Quote this article as:
P Petric & U Mahantshetty (May 2024). Treatment for Cervical Cancer Part I: Introduction to chemoradiation and external beam radiotherapy treatment. www.HPVWorld.com, 252

Introduction to chemoradiation
Radiotherapy is an anti-cancer treatment that uses radiation to kill cancer cells. In cervical cancer, it plays an important role in all stages of disease.¹ When used in curative intent, it is typically combined with weekly concurrent chemotherapy,² and the entire regimen is referred to as chemoradiation (CRT). Curative CRT combines two radiotherapy techniques: external beam radiotherapy (EBRT) and internal radiotherapy or brachytherapy (BT) (Figure 1). After radiation therapy, the patient emits no radioactivity and can return to normal life.



Indications for chemoradiation
For early stages of cervical cancer, level 1 evidence suggests oncological equivalence of CRT and surgery. A randomized trial showed no significant differences in 20-year overall survival and disease-free survival between surgery +/- radiotherapy and radiotherapy alone for FIGO stages IB-IIA.³ These results were obtained despite the use of old radiotherapy techniques which are nowadays considered suboptimal, and despite the lack of concomitant chemotherapy. Recently, the large retrospective retroEMBRACE study confirmed that chemoradiotherapy with modern, image-guided brachytherapy in stage IB cervical cancer results in excellent outcomes which compare favourably to surgery.⁴ In summary, although surgery remains standard treatment in patients with small tumors without nodal metastases, radiotherapy can be used as an oncologically equivalent alternative in case of inoperability due to comorbidities, patient refusal or unavailability of surgery. In technically operable tumors with unfavorable pre-treatment properties, radiochemotherapy is the first choice to avoid a combination of surgery and adjuvant therapy.

According to the National Institutes of Health, stages IB-IIA can be adequately treated with either surgery or RT, but not both, with equal efficacy to avoid increased costs and morbidity.⁵ For stages T2b and higher and/or when metastases in the lymph nodes are present, definitive chemoradiotherapy with brachytherapy is preferred in all cases.^1,6,7 Neoadjuvant chemotherapy followed by surgery should not be used in this group of patients.⁸ If cervical cancer has already spread, so-called palliative radiation therapy can prevent or alleviate the symptoms caused by metastases, for example pain and bleeding.

External beam radiotherapy (EBRT)
EBRT employs high-energy photon beams directed to the target volume. The EBRT target volume includes the tumor, cervix, uterus, parametria, part of vagina, and in case of tumor invasion also parts of pelvis organs. In addition, affected lymph nodes, and unaffected nodal regions at risk for microscopic infiltration are included in the target volume. This always includes the pelvic nodal stations and, in some patients, also the paraaortic and/or inguinal stations. EBRT is most often performed on outpatient basis, requires no anesthesia, and can be integrated into patient’s everyday life. Typically, it consists of 25 daily treatments over 5 weeks.

In countries with high human development index (HDI), the EBRT machines are most commonly linear accelerators, capable of computer-guided shape and intensity modulation of the radiation beams. Beam modulation and dose calculation are based on computed tomography (CT) and magnetic resonance imaging (MRI) definition of the target volume and surrounding normal tissues. Intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and daily image-guidance radiotherapy (IGRT), achieve personalized dose distributions in the tissues, delivering high doses to the target volume, while sparing the surrounding normal tissues (Figure 2). These characteristics reduce the probability of treatment side effects without compromising the oncologic outcomes.



In countries with low HDI (which carry the highest epidemiological burden of cervical cancer), these techniques are not widely available.⁹ Instead, Co-60 devices and less sophisticated linear accelerators are commonly used. They enable high patient throughput and are relatively robust and affordable, but this comes at a cost of a lower ability for beam modulation. Therefore, less sophisticated 2D to 3D conformal radiotherapy is often employed instead of IMRT, VMAT, and IGRT.

• Mahantshetty U, Poetter R, Beriwal S, et al. IBS-GEC ESTRO-ABS recommendations for CT based contouring in image guided adaptive brachytherapy for cervical cancer. Radiotherapy. and Oncol. 2021;160:273–84. Available from: https://www.thegreenjournal.com/article/S0167-8140(21)06248-4/fulltext
  
• Perez CA, Grigsby PW, Chao KSC, et al. Tumor Size, Irradiation Dose, and Long-Term Outcome of Carcinoma of Uterine Cervix. Int J Radiat Oncol Biol Phys. 1998;41(2):307–17. Available from: https://www.redjournal.org/article/S0360-3016(98)00067-4/fulltext
  
• Barillot I, Horiot JC, Pigneux J, et al. Carcinoma of the intact uterine cervix treated with radiotherapy alone: a French cooperative study: Update and multivariate analysis of prognostics factors. Int J Radiat Oncol Biol Phys. 1997;38(5):969–78. Available from: https://www.redjournal.org/article/S0360-3016(97)00145-4/pdf
  
• Castelnau-Marchand P, Chargari C, Maroun P, et al. Clinical outcomes of definitive chemoradiation followed by intracavitary pulsed-dose rate image-guided adaptive brachytherapy in locally advanced cervical cancer. Gynecol Oncol. 2015; 139(2):288–94. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(15)30125-6
  
• Nomden CN, de Leeuw AAC, Roesink JM, et al. Clinical outcome and dosimetric parameters of chemo-radiation including MRI guided adaptive brachytherapy with tandem-ovoid applicators for cervical cancer patients: A single institution experience. Radiother Oncol. 2013;107(1):69–74. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0167-8140(13)00181-3
  
• Charra-Brunaud C, Harter V, Delannes M, et al. Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: Results of the French STIC prospective study. Radiother Oncol. 2012;103(3):305–13. Available from: https://www.thegreenjournal.com/article/S0167-8140(12)00209-5/fulltext
  
• Lindegaard JC, Fokdal LU, Nielsen SK, et al. MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective. Acta Oncol. 2013;52(7):1510–9. Available from: https://www.tandfonline.com/doi/full/10.3109/0284186X.2013.818253
  
• Pötter R, Dimopoulos J, Georg P, et al. Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer. Radiother Oncol. 2007;83(2):148–55. Available from: https://www.thegreenjournal.com/article/S0167-8140(07)00167-3/fulltext

• P Petric, U Mahantshetty. Treatment for cervical cancer-Part II: brachytherapy and imaging techniques.
  
• P Petric, U Mahantshetty. Treatment for cervical cancer-Part III: clinical results and conclusions.
  
• D Najjari-Jamal, S Córdoba Largo, B Gil Haro. Disease and treatment-related effects on sexual dysfunction and quality of life in cervical cancer survivors.