Elsevier

Gynecologic Oncology

Volume 120, Issue 2, February 2011, Pages 224-228
Gynecologic Oncology

Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: A phase I study of the Gynecologic Oncology Group

https://doi.org/10.1016/j.ygyno.2010.10.018Get rights and content

Abstract

Objectives

The aim of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of whole abdomen radiation as a chemosensitizer of weekly docetaxel for women with recurrent epithelial ovarian fallopian tube, or peritoneal cancers.

Patients and methods

Women were enrolled on one of three dose levels of docetaxel (20, 25, or 30 mg/m2) administered weekly with concurrent low-dose whole abdominal radiation given as 60 cGy bid 2 days weekly for a total of 6 weeks.

Results

Thirteen women were enrolled and received 70 weekly treatments of docetaxel in combination with radiation therapy. At the first dose level, docetaxel 25 mg/m2, grade 3 fatigue and thrombocytopenia were observed. At the next dose level, docetaxel 30 mg/m2, grade 3 febrile neutropenia, grade 4 thrombocytopenia with epistaxis, and grade 3 diarrhea were observed. Given these dose-limiting toxicities, a lower dose of docetaxel 20 mg/m2 was administered and found to be tolerable. No objective responses were observed among the 10 patients with measurable disease; however, the median progression-free survival (PFS) in all patients was 3.3 months, and 3 of the patients with measurable disease were free of tumor progression after 6 months (30%; 90% confidence interval 8.7–61%).

Conclusions

Twice weekly low-dose whole abdomen radiation during weekly docetaxel 20 mg/m2 was well-tolerated. Given the PFS demonstrated in these women with resistant ovarian cancer, further study of whole abdominal radiation and concurrent chemotherapy may be warranted.

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

References (25)

  • M. Engelen et al.

    Long-term morbidity of adjuvant whole-abdominal radiotherapy (WART) or chemotherapy for early stage ovarian cancer

    Eur J Cancer

    (2009)
  • A. Jemal et al.

    Cancer statistics, 2009

    CA Cancer J Clin

    (2009)
  • Cited by (46)

    • Exploring low-dose radiotherapy to overcome radio-immunotherapy resistance

      2023, Biochimica et Biophysica Acta - Molecular Basis of Disease
    • Opportunities and challenges of low-dose radiation to enable immunotherapy efficacy

      2023, International Review of Cell and Molecular Biology
    • Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01)

      2021, International Journal of Radiation Oncology Biology Physics
      Citation Excerpt :

      Intriguingly, the observed HRS phenomenon using LDFRT as a chemotherapy potentiator has been described to be enhanced in cells harboring mutant P53 expression compared with wildtype P53, supporting the rationale for this technique to be studied in HGSOC, in which P53 mutations are ubiquitous.14 A previous study by the Gynecologic Oncology Group has demonstrated the feasibility of low-dose fractionated whole abdominal radiation therapy (LDFWART) as a chemo-potentiator of docetaxel, dosed at 20 mg/m2 weekly, in recurrent EOC.15 Although no objective responses were observed, the median PFS was noted to be 3.3 months, and the 6-month PFS rate in patients with measurable disease was 30% (90% confidence interval [CI], 8.7%-61%).15

    • Rational combinations of immunotherapy with radiotherapy in ovarian cancer

      2019, The Lancet Oncology
      Citation Excerpt :

      Of the three patients (23% of the 13 cases) with radiologically non-measurable disease, one patient (33%) had a disease-free interval of 21·2 months. Dose-limiting toxic effects were primarily haematological but also included grade 3 diarrhoea in one patient.33 Reducing radiotherapy doses to the whole abdomen while potentiating synergy with systemic therapies was also shown in other studies.

    View all citing articles on Scopus
    1

    Dr. Mohiuddin's current position is Director of the Oncology Centre at King Faisal Specialist Hospital and Research Center in Saudi Arabia.

    View full text