Treatment-related toxicity from the use of radiation therapy for gynecologic malignancies
- Kristin A Bradley, MD
Kristin A Bradley, MD
- Associate Professor
- University of Wisconsin School of Medicine and Public Health
- Derek R McHaffie, MD
Derek R McHaffie, MD
- Attending Physician
- Levine Cancer Institute
- Carolinas Medical Center
- Section Editors
- Barbara Goff, MD
Barbara Goff, MD
- Section Editor — Gynecologic Oncology
- Professor of Gynecologic Oncology
- University of Washington
- Arno J Mundt, MD
Arno J Mundt, MD
- Section Editor — Radiation Therapy
- Chairman of Radiation Oncology
- University of California, San Diego
- Don S Dizon, MD, FACP
Don S Dizon, MD, FACP
- Section Editor – Gynecologic Oncology
- Head of Women's Cancers, Lifespan Cancer Institute
- Director of Medical Oncology, Rhode Island Hospital
- Associate Professor of Medicine, Warren Alpert Medical School of Brown University
Radiation therapy (RT) represents an important therapeutic component in the management of many gynecologic malignancies. Based upon evidence-based treatment guidelines, RT is indicated in up to 60 percent of cervical cancer patients, 45 percent of endometrial cancer patients, 35 percent of vulvar cancer patients, 100 percent of vaginal cancer patients, and 5 percent of patients with ovarian cancer [1,2].
In this topic, the spectrum of both acute and late side effects associated with RT, specifically as it relates to the treatment of gynecologic malignancies, will be reviewed. An understanding of potential side effects is important for patient management and survivorship issues. An overview of the general principles, modalities, and techniques of RT is found elsewhere. A more detailed discussion of the indications for RT for specific cancer sites and stages can be found in topic reviews for each cancer site. (See "Radiation therapy techniques in cancer treatment".)
Radiation therapy (RT) for gynecologic cancers can be employed as primary treatment or following surgery or before surgery (ie, adjuvant therapy) in order to reduce the risk of recurrence. For some tumors, RT is often administered with concurrent chemotherapy (chemoradiation) and may incorporate brachytherapy. The normal tissues of the cervix and corpus of the uterus can tolerate high doses of radiation and can recover remarkably well from radiation injury. However, the surrounding normal tissues are more susceptible to radiation injury.
The incidence and severity of RT side effects depend upon the site, volume of tissue exposed, and treatment schedule, including total dose, dose per fraction, and type of radiation. Modifying factors such as previous surgery, concomitant chemotherapy, and comorbid illness are also influential. At least one large report indicates that smoking history is a strong predictor for both bowel and bladder complications from treatment .
Some patients may be at higher risk for RT-related toxicity. These include patients with:To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Delaney G, Jacob S, Barton M. Estimation of an optimal radiotherapy utilization rate for gynecologic carcinoma: part II--carcinoma of the endometrium. Cancer 2004; 101:682.
- Delaney G, Jacob S, Barton M. Estimation of an optimal radiotherapy utilization rate for gynecologic carcinoma: part I--malignancies of the cervix, ovary, vagina and vulva. Cancer 2004; 101:671.
- Eifel PJ, Jhingran A, Bodurka DC, et al. Correlation of smoking history and other patient characteristics with major complications of pelvic radiation therapy for cervical cancer. J Clin Oncol 2002; 20:3651.
- Wo J, Taghian A. Radiotherapy in setting of collagen vascular disease. Int J Radiat Oncol Biol Phys 2007; 69:1347.
- Willett CG, Ooi CJ, Zietman AL, et al. Acute and late toxicity of patients with inflammatory bowel disease undergoing irradiation for abdominal and pelvic neoplasms. Int J Radiat Oncol Biol Phys 2000; 46:995.
- Green S, Stock RG, Greenstein AJ. Rectal cancer and inflammatory bowel disease: natural history and implications for radiation therapy. Int J Radiat Oncol Biol Phys 1999; 44:835.
- Song DY, Lawrie WT, Abrams RA, et al. Acute and late radiotherapy toxicity in patients with inflammatory bowel disease. Int J Radiat Oncol Biol Phys 2001; 51:455.
- Maruyama Y, Van Nagell JR Jr, Utley J, et al. Radiation and small bowel complications in cervical carcinoma therapy. Radiology 1974; 112:699.
- van Nagell JR Jr, Parker JC Jr, Maruyama Y, et al. Bladder or rectal injury following radiation therapy for cervical cancer. Am J Obstet Gynecol 1974; 119:727.
- Jereczek-Fossa BA, Badzio A, Jassem J. Factors determining acute normal tissue reactions during postoperative radiotherapy in endometrial cancer: analysis of 317 consecutive cases. Radiother Oncol 2003; 68:33.
- Viswanathan AN, Yorke ED, Marks LB, et al. Radiation dose-volume effects of the urinary bladder. Int J Radiat Oncol Biol Phys 2010; 76:S116.
- Klopp AH, Yeung AR, Desmukh, et al. Phase III randomized trial comparing patient-reported toxicity and quality of life during pelvic intensity modulated radiation therapy as compared to conventional radiation therapy. Int J Radiat Oncol Biol Phys 2016; Supplement S2, S3.
- Marks LB, Carroll PR, Dugan TC, Anscher MS. The response of the urinary bladder, urethra, and ureter to radiation and chemotherapy. Int J Radiat Oncol Biol Phys 1995; 31:1257.
- King LS. Editorial: The humanization of medicine. JAMA 1975; 231:738.
- Nout RA, van de Poll-Franse LV, Lybeert ML, et al. Long-term outcome and quality of life of patients with endometrial carcinoma treated with or without pelvic radiotherapy in the post operative radiation therapy in endometrial carcinoma 1 (PORTEC-1) trial. J Clin Oncol 2011; 29:1692.
- Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340:1137.
- Georg P, Pötter R, Georg D, et al. Dose effect relationship for late side effects of the rectum and urinary bladder in magnetic resonance image-guided adaptive cervix cancer brachytherapy. Int J Radiat Oncol Biol Phys 2012; 82:653.
- Perez CA, Breaux S, Bedwinek JM, et al. Radiation therapy alone in the treatment of carcinoma of the uterine cervix. II. Analysis of complications. Cancer 1984; 54:235.
- Sandhu SS, Goldstraw M, Woodhouse CR. The management of haemorrhagic cystitis with sodium pentosan polysulphate. BJU Int 2004; 94:845.
- Oscarsson N, Arnell P, Lodding P, et al. Hyperbaric oxygen treatment in radiation-induced cystitis and proctitis: a prospective cohort study on patient-perceived quality of recovery. Int J Radiat Oncol Biol Phys 2013; 87:670.
- Nout RA, Putter H, Jürgenliemk-Schulz IM, et al. Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial. J Clin Oncol 2009; 27:3547.
- Carr KE. Effects of radiation damage on intestinal morphology. Int Rev Cytol 2001; 208:1.
- Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys 2010; 76:S101.
- Creutzberg CL, van Putten WL, Koper PC, et al. The morbidity of treatment for patients with Stage I endometrial cancer: results from a randomized trial. Int J Radiat Oncol Biol Phys 2001; 51:1246.
- Nout RA, Smit VT, Putter H, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial. Lancet 2010; 375:816.
- Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999; 340:1154.
- Chen MF, Tseng CJ, Tseng CC, et al. Clinical outcome in posthysterectomy cervical cancer patients treated with concurrent Cisplatin and intensity-modulated pelvic radiotherapy: comparison with conventional radiotherapy. Int J Radiat Oncol Biol Phys 2007; 67:1438.
- Folkert MR, Shih KK, Abu-Rustum NR, et al. Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer. Gynecol Oncol 2013; 128:288.
- Barillot I, Tavernier E, Peignaux K, et al. Impact of post operative intensity modulated radiotherapy on acute gastro-intestinal toxicity for patients with endometrial cancer: results of the phase II RTCMIENDOMETRE French multicentre trial. Radiother Oncol 2014; 111:138.
- Vernia P, Fracasso PL, Casale V, et al. Topical butyrate for acute radiation proctitis: randomised, crossover trial. Lancet 2000; 356:1232.
- Hille A, Herrmann MK, Kertesz T, et al. Sodium butyrate enemas in the treatment of acute radiation-induced proctitis in patients with prostate cancer and the impact on late proctitis. A prospective evaluation. Strahlenther Onkol 2008; 184:686.
- Feyer PCh, Maranzano E, Molassiotis A, et al. Radiotherapy-induced nausea and vomiting (RINV): antiemetic guidelines. Support Care Cancer 2005; 13:122.
- Sykes AJ, Kiltie AE, Stewart AL. Ondansetron versus a chlorpromazine and dexamethasone combination for the prevention of nausea and vomiting: a prospective, randomised study to assess efficacy, cost effectiveness and quality of life following single-fraction radiotherapy. Support Care Cancer 1997; 5:500.
- National Cancer Institute of Canada Clinical Trials Group (SC19), Wong RK, Paul N, et al. 5-hydroxytryptamine-3 receptor antagonist with or without short-course dexamethasone in the prophylaxis of radiation induced emesis: a placebo-controlled randomized trial of the National Cancer Institute of Canada Clinical Trials Group (SC19). J Clin Oncol 2006; 24:3458.
- Yavuz MN, Yavuz AA, Aydin F, et al. The efficacy of octreotide in the therapy of acute radiation-induced diarrhea: a randomized controlled study. Int J Radiat Oncol Biol Phys 2002; 54:195.
- Topkan E, Karaoglu A. Octreotide in the management of chemoradiotherapy-induced diarrhea refractory to loperamide in patients with rectal carcinoma. Oncology 2006; 71:354.
- Muecke R, Schomburg L, Glatzel M, et al. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. Int J Radiat Oncol Biol Phys 2010; 78:828.
- Gandhi AK, Sharma DN, Rath GK, et al. Early clinical outcomes and toxicity of intensity modulated versus conventional pelvic radiation therapy for locally advanced cervix carcinoma: a prospective randomized study. Int J Radiat Oncol Biol Phys 2013; 87:542.
- Vistad I, Kristensen GB, Fosså SD, et al. Intestinal malabsorption in long-term survivors of cervical cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2009; 73:1141.
- Snijders-Keilholz A, Griffioen G, Davelaar J, et al. Vitamin B12 malabsorption after irradiation for gynaecological tumours. Anticancer Res 1993; 13:1877.
- Schreurs WH, Odink J, Egger RJ, et al. The influence of radiotherapy and chemotherapy on the vitamin status of cancer patients. Int J Vitam Nutr Res 1985; 55:425.
- Georg P, Boni A, Ghabuous A, et al. Time course of late rectal- and urinary bladder side effects after MRI-guided adaptive brachytherapy for cervical cancer. Strahlenther Onkol 2013; 189:535.
- Eifel PJ, Winter K, Morris M, et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01. J Clin Oncol 2004; 22:872.
- 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; 103:305.
- Kochhar R, Patel F, Dhar A, et al. Radiation-induced proctosigmoiditis. Prospective, randomized, double-blind controlled trial of oral sulfasalazine plus rectal steroids versus rectal sucralfate. Dig Dis Sci 1991; 36:103.
- Denton A, Forbes A, Andreyev J, Maher EJ. Non surgical interventions for late radiation proctitis in patients who have received radical radiotherapy to the pelvis. Cochrane Database Syst Rev 2002; :CD003455.
- Kaassis M, Oberti E, Burtin P, Boyer J. Argon plasma coagulation for the treatment of hemorrhagic radiation proctitis. Endoscopy 2000; 32:673.
- Yeoh E, Tam W, Schoeman M, et al. Argon plasma coagulation therapy versus topical formalin for intractable rectal bleeding and anorectal dysfunction after radiation therapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2013; 87:954.
- Talley NA, Chen F, King D, et al. Short-chain fatty acids in the treatment of radiation proctitis: a randomized, double-blind, placebo-controlled, cross-over pilot trial. Dis Colon Rectum 1997; 40:1046.
- Flay LD, Matthews JH. The effects of radiotherapy and surgery on the sexual function of women treated for cervical cancer. Int J Radiat Oncol Biol Phys 1995; 31:399.
- Townamchai K, Lee L, Viswanathan AN. A novel low dose fractionation regimen for adjuvant vaginal brachytherapy in early stage endometrioid endometrial cancer. Gynecol Oncol 2012; 127:351.
- Ahlström CG. [The conception of cancer in times of old; a survey with special attention to Sweden]. Sydsven Medicinhist Sallsk Arsskr 1980; :10.
- Denton AS, Maher EJ. Interventions for the physical aspects of sexual dysfunction in women following pelvic radiotherapy. Cochrane Database Syst Rev 2003; :CD003750.
- Eifel PJ, Levenback C, Wharton JT, Oswald MJ. Time course and incidence of late complications in patients treated with radiation therapy for FIGO stage IB carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1995; 32:1289.
- Williams JA Jr, Clarke D, Dennis WA, et al. The treatment of pelvic soft tissue radiation necrosis with hyperbaric oxygen. Am J Obstet Gynecol 1992; 167:412.
- Safra T, Gutman G, Fishlev G, et al. Improved quality of life with hyperbaric oxygen therapy in patients with persistent pelvic radiation-induced toxicity. Clin Oncol (R Coll Radiol) 2008; 20:284.
- Dion MW, Hussey DH, Doornbos JF, et al. Preliminary results of a pilot study of pentoxifylline in the treatment of late radiation soft tissue necrosis. Int J Radiat Oncol Biol Phys 1990; 19:401.
- Vistad I, Cvancarova M, Fosså SD, Kristensen GB. Postradiotherapy morbidity in long-term survivors after locally advanced cervical cancer: how well do physicians' assessments agree with those of their patients? Int J Radiat Oncol Biol Phys 2008; 71:1335.
- Pitkin RM, VanVoorhis LW. Postirradiation vaginitis. An evaluation of prophylaxis with topical estrogen. Radiology 1971; 99:417.
- Miles T, Johnson N. Vaginal dilator therapy for women receiving pelvic radiotherapy. Cochrane Database Syst Rev 2010; :CD007291.
- Decruze SB, Guthrie D, Magnani R. Prevention of vaginal stenosis in patients following vaginal brachytherapy. Clin Oncol (R Coll Radiol) 1999; 11:46.
- Bruner DW, Lanciano R, Keegan M, et al. Vaginal stenosis and sexual function following intracavitary radiation for the treatment of cervical and endometrial carcinoma. Int J Radiat Oncol Biol Phys 1993; 27:825.
- Robinson JW, Faris PD, Scott CB. Psychoeducational group increases vaginal dilation for younger women and reduces sexual fears for women of all ages with gynecological carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys 1999; 44:497.
- Sobotkowski J, Markowska J, Fijuth J, Pietraszek A. Preliminary results of mitomycin C local application as post-treatment prevention of vaginal radiation-induced morbidity in women with cervical cancer. Eur J Gynaecol Oncol 2006; 27:356.
- Betalli P, De Corti F, Minucci D, et al. Successful topical treatment with mitomycin-C in a female with post-brachytherapy vaginal stricture. Pediatr Blood Cancer 2008; 51:550.
- Moore KN, Gold MA, McMeekin DS, Zorn KK. Vesicovaginal fistula formation in patients with Stage IVA cervical carcinoma. Gynecol Oncol 2007; 106:498.
- Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005; 62:738.
- Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod 2003; 18:117.
- Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an underused procedure. Am J Obstet Gynecol 2003; 188:367.
- Morice P, Castaigne D, Haie-Meder C, et al. Laparoscopic ovarian transposition for pelvic malignancies: indications and functional outcomes. Fertil Steril 1998; 70:956.
- Morice P, Haie-Meder C, Pautier P, et al. Ovarian metastasis on transposed ovary in patients treated for squamous cell carcinoma of the uterine cervix: report of two cases and surgical implications. Gynecol Oncol 2001; 83:605.
- Baxter NN, Habermann EB, Tepper JE, et al. Risk of pelvic fractures in older women following pelvic irradiation. JAMA 2005; 294:2587.
- Ikushima H, Osaki K, Furutani S, et al. Pelvic bone complications following radiation therapy of gynecologic malignancies: clinical evaluation of radiation-induced pelvic insufficiency fractures. Gynecol Oncol 2006; 103:1100.
- Robins CJ, Luten AG. Sociotropy and autonomy: differential patterns of clinical presentation in unipolar depression. J Abnorm Psychol 1991; 100:74.
- Oh D, Huh SJ, Nam H, et al. Pelvic insufficiency fracture after pelvic radiotherapy for cervical cancer: analysis of risk factors. Int J Radiat Oncol Biol Phys 2008; 70:1183.
- Bliss P, Parsons CA, Blake PR. Incidence and possible aetiological factors in the development of pelvic insufficiency fractures following radical radiotherapy. Br J Radiol 1996; 69:548.
- Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000; 18:1606.
- Klopp AH, Moughan J, Portelance L, et al. Hematologic toxicity in RTOG 0418: a phase 2 study of postoperative IMRT for gynecologic cancer. Int J Radiat Oncol Biol Phys 2013; 86:83.
- Rose BS, Aydogan B, Liang Y, et al. Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys 2011; 79:800.
- Mell LK, Kochanski JD, Roeske JC, et al. Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Biol Phys 2006; 66:1356.
- Georgiou A, Grigsby PW, Perez CA. Radiation induced lumbosacral plexopathy in gynecologic tumors: clinical findings and dosimetric analysis. Int J Radiat Oncol Biol Phys 1993; 26:479.
- Gothard L, Cornes P, Brooker S, et al. Phase II study of vitamin E and pentoxifylline in patients with late side effects of pelvic radiotherapy. Radiother Oncol 2005; 75:334.
- TIMING OF RT-RELATED TOXICITIES
- GENITOURINARY SYSTEM TOXICITIES
- Acute radiation cystitis
- Late signs and symptoms
- Acute radiation injury
- Late GI toxicity
- Acute vaginal mucositis
- Vaginal ulceration or necrosis
- Vaginal stenosis
- BONE AND BONE MARROW