Gynecologic Cancer

  • Charles A. Kunos
  • Jeffrey Fabien
  • Yuxia Zhang
  • James Brindle
  • Nina A. Mayr
Part of the Medical Radiology book series (MEDRAD)


Gynecologic cancers are leading causes of death in women worldwide. When relapse occurs after initial treatment, the use of conventional radiation therapy is difficult due to relative intolerance of normal tissue to further therapy. Stereotactic body radiation therapy (SBRT) has emerged as at least one means to provide sterilizing doses of radiation among tissues that have received previous irradiation or exposed to many courses of chemotherapy. Clinical experience with SBRT now demonstrates the safety and efficacy of this treatment modality. Technical aspects, treatment parameters, management of toxicity, and comments on future directions of SBRT for gynecologic cancer management are discussed.


Gynecologic Cancer Stereotactic Body Radiation Therapy Occult Metastatic Disease Stereotactic Body Radiation Therapy Treatment Deliver Radiation Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Conflict of Interest

There are no potential conflicts of interest among the authors and this manuscript. There are no financial or non-financial competing interests. This manuscript has been seen, read, and agreed upon in its content by all the designated authors. This manuscript has not been submitted or published elsewhere.


  1. Acs G, Zhang P, McGrath C, Acs P, McBroom J, Mohyeldin A, Liu S, Lu H, Verma A (2003) Hypoxia-inducible erythropoietin singaling in squamous dysplasia and squamous cell carcinoma of the uterine cervix and its potential role in cervical carcinogenesis and tumor progression. Am J Pathol 162(6):1789–1806PubMedCrossRefGoogle Scholar
  2. Adriaens I, Smitz J, Jacquet P (2009) The current knowledge on radiosensitivity of ovarian follicle development stages. Hum Reprod Update 15(3):359–377PubMedCrossRefGoogle Scholar
  3. American Cancer Society (2010) Cancer Facts & Figures 2010. American Cancer Society, AtlantaGoogle Scholar
  4. Antypas C, Pantelis E (2008) Performance evaluation of a CyberKnife® G4 image-guided robotic stereotactic radiosurgery system. Phys Med Biol 53:4697–4718PubMedCrossRefGoogle Scholar
  5. Benedict S, Cardinale R, Wu Q, Zwicker R, Broaddus W, Mohan R (2001) Intensity-modulated stereotactic radiosurgery using dynamic micro-multileaf collimation. Int J Radiat Oncol Biol Phys 50(3):751–758PubMedCrossRefGoogle Scholar
  6. Bernhard E, Stanbridge E, Gupta S et al (2000) Direct evidence for the contribution of activated N-ras and K-ras oncogenes to increased intrinsic radiation resistance in human tumor cell lines. Cancer Res 60:6597–6600PubMedGoogle Scholar
  7. Branca M, Ciotti M, Santini D, Di Bonito L, Benedetto A, Giorgi C, Paba P, Favalli C, Costa S, Agarossi A et al (2004) Activation of the ERK/MAP kinase pathway in cervical intraepithelial neoplasia is related to grade of the lesion but not to high-risk human papillomavirus, virus clearance, or prognosis in cervical cancer. Am J Clin Pathol 122:902–911PubMedCrossRefGoogle Scholar
  8. Chiao TB, Lee AJ (2005) Role of pentoxifylline and vitamin E in attenuation of radiation-induced fibrosis. Ann Pharmacother 39(3):516–522PubMedCrossRefGoogle Scholar
  9. Choi C, Cho C, Yoo S, Kim M, Yang K, Yoo H, Seo W, Kang J, Lee D, Lee K et al (2009) Image-guided stereotactic body radiation therapy in patients with isolated para-aortic lymph node metastases from uterine cervical and corpus cancer. Int J Radiat Oncol Biol Phys 74(1):147–153PubMedCrossRefGoogle Scholar
  10. Chung E, Brown A, Asano H, Mandler M, Burgan W, Carter D, Camphausen K, Citrin D (2009) In vitro and in vivo radiosensitization with AZD6244 (ARRY-142886), an inhibitor of mitogen-activated protein kinase/extracellular signal-related kinase 1/2 kinase. Clin Cancer Res 15(9):3050–3057PubMedCrossRefGoogle Scholar
  11. Deodata F, Macchia G, Grimaldi L, Ferradina G, Lorusso D, Salutari V, Cilla S, Valenti V, Cellini N, Piermattei A et al (2009) Stereotactic radiotherapy in recurrent gynecological cancer: a case series. Oncol Rep 22(2):415–419Google Scholar
  12. Dickens C (1981) Personalized fixation using a vacuum consolidation technique. Br J Radiol 54:257–258PubMedCrossRefGoogle Scholar
  13. Du X, Jiang T, Wen Z, Li Q, Gao R, Wang F (2009) Differential expression profiling of gene response to ionizing radiation in two endometrial cancer cell lines with distinct radiosensitivities. Oncol Rep 21:625–634PubMedGoogle Scholar
  14. Duenas-Gonzalez A, Zarba J, Patel F, Alcedo J, Beslija F, Casanova L, Pattarunataporn P, Hameed S, Blair J, Barraclough H et al (2011) A phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 29(13):1678–1685PubMedCrossRefGoogle Scholar
  15. Dunst J, Kuhnt T, Strauss HG, Krause U, Pelz T, Koelbl H, Haensgen G (2003) Anemia in cervical cancers: impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys 56(3):778–787Google Scholar
  16. Echner G, Kilby W, Lee M, Earnst E, Sayeh S, Schlaefer A, Rhein B, Dooley J, Lang C, Blank O et al (2009) The design, physical properties and clinical utility of an iris collimator for robotic radiosurgery. Phys Med Biol 54:5359–5380PubMedCrossRefGoogle Scholar
  17. Eklund H, Uhlin U, Farnegardh M, Logan DT, Nordlund P (2001) Structure and function of the radical enzyme ribonucleotide reductase. Prog Biophys Mol Biol 77(3):177–268PubMedCrossRefGoogle Scholar
  18. Feldmeier J (2008) Hyperbaric oxygen therapy for delayed radiation injuries. In: Neuman T, Thom S (eds) Physiology and medicine of hyperbaric oxygen therapy. Saunders Elsevier, Philadelphia, pp 231–256CrossRefGoogle Scholar
  19. Ferlay J, Shin H, Bray F, Forman D, Mathers C, Parkin D (2010) GLOBOCAN 2008 Cancer Incidence and Mortality Worldwide. Lyon, France: International Agency for Research on Cancer
  20. Ferrandina G, Mey V, Nannizzi S, Ricciardi S, Petrillo M, Ferlini C, Danesi R, Scambia G, Tacca M (2010) Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine enzymes in primary ovarian cancer. Cancer Chemother Pharmacol 65(4):679–686PubMedCrossRefGoogle Scholar
  21. Fowler J (2010) 21 years of biologically effective dose. Br J Radiol 83(991):554–568PubMedCrossRefGoogle Scholar
  22. Fowler J, Tome W, Fenwick J, Mehta M (2004a) A challenge to traditional radiation oncology. Int J Radiat Oncol Biol Phys 60(4):1241–1256PubMedCrossRefGoogle Scholar
  23. Fowler J, Welsh J, Howard S (2004b) Loss of biological effect in prolonged fraction delivery. Int J Radiat Oncol Biol Phys 59(1):242–249PubMedCrossRefGoogle Scholar
  24. Gardner L, Li Q, Park M, Flanagan W, Semenza G, Dang C (2001) Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem 276:7919–7926PubMedCrossRefGoogle Scholar
  25. Gerszten P, Novotny JJ, Quader M, Dewald V, Flickinger J (2010) Prospective evaluation of a dedicated spine radiosurgery program using the Elekta Synergy S system. J Neurosurg 113 Suppl:236–241.Google Scholar
  26. Goda N, Ryan H, Khadivi B, McNulty W, Rickert R, Johnson R (2003) Hypoxia-inducible factor 1α is essential for cell cycle arrest during hypoxia. Mol Cell Biol 23(1):359–369PubMedCrossRefGoogle Scholar
  27. Gothard L, Cornes P, Brooker S, Earl J, Glees J, Hall E, Peckitt C, Tait D, Yarnold J (2005) Phase II study of vitamin E and pentoxifylline in patients with late side effects of pelvic radiotherapy. Radiother Oncol 75(3):334–341PubMedCrossRefGoogle Scholar
  28. Grigsby PW, Siegel BA, Dehdashti F (2001) Lymph node staging by positron emission tomography in patients with carcinoma of the cervix. J Clin Oncol 19(17):3745–3749PubMedGoogle Scholar
  29. Hall EJ (2000) Radiobiology for the radiologist. Lippincott Williams & Wilkins: Philadelphia. p 588 Google Scholar
  30. Hall EJ, Hei TK (2003) Genomic instability and bystander effects induced by high-LET radiation. Oncogene 22(45):7034–7042PubMedCrossRefGoogle Scholar
  31. Higginson D, Morris D, Jones E, Clarke-Pearson D, Varia M (2011) Stereotactic body radiotherapy (SBRT): Technological innovation and application in gynecologic oncology. Gynecol Oncol 120(3):404–412PubMedCrossRefGoogle Scholar
  32. Holmes W, Soprano D, Soprano K (2003) Early events in the induction of apoptosis in ovarian carcinoma cells by CD437: activation of the p38 MAP kinase signal pathway. Oncogene 22:6377–6386PubMedCrossRefGoogle Scholar
  33. Homesley H, Filiaci V, Gibbons S, Long H, Cella D, Spiritos N, Morris R, DeGeest K, Lee R, Montag A (2009) A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol 112(3):543–552PubMedCrossRefGoogle Scholar
  34. Hoogeman M, Prévost J-B, Nuyttens J, Pöll J, Levandag P, Heijmen B (2009) Clinical Accuracy of the Respiratory Tumor Tracking System of the Cyberknife: Assessment By Analysis of Log Files. Int J Radiat Oncol Biol Phys 74(1):297–303PubMedCrossRefGoogle Scholar
  35. Hsu C-Y, Bristow R, Cha M, Wang B, Ho C-L, Kurman R, Wang T-L, Shih I-M (2004) Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas. Clin Cancer Res 10:6432–6436PubMedCrossRefGoogle Scholar
  36. Kamei H, Jackson R, Zheleva D, Davidson F (2010) An integrated pharmacokinetic-pharmacodynamic model for an Aurora kinase inhibitor. J Pharmacokinet Pharmacodyn 37:407–434PubMedCrossRefGoogle Scholar
  37. Karlsson A, Helou K, Walentinsson A, Hedrich H, Szpirer C, Levan G (2001) Amplification of Mycn, Ddx1, Rrm2, and Odc1 in rat uterine endometrial carcinomas. Genes Chromosom Cancer 31(4):345–356PubMedCrossRefGoogle Scholar
  38. Kilby W, Dooley J, Kuduvalli G, Sayeh S, Maurer C (2010) The Cyberknife robotic radiosurgery system in 2010. Technol Cancer Res Treat 9(5):431–438Google Scholar
  39. Kim Y, Kim J, Jeong K, Seong J, Suh C, Kim G (2009) Dosimetric comparisons of three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and helical tomotherapy in whole abdominopelvic radiotherapy for gynecologic malignancy. Technol Cancer Res Treat 8(5):369–377PubMedGoogle Scholar
  40. Kolberg M, Strand KR, Graff P, Andersson KK (2004) Structure, function, and mechanism of ribonucleotide reductases. Biochim Biophys Acta 1699(1–2):1–34PubMedGoogle Scholar
  41. Kunos C, Von Gruenigen V, Waggoner S, Brindle J, Zhang Y, Myers B, Funkhouser G, Wessels B, Einstein D (2008) Cyberknife radiosurgery for squamous cell carcinoma of the vulva after prior pelvic radiation therapy. Technol Cancer Res Treat 7(5):375–380PubMedGoogle Scholar
  42. Kunos C, Chen W, DeBernardo R, Waggoner S, Brindle J, Zhang Y, Williams J, Einstein D (2009a) Stereotactic body radiosurgery for pelvic relapse of gynecologic malignancies. Technol Cancer Res Treat 8(5):393–400PubMedGoogle Scholar
  43. Kunos C, Chiu S, Pink J, Kinsella T (2009b) Modulating radiation resistance by inhibiting ribonucleotide reductase in cancers with virally or mutationally silenced p53 protein. Radiat Res 172(6):666–676PubMedCrossRefGoogle Scholar
  44. Kunos C, Sill M, Waggoner S, Fracasso P (2009c) A phase 1 study using low dose abdominal radiation as a docetaxel chemosensitizer for recurrent, persistent or advanced ovarian, peritoneal, or fallopian tube cancer. Gynecol Oncol (in press)Google Scholar
  45. Kunos C, Radivoyevitch T, Pink J, Chiu S, Stefan T, Jaccobberger J, Kinsella T (2010) Ribonucleotide Reductase Inhibition Enhances Chemoradiosensitivity of Human Cervical Cancers. Radiation Res 174(5):574–581PubMedCrossRefGoogle Scholar
  46. Kunos C, Brindle J, Zhang Y, DeBernardo R (2011) A prospective phase 2 evaluation of stereotactic body radiosurgery for gynecologic malignancies. Cyberknife Robotic Radiosurgery Summit February 12, San Francisco, CAGoogle Scholar
  47. Lee Y, Park N, Kim J, Song Y, Kang S, Lee H (2008) Gamma-knife radiosurgery as an optimal treatment modality for brain metastases from epithelial ovarian cancer. Gynecol Oncol 108(3):505–509PubMedCrossRefGoogle Scholar
  48. Mackie T, Holmes T, Swerdloff S, Reckwerdt P, Deasy J, Yang J, Paliwal B, Kinsella T (1993) Tomotherapy: a new concept for the delivery of dynamic conformal radiotherapy. Med Phys 20(6):1709–1719PubMedCrossRefGoogle Scholar
  49. Markman M (2006) Clinical efficacy supporting the role of intraperitoneal drug delivery in the primary chemotherapeutic management of small-volume residual advanced ovarian cancer. Semin Oncol 33 (6 (Suppl 12)):S3–S7Google Scholar
  50. Monk B, Sill M, McMeekin D, Cohn D, Ramondetta L, Boardman C, Benda J, Cella D (2009) Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a gynecologic oncology group study. J Clin Oncol 27(28):4649–4655PubMedCrossRefGoogle Scholar
  51. Munro T (1970) The relative radiosensitivity of the nucleus and cytoplasm of the Chinese hamster fibroblast. Radiat Res 42:451–470PubMedCrossRefGoogle Scholar
  52. Murphy J, Christman-Skieller C, Kim J, Dietrich S, Chang D, Koong A (2010) A dosimetric model of duodenal toxicity after stereotactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys 78(5):1420–1426PubMedCrossRefGoogle Scholar
  53. Ozhasoglu C, Saw C, Hungcheng C, Burton S, Komanduri K, Huq S, Heron D (2008) Synchrony–Cyberknife Respiratory Compensation Technology. Med Dosimetry 33(2):117–123CrossRefGoogle Scholar
  54. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R et al (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a gynecologic oncology group study. J Clin Oncol 21(17):3194–200PubMedCrossRefGoogle Scholar
  55. Park C, Papiez L, Zhang S, Story M, Timmerman R (2008) Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol Phys 70(3):847–852PubMedCrossRefGoogle Scholar
  56. Piao C, Jin M, Lee S, Amatya P, Hyun J-W, Chang I-Y, You H (2009) Ribonucleotide reductase small subunit p53R2 suppresses MEK-ERK activity by binding to ERK kinase 2. Oncogene 28:2173–2184PubMedCrossRefGoogle Scholar
  57. Pollock P, Gartside M, Dejeza L et al (2007) Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26:7158–7162.Google Scholar
  58. Randall M, Filiaci V, Spirtos N, Mannel R, Fowler J, Thigpen J, Benda J (2006) Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a gynecologic oncology group study. J Clin Oncol 24(1):36–44PubMedCrossRefGoogle Scholar
  59. Rochet N, Sterzing F, Jensen A, Dinkel J, Herfarth K, Schubert K, Eichbaum M, Schneeweiss A, Sohn C, Debus J et al (2008) Helical tomotherapy as a new treatment technique for whole abdominal irradiation. Strahlenther Onkol 184(3):145–149PubMedCrossRefGoogle Scholar
  60. Rose PG, Adler LP, Rodriguez M, Faulhaber PF, Abdul-Karim FW, Miraldi F (1999) Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: a surgicopathologic study. J Clin Oncol 17(1):41–45PubMedGoogle Scholar
  61. Rose P, Ali S, Watkins E, Thigpen J, Deppe G, Clark-Pearson D, Insalaco S (2007) Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a gynecologic oncology group study. J Clin Oncol 25(19):2804–2810PubMedCrossRefGoogle Scholar
  62. Schwartz J, Siegel B, Dehdashti F, Grigsby P (2007) Association of post-therapy positron emission tomography with tumor response and survival in cervical carcinoma. JAMA 298(19):2289–2295CrossRefGoogle Scholar
  63. Shaw E, Scott C, Souhami L, Dinapoli R, Kline R, Loeffler J, Farnan N (2000) Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metases: Final report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys 47(2):291–298PubMedCrossRefGoogle Scholar
  64. Shenouda G, Mehio A, Souhami L, Duclos M, Portelance L, Belenkov A, Chow T (2006) Erythropoietin receptor expression in biopsu specimens from patients with uterine cervix squamous cell carcinoma. Int J Gynecol Cancer 16(2):752–756PubMedCrossRefGoogle Scholar
  65. Sherouse G, Bourland J, Reynolds K et al (1990) Virtual simulation in the clinical setting: some practical considerations. Int J Radiat Oncol Biol Phys 19:1059–1065PubMedCrossRefGoogle Scholar
  66. Sklar M (1988) The ras oncogenes increase the intrinsic resistance of NIH 3T3 cells to ionizing radiation. Science 239:645–647PubMedCrossRefGoogle Scholar
  67. Swamidas V, Mahantshetty U, Goel V, Engineer R, Deshpande D, Sarin R, Shrivastava S (2009) Treatment planning of epithelial ovarian cancers using helical tomotherapy. J Appl Clin Med Phys 10(4):96–105CrossRefGoogle Scholar
  68. Thomas G, Ali S, Hoebers F, Darcy K, Rodgers W, Patel M, Abulafia O, Lucci Jr, Begg A (2008) Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 108(2):317–325.Google Scholar
  69. Wang J, Huang H, Lo S, Yuh W, Mayr N (2010) A generalized linear-quadratic model for radiosurgery, stereotactic body radiation therapy, and high-dose rate brachytherapy. Sci Transl Med 2(39):39–48CrossRefGoogle Scholar
  70. Wilcox E, Daskalov G (2007) Evaluation of GAFCHROMIC EBT film for Cyberknife® dosimetry. Med Phys 34(6):1967–1974PubMedCrossRefGoogle Scholar
  71. Winter Wr, Maxwell G, Tian C, Sobel E, Rose G, Thomas G, Carlson J (2004) Association of hemoglobin level with survival in cervical carcinoma patients treated with concurrent cisplatin and radiotherapy: a Gynecologic Oncology Group Study. Gynecol Oncol 94(2):495–501PubMedCrossRefGoogle Scholar
  72. Wunderink W, Mendez Romero A, de Kruijf W, de Boer H, Levendag P, Heijmen B (2008) Reduction of respiratory liver tumor motion by abdominal compression in stereotactic body frame, analyzed by tracking fiducial markers implanted in liver. Int J Radiat Oncol Biol Phys 71(3):907–915PubMedCrossRefGoogle Scholar
  73. Yeh T, Marsh V, Bernat B et al (2007) Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 13:1576–1583PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Charles A. Kunos
    • 1
    • 3
  • Jeffrey Fabien
    • 1
  • Yuxia Zhang
    • 1
  • James Brindle
    • 1
  • Nina A. Mayr
    • 2
  1. 1.Department of Radiation Oncology and Case Comprehensive Cancer CenterUniversity Hospitals Seidman Cancer Center and Case Western Reserve University School of MedicineClevelandUSA
  2. 2.Department of Radiation Oncology, Arthur G. James Cancer HospitalOhio State University College of MedicineColumbusUSA
  3. 3.Department of Radiation OncologyUniversity Hospitals of ClevelandClevelandUSA

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