Radiation Therapy for Vulvar Cancer
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Over the past several decades, methods to plan and deliver radiation therapy have evolved in ways that permit more precise targeting of tumors with complex geometries. Earlier methods involved two-dimensional treatment planning based on flat images, and radiation beams with cross-sections of uniform intensity that were sequentially aimed at the tumor along 2 or 3 intersecting axes. These methods were collectively termed conventional external beam radiation therapy (EBRT).
Subsequent enhancement evolved using 3-dimensional images, usually from computed tomography (CT) scans, to delineate the tumor, its boundaries with adjacent normal tissue, and organs at risk for radiation damage. Radiation oncologists used these images, displayed from a "beam's-eye-view", to shape each of several beams (e.g., with compensators, blocks, or wedges) to conform to the patient's tumor geometry perpendicular to the beam's axis. Computer algorithms were developed to estimate cumulative radiation dose delivered to each volume of interest by summing the contribution from each shaped beam. Methods also were developed to position the patient and the radiation portal reproducibly for each fraction, and immobilize the patient, thus maintaining consistent beam axes across treatment sessions. However, "forward" planning used a trial and error process to select treatment parameters (the number of beams and the intensity, shape, and incident axis of each beam). The planner/radiotherapist modified one or more parameters and recalculated dose distributions, if analysis predicted underdosing for part of the tumor or overdosing of nearby normal tissue. Furthermore, since beams had uniform cross-sectional intensity wherever they bypassed shaping devices, it was difficult to match certain geometries (e.g., concave surfaces). Collectively, these methods are termed 3-dimensional conformal radiation therapy (3D-CRT).
Other methods were subsequently developed to permit beam delivery with non-uniform cross-sectional intensity. This often relies on a device (multi-leaf collimator, MLC) situated between the beam source and patient that moves along an arc around the patient. As it moves, a computer varies aperture size independently and continuously for each leaf. Thus, MLCs divide beams into narrow "beamlets", with intensities that range from zero to 100% of the incident beam. Beams may remain on as MLCs move around the patient (dynamic MLC), or they may be off during movement and turned on once the MLC reaches prespecified positions ("step and shoot" technique). Another method of delivering radiation beam uses a small radiation portal emitting a single narrow beam that moves spirally around the patient, with intensity varying as it moved. This method, also known as tomotherapy or helical tomotherapy, is described as the use of a linear accelerator inside a large "donut" that spirals around the body while the patient laid on the table during treatment. Each method (MLC-based or tomotherapy) is coupled to a computer algorithm for "inverse" treatment planning. The planner/radiotherapist delineates the target on each slice of a CT scan, and specifies that target's prescribed radiation dose, acceptable limits of dose heterogeneity within the target volume, adjacent normal tissue volumes to avoid, and acceptable dose limits within the normal tissues. Based on these parameters and a digitally-reconstructed radiographic image of the tumor and surrounding tissues and organs at risk, computer software optimizes the location and shape of beam ports, and beam and beamlet intensities, to achieve the treatment plan's goals. Collectively, these methods are termed intensity-modulated radiation therapy (IMRT).
According to ECRI Institute, there are two different approaches to image-guided radiation therapy that are in current use: pre-treatment imaging and real-time guidance. IMRT is an example of a method that uses pre-treatment imaging to prepare a treatment plan. In contrast, real-time guidance utilizes real-time imaging (at the time of treatment) to guide treatment. It provides real-time, online images of the radiation target area from a computed tomography (CT) scanner before, during, and after therapy. Patient positioning, radiation field alignment, and collimator positioning can be verified and adjusted before and during irradiation. This approach should, in theory, provide more accurate radiation delivery than conventional IMRT. Organ motion, day-to-day variations in tumor position, and differences in patient positioning in each treatment session could be taken into account with real-time imaging.
(NOTE: This policy only applies to adult members. It does not apply to pediatric members.)
I. External beam radiation therapy is medically necessary for the following clinical situations:
A. Adjuvant therapy following initial surgery
B. Preoperative therapy for locally advanced disease
C. Definitive therapy
D. Recurrent vulvar cancer without evidence of distant spread of disease.
E. Palliation of disease
A. For resectable disease, 45-64.8 Gy in 25-36 fractions is considered medically necessary when any of the following risk factors are present: close or positive margins, involved lymph nodes, LVI, ECE, deep invasion, large tumor
B. For unresectable disease or gross residual disease involving the primary or inguinal nodes following surgery, 60-70 Gy in 33-39 total fractions is considered medically necessary
C. For isolated local recurrence with a curative intent, 60-70 Gy in 33-39 total fractions is considered medically necessary
D. For palliation up to 15 fractions is medically necessary
A. External beam photon radiation therapy using three-dimensional conformal radiation therapy (3DCRT) or IMRT is medically necessary for definitive therapy
B. 3DCRT is considered medically necessary for palliation
A. Low Dose Rate (LDR) or High Dose Rate (HDR) is medically necessary in select cases of vulvar cancer. Brachytherapy may be considered for recurrent disease or as a boost to conventional fractionation.
B. Brachytherapy for vulvar cancer should be performed only by those radiation oncologists specifically trained in its use.
[INFORMATIONAL NOTE: Vulvar cancer comprises 5% of all gynecologic malignancies. The majority of vulvar cancers present at an early stage with localized disease and no lymph node involvement (Gaffney et al, 2016). Given the low incidence of vulvar cancer, there is limited randomized data to guide treatment recommendations. When there is no evidence of distant disease spread, radiation therapy can be utilized in the preoperative, postoperative, or definitive setting for the management of vulvar cancer.
I. INDICATIONS FOR RADIATION
Vulvar cancer patients with early stage disease are generally managed with surgical excision of the primary (wide local excision or modified radical vulvectomy) combined with lymph node evaluation (sentinel lymph node biopsy or lymph node dissection) (Jolly et al, 2015). The role for radiation therapy in the postoperative setting is guided by pathologic evaluation of the primary tumor and the lymph nodes. For patients with early stage cancer with wide negative margins, uninvolved groin nodes, and no adverse risk factors, radiation therapy is generally not recommended (Jolly et al, 2015). The Gynecologic Cancer Intergroup patterns of care study on vulvar cancer found that the most common indications for postoperative radiation therapy are positive margins and involved nodes (Gaffney et al, 2009). In a retrospective study of 135 vulvar cancer patients, Heaps and colleagues (1990) identified the following factors as predictive of increased risk of local vulvar recurrence: close margins, tumor thickness > 1 cm The presence of these variables are associated with increased risk of local vulvar recurrence and provide the foundation for recommending adjuvant radiation therapy following surgery. For these patients with good prognosis, postoperative radiation therapy to the primary/pelvis is recommended based on the Heaps criteria: positive or close margins, lymphovascular space invasion, lesions >5 mm deep (Heaps et al, 1990). Viswanathan and colleagues (2013) performed a retrospective review of 205 patients with vulvar cancer and concluded that close and positive margins were associated with increased rates of vulvar recurrence. As failure in the groin strongly impacts prognosis in vulvar cancer, postoperative radiation therapy to the inguinal nodes/pelvis is recommended in the setting of positive lymph nodes or nodal extracapsular extension (Homesley et al, 1986; Nooj et al, 2016). Homesely et al (1993) reported on GOG 37 which randomized 114 vulvar patients who had positive groin nodes after radical vulvectomy and bilateral groin lymphadenectomy to either radiation therapy or additional surgical resection and found a survival benefit with the addition of radiation. Based on GOG 37 and retrospective studies examining risk factors for groin recurrence,
Vulvar cancer patients with locally advanced or unresectable disease are increasingly being treated with definitive chemoradiation therapy (Stroup et al, 2008). GOG 205 examined the clinical and pathologic response of 58 unresectable vulvar cancer patients with T3 or T4 lesions who received chemoradiation therapy (Moore et al, 2012). These patients all received radiation therapy to 57.6 Gy in 33 fractions combined with weekly cisplatin (Moore et al, 2012). This study found a 64% complete clinical response rate and a 78% pathologic response rate with a radiation dose of 57.6 Gy. The authors concluded that radiation therapy combined with chemotherapy resulted in high clinical and pathologic response rates for patients with locally advanced vulvar cancer (Moore et al, 2012). In a retrospective analysis of 2046 women with vulvar cancer in the National Cancer Database, Natesan et al (2017) found that definitive treatment with a dose of 55 Gy or greater combined with chemotherapy was associated with similar survival as preoperative radiation/chemoradiation therapy followed by surgery.
There is no consensus on the optimal radiation therapy volume to include when treating vulvar cancer. GOG 37 which demonstrated a survival benefit with postoperative radiation therapy only included the nodes in the pelvis and inguinal region and excluded the vulva (Homesley et al, 1986). GOG 37 randomized 114 vulvar patients who had positive groin nodes after radical vulvectomy and bilateral groin lymphadenectomy to either radiation therapy or additional surgical resection with an ipsilateral pelvic lymph node dissection. Postoperative radiation therapy was delivered to the bilateral pelvic and inguinal lymph nodes and excluded the vulva and was associated with improved two year overall survival compared to surgical resection (68% vs 54%, p=0.03) (Homesley et al, 1986). This study demonstrated a vulvar failure rate of 7-9 % with the omission of radiation directly to the vulva (Homesley et al, 1986). In contrast, in a retrospective review of 27 vulvar cancer patient who received surgery followed by radiation directed only at the inguinal and pelvic nodes and using a midline vulvar block, there was a 48% vulvar recurrence rate associated with the use of the midline vulvar block. (Dusenbery et al, 1994). The Consensus Recommendations for Radiation Therapy Contouring and Treatment of Vulvar Carcinoma committee recommends a conservative approach in treating vulvar cancer with the inclusion of the vulva, inguinal, and pelvic nodes in the treatment volume for the majority of definitive cases (Gaffney et al, 2016). The NCCN Guidelines for vulvar cancer note that there are very select cases where superficial treatment to the vulva alone with electrons may be used
There are no prospective studies evaluating the use of IMRT in vulvar cancer. Based on conclusions from the treatment of anal cancer in RTOG 0529, Intensity Modulated Radiation Therapy (IMRT) is accepted in the management of vulvar cancer (Kachnic et al, 2013). There are several retrospective studies evaluating the use of IMRT in vulvar cancer. In a retrospective review of 39 vulvar cancer patients treated with IMRT, Rao and colleagues (2017) found a 3 year locoregional control rate of 89% for patients receiving postoperative IMRT and 42% for patients receiving definitive IMRT. GOG 0279 is an ongoing Phase II trial evaluating the efficacy of IMRT combined with cisplatin and gemcitabine in locally advanced vulvar cancer patients.
There is limited prospective data detailing the ideal dose response relationship in vulvar cancer. Based on GOG 37, 45-50 Gy to the pelvis and groin is recommended for postoperative treatment in vulvar cancer (Homesley et al, 1986). Postoperative radiation therapy employing 45-50 Gy was associated with an improved two year overall survival compared to surgical resection (68% vs 54%, p=0.03) (Homesley et al, 1986). In a retrospective review of 205 patients with vulvar cancer, radiation doses of >56 Gy were associated with decreased risk of vulvar recurrence compared to those who received < 50.4 Gy (Viswanathan et al., 2013). Perez and colleagues (1998) found that 60-70 Gy was associated with 75-80% local control rate in the setting of N2 or N3 disease. The Consensus Recommendations for Radiation Therapy Contouring and Treatment of Vulvar Carcinoma committee recommends 60-70 Gy for gross disease.
In an analysis of Surveillance, Epidemiology, and End Results (SEER) data, Rao et al (2017) note that the use of brachytherapy after external beam radiation therapy (EBRT) for treatment of vulvar cancer is declining in the United States. In the SEER database, there was no benefit to EBRT combined with brachytherapy followed by brachytherapy alone. There was no benefit in disease free survival or overall survival. The SEER data suggest that brachytherapy after external beam radiation therapy was associated with improved disease specific survival in patients with Stage IVA disease, tumor > 4 cm, or node positive disease. There are several single institution reports of the feasibility of brachytherapy in recurrent disease associated with an acceptable toxicity profile (Castelnau-Marchand et al, 2017; Kellas-Œlęczka S et al, 2016; Mahantshetty et al, 2017). Brachytherapy may be considered as a boost to conventional fractionation or for recurrent disease.]
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Radiation Therapy for Vulvar Cancer
Vulvar Cancer, Radiation Therapy for
1. Castelnau-Marchand P, Escande A, Mazeron R, Bentivegna E, Cavalcanti A, Gouy S, Baratiny C1, Maroun P, Morice P, Haie-Meder C, Chargari C. Brachytherapy as part of the conservative treatment for primary and recurrent vulvar carcinoma. Brachytherapy. 2017 May - Jun;16(3):518-525.
2. Dusenbery KE, Carlson JW, LaPorte RM, Unger JA, Goswitz JJ, Roback DM, Fowler JM, Adcock LL, Carson LF, Potish RA. Radical vulvectomy with postoperative irradiation for vulvar cancer: therapeutic implications of a central block. Int J Radiat Oncol Biol Phys. 1994 Jul 30;29(5):989-98.
3. Gaffney DK, Du Bois A, Narayan K, Reed N, Toita T, Pignata S, Blake P, Portelance L, Sadoyze A, Potter R, Colombo A, Randall M, Mirza MR, Trimble EL. Patterns of care for radiotherapy in vulvar cancer: a Gynecologic Cancer Intergroup study. Int J Gynecol Cancer. 2009 Jan;19(1):163-7. doi: 10.1111/IGC.0b013e3181996ac3.
4. Gaffney DK, King B, Viswanathan AN, Barkati M, Beriwal S, Eifel P, Erickson B, Fyles A, Goulart J, Harkenrider M, Jhingran A, Klopp A, Koh WJ, Lim K, Petersen I, Portelance L, Small W Jr, Stewart A, Wiebe E, Wolfson A, Yashar C, Bosch W. Consensus Recommendations for Radiation Therapy Contouring and Treatment of Vulvar Carcinoma. Int J Radiat Oncol Biol Phys. 2016 Jul 15;95(4):1191-200. doi: 10.1016/j.ijrobp.2016.02.043. Epub 2016 Feb 21.
5. Gynecologic Oncology Group (GOG) 0279. A Phase II Trial Evaluating Cisplatin (NSC #119875) and Gemcitabine (NSC #613327) Concurrent With Intensity-Modulated Radiation Therapy (IMRT) in the Treatment of Locally Advanced Squamous Cell Carcinoma of the Vulva (NCT #01595061)https://clinicaltrials.gov/ct2/show/NCT01595061
6. Homesley HD, Bundy BN, Sedlis A, Adcock L. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol. 1986 Dec;68(6):733-40.
7. Jolly et al Shruti Jolly, MD1; Payal Soni, MD2; David K. Gaffney, MD, PhD3; Matthew Biagioli, MD4; Mohamed A. Elshaikh, MD5; Anuja Jhingran, MD6; Elizabeth Kidd, MD7; Larissa J. Lee, MD8; Linna Li, MD9; David H. Moore, MD10; Gautam G. Rao, MD11; Andrew O. Wahl, MD12; Ned L. Williams, DO13; Catheryn M. Yashar, MD14; William Small Jr, MD.15 American College of Radiology ACR Appropriateness Criteria® ADJUVANT THERAPY IN VULVAR CANCER
8. Kachnic LA, Winter K, Myerson RJ, Goodyear MD, Willins J, Esthappan J, Haddock MG, Rotman M, Parikh PJ, Safran H, Willett CG. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys. 2013 May 1;86(1):27-33. doi: 10.1016/j.ijrobp.2012.09.023.
9. Kellas-Œlęczka S, Białas B, Fijałkowski M, Wojcieszek P, Szlag M, Cholewka A, Œlęczka M, Kołosza Z. Interstitial high-dose-rate brachytherapy in locally advanced and recurrent vulvar cancer. J Contemp Brachytherapy. 2016 Feb;8(1):32-40.
10. Mahantshetty U, Naga P, Engineer R, Sastri S, Ghadi Y, Upreti U, Somesan V, Kadam S, Kohle S, Deshpande D, Shrivastava SK. Clinical outcome of high-dose-rate interstitial brachytherapy in vulvar cancer: A single institutional experience. Brachytherapy. 2017 Jan - Feb;16(1):153-160.
11. Mitra S, Sharma MK, Kaur I, Khurana R, Modi KB, Narang R, Mandal A, Dutta S. Vulvar carcinoma: dilemma, debates, and decisions. Cancer Manag Res. 2018 Jan 9;10:61-68. doi: 10.2147/CMAR.S143316
12. Moore DH, Ali S, Koh WJ, Michael H, Barnes MN, McCourt CK, Homesley HD, Walker JL. A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a gynecologic oncology group study. Gynecol Oncol. 2012 Mar;124(3):529-33. doi: 10.1016/j.ygyno.2011.11.003. Epub 2011 Nov 9.
13. Natesan D, Hong JC, Foote J, Sosa JA, Havrilesky L, Chino J. Primary Versus Preoperative Radiation for Locally Advanced Vulvar Cancer. Int J Gynecol Cancer. 2017 May;27(4):794-804. doi: 10.1097/IGC.0000000000000938.
14. Nooij LS, Brand FA, Gaarenstroom KN, Creutzberg CL, de Hullu JA, van Poelgeest MI. Risk factors and treatment for recurrent vulvar squamous cell carcinoma. Crit Rev Oncol Hematol. 2016 Oct;106:1-13. doi: 10.1016/j.critrevonc.2016.07.007. Epub 2016 Jul 25.
15. Perez CA, Grigsby PW, Chao C, Galakatos A, Garipagaoglu M, Mutch D, Lockett MA. Irradiation in carcinoma of the vulva: factors affecting outcome. Int J Radiat Oncol Biol Phys. 1998 Sep 1;42(2):335-44.
16. Rao YJ, Chundury A, Schwarz JK, Hassanzadeh C, DeWees T, Mullen D, Powell MA, Mutch DG, Grigsby PW. Intensity modulated radiation therapy for squamous cell carcinoma of the vulva: Treatment technique and outcomes. Adv Radiat Oncol. 2017 Apr-Jun; 2(2): 148–158. doi: [10.1016/j.adro.2017.02.006]
17. Rao YJ, Hui C, Chundury A et al. Which patients with inoperable vulvar cancer may benefit from brachytherapy in addition to external beam radiation? A Surveillance, Epidemiology, and End Results analysis. Brachytherapy: An International Multidiciplinary Journal. July–August, 2017 Volume 16, Issue 4, Pages 831–840.
18. Stroup AM, Harlan LC, and Trimble EL. Demographic, Clinical, and Treatment Trends Among Women Diagnosed with Vulvar Cancer in the U.S. Gynecol Oncol. 2008 Mar; 108(3): 577–583. doi: [10.1016/j.ygyno.2007.11.011]
19. Viswanathan AN, Pinto AP, Schultz D, Berkowitz R, Crum CP. Relationship of margin status and radiation dose to recurrence in post-operative vulvar carcinoma. Gynecol Oncol. 2013 Sep;130(3):545-9. doi: 10.1016/j.ygyno.2013.05.036. Epub 2013 Jun 5.
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