Radiotherapy for successful symptom control in recurrent refractory endometriosis: A case report

Endometriosis is a gynecological condition defined as the presence of endometrium-like tissue outside the uterus.[] Approximately 10% of reproductive-age women are estimated to be affected by endometriosis.[] Symptoms of endometriosis ranges from dysmenorrhea, acyclic pelvic pain, dyspareunia, dysuria, infertility, and fatigue. The postulated origins of endometriotic lesions, peritoneal lesions, extra pelvic lesions in endometriosis are retrograde menstruation, coelomic metaplasia and lymphatic and vascular metastasis, respectively.[] Apart from proliferation and vascularization, the endocrine and proinflammatory microenvironment around these lesions can also promote nociception, which in turn results in pain.[] Due to the limitation of imaging and lack of biomarkers, laparoscopic visualization is the standard for diagnosing endometriosis.[] Revised American Society for Reproductive Medicine scoring system (ASRM) is used to surgically stage the disease.[] Treatment options for endometriosis include medical, surgical, or both.[,] Irrespective of the treatment approach, recurrence of symptoms is not rare.[,] Recurrence has been reported even after total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH and BSO).[,] There is a paucity of data in the management of recurrent refractory endometriosis. Few case reports have stated successful control of symptoms of refractory endometriosis by radiation treatment in those patients who had undergone TAH and BSO and the radiotherapy target being either the residual endometriotic tissue or ovarian remnants.[] There have been no prior publications from India with regards to the use of radiotherapy for endometriosis. We report the use of radiotherapy for recurrent refractory endometriosis in a patient who had undergone TAH and BSO, which resulted in successful control of pelvic pain and bleeding along with the radiobiological explanation. CASE HISTORY A 39-year-old woman presented with a prolonged history of pelvic pain and recurrent vaginal bleeding. She had menarche at the age of 13 years. She was married at the age of 19 years and first childbirth was at the age of 20 years. At the age of 21 years, she had an unplanned pregnancy which was followed by a medical termination. From the age of 25 years, she was initiated on infertility treatment. Meanwhile, she also noticed to have dysmenorrhoea and dyspareunia. At the age of 32 years, as her symptoms were progressing, she underwent a laparoscopy, diagnosed to have endometriosis, and was stared on non-steroidal anti-inflammatory drugs. Later she was diagnosed to have a left ovarian chocolate cyst and underwent left salpingo-oophorectomy. At the age of 34 years, her symptoms aggravated and on evaluation she was diagnosed to have ASRM stage 4 endometriosis. As her symptoms were not controlled with hormone therapy, she underwent TAH and Right salpingo-oophorectomy at the age of 35 years. Within five months of surgical management, she again developed vaginal bleeding. Ultrasound imaging was within normal limits, hence considering a clinical diagnosis of an aorto-venous malformation she underwent ligation of bilateral internal iliac artery and was initiated on three-monthly depot-medroxyprogesterone acetate (DMPA). She had a mild control of the symptoms for next three years. At the age of 39 years, her symptoms start progressing, and she also reported difficulty in passing urine. She was evaluated under urologist and on imaging 2.5 cm × 1.6 cm sized ovarian remnant in the left para ovarian region and bilateral hydroureteronephrosis was identified. She underwent bilateral ureteric stenting for the same. Even after offering almost all the conventional treatments, as her symptoms of endometriosis were progressing, she was referred by the gynecologist for the possible radiation treatment. At current presentation, she had intermittent vaginal bleeding (requiring 1-2 pads per day) and pelvic pain. On examination, she had pallor and per vaginally no lesions were palpable. As she had recurrent refractory endometriosis which was not responding to medical and surgical treatment multidisciplinary tumour board decided for radiotherapy. Patient was explained regarding the treatment, potential benefits, acute and late side effects, and risk of second malignancy. After getting an informed consent she was offered radiation treatment. Computed tomography (CT) simulation was done with a ray cast in supine position with a comfortably full bladder and a scan of 2.5 mm slices was obtained. She was treated using 6MV photons with a four-field box to a total dose of 30Gy in 10 fractions. The pelvic field borders extended superiorly from the L5-S1 vertebral body level, inferiorly below the obturator canal, and laterally 1.5 cm lateral to the pelvic brims [Figure 1]. And for the lateral fields, anteriorly covering the pubic symphysis, and the posteriorly covering the sacrum. The pelvic field also included the ovarian remnant. After completing five fractions of radiotherapy, she had a good control of bleeding. During the post-treatment follow-up at six weeks, she reported that her vaginal bleeding completely resolved within one week of completion of radiotherapy along with regression of pelvic pain. A follow-up at six months, her follicle-stimulating hormone (FSH) level was found to be 83.3 IU/L; which was suggestive of post-menopausal status and she also reported a good quality of life with complete regression of symptoms.

Endometriosis is a benign disease. However, as it induces a chronic inflammatory process the clinical spectrum varies widely.[] Recommended treatments are either hormonal-based therapy or surgical excision depending on response and tolerability to medical therapy.[,] Current first-line and second-line hormonal treatment for endometriosis are oral contraceptive pills and gonadotropin-releasing hormone (GnRH) agonists, respectively. Aromatase inhibitors are also used in women with symptoms that are resistant to the above agents.[] Surgical treatment is considered in patients with hormone resistant endometriosis. Conservative surgery which involves excision or ablation of endometriotic lesions alone is the first-line option and in those with progressive symptoms, definitive surgery which involves hysterectomy, with or without oophorectomy is the next option.[] The overall recurrence rates in endometriosis range between 6 and 67% and this discrepancy in the recurrence rate is due to the ambiguity in definition of recurrence among various studies.[] After surgery for endometriosis, median time of 30 months is noted for first recurrence.[] Recurrence has been reported in 10% of women who had even undergone TAH and BSO.[] Underlying pathophysiology of recurrence is unclear and whether it derives from residual endometriotic cells or from de novo lesions through retrograde bleeding is a matter of debate.[] Lymph node involvement and lymphovascular invasion of the endometriotic foci is also considered as a possibility of recurrence.[] Management of endometriosis can be difficult in patients who have refractory endometriosis despite medical and surgical treatment. Our patient was a 39-year-old woman with refractory endometriosis and had recurrence of symptoms even after multiple surgical and medical therapy. Hence, she was referred for the possible radiation treatment. Radiotherapy have now been used in the treatment of number of benign conditions.[] Radiobiology behind the radiation effects on benign diseases are not well understood. At lower doses, radiation can inhibit cell proliferation, suppress cell differentiation, and can even induce apoptosis by affecting the cytokine expression and inflammatory cascade modulation.[] Proliferation, vascularization, and a proinflammatory microenvironment is associated with endometriosis, so the above radiobiological principle is applicable in treating refractory endometriosis with radiotherapy. Apart from this effect, at lower doses, radiation also results in ovarian ablation.[] One reason for refractory endometriosis in those who have underwent TAH + BSO is an ovarian remnant, use of radiotherapy also does an ovarian remnant ablation.[] There have been only a few case reports in the literature where radiation treatment has been successfully offered for refractory endometriosis in patients who had undergone TAH and BSO.[] Considering the above radiobiology and the result from previous case reports we also took the decision of offering radiation treatment to our patient and had a complete regression of symptoms. All the published reports which used radiotherapy for refractory endometriosis have used a total dose of 20-30Gy and the similar dose schedule is used for ovarian ablation as well as in the palliative setting for achieving haemostasis.[,,] Considering these points, we treated her to a total dose of 30Gy delivered in 10 fractions. Although ovarian remnant was our primary target, to ensure the irradiation of any residual microscopic endometriotic tissue in the pelvic region, we treated the whole pelvis with four field box technique. The only concern about use of radiotherapy for benign diseases is the incidence of radiation-induced cancer (RIC). However, the risk has been considered very small with intermediate dose radiation.[] Our patient was also informed about the RIC and after assessing the risk versus benefit evaluation she opted for radiation treatment. As we have used a low dose, except a grade 1 (RTOG) skin toxicity she did not have any acute bowel or bladder toxicity. Post-treatment, she reported a good quality of life with complete regression of symptoms. In our experience we could conclude that recurrent endometriosis, that is not responding to conventional treatments can be successfully treated with radiotherapy. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

1 Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, Vigan P Endometriosis. Nat Rev Dis Primers 2018:4;9.2 Shafrir AL, Farland LV, Shah DK, Harris HR, Kvaskoff M, Zondervan K, et al. Risk for and consequences of endometriosis: A critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol 2018:51;1–15.3 Sampson JA Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927:14;422–69.4 Suginami H A reappraisal of the coelomic metaplasia theory by reviewing endometriosis occurring in unusual sites and instances. Am J Obstet Gynecol 1991:165;214–8.5 Jerman LF, Hey-Cunningham AJ The role of the lymphatic system in endometriosis: A comprehensive review of the literature. Biol Reprod 2015:92;64.6 Laux-Biehlmann A, d'Hooghe T, Zollner TM Menstruation pulls the trigger for inflammation and pain in endometriosis. Trends Pharmacol Sci 2015:36;270–6.7 Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, et al. ESHRE guideline: Management of women with endometriosis. Hum Reprod 2014:29;400–12.8 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997:67;817–21.9 Zondervan KT, Becker CM, Missmer SA Endometriosis. N Engl J Med 2020:382;1244–56.10 Becker CM, Gattrell WT, Gude K, Singh SS Reevaluating response, and failure of medical treatment of endometriosis: A systematic review. Fertil Steril 2017:108;125–36.11 Alkatout I, Mettler L, Beteta C, Hedderich J, Jonat W, Schollmeyer T, et al. Combined surgical and hormone therapy for endometriosis is the most effective treatment: Prospective, randomized, controlled trial. J Minim Invasive Gynecol 2013:20;473–81.12 Clayton RD, Hawe JA, Love JC, Wilkinson N, Garry R Recurrent pain after hysterectomy and bilateral salpingo-oophorectomy for endometriosis: Evaluation of laparoscopic excision of residual endometriosis. Br J Obstet Gynaecol 1999:106;740–4.13 Namnoum A, Hickman T, Goodman S, Gehlbach DL, Rock JA Incidence of symptom recurrence after hysterectomy for endometriosis. Fertil Steril 1995:64;898–902.14 Kim KS, Moon WS, Song HW, Kim JH, Cho SN A case of persistent endometriosis after total hysterectomy with both salpingo oophorectomy managed by radiation therapy. Arch Gynecol Obstet 2001:265;225–7.15 Prabhu AV, Schad MD, Burnett AF, Lewis GD Radiation treatment for refractory endometriosis: A 38-year-old female presenting with vaginal bleeding. Rep Pract Oncol Radiother 2021:26;457–62.16 Haglund KE, Viswanathan AN Computed tomography- based radiation therapy of ovarian remnants for symptomatic persistent endometr iosis. Obstet Gynecol 2008:111;579–83.17 Selçuk I, Bozdağ G Recurrence of endometriosis;risk factors, mechanisms, and biomarkers; review of the literature. J Turk Ger Gynecol Assoc 2013:14;98–103.18 Nirgianakis K, Ma L, McKinnon B, Mueller MD Recurrence patterns after surgery in patients with different endometriosis subtypes: A long-term hospital-based cohort study. J Clin Med 2020:9;496.19 Guo SW Recurrence of endometriosis and its control. Hum Reprod Update 2009:15;441–61.20 McKeown SR, Hatfield P, Prestwich RJD, Shaffer RE, Taylor RE Radiotherapy for benign disease;assessing the risk of radiation-induced cancer following exposure to intermediate dose radiation. Br J Radiol 2015:88;20150405.21 Rodel F, Keilholz L, Herrmann M, Sauer R, Hildebrandt G Radiobiological mechanisms in inflammatory diseases of low-dose radiation therapy. Int J Radiat Biol 2007:83;357–66.22 The Adjuvant Breast Cancer Trials Collaborative Group Ovarian ablation or suppression in premenopausal early breast cancer: Results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst 2007:99;516–25.23 Hughes LL, Gray RJ, Solin LJ, Robert NJ, Martino S, Tripathy D, et al. Efficacy of radiotherapy for ovarian ablation: Results of a breast intergroup study. Cancer 2004:101;969–72.24 Mishra K Gynaecological malignancies from palliative care perspective. Indian J Palliat Care 2011:17 Suppl S45–51.