Handbook of Evidence-Based Radiation Oncology

By Eric K. Hansen

The Third Edition of Handbook of Evidence-Based Radiation Oncology updates and revises the previous successful editions and serves as a key reference for radiation oncology professionals. Organized by body site, concise clinical chapters provide easy access to critical information. Important "pearls" of epidemiology, anatomy, pathology, and clinical presentation are highlighted. The key elements of the work-up are listed, followed by staging and/or risk classification systems. Treatment recommendations are discussed based on stage, histology, and/or risk classification. Brief summaries of key trials and studies provide the rationale for the recommendations. Practical guidelines for radiation techniques are described and  complications and follow-up guidelines are outlined. The Third Edition incorporates new key studies and trials to reflect current radiation oncology practice; includes the most recent staging systems; and features new color illustrations and anatomic atlases to aid in treatment planning. This book is a valuable resource for students, resident physicians, fellows, and other practitioners of radiation oncology. 

• Language: English
• Publisher: Springer
• Release date: May 7, 2018
• ISBN: 9783319626420

Book preview

PART ISkin

© Springer International Publishing AG, part of Springer Nature 2018

Eric K. Hansen and Mack Roach III (eds.)Handbook of Evidence-Based Radiation Oncologyhttps://doi.org/10.1007/978-3-319-62642-0_1

1. Skin Cancer

Lisa Singer¹ and Sue S. Yom²  

(1)

Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

(2)

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA

Sue S. Yom

Email: [e-mail]

Keywords

Basal cell carcinomaSquamous cell carcinomaMerkel cell carcinomaMelanoma

Pearls

Skin is composed of 3 layers: epidermis (melanocytes), dermis (hair follicles, sweat glands), and subcutis.

Skin cancers can be divided into melanoma and non-melanoma skin cancers; sun/UV exposure is a major cause for both subtypes.

Skin cancers can also be associated with immunosuppression, chronic irritation, and certain genetic disorders (Jaju, J Am Acad Dermatol 2016):

Gorlin syndrome (basal cell nevus syndrome, PTCH mutations): autosomal dominant, associated with multiple BCCs, rhabdomyosarcomas, fibrosarcomas, palmar/plantar pits

Xeroderma pigmentosum : X-linked, increased sensitivity to UV radiation, 1000× increased risk of skin cancer

Non-melanoma skin cancers are the most common malignancies in the USA, with millions diagnosed each year, but true incidence is unknown as cases are not required to be reported to cancer registries (Siegel, CA Cancer J Clin 2015).

Major subtypes of non-melanoma skin cancers include basal cell carcinoma (BCC) , squamous cell carcinoma (SCC) , and Merkel cell carcinoma (MCC) :

BCC

80% of non-melanoma skin cancers; common in sun-exposed areas .

>90% of cases associated with abnormal hedgehog pathway signaling (Lacouture, Oncologist 2016).

Pathologic subtypes : nodular (most common, papule); superficial (scaly macule); morpheaform (sclerosing, can have PNI); infiltrative (Veness and Howle 2016).

Only 0.1% have perineural spread; most common affected CN are V and VII.

<1% metastasize (Ganti, Cancer Manag Res 2013).

SCC

Common in sun-exposed areas .

Actinic keratosis (AK) is a premalignant lesion that can develop into SCC, with multiple AKs, 6–10% chance of invasive SCC in 10 years.

Pathologic subtypes : SCC in situ (Bowen’s disease), superficial, spindle cell (may require IHC for diagnosis) (Veness and Howle 2016)

More frequently metastasizes than BCC: about 5%.

MCC

Rare, aggressive neuroendocrine cancer of the skin with more frequent local, regional, and distant recurrence rates than other cutaneous carcinomas.

Cell of origin is Merkel cell (aka Tastzellen or touch cell), a tactile neuroendocrine epithelial cell, first described by Friedrich Sigmund Merkel in 1875 (Erovic and Erovic 2013).

Merkel cell virus (MCV): polyomavirus , found to be pathogenic factor in 60–80% MCC (Feng, Science 2008).

Cutaneous Melanoma

Rising incidence.

Melanoma once viewed as radioresistant, but this is not supported by data.

ABCDE mnemonic raises awareness of suspicious lesions (A = asymmetry, B = borders not smooth, C = color change/variegation, D = diameter > pencil eraser, E = evolving) (Chair, J Am Acad Dermatol 2015).

Pathologic subtypes: superficial spreading, nodular, lentigo maligna (best prognosis; Hutchinson’s freckle involves epidermis only), acral lentiginous (usually presents on soles, palms), desmoplastic (recurs locally).

85% of patients (pts) present with localized disease with 5-yr survival >90% for pts with tumor ≤1 mm thick vs 50–90% for pts with primary >1 mm thick depending on thickness, ulceration, and mitotic rate.

LN status: most prognostic factor for recurrence and survival. In the absence of risk factors, there is <5–7% risk of +SLN if primary <1 mm thick.

About 10% of pts present with regional disease, with 5-yr. survival 20–70% depending primarily on nodal burden.

Historically, long-term survival was <10% for stage IV disease, but some pts have a distinct indolent course, and emerging effective systemic therapies have made long-term remission possible in more pts.

Other prognostic factors: ulceration, thickness, anatomic site (trunk worse), gender (male worse), age (older worse), #LN involved, and mitotic rate.

Work-up

H&P. Describe the primary lesion (see Table 1.1); identify lesion number, location/distribution, borders, color, shape (linear, round, etc.), and any secondary features (scale, induration, erosion, ulceration, etc.). Palpate for the deep edge of the tumor. For head/neck lesions, do a cranial nerve exam. Palpate for lymph node involvement.

Table 1.1

Primary lesion characteristics

Biopsy the lesion and suspicious lymph nodes.

Breslow thickness = measured depth of lesion.

Clark level = related to histologic level of dermis (I = epidermis only, II = invasion of papillary dermis, III = filling papillary dermis compressing reticular dermis, IV = invading reticular dermis, V = invades subcutaneous tissues).

SLN biopsy is typically performed in clinically node-negative patients with MCC or with >0.75 mm thick melanoma.

Additional imaging: MRI if PNI suspected and for lesions of medial/lateral canthi, to rule out orbit involvement. CT is useful to rule out suspected bone invasion.

Melanoma: imaging to work-up suspected sites of additional disease.

PET/CT often ordered for melanoma and MCC due to high rates of metastasis.

Basal Cell Carcinoma and Squamous Cell Carcinoma

Staging

Editors’ note: All TNM stage and stage groups referred to elsewhere in this chapter reflect the 2010 AJCC staging nomenclature unless otherwise noted as the new system below was published after this chapter was written (Tables 1.2, 1.3, 1.4, and 1.5).

Table 1.2

(AJCC 7TH ED., 2010 )

*Note: Excludes cSCC of the eyelid

**High-risk features for the primary tumor (T) staging

Depth/invasion: >2 mm thickness, Clark level ≥ IV, perineural invasion

Anatomic location: primary site ear, primary site non-hair-bearing lip

Differentiation: poorly differentiated or undifferentiated

Used with the permission from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010), published by Springer Science + Business Media

Table 1.3

(AJCC 8TH ED., 2017 )

*Deep invasion is defined as invasion beyond the subcutaneous fat or> 6 mm (as measured from the granular layer of the 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 or larger in caliber or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression

Definition of regional lymph node (N)

Clinical N (cN)

Table 1.4

(AJCC 8TH ED., 2017 )

Note: A designation of U or L may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L)

Similarly, clinical and pathological ENE should be recorded as ENE(-) or ENE(+)

Pathological N (pN)

Table 1.5

(AJCC 8TH ED., 2017 )

Note: A designation of U or L may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L)

Similarly, clinical and pathological ENE should be recorded as ENE(-) or ENE(+)

Definition of distant metastasis (M)

Table 1.6

(AJCC 8TH ED., 2017 )

AJCC Prognostic Stage Groups

Table 1.7

(AJCC 8TH ED., 2017 )

Used with permission from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

Table 1.8

NCCN BCC and SCC risk factors for recurrence

Table 1.9

TREATMENT RECOMMENDATIONS

Other topical therapies :

Imiquimod: topical immunomodulator FDA approved for <2 cm trunk/extremity superficial BCC (5× weekly for 6 weeks) or actinic keratosis (2× weekly for 16 weeks) (Hanna, Int J Dermatol 2016).

Topical 5-fluorouracil: can be used for superficial BCC or AKs (Moore, J Dermatolog Treat 2009).

Studies

Identifying Points that May Benefit from Post-op RT

Review of 1818 cutaneous SCC cases identified 4 risk factors for recurrence: size ≥2 cm, poorly differentiated, PNI (≥0.1 mm nerves), and tumor invasion beyond fat. 10-yr. local recurrence: 0 factors = 0.6%, 1 factor = 5%, 2–3 factors = 21%, 4 factors or bone invasion = 67%. 10-yr nodal mets: 0 factors = 0.1%, 1 factor = 3%, 2–3 factors = 21%, 4 factors or bone invasion = 67% (Karia, JCO 2014).

122 pts with cutaneous SCC of head and neck with cervical LN involvement. Post-op RT reduced LRR (23% vs 55%) and improved DFS (74% vs 34%) and OS (66% vs 27%) (Wang, Head Neck 2011).

Multi-institutional retrospective review of SCC found that immunocompromised status was associated with higher locoregional recurrence (Manyam, IJROBP 2016).

Multiple Retrospective Studies Report Excellent LC with RT

389 patients with BCC were included in a retrospective study at Washington University in St. Louis; excellent outcomes were achieved for RT alone (LC >90% for tumors <=3 cm treated with SRT and >80% for tumors <=3 cm treated with electrons; for tumors >5 cm treated w/electrons, LC was 100% w/margins >2 cm, 67% for margins 1.1–2 cm, and 80% for margins <=1 cm) (Locke, IJROBP 2001).

604 BCCs and 106 SCCs treated with RT. 97% of lesions involved face and head. 18% of lesions were recurrent. 5/15-yr. LC: BCC 94%/85%, SCC 93%/79%. Tumor size >1 cm and nasolabial fold location were independent predictors for BCC recurrence. Recurrent SCC had higher recurrence risk (Hernández-Machin, Int J Dermatol 2007).

129 eyelid and 857 lesions overlying nasal cartilage treated with RT, 98% BCC, 2% SCC. 5-yr. LC eyelid 96%, nose 92% (Caccialanza, G Ital Dermatol Venereol 2013).

712 BCCs and 994 SCCs treated with RT. 5-yr. LC: BCC 96%, SCC 94%. Tumors >2 cm had increased recurrence risk (Cognetta, J Am Acad Dermatol 2012).

Other Studies

Vismodegib: ERIVANCE was a single-arm phase II study of vismodegib; of the 33 patients in the study with metastatic BCC, 30% responded; of the 63 with locally advanced BCC, 43% responded (response was defined as a decrease of at least 30% in the externally visible or radiographic dimension of the lesion or complete resolution of ulceration) (Sekulic, NEJM 2012).

p16 status: positive in 31% of SCC but not prognostic in an Australian study of 143 patients with cutaneous SCC of the head and neck (McDowell, Cancer 2016).

Radiation Techniques

Simulation and Field Design

Most skin cancers are treated with superficial radiation therapy (SRT) (50–100 kVp), orthovoltage (150–300 kVp), or with megavoltage electrons (McDermott and Orton 2010).

SRT advantages (vs electrons): less margin (electrons require additional margin at skin surface), less expensive, maximum dose at surface (vs electrons which have built up and require bolus) (Cognetta and Mendenhall 2013); disadvantages: SRT not appropriate for >1 cm deep lesion.

For SRT a photon energy is selected, so tumor is encompassed by 90% depth dose (90% IDL: 50 kV [0.7 mm Al] ~1 mm; 100 kV [4–7 mm Al] ~5 mm; 150 kV [0.52 mm Cu] ~1.0 cm).

At energies below 300 kV, photoelectric effect is dominant, varying with Z³; bone is high Z due to calcium, and therefore f-factor, or Roentgen to rad conversion, is important (note that cartilage is not similar to bone in terms of absorption) (Atherton, Clin Oncol 1993).

Lead shields should be used to block the lens, cornea, nasal septum, oral cavity, etc.; backscattered electrons/photons can lead to conjunctival/mucosal irritation; therefore, for eyelids, thin coating of wax or porcelain can be used over lead.

Margins

Orthovoltage: Tumor size <2 cm = 0.5–1.0 cm horizontal margin; tumor size >2 cm = 1.5–2 cm horizontal margin. Deep margin should be at least 0.5 cm deeper than the suspected depth of tumor.

Electron margins: Add additional 0.5 cm margin at skin surface due to lateral constriction of isodose curves in deep portion of tumor volume, respecting adjacent normal tissues such as orbit.

Recurrent and morpheaform BCCs are more infiltrative, requiring 0.5–1.0 cm additional margin at skin surface.

High-risk SCC: Add 2 cm margin around tumor if possible.

Gross or extensive PNI: consider IMRT to cover named nerve from the primary to skull base.

Recommend careful review of target volumes following cranial nerves V and/or VII as appropriate (Anwar, Pract Radiat Oncol 2016; Gluck, IJROBP 2009).

Elective nodal treatment should be considered for recurrences after surgery and is indicated for poorly differentiated, >3 cm tumors, and/or large infiltrative-ulcerative SCC.

Irradiation of a graft should not begin until after it is well healed; entire graft should be included in the target volume.

Dose Prescriptions

For SRT or orthovoltage prescribe to surface Dmax.

For electrons, prescribe to 90% to account for lower RBE.

Fractionation

Size <2 cm: 64 Gy/32 fx, 55 Gy/20 fx, 45–51 Gy/15–17 fx, 40–44 Gy/10 fx, 35 Gy/5 fx.

Size >2 cm and no cartilage involvement: 55 Gy at 2.5 Gy/fx.

Size >2 cm and cartilage involved: 64–66 Gy at 2 Gy/fx.

While treating cartilage, always keep daily dose <3 Gy/fx.

Hypofractionation reduces long-term cosmesis but is an option for selected patients or for palliative treatment.

Elective LN (high-risk SCC; rarely BCC): 50 Gy/25 fx.

Grossly involved LN 66–70 Gy at 2 Gy/fx:

Post-op adjuvant

Primary negative margins: 60 Gy/30 fx or 50 Gy/20 fx

Primary, +margin: as primary definitive

LN: 50–56 Gy at 2 Gy/fx if no ECE; 60 Gy if ECE.

Electronic surface brachytherapy: 5 Gy/fraction given twice a week to 40 Gy.

Dose Limitations

Cartilage: Chondritis rare if fraction size <3 Gy.

Skin: Larger volumes of tissue require smaller daily fractions; moist desquamation is expected for larger surface areas.

Complications

Telangiectasias, skin atrophy, hypopigmentation, alopecia, loss of sweat glands, skin necrosis (~3%), osteoradionecrosis (~1%), chondritis/cartilage necrosis (rare if fx <3Gy)

Follow-u p (Based on NCCN Guidelines)

BCC: H&P every 6–12 months for life with sun protection education

Localized SCC: H&P every 3–12 months × 2 years, then every 6–12 months × 3 years, then annually; sun protection education

Regionally metastatic SCC: H&P every 1–3 months × 1 year, then every 2–4 months × 1 year, then every 4–6 months × 3 years, then every 6–12 months long term; sun protection education

Merkel Cell Carcinoma (MCC)

Table 1.10

Staging (AJCC 7TH ED., 2010 ): Merkel cell carcinoma

*Note: Clinical detection of nodal disease may be via inspection, palpation, and/or imaging

**Micrometastases are diagnosed after sentinel or elective lymphadenectomy

***Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or needle biopsy

****In-transit metastasis: a tumor distinct from the primary lesion and located either (1) between the primary lesion and the draining regional lymph nodes or (2) distal to the primary lesion

Table 1.11

(AJCC 7TH ED., 2010 )

Anatomic stage/prognostic groups

Patients with primary Merkel cell carcinoma with no evidence of regional or distant metastases (either clinically or pathologically) are divided into two stages: Stage I for primary tumors ≤2 cm in size and stage II for primary tumors >2 cm in size. Stages I and II are further divided into A and B substages based on the method of nodal evaluation

Patients who have pathologically proven node-negative disease (by microscopic evaluation of their draining lymph nodes) have improved survival (substaged as A) compared with those who are only evaluated clinically (substaged as B). Stage II has an additional substage (IIC) for tumors with extracutaneous invasion (T4) and negative node status, regardless of whether the negative node status was established microscopically or clinically. Stage III is also divided into A and B categories for patients with microscopically positive and clinically occult nodes (IIIA) and macroscopic nodes (IIIB). There are no subgroups of stage IV Merkel cell carcinoma

Table 1.12

(AJCC 7TH ED., 2010 )

Used with the permission from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010), published by Springer Science + Business Media

Table 1.13

(AJCC 8TH ED., 2017 )

Definition of regional lymph node (N)

Clinical (N)

Table 1.14

(AJCC 8TH ED., 2017 )

Pathological (pN)

Table 1.15

(AJCC 8TH ED., 2017 )

Definition of distant metastasis (M)

Clinical (M)

Table 1.16

(AJCC 8TH ED., 2017 )

Pathological (M)

Table 1.17

(AJCC 8TH ED., 2017 )

AJCC Prognostic Stage Groups

Clinical stage group (cTNM)

Table 1.18

(AJCC 8TH ED., 2017 )

Pathological stage group (pTNM)

Table 1.19

(AJCC 8TH ED., 2017 )

Used with permission from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

Treatment Recommendations

cN0: Wide local excision with 1–2 cm margin and sentinel lymph node biopsy (SLNB) followed always by adjuvant RT to primary site.

If SLN negative, elective nodal RT should be considered due to higher false-negative SLNB rates for head and neck regions, prior surgery, failure to perform ICH on sentinel node, immunosuppression, or SLNB operator concerns.

Post-op nodal RT always indicated for multiple involved LN or ECE.

cN+: Node dissection or nodal RT is indicated.

Chemotherapy is not routinely recommended but may be considered on a case-by-case basis, such as cisplatin or carboplatin +/− etoposide.

M1: clinical trial, chemotherapy (cisplatin or carboplatin +/− etoposide, topotecan, cyclophosphamide, doxorubicin, vincristine), immunotherapy (pembrolizumab, atezolizumab), and/or palliative RT.

Radiation Techniques

At UCSF, adjuvant radiation therapy for Merkel cell carcinoma (MCC) is as follows:

Primary site is covered, as well as in-transit lymphatics, regional LN with wide margins.

May consider eliminating regional LN RT if primary small with negative SLN or if regional lymph node dissection is performed and patient cN0.

Margins on primary site: ≥2 cm in head and neck, 3–5 cm elsewhere (Lok, Cancer 2012).

Dose (at 1.8–2 Gy/fx):

Tumor bed, negative margins: 50–56 Gy.

Tumor bed, positive margins: 56–60 Gy.

Gross residual and/or gross nodal disease: 60–66 Gy.

Clinically N0 nodes: 45–50 Gy.

Negative nodal post-op bed: 46–50 Gy.

Nodal bed with multiple nodes or ECE: 50–60 Gy.

Inoperable: 60–66 Gy.

Palliation: 30 Gy/10 fx.

Studies

SLN biopsy: In a study at University of Michigan, no subgroup of clinically node-negative patients had less than 15–20% likelihood of +SLN; thus, SLNB is advised for all patients (Swartz, JCO 2011).

Adjuvant RT:

In a randomized study, 83 stage I patients receiving WLE and primary site post-op RT were randomized to adjuvant nodal RT. Regional RT reduced regional recurrence (0% vs 17%) but did not improve PFS or OS. Study terminated early due to decline in accrual due to increasing use of SLNB (Jouary, Ann Oncol 2012).

In a retrospective SEER study of 1665 stage I–III cases, adjuvant RT improved MS for all patients (63 vs 45 mo), including <1 cm (93 vs 48 mo), 1–2 cm (86 vs 52 mo), and >2 cm (50 vs 21 mo) (Mojica, JCO 2007).

In a NCDB study of 4815 pts with head/neck MCC, post-op RT or chemoRT improved 5-yr. OS (43–48% vs 39%) (Chen, JAMA Otolaryngol Head Neck Surg 2015).

In a systematic review of 34 studies with 4475 pts, post-op RT or chemoRT improved 3-yr. LC (65–67% vs 20%) and OS (70–73% vs 56%) (Hasan, Frontiers Oncol 2013).

Margins: In a retrospective study of RT failures, 5 locoregional failures were identified, and 2 were at the field edge with margin >2 cm; margins > > 2 cm were therefore suggested when feasible (Lok, Cancer 2012).

MCV Antibodies: Higher MCV antibody titers have been found to be associated with better PFS; titers are expected to decline after completion of treatment (Touzé, JCO 2011).

Follow-up (Based on NCCN Guidelines)

H&P every 3–6 months × 3 years, then every 6–12 months; cross-sectional imaging for high-risk patients

Melanoma

Staging

Editors’ note: All TNM stage and stage groups referred to elsewhere in this chapter reflect the 2010 AJCC staging nomenclature unless otherwise noted as the new system below was published after this chapter was written (Table 1.8).

Table 1.20

(AJCC 7TH ED., 2010 )

Note: a and b subcategories of T are assigned based on ulceration and number of mitoses per mm² as shown below.

Table 1.21

(AJCC 7TH ED., 2010 )

Regional lymph nodes (N)

Table

1.22

Note: N1–3 and a–c subcategories assigned as shown below

Table

1.23

*Micrometastases are diagnosed after sentinel lymph node biopsy and completion of lymphadenectomy (if performed)

***Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension

Distant metastasis (M)

Table

1.24

Note: Serum LDH is incorporated into the M category as shown below

Table

1.25

Anatomic stage/prognostic groups

Table

1.26

*Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases

**Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes

Used with the permission from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010), published by Springer Science + Business Media

Table 1.27

(AJCC 8TH ED., 2017 )

Definition of regional lymph node (N)

Table

1.28-

Definition of distant metastasis (M)

Table

1.29-

Suffixes for M category: (0) LDH not elevated, (1) LDH elevated. No suffix is used if LDH is not recorded or is unspecified

Clinical (cTNM)

Table

1.30-

Used with the permission from the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

Treatment Recommendations

Primary Therapy for Localized Disease

cN0: SLN biopsy and WLE, with completion LND if SLN+.

Minimal surgical margins are Tis = 5–10 mm, T1 = 1 cm, T2 = 1-2 cm, and T3–4 = 2 cm.

SLNB improves staging to identify pts who may need completion node dissection and/or adjuvant therapy. SLNB improved DSS for pts with intermediate thickness (1.2–3.5 mm) primary who had microscopic (vs subsequent macroscopic) nodal involvement in MSLT-I trial (Morton, NEJM 2014).

Elective lymph node dissection (ELND) is controversial as multiple RCTs report no survival benefit to ELND vs observation with delayed LND (Balch, Ann Surg Oncol 2000; Cascinelli, Lancet 1998; Sim, Mayo Clin Proc 1986; Veronesi, Cancer 1982).

Clinically N+: therapeutic nodal dissection and WLE.

Primary RT is rarely indicated with the exception of lentigo maligna melanomas on the face that would cause severe cosmetic/functional deficits with surgery. These can be treated with a 1.5 cm margin with 50–100 Gy/10–20fx with 100–250 kV photons. For medically inoperable patients, hyperthermia can improve response and local control, especially for tumors >4 cm (Overgaard, Lancet 1995).

Adjuvant Systemic Therapy

See NCCN guidelines.

For node-negative early stage: observation or clinical trial

For node-negative IIB–IIC: observation vs clinical trial vs high-dose IFN

For node positive: observation, clinical trial, interferon alfa, ipilimumab, or other biochemotherapy agents

Adjuvant RT

Adjuvant primary site RT is considered to reduce LRR for deep desmoplastic melanoma with narrow margins, extensive neurotropism, or locally recurrent disease.

Adjuvant nodal radiotherapy indications:

Parotid LN: extracapsular extension (ECE) and/or ≥1 involved LN

Cervical LN: ECE, node >3 cm, ≥2 involved LN, or recurrent disease

Axillary nodes: ECE, node >3–4 cm, ≥2–4 involved LN, recurrent disease

Groin/pelvic nodes: higher threshold for elective nodal RT due to morbidity of lymphedema

BMI <25 kg/m²: presence of any 1 of the following: ECE, >3–4 involved lymph nodes, recurrent disease, node >3–4 cm

BMI >25 kg/m²: presence of ECE and 1 of the following: >3–4 involved lymph nodes, node >3–4 cm

Consider elective nodal RT in high-risk pts unable to undergo completion surgery due to medical comorbidities

Metastatic Disease

Biopsy for genetic analysis (e.g., BRAF mutation, c-KIT).

Consider resection of limited resectable metastasis.

Disseminated metastases: clinical trial, systemic therapy, palliative resection, or RT:

Immunotherapy: interferon alfa-2b, interleukin-2, anti-CTLA4 (ipilimumab), anti PD-1 (pembrolizumab, nivolumab), injectable oncolytic virus (talimogene laherparepvec).

Targeted therapy: BRAF (dabrafenib, vemurafenib), MEK (trametinib, cobimetinib).

Chemotherapy: dacarbazine, temozolomide (for brain metastases).

Radiotherapy Studies

ANZMTG 01.02/TROG 02.01: 250 pts with nonmetastatic palpable LN at diagnosis or isolated palpable LN relapse treated with lymphadenectomy randomized to adjuvant RT (48 Gy/20 fx) or observation. RT reduced 5-yr. LN relapse (18% vs 33%) but did not improve RFS or OS (Henderson, Lancet Oncol 2015).

615 pts had therapeutic lymphadenectomy and were at high risk of regional recurrence due to ECE and multiple or enlarged nodes. Adjuvant RT reduced 5-yr. regional recurrence (10% vs 41%) (Agrawal, Cancer 2009).

LRC control is similar with hypofractionated RT or standard fractionated RT.

In data from University of Florida, 82 high-risk pts were treated with surgery and adjuvant RT, 47% with hypofractionated RT (mostly 30 Gy in 5 fx at 2 fx per week) or conventional fractionation. No significant difference in 5-yr. LRC (87% hypofx vs 78% conventional fx) (Mendenhall, Am J Otolaryngol 2013).

MDACC has the largest published experience with 30 Gy/5 fx over 2.5 wks hypofractionation, reporting regional control 88–94% (Ballo, Cancer 2003; Beadle, IJROBP 2009).

In a retrospective study of 277 pts with nonmetastatic desmoplastic melanoma, 41% received adjuvant RT. Adjuvant RT improved 5-yr. LC (95% vs 76%) especially for +margin or pts with negative margin and high-risk features (head and neck location, depth > 4 mm, Clark level V) (Strom, Cancer 2014).

RTOG 8305 was a prospective study randomizing 137 patients to 32 Gy in 4 fx once weekly or 50 Gy in 20 fx. No difference in response rate between arms: 23.8% complete remission and 34.9% partial remission. Study included large tumors (56% were ≥5 cm) (Sause, IJROBP 1991).

Patients with recurrent/metastatic melanoma randomized to 24 or 27 Gy in 3 fx over 8 days +/− hyperthermia (43 °C for 60 min). LC was improved with HT (26 vs 46%; LC was 25% vs 56% with 24 vs 27 Gy (Overgaard, Lancet 1995).

RT may optimize systemic antitumor immune response induced by immunotherapy (Chandra, Oncoimmunology 2015; Grimaldi, Oncoimmunology 2014).

Radiation Techniques

Simulation and Field Design

Treatment setup

Head and neck: supine or open neck position; depending on tumor location, bolus can be used to reduce dose to temporal lobe, larynx, ear canal.

Axilla: supine with treatment arm akimbo, AP/PA.

Groin: unilateral frog-leg position.

Target volume for primary lesion: primary site +2–4 cm margin.

Nodal target volume depends on primary site:

H&N: preauricular, postauricular LN for facial and posterior scalp primaries, and ipsilateral cervical LN levels I through V, including ipsilateral supraclavicular fossa, for tumors at high risk.

Axilla: levels I through III; for bulky high axillary disease, include supraclavicular fossa and low cervical LN.

Groin: include entire scar and regions with confirmed nodal disease. Can include external iliac LNs for cases with positive inguinal lymphadenopathy, but toxicity will increase.

Dose Prescriptions

Dose recommendations for SCC/BCC can be followed, but hypofractionation approaches are well tolerated and more convenient.

If hypofractionating, adjuvant RT is 30 Gy in 5 fractions twice weekly; if microscopic residual disease is present in the H&N, 1 boost fraction is added to total dose 36 Gy.

Dose Limitations

Hypofractionation: spinal cord or small bowel Dmax <24 Gy over 5 fractions

Complications

Site dependent:

Most sites: erythema, tanning, dry or moist desquamation

Late complications: thinning of subcutaneous fat; mild to moderate fibrosis

Postoperative lymphedema, particularly in patients with high body mass index or treated with adjuvant RT to groin

Other late effects: osteitis, fracture, joint stiffness, and neuropathy

Follow-up (Based on NCCN Guidelines)

Stage IA–IIA: H&P every 6–12 months × 5 years, then annually; LN US considered in patients who did not undergo successful SLNB or if +SLNB and no LND.

Stage IIB–IV: H&P every 3–6 months × 2 years, every 3–12 months × 3 years, then annually for life; if NED, imaging can be considered every 3–12 months to screen for recurrence; additionally, LN US can be considered in patients who did not undergo successful SLNB or if +SLNB and no LND.

Acknowledgment

We thank Tania Kaprealian, MD, James Rembert, MD, and Lawrence W. Margolis, MD, for their work on prior editions of this chapter.

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PART IICentral Nervous System

© Springer International Publishing AG, part of Springer Nature 2018

Eric K. Hansen and Mack Roach III (eds.)Handbook of Evidence-Based Radiation Oncologyhttps://doi.org/10.1007/978-3-319-62642-0_2

2. Central Nervous System

Yao Yu¹, Steve E. Braunstein², Daphne A. Haas-Kogan³, ⁴, ⁵, ⁶ and Jean L. Nakamura¹  

(1)

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA

(2)

Radiation Oncology, University of California San Francisco, San Francisco, CA, USA

(3)

Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA

(4)

Dana-Farber Cancer Institute, Boston, MA, USA

(5)

Boston Children’s Hospital, Boston, MA, USA

(6)

Harvard Medical School, Boston, MA, USA

Jean L. Nakamura

Email: [e-mail]

Keywords

Malignant gliomasLow-grade gliomasCNS lymphomasEpendymomasChoroid plexus tumorsPediatric gliomasCraniopharyngiomasPineal tumorsMedulloblastomasMeningiomasAcoustic neuromasPituitary tumorsPrimary spinal cord tumorsArteriovenous malformationsTrigeminal neuralgia

Anatomy

Meninges: dura mater, arachnoid mater, pia mater

Precentral gyrus: primary motor strip

Postcentral gyrus: primary somatosensory cortex

Broca’s area: dominant frontal lobe. Injury leads to expressive aphasia

Wernicke’s area: dominant temporal lobe. Injury leads to receptive aphasia

Ventricular structures: foramen of Monroe, 3rd ventricle, aqueduct of Sylvius, 4th ventricle, foramen of Magendie, foramina of Lushka

Cavernous sinus contents: CN III, IV, V1, V2, VI and internal carotid artery. Cavernous involvement commonly produces CN VI palsy

Tumors with propensity for CSF spread: pineoblastoma, medulloblastoma, primitive neuroectodermal tumors (PNET), CNS lymphoma, germ cell tumors, ATRT.

CN exits:

Superior orbital fissure = CN III, IV, VI, V1

Foramen rotundum = V2

Foramen ovale = V3

Foramen spinosum = middle meningeal artery and vein

Internal auditory meatus = CN VII, VIII

Jugular foramen = CN IX, X, XI

Hypoglossal canal = CN XII

Lateral plain film.

Hypothalamus = 1 cm superior to sellar floor.

Optic canal = 1 cm superior and 1 cm anterior to the hypothalamus.

Pineal body (supratentorial notch) = 1 cm posterior and 3 cm superior to external acoustic meatus.

Lens = 1 cm posterior to anterior eyelid, 8 mm posterior to line connecting lateral canthus. Median globe size = 2.5 cm.

Location of cribriform plate cannot always be correctly identified with lateral plain film alone (Gripp IJROBP 2004).

Spinal cord.

Thirty-one pairs of spinal nerves: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 1 coccygeal.

Spinal cord white matter is peripheral and gray matter is central.

Pia mater covers cord and condenses into dentate ligaments.

Arachnoid contains CSF (normal pressure 70–200 mm H2O lying down, 100–300 mm H2O sitting or standing, ~150 mg total volume).

Dura ends at S2.

Cord ends at L1 in adults, conus medullaris ends at ~L2 in adults; cord ends ~L3–4 in newborns.

Epidemiology

US Incidence: 77,670 primary brain tumors, including 24,790 malignant and 52,880 non-malignant brain tumors per year. 16,616 deaths attributable to malignant brain tumors. (Ostrom Neuro Oncol 2015)

Malignant tumors comprise ~40% of all primary brain/CNS tumors.

Adult primary CNS tumors: 30–35% meningioma, 20% GBM, 10% pituitary, 10% nerve sheath, 5% low-grade glioma, <5% anaplastic astrocytoma, <5% primary CNS lymphoma.

Of adult gliomas, ~80% are high-grade and ~20% are low-grade.

Children: 20% of all pediatric tumors (second to ALL). Twenty percent pilocytic astrocytoma, 15–20% malignant glioma/GBM, 15% medulloblastoma, 5–10% pituitary, 5–10% ependymoma, <5% optic nerve glioma.

Possible etiologic associations: rubber compounds, polyvinyl chloride, N-nitroso compounds, and polycyclic hydrocarbons.

Prior ionizing RT has been associated with new meningiomas, gliomas, and sarcomas (~2% at 20-years).

Genetic Syndromes

NF-1: von Recklinghausen, chromosome 17q11.2, 1/3500 live births, NF1 encodes neurofibromin, autosomal dominant, 50% germline, 50% de novo, peripheral nerve sheath neurofibromas, café au lait spots, optic and intracranial gliomas, and bone abnormalities.

NF-2: chromosome 22, 1/50,000 live births, NF2 encodes merlin, autosomal dominant, bilateral acoustic neuromas, gliomas, ependymomas, and meningiomas.

von Hippel-Lindau: chromosome 3, autosomal dominant, renal clear cell carcinoma, pheochromocytoma, hemangioblastoma, pancreatic tumors, and renal cysts.

Tuberous sclerosis (Bourneville’s disease): TSC1 on chromosome 9, TSC2 on chromosome 16, autosomal dominant, subependymal giant cell astrocytoma, retinal and rectal hamartomas.

Retinoblastoma: Rb tumor suppressor gene, chromosome 13.

Li-Fraumeni syndrome: germline p53 mutation.

Turcot’s syndrome: primary brain tumors with colorectal CA.

Neuroblastoma: MYCN amplification commonly seen and serves as a prognostic factor.

Imagin g

Common MRI sequences: T1 pre- and postgadolinium, T2, fluid attenuation inversion recovery (FLAIR), diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), perfusion, dynamic contrast enhanced (DCE), Spectroscopy.

Enhancement with gadolinium is indicative blood–brain barrier (BBB) disruption.

Acute blood is bright on T1 pregadolinium.

Postop MRI with DWI should be completed within 48 h. Devascularized normal tissue at the resection cavity border can exhibit reduced diffusion and can enhance on subsequent scans. Must take caution to distinguish this enhancement from tumor recurrence or treatment effect.

Radiation Technique

Fractionated EBRT

Simulate patient with head mask.

3DCRT or IMRT for most lesions. 3DCRT provides better dose homogeneity, fewer hot spots. Inverse planning may allow greater sparing of critical structures and/or deliver hot spots in center of (hypoxic) tumor. Must be determined on a case-by-case basis.

Fuse planning CT and MRI (preop vs. postop) to help delineate target volume. Postop MRs are better than preop MRs in most cases.

Table 2.1

Dose tolerance guidelines

Fetal dose from cranial RT = 0.05–0.1% of total dose (<0.1 Gy).

Individual patient dose constraints should be determined based on physicians’ clinical judgment and experience.

Possible Radiation Complications

Acute: alopecia, radiation dermatitis, fatigue, transient worsening of symptoms due to edema, nausea, and vomiting (particularly with brainstem [area postrema] and posterior fossa [PF] radiation), and otitis externa. Mucositis, esophagitis, and myelosuppression are associated with craniospinal irradiation and subside within 4–6 weeks after radiation (dose-related).

Subacute (6 weeks to 6 months after RT): somnolence syndrome, fatigue, neurologic deterioration, perhaps caused by changes in capillary permeability and transient demyelination.

Late (6 months to many years after RT): radiation necrosis, diffuse leukoencephalopathy (especially with chemo, but not necessarily correlated with clinical symptoms), hearing loss, retinopathy, cataract, visual changes, endocrine abnormalities (if hypothalamic-pituitary axis is irradiated), cerebrovascular accidents, cavernous malformations, Moyamoya syndrome, decreased new learning ability, short-term memory, and problem solving skills.

Functional Status

See Appendix A.

High Grade Glioma

Pearls

Most common primary malignant CNS tumor in adults.

IDH mutant GBMs (6%), or secondary GBMs, have improved prognosis compared with IDH wild-type primary GBMs. (Sanson, JCO 2009; Yan, NEJM 2009)

Multicentric tumors in <5% of cases.

Incidence rises with age, peaks at 45–55 years (bimodal based on primary vs. transformation).

Presentation: headache (50%), seizures (20%).

Clinical prognostic factors : age, histology, KPS, extent of surgery, duration of symptoms (see RPA below)

Molecular prognostic factors (favorable): IDH1/2 mutation, 1p/19q codeletion, ATRX loss, TP53 wt., TERT promoter wt., MGMT promoter hypermethylation.

ATRX and TERT promotor mutations provide mechanism for telomere lengthening via alternative lengthening of telomeres and telomerase, respectively. ATRX is mutually exclusive with 1p/19q codeletion. (Abedalthagafi Modern Path 2013; Eckel-Passow NEJM 2015)

Molecular characteristics have been integrated into pathologic diagnostic criteria. (Louis Acta Neuropath 2016)

Imaging

MR spectroscopy: Tumors have high choline, decreased creatine and NAA (neuronal marker). Necrosis has high lactate, decreased choline, creatine, and NAA.

Dynamic MR perfusion: Astrocytomas have high CBV, increasing with grade. Oligodendrogliomas have high CBV due to hypervascularity. Radiation necrosis and tumefactive demyelinating lesions have low CBV.

Pathology

Updated WHO diffuse glioma classification (2016)

Oligodendroglioma grade 2 or anaplastic oligodendroglioma grade 3: IDH mutant and 1p/19q codeleted (MS >8–10 yrs)

Diffuse astrocytoma grade 2 or anaplastic astrocytoma grade 3: IDH mutant, 1p/19q intact (MS 6–8 yrs)

IDH wild-type diffuse astrocytoma grade 2 is uncommon (review carefully