Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: A phase I study of the Gynecologic Oncology Group
Research Highlights
►Radiotherapy is a chemosensitizer to docetaxel in the treatment of ovarian cancer. ►Chemoradiation resulted in stable disease in women with recurrent ovarian cancer. ►Radiotherapy with docetaxel is tolerable in women with recurrent ovarian cancer.
Introduction
In 2009, it is estimated that 21,550 women will be diagnosed and 14,600 women will die of epithelial ovarian cancer in the United States [1]. Despite aggressive primary therapy with debulking surgery followed by platinum and taxane chemotherapy, disease recurs in most women [2]. Chemotherapeutic agents administered to treat this recurrence include the semisynthetic taxane, docetaxel. Docetaxel promotes tubulin assembly and stabilizes microtubules, suggesting an antitumor cytotoxic effect during the G2/M phase of the cell cycle [3], [4]. Clinical response rates of docetaxel in women with the persistent or recurrent disease setting are 22% to 28% [5], [6], [7], [8]. The Gynecologic Oncology Group (GOG) noted a 22% clinical response rate to docetaxel in women with paclitaxel-resistant ovarian and peritoneal cancer who had recurrence within 3 months of completion of paclitaxel and carboplatin [8]. As such, docetaxel is active in paclitaxel-resistant ovarian and peritoneal cancer, but whether other therapeutics may improve upon its antitumor drug effect remains uncertain.
Abdominopelvic radiation has been shown to sterilize ovarian and peritoneal cancers, as a consequence of relatively high intrinsic ovarian or peritoneal cell radiosensitivity [9], [10], [11], [12], [13]. Despite radiation targeting the whole abdomen (i.e., 2250 to 3000 cGy) and pelvis (i.e., pelvic dose of 4500 to 5000 cGy) for treatment of women with suboptimal cytoreductive surgery, intraperitoneal disease persisted in 41% and 44% of women 5 years after treatment [14], [15]. Yet, the use of radiation for intraperitoneal spread of ovarian cancer disease has been limited secondary to radiation-mediated acute toxicities of nausea, emesis, diarrhea, and chronic bowel injury, and treatment delaying myelosuppression [10], [11], [12], [13], [14], [15]. Radiation-mediated toxicities are exacerbated if full-dose cisplatin and paclitaxel chemotherapies are added to treatment together or in sequence [10], [11], [12], [13].
In preclinical experiments, low-dose radiation (50 cGy × 4 fractions) enhanced p53-mutated colon cancer cytotoxicity as compared to single fraction (200 cGy) radiation [16]. Enhanced cytotoxicity is speculated to occur from first dose fraction arrest of cells in the radiosensitive G2/M phase of the cell cycle and subsequent low-dose fractions resulting in cell cytotoxicity [17]. Given that the cytotoxicity of docetaxel is enhanced in G2/M phase cells, we hypothesized that fractionated whole abdominal radiation, through its G2/M phase synchronization, may enhance the sensitivity of ovarian and peritoneal cancers to docetaxel with an acceptable toxicity profile. Therefore, the GOG performed a phase I study using low-dose whole abdominal radiotherapy as a docetaxel chemosensitizer in women with persistent or recurrent advanced ovarian, peritoneal, or fallopian tube cancer. In this study, docetaxel was chosen for dose escalation due to its modest anticancer effect upon chemoresistant ovarian and peritoneal cancers. In GOG-9915, the maximum tolerated dose and dose-limiting toxicities on this regimen were evaluated.
Section snippets
Eligibility criteria
Patients ≥ 18 years of age were eligible if they had persistent or recurrent histologically or cytologically confirmed diagnosis of advanced epithelial ovarian carcinoma, peritoneal carcinoma, or fallopian tube carcinoma following first or subsequent relapse after taxane and platinum-based chemotherapy. All patients had a GOG performance status of 0 or 1, and measurable disease was not required. Laboratory criteria for eligibility included an absolute neutrophil count (ANC) ≥ 1500/μL, platelet
Patient characteristics
Thirteen eligible patients were enrolled from June 2004 to June 2008. Characteristics of those enrolled are summarized in Table 1. All patients had received at least one prior chemotherapy regimen, and all 13 patients had received a taxane.
Treatment and toxicities
Thirteen patients received 70 cycles (median, 6 cycles) of treatment, and all were evaluable for toxicity. Eleven patients were evaluable for dose-limiting toxicities over the full course of treatment (3 patients on dose level 1, 2 patients on dose level 2,
Discussion
Epithelial ovarian cancer is known to be a chemosensitive disease with initial response rates to systemic therapy exceeding 80% following cytoreductive surgery. However, intraperitoneal persistence or recurrence of disease after chemotherapy remains a significant impediment to the cure of this disease. In women with recurrent ovarian and peritoneal cancer, the taxane derivative, docetaxel, has shown clinical activity and a favorable toxicity profile [8], [9], [10], [11]. This phase I study
Conflict of interest statement
The authors wish to report that there are no conflicts of interest.
Acknowledgments
This study was supported in part by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517).
The following Gynecologic Oncology Group member institutions participated in this study: Case Western Reserve University, Indiana University School of Medicine, University of Chicago, University of Iowa Hospitals and Clinics, University of Kentucky, and University of Oklahoma. The authors
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Dr. Mohiuddin's current position is Director of the Oncology Centre at King Faisal Specialist Hospital and Research Center in Saudi Arabia.