbreviations: BCC = basal cell carcinoma; cGy = centigray; cSCC = cutaneous squamous cell carcinoma; fx = fraction; KQ = key question; PORT = postoperative radiation therapy; RT = radiation therapy.

Regional node metastasis is a rare event for BCC and cSCC with an overall rate of <1% for BCC and <5%

for cSCC.86,87 Nevertheless, a management strategy for the regional lymphatics is critical in treatment planning.

Management of the regional lymph node basin is guided by the presence or absence of clinically or

radiographically apparent metastasis, as well as the estimated risk of subclinical lymph node involvement.

Patients with clinically or radiographically apparent lymph node metastasis should undergo

therapeutic lymphadenectomy unless they are medically inoperable or the lymphadenopathy is surgically

unresectable. Retrospective studies (online supplement Table E-1) have demonstrated an association of higher

regional disease control rates with surgery and adjuvant RT (median 2-year regional relapse free and overall

survival of 87% and 77%). This is compared to patients treated with surgery alone (median 2-year regional

relapse free and overall survival of 72% and 62%) or RT alone (median 2-year regional relapse free and overall

survival of 63% and 50%). Patients harboring a lymph node metastasis >3 cm, multiple lymph nodes involved

with carcinoma, or extension of carcinoma outside the lymph node capsule are at sufficient risk of regional

recurrence after therapeutic lymphadenectomy to warrant adjuvant RT. However, at least 1 study has

suggested that for patients with a small (<3 cm), single, cervical lymph node metastasis not exhibiting

extranodal extension, the risk of regional recurrence after therapeutic lymphadenectomy is low (<10%) which

may limit the yield of adjuvant RT, and should prompt consideration on a case-by-case basis.58 For instance,

the quality of the neck dissection is an important factor in the decision-making algorithm. In patients with

clinically or radiographically apparent lymph node metastasis that are ineligible for surgery (medically

inoperable or technically unresectable), definitive RT for lymph node metastasis is appropriate, albeit with

anticipated outcomes inferior to that of surgery and adjuvant RT. Although some practitioners consider adding

systemic therapy to definitive RT in this situation, there is no high-quality evidence demonstrating that this

improves outcomes, as discussed further in KQ5.

A prospective clinicopathologic correlation study incorporating a comprehensive multivariable analysis

of all putative risk factors associated with regional lymph node basin recurrence demonstrated that among 615

patients without clinically apparent lymph node metastasis from cSCC undergoing a margin-negative excision,

regional metastasis did not occur if the tumor was ≤2.0 mm thick.46 The risk of metastasis at 4 years was

approximately 5% for tumors 2.1 to 6.0 mm thick (crude rate 3.8%), and approximately 20% for tumors >6.0

mm thick (crude rate 15.6%, hazard ratio 4.79). Other factors associated with regional recurrence on

multivariable analysis included immunosuppression (crude rate 16.1%, hazard ratio 4.32), primary tumor

location on the ear (crude rate 9.9%, hazard ratio 3.61), and larger tumor horizontal size (crude rate 1.9% for

tumors ≤20 mm, 7.5% for tumors 21 to 50 mm, 20% for tumors >50 mm, hazard ratio 2.22). Tumor

differentiation, desmoplastic growth (including the presence of lymphovascular or PNI) and having >1 prior

primary cSCC were not associated with regional recurrence on multivariable analysis.46

The factors associated with regional recurrence in patients without clinically apparent regional

metastasis (tumor >6.0 mm thick or >5 cm in diameter, located on the ear, or in an immunosuppressed

patient) can be used to predict patients at highest risk for regional recurrence after primary tumor

management, and who might benefit from more comprehensive lymph node evaluation (with imaging and

sentinel lymph node biopsy).46 Radiographically-identified regional lymph node metastases would be managed

as noted above. However, the optimal management of clinically occult lymph node metastases identified only

on sentinel lymph node biopsy is not well defined by data, and could entail completion lymphadenectomy

and/or lymph node basin RT.



Limited data support the use of elective lymph node basin RT in patients at high risk for recurrence

(online supplement Table E-2) but do suggest a lower than expected rate of regional recurrence in high-risk

patients (median 5-year regional relapse free survival of 99%), suggesting that the elective treatment is

effective. To balance the benefits and risk of elective nodal radiation in the absence of quality evidence,

practitioners may choose to selectively target the high-risk echelons of the draining lymphatics. Nevertheless,

lymph node basin RT is associated with adverse events (eg, dermatitis, lymphedema, mucositis), so careful

selection of patients for this treatment is encouraged. Patients who are having adjuvant RT to a high-risk

primary tumor located at a site that overlaps a draining lymph node basin may be good candidates for elective

lymph node basin RT. There are no data to address this issue, but it may be prudent in selected patients to

decrease the probability of requiring reirradiation of the same anatomic site. Adding this first echelon of

lymphatics should not increase the patient’s morbidity significantly. The task force initially discussed a

recommendation against routine elective lymph node basin RT, but ultimately it was felt that insufficient data

were available to make that recommendation.

Finally, the radiation doses used as part of lymph node management should be considered carefully

given the potential morbidity of treatment. There are no prospective trials defining the optimal dose for

regional RT in BCC and cSCC. Current standards of care are largely derived from experience in the treatment of

other cancers from the same anatomic sites in which regional lymph node metastases from these skin cancers

occur. A prospective clinical trial of patients with locally advanced cSCC receiving adjuvant RT required 6000 to

6600 cGy to be given at 200 cGy/fraction. Approximately 85% of study participants received a dose of 6000 cGy

at 200 cGy/fraction, and outcomes were excellent (2-year locoregional relapse free and overall survival of 88%

and 88%, respectively).64 This observation, in addition to a single-institution study of adjuvant RT for mucosal

SCC demonstrating no benefit of adjuvant RT with doses >6000 cGy at 200 cGy/fraction, suggest that a dose of

6000 cGy at 200 cGy/fraction is sufficient after a therapeutic lymphadenectomy has been performed.83-85

While some practitioners favor a dose of 6600 cGy at 200 cGy/fraction in situations of microscopically positive

margins or extranodal extension of carcinoma, no data support use of this higher adjuvant dose. In

extrapolation from head and neck mucosal SCC, RT should begin as healing from surgery is complete,

preferably within 6 weeks of surgery.83-85 Far less data are available on the outcome of elective lymph node

basin RT, but the existing series have generally used a dose of 5000 cGy at 200 cGy/fraction or an equivalent

regimen (ie, 5400 cGy at 180 cGy/fraction).24,28,44,46,71-82

3.4. Key Question 4: Radiation techniques and dose-fractionation schedules for primary site management (Table 7)


What are the preferred dose-fractionation schedules and radiation techniques for the management of the primary site in BCC and cSCC?




Table 7. Recommendations for radiation techniques and dose-fractionation schedules for primary site management


Recommendation

Quality of

Evidence (Refs)

1. In patients with BCC and cSCC receiving RT in the definitive

setting, the following dose-fractionation schemes* are

recommended:

o Conventional (180–200 cGy/fx): BED10 70–93.5

o Hypofractionation (210–500 cGy/fx): BED10 56–88

Implementation Remark: Conventional fractionation is delivered

5 days per week; hypofractionation is delivered daily or 2-4 times

per week.

Strong Low

10,79,80,82,88-94

2. In patients with BCC and cSCC receiving RT in the

postoperative setting, the following dose-fractionation

schemes* are recommended:

o Conventional (180–200 cGy/fx): BED10 59.5–79.2

o Hypofractionation (210-500 cGy/fx): BED10 56–70.2

Implementation Remark: Conventional fractionation is delivered

5 days per week; hypofractionation is delivered daily or 2-4 times

per week.

Strong Low

5,48,90,93,95-100

Abbreviations: BCC = basal cell carcinoma; BED10 = biologically effective dose assuming an = 10; cSCC = cutaneous squamous cell carcinoma; fx = fraction; KQ = key question; RT = radiation therapy. * See Table 8 with specific fractionation schemes.

Multiple RT modalities can be used to appropriately treat BCC and cSCC. Megavoltage (MV) electrons,

brachytherapy (low-dose-rate [LDR] and high-dose-rate [HDR]), kilovoltage (KV), and MV photons have been

successfully used to treat BCC and cSCC.7,79,94,100,101 Historically, photon radiation in the KV range was the

predominant modality used to treat superficial BCC and cSCC. These lower energy therapies include

orthovoltage, contact, soft x-ray, intermediate x-ray, electronic brachytherapy and superficial x-ray therapy.

Compared with high energy photons, lower energy photons and electrons produce more dense ionization that

may result in more complex cell damage and higher relative biological effectiveness. The American College of

Radiology and American Brachytherapy Society published a practice parameter in 2017 defining a term that

grouped all of these low energy forms of RT into 1 category called electronically generated low-energy sources

(ELS). ELS are defined as equipment using x-ray sources with a peak voltage of up to 120 kVp to deliver a

therapeutic radiation dose to clinical targets.102 Although electronic brachytherapy is classified within this ELS

category, the authorized user requirements for this particular modality are different than those of superficial x-

ray therapy. ELS do not require special shielding or compliance with the Nuclear Regulatory Commission

regulations that are imposed on authorized users of LDR brachytherapy, HDR brachytherapy or MV equipment.

A thorough literature review on this topic suggests that appropriate use of any of the 4 major radiation

modalities results in similar local control and cosmetic outcome.4,5,10,16,48,78-80,82,88-100,103-105 Thus, the decision of

which modality and fractionation scheme to use should be based on both tumor characteristics (eg, shape,

contour, depth, and location) and normal tissue considerations.


Clinical studies using electrons, ELS, and brachytherapy report 5-year local control between 75% to

100%.5,12,48,90,91,93,95-97,99,106 The reported 5-year local control rates for photon therapy are between 54% to 80%

and can be attributed to a disproportionate number of studies that included patients with high-risk and locally

advanced disease.5,95,96,98,99,106 It is believed that any differences in local control rates between different

treatment modalities can be attributed to varying tumor characteristics rather than a fundamental difference

in biologic response (ie, tumors that require MV photon treatment are much larger than those treated with

ELS). The newest modality in the ELS category is electronic brachytherapy. Because of its relative novelty, there

are no long-term follow-up studies (>10 years) involving electronic brachytherapy which evaluate local control

and toxicity. Therefore, caution should be made in extrapolating electronic brachytherapy local control and

toxicity from the other older modalities within ELS.

ELS are typically appropriate for treatment of superficial T1/T2 BCC and cSCC with thicknesses of up to

0.5 cm. When creating the treatment field from the gross tumor volume (GTV) consider margins of 1 cm to

provide adequate coverage of microscopic disease spread (0.5 cm for BCC and 0.6 cm for cSCC) and treatment

set-up.94,107 These margins are recommended with the caveat that it is often not anatomically feasible to have

such margins in many critical anatomic locations. ELS treatments planning does not require 3-D reconstruction,

although it may be appropriate to obtain 3-D imaging when treating cutaneous targets near critical structures.

Brachytherapy uses a radioactive isotope to deliver therapeutic radiation near or inside the tumor

target. Although the use of LDR brachytherapy remains historically significant, HDR has become more common

after the advent of HDR afterloaders, which offer versatility in treatment volume design, minimal exposure to

the staff and shorter treatment times. Since most centers have replaced the use of LDR brachytherapy with

HDR, the task force has chosen to focus its dose recommendations for brachytherapy on HDR treatments.

Similar to ELS, surface brachytherapy may be used to treat T1/T2 BCC and cSCC with depths between 0.3 to 0.5

cm.93,108 Common applicators used with brachytherapy treatment include solid conical applicators, surface

molds, flap-style applicators, and interstitial catheters. Different applicators may be preferentially used for

specific anatomic locations to allow for appropriate tumor coverage while allowing for normal tissue sparing.

For instance, solid conical applicators are commonly used for flat surfaces (eg, cheek). Surface molds and flap-

style applicators may be used for curved surfaces with complicated topology (eg, canthus, eyelid, or

extremity). Finally, interstitial HDR may be used for thicker targets (>0.5 cm depth). When creating a planning

treatment volume from a GTV for brachytherapy, the use of narrow margins of 0.25 cm have been

reported.93,108,109 However, the task force considered more appropriate margins to be at least 0.5 cm. Similar to

ELS therapy, the margin may be decreased if there is an adjacent critical structure. For a single-channel solid

conical applicator, brachytherapy may be planned using nomograms considering the prescription depth,

source strength, and the prescribed dose. Alternatively, if the tumor has a more complex geometry, is more

deeply invasive or is in close proximity to critical structures, brachytherapy should be planned with a 3-D

planning system. It should be noted that both ELS and skin surface brachytherapy lend themselves particularly

well to moderate and extreme hypofractionation. Dose falloff for these modalities is rapid resulting in relative

sparing of deeper structures.

MeV electron therapy (6-20 MeV) may be used to treat both T1–T3 superficial and more deeply

invasive BCC and cSCC. When using electron therapy, bolus is commonly applied to the surface of skin in order

to increase the surface dose and/or to take advantage of the rapid dose falloff of electrons to spare deeper

normal tissues. Users are encouraged to consult their department’s machine commissioning data for precise

depth dose characteristics of the electron beams. When creating an electron field consider margins of at least

1 to 2 cm on the GTV to ensure adequate coverage.103,110 This is particularly significant when using lower

electron energies and smaller field sizes because of the constriction of the prescription isodose lines with these


parameters. Further, skin surface collimation is commonly used for field sizes <4 cm.111 The intended dose is

commonly prescribed to the 80% to 90% isodose line to ensure prescription dose at the surface given the

depth-dose curves of low energy electrons.110 Electron treatments may be prescribed clinically using a Monitor

Unit (MU) calculation; however, 3-D computer plan with dose modelling is encouraged to allow for more

accurate assessment of tumor coverage and normal tissue sparing.

MV photon therapy (6-15 MV) is often used to treat T3/T4 larger or more deeply invasive BCC and

cSCC. These tumors typically have a thickness >3 cm, have bone and/or cartilage involvement, or are adjacent

to critical structures for which advanced techniques such as 3-D conformal RT or intensity modulated RT would

be indicated.98 MV photons are also the preferred modality when treating lymphatics or tracking clinical or

subclinical PNI.98 Due to the build-up characteristics of MV photon beams, bolus of at least 0.5 to 1.0 cm needs

to be applied to the target surface to ensure adequate dose at the skin. When creating the planning treatment

volume from the GTV consider margins of at least 2 cm to account for microscopic spread and setup error.41,98

As opposed to superficial radiation modalities (low-energy electrons, ELS and surface brachytherapy) for which

clinical set up may often be sufficient for treatment planning, use of MV photons almost always necessitates a

CT simulation and 3-D treatment planning to accurately assess tumor coverage and sparing of normal

tissues.41,98

There are no prospective randomized data comparing different dose-fractionation regimens for the

primary site in both the definitive and postoperative setting for BCC and cSCC. The fractionation schemes

outlined in this guideline were drawn from studies that met our inclusion criteria (outlined in Section 2.3), and

we recognize that these schemes are not all-inclusive. These recommendations aim to summarize the wide

variety of appropriate regimens that have been reported to provide excellent local control with good cosmetic

outcomes. Biological effective dose (BED) ranges are used instead of specific doses and fractionation in an

attempt to address the wide variation in dosing schemes within the examined literature. BED calculations

involve the use of an established radiobiological equation to compare different fractionation regimens by

converting them to comparable values for a given tissue of interest. BED10 refers to the equivalent dose for

cells with an alpha/beta ratio of 10, which is considered typical for skin carcinomas. BED calculations are most

appropriately determined and compared within a specific modality; for example, the BED for superficial x-rays

is not necessarily comparable with BED for megavoltage x-rays. The Radiation Oncology Institute’s tool box

includes a BED calculator which is available at https://rotoolbox.com/calculators/eqd2/. Figure 2 offers a

reference for common dose/fractionation schemes as well as depicts the general inverse relationship between

increasing dose and decreasing fractionation when adhering to a predefined BED range. Table 8 provides

further details of fractionation schemes according to each modality. It is important to remember that the dose

delivered to the skin can vary based on multiple factors including modality, the energy of the beam, field size,

bolus thickness, and filters. Therefore, when reviewing the data in Table 8, it is essential to recognize that the

total skin dose may not be the same as the prescription dose.

The process of care in radiation oncology is an involved undertaking requiring coordination of many

complex activities. Readers may refer to ASTRO’s update to the Safety Is No Accident publication, which

provides a framework for high-quality radiation treatment preparation and delivery.112 Image-guided RT is

instrumental for accurate delivery of photon-based RT when treating regional lymphatics and nerve tracks in

the head and neck. For local treatment of skin targets, the task force emphasizes the importance of regular

and frequent visual confirmation of surface coverage by the treating radiation oncologist (ie, biweekly “see-on-

table” verification). Daily imaging is neither necessary nor useful when treating with electron beam, ELS, or

skin surface brachytherapy. Anatomical location, patient preference, and cost of treatment should be part of

the consideration when choosing the treatment regimen. Choice of hypofractionated regimens using

https://rotoolbox.com/calculators/eqd2/


superficial therapy or electron beam therapy without 3-D planning are considered more cost-effective.113

However, caution should be exercised when treating anatomically sensitive areas (ie, periorbital and perioral

skin) with hypofractionated regimens. Compared with standard fractionation, hypofractionation, especially

when used with more deeply penetrating modalities (eg, MV electrons and photons), can lead to more skin

atrophy and fibrosis potentially jeopardizing otherwise excellent functional outcomes. Conventional regimens

are typically delivered on a daily basis, whereas hypofractionated regimens can be delivered daily or 2 to 4

times per week with a goal of achieving even spacing between the fractions in any given week.

Table 8. Dose fractionation schemes (derived from studies with at least 50 patients* treated with definitive or postoperative RT)

Total dose, cGy

No. of fx

Fx size, cGy

Weekly fx BED10 Definitive† Postop† Modality Refs

Conventional Fractionation

5040 28 180 5 59.5 --- X ELS 5

5940 33 180 5 70.1 X --- HDR 12

6000 30 200 5 72 --- X ELS, Electrons, MV 5,99

6480 36 180 5 76.5 X --- HDR 12

6600 33 200 5 79.2 X X ELS, MV 106

7000 35 200 5 84 X --- ELS, MV 106

7400 37 200 5 88.8 X --- ELS 5

7920‡ 44 180 5 93.5 X --- HDR 12

Hypofractionation

4000 8 500 2 60 X --- HDR 93

4050 9 450 bid for 9

fx/wk 58.7 X X HDR 90

4400 10 440 4 63.4 X X Electrons 97

4400 14 300 (first

dose); 400 (last dose)

bid for 10 fx/wk

58.0 X --- HDR 91

4500 9 500 bid for 9

fx/wk 67.5 X X HDR 90

4500 10 450 4 65.3 X X ELS 48,95

4500 15 300 5 58.5 X X ELS, Electrons, MV 5,99

4800 16 300 5 62.4 X --- HDR 93

5000 20 250 5 62.5 X X ELS, Electrons, MV 95,96,99

5100 17 300 5 66.3 X --- ELS 5

5400 18 300 4–5 70.2 X X Electrons, ELS 48,97

5500 20 275 5 70.1 X X ELS, MV 5,96

6120 18 340 5 82 X X HDR, ELS, MV 106

Abbreviations: BED10 = biologically effective dose assuming an = 10; bid = twice daily; ELS = electronically generated,

low-energy radiation sources; fx = fraction; HDR = high-dose-rate; MV = megavoltage photons.

* The majority of these studies included over 100 patients. † Some studies included both definitive and postoperative cases, and the distinction in dose for the different treatment times were not necessarily outlined in the studies. ‡ Lesions >4 cm were boosted up to 8000 Gy after a 3-week break.


Figure 2. Dose fractionation summary

# of Fractions 8 9 10 11 14 15 16 17 18 20 28 30 33 35 36

Dose (cGy)

180 5040 5940 6480

200 6000 6600 7000

250 5000

275 5500

300 4200 4500 4800 5100 5400

340 6120

400 4400

440 4400

450 4050 4500

500 4000

3.5. Key Question 5: Use of chemotherapy, biologic, and immunotherapy agents before, during or after RT (Table 9)


When is it appropriate to use chemotherapy, biologic, and immunotherapy agents before, during, or after RT in the treatment of BCC or cSCC?

Table 9. Recommendations for use of chemotherapy, biologic, and immunotherapy agents before, during, or after RT



Evidence (Refs)

1. In patients with resected locally advanced cSCC, the addition

of concurrent carboplatin to adjuvant RT is not recommended. Strong Moderate

64

2. In patients with unresected locally advanced cSCC, the

addition of concurrent drug therapies to definitive RT is

conditionally recommended.

Conditional Low

114

Abbreviations: cSCC = cutaneous squamous cell carcinoma; KQ = key question; RT = radiation therapy.

Systemic therapy in BCC and cSCC is considered an adjunct to the definitive modalities of surgical

excision and RT in various clinical scenarios deemed at high risk for recurrence. Although a benefit to the

addition of radiosensitizing cisplatin to RT in the adjuvant setting was demonstrated for mucosal head and

neck squamous cell carcinoma,115,116 a prospective randomized trial failed to demonstrate a benefit when

weekly-administered radiosensitizing carboplatin was added to PORT in patients with high-risk resected cSCC.64

Nevertheless, multiple retrospective and single arm prospective studies characterize favorable outcomes for

resected cSCC treated with adjuvant RT and various systemic agents, including cytotoxic chemotherapy and

targeted biologic agents.41,117-120 Similarly, the use of concurrent platinum-based chemoradiation is well

established in advanced mucosal SCC through randomized trials and meta-analyses.121,122 In cSCC, however, the

data are much less robust and consists only of small retrospective reports123,124 and a small phase II study.114



Single-arm prospective evidence for use of targeted therapy in the neoadjuvant setting125 has also been

described in cSCC.

The definition of “high-risk” in these studies varies, highlighting the need for a consensus in defining

the population studied, the timing and the choice of therapy in nonmelanoma skin cancers in future

investigations. Approved systemic therapies exist for both BCC and cSCC in unresectable or metastatic settings.

Hedgehog inhibitors are specifically indicated for the treatment of adult patients with metastatic BCC, or with

locally advanced BCC that has recurred after surgery or who are not candidates for surgery or RT,126,127 while

an immunotherapy checkpoint inhibitor is approved for the treatment of patients with metastatic cSCC or

locally advanced cSCC who are not candidates for curative surgery or RT.128 Investigation into the use of such

agents in the neoadjuvant, adjuvant, and definitive settings is justified in these diseases. As hedgehog

inhibitors (vismodegib and sonidegib) and immunotherapy agents (cemiplimab) are approved palliative

therapies in patients with BCC and cSCC; thus, treating physicians are strongly advised to avoid their use in

settings where curative-intent surgery or RT is feasible.

4. Conclusion/Future Directions

The paucity of prospective and randomized data both hinders RT use for BCC and cSCC and offers a

ripe opportunity for future research to characterize the role of RT in management of this disease. Whenever

possible, patient outcomes should be collected as part of clinical trials and prospective registries to bolster the

overall quality of data on this topic. It is our hope that this guideline will help further this goal. Specific areas of

interest identified by our task force are standardization of radiation fractionation schemes, defining optimal

management of microscopic PNI and management of regional nodal basins.

Microscopic extensive PNI has been reported to portend a worse prognosis and to derive a greater

benefit from adjuvant RT compared to focal PNI. However, the definition of extensive PNI is variable in the

current literature and needs further validation as a predictive marker for local and regional recurrence after

radiation. The elective volume to be irradiated beyond an involved nerve needs to be balanced against the risk

of morbidity from treatment and requires further study.

A better understanding of patients who are at highest risk for regional recurrence after

lymphadenectomy is needed, with strategies focused on identifying clinical, pathological and molecular risk

factors. Given that most studies of regional lymph node basin management are based on head and neck

primary tumors, additional studies on non-head and neck cases are needed. Also, studies which identify the

optimal technique, dose and fractionation strategy in the treatment of lymph node basins are needed to

ensure RT is used in the most effective and least morbid fashion.

At the time of publication, systemic therapy was only approved for treatment of BCC and cSCC in the

palliative setting when the BCC or cSCC is metastatic, or locally advanced disease where curative RT or surgery

is not an option. Therefore, investigation is warranted in all settings including neoadjuvant, adjuvant, and

definitive settings. Several trials are ongoing to assess safety and efficacy of immunotherapy in both

malignancies when combined with RT, and neoadjuvant systemic therapy is an attractive option in efforts to

ameliorate surgical intervention or need for RT.

In summary, prospective trial design and multidisciplinary collaboration to study the optimal roles of

RT in treatment of BCC and cSCC will further increase curability of this disease while minimizing toxicity.


5. Acknowledgements

We are grateful to Yimin Geng, MSLIS, MS, the University of Texas MD Anderson research medical

librarian, for her assistance with creating the search strategy for this guideline. The task force also thanks

Musaddiq Awan, MD, Nicholas DeNunzio, MD, PhD, Elisha Fredman, MD, William Grubb, MD, Blair Murphy,

MD, Steven Seyedin, MD, Fauzia Shaikhfor, MD, and Michael Stolten, MD, for literature review assistance and

Dean Shumway, MD, who contributed to the guideline during the early phase of development.

The task force thanks the peer reviewers for their comments and time reviewing the guideline (see

Appendix 1 for their names and disclosures), and Michael Diehl who served as the patient representative of

the task force.

We also thank task force participants Murad Alam, MD, for providing a dermatologic perspective and

Valencia Thomas, MD and Michael Tetzlaff, MD, for providing a dermatopathologic perspective who withdrew

from authorship.

Figure 1. PRISMA Diagram

PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses Created based on Moher D, Liberati A, Tetzlaff J, and Altman DG, 2009.129


Appendix 1. Peer Reviewers and Disclosures (Comprehensive)

Name Employment Disclosure Company/

Organization Disclosure Category

Genevieve Boland, MD (SSO Reviewer)

Massachusetts General Hospital – Surgical Director, Termeer Center for Targeted Therapies; Harvard Medical School – Assistant Professor

• Takeda Oncology • Research funding

Mark Buyyounouski, MD

(Content Reviewer) Stanford University Medical Center – Professor of Radiation Oncology

• Elsevier

• Wolters Kluwer

• Varian

• Honoraria

• Research funding

Ravi Chandra, MD (Guideline Subcommittee Lead Reviewer)

Compass Oncology – Medical Director

None N/A

Jonathan Cook, MD

(Content Reviewer) Duke University Medical Center – Professor of Dermatology, Assistant Professor of Surgery

None N/A

Avraham Eisbruch, MD (Content Reviewer)

University of Michigan, University Hospital, Department of Radiation Oncology – Professor

• NIH • Research funding

Jeremy Etzkorn, MD

(AAD Reviewer) University of Pennsylvania – Assistant Professor of Dermatology

• Dermatology Foundation


Gregg Franklin, MD

(ASCO Reviewer) New Mexico Cancer Center, Radiation Oncologist – Clinical Director

• Varian

• Bayer

• C4 Imaging

• Consultant

• Speakers Bureau

• Other-Partnership

Dale Han, MD (SSO Reviewer)

Oregon Health and Science University, Division of Surgical Oncology – Associate Professor of Surgery

None N/A

Peter Johnstone, MD (Content Reviewer)

Moffitt Cancer Center, Radiation Oncology – Senior Member and Vice Chair

None N/A

Tim Kruser, MD (Guideline Subcommittee Lead Reviewer)

Northwestern Memorial Hospital, Department of Radiation Oncology –

Assistant Professor and Director of Stereotactic Body Radiotherapy

• AstraZeneca • Speakers Bureau

Michael Moravan, MD, PhD (Content Reviewer)

Duke University Medical Center, Department of Radiation Oncology – Assistant Professor

None N/A

Peter F. Orio, III, DO, MS (ABS Reviewer)

Brigham & Women's Hospital, Radiation Oncology – Vice Chair Network Operations

• ABS

• ASTRO

• President

• Chair, CDVC

Jose Perez-Calatayud, PhD (Content Reviewer)

La Fe University Hospital – Radiotherapy Department

None N/A

Cristina Rodriguez, MD • CUE • Advisory board


(Content Reviewer) University of Washington, Department of Medicine, Division of Medical Oncology – Associate Professor

• Bristol-Myers Squibb Merck

• Ayalia Pharmaceuticals

• AstraZeneca


• Acerta Pharmaceuticals AstraZeneca

• Genentech

• Incyte

• Merck

• Portola

• Research funding–family member

Kilian Salerno, MD (Guideline Subcommittee Lead Reviewer)

NIH/NCI, Center for Cancer Research, Radiation Oncology Branch – Associate Research Physician

• Johnson & Johnson

• American College of Radiology

• Stock–family member

• Travel expense

Rahul Seth, DO (ASCO Reviewer)

Upstate Medical University, Medical Oncology – Assistant Professor of Medicine

None N/A

Cloyce Stetson, MD (ASDP Reviewer)

Texas Tech University Health Sciences – Professor of Dermatology and Pathology, Dermatology Chairman

• Abbvie Pharmaceuticals

• Other

Abbreviations: AAD = American Academy of Dermatology; ABS = American Brachytherapy Society; ASCO = American Society for Clinical Oncology; ASDP = American Society of Dermatopathology; N/A = not applicable; NCI = National Cancer Institute; NIH = National Institutes of Health; and SSO = Society of Surgical Oncology. This table represents the reviewers reported disclosures at the time this document was under review (March 2019); not necessarily their disclosures at the time of publication.

Appendix 2. Abbreviations

3-D = three-dimensional

BED = biologically effective dose

BCC = basal cell carcinoma

cGy = centigray

cSCC = cutaneous squamous cell carcinoma

ELS = electronically generated, low-energy radiation sources

HDR = high-dose-rate

GTV = gross tumor volume

KQ = key question

KV = kilovoltage

LDR = low-dose-rate

MV = megavoltage

PICOTS = Population, Intervention, Comparator, Outcome, Timing, Setting framework

PNI = perineural invasion

PORT = postoperative radiation therapy

RT = radiation therapy

SCC = squamous cell carcinoma


Appendix 3. Literature Search Strategies

Search Limits:

Age Range Adult (≥18 years old)

Language English only

Species Humans

Publication Date 5/1/1988 to 6/5/2018 (30 years)

Publication Types All

Rationale for abstract exclusion:

• Detailed discussion of diagnostic methods

• Preclinical/non-human studies

• Dosimetric studies without clinical outcomes

• Re-irradiation

• Hematogenously spread distant metastatic disease

• Dermatopathologic evaluation

• Surgical technique

• Health economics / cost analysis studies

• Studies available in abstract only

• Comment or editorial

• Otherwise not relevant or out of scope

Patient number thresholds:

• Key Questions 1: Studies with ≥100 patients

• Key Questions 2-4: Studies with ≥50 patients

• Key Question 5: Studies with ≥15 patients

Database(s): Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present, search completed on 6/11/208 Search Strategy:

# Searches

1 Skin Neoplasms/

2 ((skin or cutaneous) adj5 (carcinoma* or cancer* or neoplasm* or malignanc*)).ti,kf.

3 exp Carcinoma, Basal Cell/

4 (("non melanoma" or nonmelanoma) adj3 (skin or cutaneous) adj3 (cancer* or carcinoma*)).ab.

5 ((skin or cutaneous) adj5 Squamous adj5 Carcinoma*).ti,ab,kf.

6 keratinocyte carcinoma*.ti,ab,kf.

7 (basal adj5 (carcinoma* or epithelioma*)).ti,ab,kf.


8 Carcinoma, Squamous Cell/

9 (skin or cutaneous).ti,kf,sh.

10 (skin or cutaneous).ab. /freq=2

11 9 or 10

12 8 and 11

13 exp facial neoplasms/

14 lip neoplasms/

15 1 or 2 or 3 or 4 or 5 or 6 or 7 or 12 or 13 or 14 [non melanoma skin cancer]

16 ("merkel cell" not ("non melanoma" or nonmelanoma)).ti.

17 15 not 16 [nonmelanoma skin cancer removed merkel cell carcinoma]

18 exp RADIOTHERAPY/

19 (radiotherap* or irradiat* or radiat*).ti,kf.

20 (radiotherap* or irradiat* or radiat*).ab. /freq=2

21 exp Radiotherapy Planning, Computer-Assisted/

22 exp Radiation Oncology/

23 ((proton* or photon) adj3 (therap* or radiat*)).ti,kf.

24 ((proton* or photon) adj3 (therap* or radiat*)).ab. /freq=2

25 (brachytherapy or orthovoltage or megavoltage or IMRT or "intensity modulated" or EBRT or "external beam").ti,kf.

26 (brachytherapy or orthovoltage or megavoltage or "intensity modulated" or IMRT or "external beam" or EBRT).ab. /freq=2

27 (("electron beam" or x-ray*) adj15 (therap* or radiat* or treatment)).ti,kf.

28 (("electron beam" or x-ray*) adj15 (therap* or radiat* or treatment)).ab. /freq=2

29 (superficial adj3 (radiotherap* or irradiat* or radiat* or x-ray*)).ab.

30 or/18-29 [radiotherapy]

31 17 and 30

32 limit 31 to english language

33 (animals not (humans and animals)).sh.

34 32 not 33 [nonmelanoma skin cancer radiotherapy]

35 (mice or mouse or rat or rats or "in vitro" or xenograft*).ti.

36 34 not 35

37 ((child or children or adolescent or pediatric* or paediatric*) not childhood).ti.

38 36 not 37 [nonmelanoma skin cancer radiotherapy removed pediatric population]

39 case reports.pt.

40 exp clinical study/ or comparative study/ or evaluation studies/ or meta-analysis/ or multicenter study/ or validation studies/ or letter.pt.

41 39 not 40

42 case report*.ti.

43 41 or 42


44 38 not 43 [nonmelanoma skin cancer radiotherapy human, English, Adult, remove case reports]

45 ((definitive or primary or alternative or alternate or curative* or remission) adj15 (radiotherap* or radiat* or irradiat* or RT or therap* or treatment)).ti,ab,kf.

46 ((option or choice) adj5 treatment adj15 (radiotherap* or radiat* or irradiat* or RT)).ti,ab.

47 ((single or only or monotherapy or curative or alone) adj3 (radiotherap* or radiat* or irradiat* or RT)).ti,ab,kf.

48 ((unsuitable or "not") adj3 (operable or resectable or surgery or surgical)).ti,ab.

49 (inoperable or unresectable or non-surgical or nonsurgical).ti,ab.

50 45 or 46 or 47 or 48 or 49

51 44 and 50 [definitive radiotherapy for nmsc]

52 *Skin Neoplasms/rt [Radiotherapy]

53 exp *Carcinoma, Basal Cell/rt [Radiotherapy]

54 exp *Carcinoma, Squamous Cell/rt [Radiotherapy]

55 (skin or cutaneous).ti.

56 54 and 55

57 52 or 53 or 56

58 ((basal or nonmelanoma or "non melanoma" or squamous or skin or cutaneous) and carcinoma* and (radiation or irradiation or radiotherapy)).ti.

59 57 and 58 [addition broad RT+nmsc]

60 51 or 59

61 limit 60 to english language

62 (adjunctive or adjuvant).ti.

63 61 not 62 [definitive radiotherapy for nmsc final]

64 ((skin or cutaneous or basal or carcinoma* or squamous or face or eyelid or facial or lip or scalp or skull or nose or ear or periauricular or periocular) and (carcinoma* or cancer* or neoplasm* or malignanc* or lesion or lesions or tumo?r*)).ti.

65 (skin adj5 (carcinoma* or cancer* or neoplasm*)).ab. /freq=2

66 (skin adj3 (carcinoma* or cancer*)).kf.

67 *Carcinoma, Basal Cell/

68 (cutaneous adj3 Squamous adj3 Carcinoma*).kf.

69 64 or 65 or 66 or 67 or 68

70 63 and 69 [definitive radiotherapy NMSC final focused]

71 (postoperative or postop or "post op" or "post operative").ti,ab,kf.

72 (surger* or surgical or excision* or operation or resect*).ti,kf.

73 (surger* or surgical or excision* or operation or resect*).ab. /freq=2

74 Neck Dissection/

75 "neck dissection".ti,kf.

76 "neck dissection".ab. /freq=2

77 exp Radiotherapy, Adjuvant/

78 ((adjuvant or adjunctive) adj3 (radiotherap* or irradiat* or radiat*)).ti,ab,kf.


79 or/71-78 [post op adjuvant RT]

80 44 and 79 [nmsc post op adjuvant RT]

81 80 and 69 [nmsc postop adjuvant RT focused]

82 81 not 70 [nmsc postop anondjuvant RT focused, exclude definitive RT search set]

83 exp Lymph Nodes/

84 lymph node*.ti,ab,kf.

85 exp Lymphatic Metastasis/

86 (Lymphatic adj3 Metastas?s).ti,kf.

87 (Lymphatic adj3 Metastas?s).ab. /freq=2

88 exp Lymphatic Irradiation/

89 ((lymphoid or lymphatic or node* or nodal) adj5 (radiotherap* or irradiat* or radiat*)).ti,ab,kf.

90 ((regional or parotid or cervical or axilla* or groin* or neck) adj6 (nodal or node* or Metastas?s or metastatic or radiotherap* or irradiat* or radiat*)).ti,ab,kf.

91 "high risk*".ti,ab. and ((basal or cutaneous) adj5 carcinoma*).ti,kf.

92 or/83-91 [regional lymph nodes]

93 44 and 92 [nmsc radiotherapy regional nodes]

94 93 and 69 [nmsc radiotherapy regional nodes focused]

95 94 not (70 or 82) [nmsc radiotherapy regional nodes focused, exclude previous set KQ1+2]

96 exp Radiation Dosage/

97 exp radiotherapy dosage/

98 ((dose or doses or dosage or dosages) adj3 (radiotherap* or irradiat* or radiat* or fractionation* or hypofractionat*)).ti,kf.

99 exp proton therapy/

100 ((proton* or photon) adj3 (therap* or radiat*)).ti,kf.

101 ((proton* or photon) adj3 (therap* or radiat*)).ab. /freq=2

102 exp brachytherapy/

103 exp radiotherapy, high-energy/

104 (brachytherapy or orthovoltage or megavoltage or IMRT or "intensity modulated" or EBRT or "external beam").ti,kf.

105 (brachytherapy or orthovoltage or megavoltage or "intensity modulated" or IMRT or "external beam" or EBRT).ab. /freq=2

106 exp x-ray therapy/

107 ("electron beam" or x-ray*).ti,kf.

108 ("electron beam" or x-ray*).ab. /freq=2

109 (superficial adj3 (radiotherap* or irradiat* or radiat*)).ti,ab,kf.

110 ((2D or 2-D or 2-dimension* or two-dimension* or 3D or 3-D or 3-dimension* or three-dimension*) adj5 (radiotherap* or irradiat* or radiat*)).ti,ab,kf.

111 or/96-110

112 44 and 111 [nmsc radiotherapy techniques]

113 112 and 69 [nmsc radiotherapy techniques focused]


114 113 not (70 or 82 or 95) [nmsc radiotherapy techniques focused, excluded previous search sets for KQ1+2+3]

115 exp *drug therapy/

116 exp Antineoplastic Agents/

117 exp Antineoplastic Protocols/

118 exp Combined Modality Therapy/

119 exp chemoradiotherapy/

120 ((systemic or target* or biologic* or concurrent or concomitant or adjuvant or sequential or neoadjuvant) adj3 therap*).ti,kf.

121 ((systemic or target* or biologic* or concurrent or concomitant or adjuvant or sequential or neoadjuvant) adj3 therap*).ab. /freq=2

122 (chemotherap* or immunotherap*).ti,kf.

123 (chemotherap* or immunotherap*).ab. /freq=2

124 (chemoradiation or "chemo-radiation" or "chemo-radiotherapy*" or chemoradiotherapy or radiochemo* or radio-chemo*).ti,kf.

125 (chemoradiation or "chemo-radiation" or "chemo-radiotherapy*" or chemoradiotherapy or radiochemo* or radio-chemo*).ab. /freq=2

126 (Hedgehog adj4 pathway adj4 inhibit*).ti,ab,kf.

127 (ERIVEDGE* or vismodegib*).mp,rn.

128 (ODOMZO* or sonidegib*).mp,rn.

129 cisplatin*.mp,rn.

130 Fluorouracil*.mp,rn.

131 Doxorubicin*.mp,rn.

132 5-FU.ti,kf.

133 VINDESINE*.mp,rn.

134 "cis-retinoic acid*".mp.

135 isotretinoin*.mp.

136 exp Interferon-alpha/

137 interferon alfa.ti,kf.

138 nivolumab*.mp,rn.

139 lapatinib*.mp,rn.

140 erlotinib*.mp,rn.

141 Antibodies, Monoclonal/tu

142 pembrolizumab*.mp,rn.

143 ipilimumab*.mp,rn.

144 cetuximab*.mp,rn.

145 (immun* adj3 checkpoint adj3 (inhibit* or modulator* or antibod* or block*)).mp.

146 (("cytotoxic T lymphocyte associated" adj3 "4") or "CTLA 4" or CTLA4).mp.

147 ("programmed death ligand 1" or "PD L1" or PDL1).mp.

148 or/115-147


149 44 and 148 [nmsc radiotherapy with drug therapy]

150 149 and 69 [nmsc radiotherapy with drug therapy focused]

151 150 not (70 or 82 or 95 or 114) [nmsc radiotherapy with drug therapy focused, exclude previous search set for KQ1+2+3+4]

152 70 or 82 or 95 or 114 or 151

153 remove duplicates from 152

154 44 and 69

155 154 not 153

156 ((basal or nonmelanoma or "non melanoma" or skin or cutaneous) and carcinoma* and (radiation or radiotherapy)).ti.

157 155 and 156 [extra]

158 153 or 157

159 remove duplicates from 158

160 limit 159 to yr="1988 -Current"

161 16 or 33 or 35 or 37 or 43

162 160 not 161

PubMed search for non-MEDLINE records:

(((((radiotherapy[tiab] or irradiation[tiab] or radiation[tiab])) AND ("non melanoma"[tiab] or nonmelanoma

[tiab] or basal [tiab] or skin[tiab] or cutaneous[tiab])) AND (cancer[tiab] or carcinoma[tiab]))) AND

publisher[sb]

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63. Khurana VG, Mentis DH, O'Brien CJ, Hurst TL, Stevens GN, Packham NA. Parotid and neck metastases from cutaneous squamous cell carcinoma of the head and neck. American journal of surgery. 1995;170(5):446-450.

64. Porceddu SV, Bressel M, Poulsen MG, et al. Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial. Journal of Clinical Oncology. 2018;36(13):1275-1283.

65. delCharco JO, Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Mendenhall NP. Carcinoma of the skin metastatic to the parotid area lymph nodes. Head & neck. 1998;20(5):369-373.

66. Hirshoren N, Ruskin O, McDowell LJ, Magarey M, Kleid S, Dixon BJ. Management of Parotid Metastatic Cutaneous Squamous Cell Carcinoma: Regional Recurrence Rates and Survival. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2018:194599818764348.

67. Palme CE, Brien CJO, Veness MJ, McNeil EB, Bron LP, Morgan GJ. Extent of parotid disease influences outcome in patients with metastatic cutaneous squamous cell carcinoma. Archives of Otolaryngology -- Head & Neck Surgery. 2003;129:750-753.

68. Shimm DS, Wilder RB. Radiation therapy for squamous cell carcinoma of the skin. American journal of clinical oncology. 1991;14(5):383-386.

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Definitive and Postoperative Radiation Therapy for Basal and … Care and... · 2020-01-22 · 6...

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