Practical Radiation Oncology (2015) 5, e263–e266
www.practicalradonc.org
Teaching Case
Successful pregnancy after uterus-sparing chemoradiation therapy for vaginal cancer Mark J. Amsbaugh MD a,⁎, Moataz El-Ghamry MD a , Daniel Metzinger MD b , Thomas Hunter BS a , Neal E. Dunlap MD a a
Department of Radiation Oncology, University of Louisville, Louisville, Kentucky Department of Obstetrics, Gynecology and Women’s Health, University of Louisville, Louisville, Kentucky
b
Received 20 August 2014; revised 21 October 2014; accepted 24 October 2014
Introduction Vaginal cancer is a rare malignancy. An estimated 3170 women will be diagnosed and 880 will die of the disease in 2014. 1 Given these small numbers, treatment approaches have been extrapolated from data in other cancer sites. Brachytherapy with or without external beam radiation therapy (RT) and surgery have been the traditional treatment, but high rates of pelvic failure in more advanced disease have led to increasing use of chemoradiation therapy (CRT). 2 Approximately one fourth of patients are premenopausal at diagnosis. 3 Although not a traditional goal of therapy, fertility is an increasing consideration. It has been shown that women who become infertile as a result of treatment for cancer have high levels of stress, depression, and lower quality of life. 4 Patients who wish to maintain fertility require preservation of oncologic outcomes while being provided with the best chance for future successful pregnancy. Maintenance of ovarian function has been demonstrated by multiple series using different surgical techniques, but reports of successful pregnancy after treatment with pelvic RT are rare. 5-7 We present a case of a young woman with vaginal cancer treated with definitive CRT followed by brachy-
Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation Oncology, Brown Cancer Center, 529 S Jackson St, Louisville, KY 40206. E-mail address: [email protected] (M.J. Amsbaugh).
therapy who spontaneously became pregnant, delivered a healthy child, and currently has no evidence of disease. Special techniques, including daily image guidance, intensity modulation (IG-IMRT), and ovarian transposition, were used.
Teaching case The patient is a 26-year-old woman who presented to her gynecologist with postcoital bleeding. Pelvic examination revealed a mass involving the mucosa, 2 cm from the introitus at the 1-o’clock position in the lower one-third of the vagina. It was fixed to the underlying tissue. Magnetic resonance (MR) imaging of the pelvis demonstrated a 1.6 cm mass, and the patient was taken for an examination under anesthesia with excisional biopsy and cystoscopy. Pathology was consistent with invasive adenocarcinoma, confined to the vagina. Immunohistochemistry identified the tumor as positive for vimentin, cytokeratin AE1/3, CD10, and CK7 (cytokeratin 7); focally positive for CA125 (cancer antigen 125), CD15, CAM5.2, CK20 (cytokeratin 20), and estrogen receptor; and negative for carcinoembryonic antigen, thyroglobulin, thyroid transcription factor-1, synaptophysin, B72.3, CDX2, GCDFP (gross cystic disease fluid protein), calretinin, and thrombomodulin. The patient’s cancer was staged with a mammogram, colonoscopy, and positron emission tomography/computed tomography scan, which revealed a fluorodeoxyglucose-avid tumor
http://dx.doi.org/10.1016/j.prro.2014.10.009 1879-8500/© 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
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M.J. Amsbaugh et al
(standardized uptake value 11.6) and no areas that raised concern regarding distant metastatic spread. On the basis of the clinical examination and subsequent workup, the patient was determined to have a stage II adenocarcinoma of the vagina (International Federation of Gynecology and Obstetrics staging). Our multidisciplinary tumor board recommended CRT followed by brachytherapy in accordance with our institutional practice; however, the patient wished to maintain childbearing potential, so robotic-assisted ovarian transposition was performed 3 weeks before RT was initiated. After supine simulation, organs at risk were contoured in the TomoTherapy planning software (Accuray, Sunnyvale, CA), including the ovaries, bladder, rectum, femoral heads, uterine fundus, and lower uterine segment. Pelvic lymph nodes, medial inguinal lymph nodes, and tumor with margin were delineated. Every effort was made to avoid dose spillage to the uterus. The uterine fundus was assigned an importance value of 75 (compared with 135 for the vaginal lesions, and 100 for the
Figure 1
Practical Radiation Oncology: May-June 2015
nodal target volume) in the treatment planning software. The right and left ovaries were given lower importance values of 35 and 4, respectively. IG-IMRT was used to deliver 50.4 Gy at 1.8 Gy per fraction to 95% of the target volume (Fig 1A). The maximum dose was 2.05 Gy to the right ovary and 27.59 Gy to the left ovary. The lower uterine segment received a mean dose of 34.53 Gy. The dose-volume histogram is shown in Fig 2. Concurrent with RT, the patient received cisplatin 40 mg/m 2 weekly. Five days after CRT, she received interstitial brachytherapy. Six iridium 192 lowdose-rate ribbons were implanted with an active length of 6 cm and delivered 25 Gy prescribed to the minimum peripheral dose at 0.5 Gy/h over 50 hours (Fig 1B). The patient developed mild mucositis and diarrhea, which resolved shortly after her CRT. One year after treatment, the patient became pregnant. At 35 weeks, she presented in preterm labor and underwent a cesarean section, delivering a healthy 2300-g baby boy with an Apgar score of 9 and 9. Four years after
(A) External beam radiation dose distribution; (B) brachytherapy dose distribution.
Practical Radiation Oncology: May-June 2015
Figure 2
Pregnancy after CRT for vaginal cancer
e265
Dose-volume histogram for external beam radiation.
treatment, she is free from disease, and her child is healthy and meeting all age-appropriate milestones.
Discussion Gynecological cancers present a management challenge in women who wish to maintain fertility, because traditional treatment strategies have not considered the importance of psychosocial outcomes. Carter et al examined 120 cancer survivors with infertility related to treatment. 4 These women had high levels of depression, distress, and reproductive concerns. New treatment approaches have been developed in an effort to maintain current disease-specific outcomes while addressing fertility. These approaches have been used successfully to maintain childbearing potential; however, this becomes difficult when RT or CRT is indicated. 8 Both hormonal ablation and oocyte dysfunction are dose dependent. Premature menopause is seen in virtually all women who receive 8 Gy in a single fraction or 15 Gy in multiple fractions to the ovaries. Doses less than 1.5 Gy are generally considered safe in all women. Intermediate doses appear to increase the risk of premature menopause depending on the age of the patient. 9 The median lethal dose (LD50) for oocytes is approximately 2 Gy, depending on the patient’s age at the time of irradiation, but the effect of radiation on fertility is more complex than oocyte depletion and hormonal ablation alone. 10 Data from childhood cancer survivors receiving abdominal RT
demonstrated an elevated rate of spontaneous abortion and smaller birth weight infants. 11 This is caused by a combination of ovarian effects coupled with uterine changes such as damaged endometrial lining (which interferes with placental attachment), changes in uterine blood supply (which lead to fetal growth restriction), and decreased uterine elasticity (which causes preterm delivery). Unfortunately, data from adult patients receiving pelvic RT are sparse. 8 Milgrom et al examined patients receiving pelvic CRT using MR perfusion. 12 They observed changes in cervical length, endometrial thickness, and junctional zone thickness likely related to atrophy and early fibrosis. In a similar study, Arrive et al used traditional MR techniques to compare patients who had received RT with 30 control subjects. 13 Decreases in uterine zonal anatomy, myometrium signal intensity, uterine size, and endometrial thickness were seen. Ovarian function after transposition has been well documented, but there are few data regarding successful pregnancy. 14 Martin et al reported the case of a 33-year-old woman with a stage IB1 cervical cancer treated with trachelectomy followed by RT and brachytherapy. 6 She became pregnant 1 year after therapy and delivered at 27 weeks because of preterm labor. Plante et al reported a case of a 25-year-old woman who underwent a trachelectomy followed by CRT for a stage IB1 cervical cancer. 7 She became pregnant but gave birth to a preterm infant who soon died. Several other cases have been described, but brachytherapy doses have not been standard, and RT usually was not given. 5
e266
M.J. Amsbaugh et al
In our case, we describe the successful treatment of a young woman with vaginal cancer. IG-IMRT was used after ovarian transposition to deliver full-dose CRT while keeping the dose to the ovary and uterus as low as possible. Future studies are needed to confirm comparable oncological outcomes to traditional treatment techniques.
References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin. 2014;64(1):9-29. 2. Lee LJ, Jhingran A, Kidd E, et al. ACR Appropriateness Criteria management of vaginal cancer. Oncology. 2013;27:1166-1173. 3. Hellman K, Silfverswärd C, Nilsson B, Hellström AC, Frankendal B, Pettersson F. Primary carcinoma of the vagina: Factors influencing the age at diagnosis: The Radiumhemmet series 1956–96. Int J Gynecol Cancer. 2004;14:491-501. 4. Carter J, Raviv L, Applegarth L, et al. A cross-sectional study of the psychosexual impact of cancer-related infertility in women: Thirdparty reproductive assistance. J Cancer Surviv. 2010;4:236-246. 5. Browde S, Friedman M, Nissenbaum M. Pregnancy after radiation therapy for carcinoma of the cervix. Eur J Gynaecol Oncol. 1986;7: 63-68.
Practical Radiation Oncology: May-June 2015 6. Martin XJ, Golfier F, Romestaing P, Raudrant D. First case of pregnancy after radical trachelectomy and pelvic irradiation. Gynecol Oncol. 1999;74:286-287. 7. Plante M, Smith EB, Cox S, Silverberg K, Reich S. The case of a viable pregnancy post vaginal radical trachelectomy followed by combined chemo-radiation therapy. Gynecol Oncol. 2011;123:421-423. 8. Noyes N, Knopman JM, Long K, Coletta JM, Abu-Rustum NR. Fertility considerations in the management of gynecologic malignancies. Gynecol Oncol. 2011;120:326-333. 9. Barahmeh S, Al Masri M, Badran O, et al. Ovarian transposition before pelvic irradiation: Indications and functional outcome. J Obstet Gynaecol Res. 2013;39:1533-1537. 10. Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys. 2009;73:1304-1312. 11. Hawkins MM, Smith RA. Pregnancy outcomes in childhood cancer survivors: Probable effects of abdominal irradiation. Int J Cancer. 1989;43:399-402. 12. Milgrom SA, Vargas HA, Sala E, Kelvin JF, Hricak H, Goodman KA. Acute effects of pelvic irradiation on the adult uterus revealed by dynamic contrast-enhanced MRI. Br J Radiol. 2013;86:20130334. 13. Arrive L, Chang YC, Hricak H, Brescia RJ, Auffermann W, Quivey JM. Radiation-induced uterine changes: MR imaging. Radiology. 1989;170(pt 1):55-58. 14. Gubbala K, Laios A, Gallos I, Pathiraja P, Haldar K, Ind T. Outcomes of ovarian transposition in gynaecological cancers: A systematic review and meta-analysis. J Ovarian Res. 2014;7:69.
www.practicalradonc.org
Teaching Case
Successful pregnancy after uterus-sparing chemoradiation therapy for vaginal cancer Mark J. Amsbaugh MD a,⁎, Moataz El-Ghamry MD a , Daniel Metzinger MD b , Thomas Hunter BS a , Neal E. Dunlap MD a a
Department of Radiation Oncology, University of Louisville, Louisville, Kentucky Department of Obstetrics, Gynecology and Women’s Health, University of Louisville, Louisville, Kentucky
b
Received 20 August 2014; revised 21 October 2014; accepted 24 October 2014
Introduction Vaginal cancer is a rare malignancy. An estimated 3170 women will be diagnosed and 880 will die of the disease in 2014. 1 Given these small numbers, treatment approaches have been extrapolated from data in other cancer sites. Brachytherapy with or without external beam radiation therapy (RT) and surgery have been the traditional treatment, but high rates of pelvic failure in more advanced disease have led to increasing use of chemoradiation therapy (CRT). 2 Approximately one fourth of patients are premenopausal at diagnosis. 3 Although not a traditional goal of therapy, fertility is an increasing consideration. It has been shown that women who become infertile as a result of treatment for cancer have high levels of stress, depression, and lower quality of life. 4 Patients who wish to maintain fertility require preservation of oncologic outcomes while being provided with the best chance for future successful pregnancy. Maintenance of ovarian function has been demonstrated by multiple series using different surgical techniques, but reports of successful pregnancy after treatment with pelvic RT are rare. 5-7 We present a case of a young woman with vaginal cancer treated with definitive CRT followed by brachy-
Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation Oncology, Brown Cancer Center, 529 S Jackson St, Louisville, KY 40206. E-mail address: [email protected] (M.J. Amsbaugh).
therapy who spontaneously became pregnant, delivered a healthy child, and currently has no evidence of disease. Special techniques, including daily image guidance, intensity modulation (IG-IMRT), and ovarian transposition, were used.
Teaching case The patient is a 26-year-old woman who presented to her gynecologist with postcoital bleeding. Pelvic examination revealed a mass involving the mucosa, 2 cm from the introitus at the 1-o’clock position in the lower one-third of the vagina. It was fixed to the underlying tissue. Magnetic resonance (MR) imaging of the pelvis demonstrated a 1.6 cm mass, and the patient was taken for an examination under anesthesia with excisional biopsy and cystoscopy. Pathology was consistent with invasive adenocarcinoma, confined to the vagina. Immunohistochemistry identified the tumor as positive for vimentin, cytokeratin AE1/3, CD10, and CK7 (cytokeratin 7); focally positive for CA125 (cancer antigen 125), CD15, CAM5.2, CK20 (cytokeratin 20), and estrogen receptor; and negative for carcinoembryonic antigen, thyroglobulin, thyroid transcription factor-1, synaptophysin, B72.3, CDX2, GCDFP (gross cystic disease fluid protein), calretinin, and thrombomodulin. The patient’s cancer was staged with a mammogram, colonoscopy, and positron emission tomography/computed tomography scan, which revealed a fluorodeoxyglucose-avid tumor
http://dx.doi.org/10.1016/j.prro.2014.10.009 1879-8500/© 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
e264
M.J. Amsbaugh et al
(standardized uptake value 11.6) and no areas that raised concern regarding distant metastatic spread. On the basis of the clinical examination and subsequent workup, the patient was determined to have a stage II adenocarcinoma of the vagina (International Federation of Gynecology and Obstetrics staging). Our multidisciplinary tumor board recommended CRT followed by brachytherapy in accordance with our institutional practice; however, the patient wished to maintain childbearing potential, so robotic-assisted ovarian transposition was performed 3 weeks before RT was initiated. After supine simulation, organs at risk were contoured in the TomoTherapy planning software (Accuray, Sunnyvale, CA), including the ovaries, bladder, rectum, femoral heads, uterine fundus, and lower uterine segment. Pelvic lymph nodes, medial inguinal lymph nodes, and tumor with margin were delineated. Every effort was made to avoid dose spillage to the uterus. The uterine fundus was assigned an importance value of 75 (compared with 135 for the vaginal lesions, and 100 for the
Figure 1
Practical Radiation Oncology: May-June 2015
nodal target volume) in the treatment planning software. The right and left ovaries were given lower importance values of 35 and 4, respectively. IG-IMRT was used to deliver 50.4 Gy at 1.8 Gy per fraction to 95% of the target volume (Fig 1A). The maximum dose was 2.05 Gy to the right ovary and 27.59 Gy to the left ovary. The lower uterine segment received a mean dose of 34.53 Gy. The dose-volume histogram is shown in Fig 2. Concurrent with RT, the patient received cisplatin 40 mg/m 2 weekly. Five days after CRT, she received interstitial brachytherapy. Six iridium 192 lowdose-rate ribbons were implanted with an active length of 6 cm and delivered 25 Gy prescribed to the minimum peripheral dose at 0.5 Gy/h over 50 hours (Fig 1B). The patient developed mild mucositis and diarrhea, which resolved shortly after her CRT. One year after treatment, the patient became pregnant. At 35 weeks, she presented in preterm labor and underwent a cesarean section, delivering a healthy 2300-g baby boy with an Apgar score of 9 and 9. Four years after
(A) External beam radiation dose distribution; (B) brachytherapy dose distribution.
Practical Radiation Oncology: May-June 2015
Figure 2
Pregnancy after CRT for vaginal cancer
e265
Dose-volume histogram for external beam radiation.
treatment, she is free from disease, and her child is healthy and meeting all age-appropriate milestones.
Discussion Gynecological cancers present a management challenge in women who wish to maintain fertility, because traditional treatment strategies have not considered the importance of psychosocial outcomes. Carter et al examined 120 cancer survivors with infertility related to treatment. 4 These women had high levels of depression, distress, and reproductive concerns. New treatment approaches have been developed in an effort to maintain current disease-specific outcomes while addressing fertility. These approaches have been used successfully to maintain childbearing potential; however, this becomes difficult when RT or CRT is indicated. 8 Both hormonal ablation and oocyte dysfunction are dose dependent. Premature menopause is seen in virtually all women who receive 8 Gy in a single fraction or 15 Gy in multiple fractions to the ovaries. Doses less than 1.5 Gy are generally considered safe in all women. Intermediate doses appear to increase the risk of premature menopause depending on the age of the patient. 9 The median lethal dose (LD50) for oocytes is approximately 2 Gy, depending on the patient’s age at the time of irradiation, but the effect of radiation on fertility is more complex than oocyte depletion and hormonal ablation alone. 10 Data from childhood cancer survivors receiving abdominal RT
demonstrated an elevated rate of spontaneous abortion and smaller birth weight infants. 11 This is caused by a combination of ovarian effects coupled with uterine changes such as damaged endometrial lining (which interferes with placental attachment), changes in uterine blood supply (which lead to fetal growth restriction), and decreased uterine elasticity (which causes preterm delivery). Unfortunately, data from adult patients receiving pelvic RT are sparse. 8 Milgrom et al examined patients receiving pelvic CRT using MR perfusion. 12 They observed changes in cervical length, endometrial thickness, and junctional zone thickness likely related to atrophy and early fibrosis. In a similar study, Arrive et al used traditional MR techniques to compare patients who had received RT with 30 control subjects. 13 Decreases in uterine zonal anatomy, myometrium signal intensity, uterine size, and endometrial thickness were seen. Ovarian function after transposition has been well documented, but there are few data regarding successful pregnancy. 14 Martin et al reported the case of a 33-year-old woman with a stage IB1 cervical cancer treated with trachelectomy followed by RT and brachytherapy. 6 She became pregnant 1 year after therapy and delivered at 27 weeks because of preterm labor. Plante et al reported a case of a 25-year-old woman who underwent a trachelectomy followed by CRT for a stage IB1 cervical cancer. 7 She became pregnant but gave birth to a preterm infant who soon died. Several other cases have been described, but brachytherapy doses have not been standard, and RT usually was not given. 5
e266
M.J. Amsbaugh et al
In our case, we describe the successful treatment of a young woman with vaginal cancer. IG-IMRT was used after ovarian transposition to deliver full-dose CRT while keeping the dose to the ovary and uterus as low as possible. Future studies are needed to confirm comparable oncological outcomes to traditional treatment techniques.
References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J Clin. 2014;64(1):9-29. 2. Lee LJ, Jhingran A, Kidd E, et al. ACR Appropriateness Criteria management of vaginal cancer. Oncology. 2013;27:1166-1173. 3. Hellman K, Silfverswärd C, Nilsson B, Hellström AC, Frankendal B, Pettersson F. Primary carcinoma of the vagina: Factors influencing the age at diagnosis: The Radiumhemmet series 1956–96. Int J Gynecol Cancer. 2004;14:491-501. 4. Carter J, Raviv L, Applegarth L, et al. A cross-sectional study of the psychosexual impact of cancer-related infertility in women: Thirdparty reproductive assistance. J Cancer Surviv. 2010;4:236-246. 5. Browde S, Friedman M, Nissenbaum M. Pregnancy after radiation therapy for carcinoma of the cervix. Eur J Gynaecol Oncol. 1986;7: 63-68.
Practical Radiation Oncology: May-June 2015 6. Martin XJ, Golfier F, Romestaing P, Raudrant D. First case of pregnancy after radical trachelectomy and pelvic irradiation. Gynecol Oncol. 1999;74:286-287. 7. Plante M, Smith EB, Cox S, Silverberg K, Reich S. The case of a viable pregnancy post vaginal radical trachelectomy followed by combined chemo-radiation therapy. Gynecol Oncol. 2011;123:421-423. 8. Noyes N, Knopman JM, Long K, Coletta JM, Abu-Rustum NR. Fertility considerations in the management of gynecologic malignancies. Gynecol Oncol. 2011;120:326-333. 9. Barahmeh S, Al Masri M, Badran O, et al. Ovarian transposition before pelvic irradiation: Indications and functional outcome. J Obstet Gynaecol Res. 2013;39:1533-1537. 10. Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys. 2009;73:1304-1312. 11. Hawkins MM, Smith RA. Pregnancy outcomes in childhood cancer survivors: Probable effects of abdominal irradiation. Int J Cancer. 1989;43:399-402. 12. Milgrom SA, Vargas HA, Sala E, Kelvin JF, Hricak H, Goodman KA. Acute effects of pelvic irradiation on the adult uterus revealed by dynamic contrast-enhanced MRI. Br J Radiol. 2013;86:20130334. 13. Arrive L, Chang YC, Hricak H, Brescia RJ, Auffermann W, Quivey JM. Radiation-induced uterine changes: MR imaging. Radiology. 1989;170(pt 1):55-58. 14. Gubbala K, Laios A, Gallos I, Pathiraja P, Haldar K, Ind T. Outcomes of ovarian transposition in gynaecological cancers: A systematic review and meta-analysis. J Ovarian Res. 2014;7:69.
