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Dose-Escalated IMRT Plus Chemo Studied in Locally Advanced Cervical Cancer

Dose-Escalated IMRT Plus Chemo Studied in Locally Advanced Cervical Cancer

BIRMINGHAM, AL-Paraaortic lymph node metastases are a particularly bad finding in cervical cancer, predicting extrapelvic relapse, more rapid progression, and a shorter survival duration. Combined- modality chemotherapy plus radiation improves outcomes, but radiation is dose-limiting because many vulnerable organs are located in the target area. Jennifer F. De Los Santos, MD, and colleagues will attempt to overcome the dose-limitation problem in a phase I trial of dose-escalated intensity-modulated radiation therapy (IMRT) plus cisplatin (Platinol), coupled with amifostine (Ethyol) cytoprotection, in patients with intact cervical carcinoma and positive para-aortic nodes. Dr. De Los Santos, an assistant professor of radiation oncology at the University of Alabama, Birmingham, noted that the planned study will include researchers not only from her own institution but also from the University of Chicago, the Fox Chase Cancer Center, and the University of Oklahoma. GI Toxicity Historically High
"The 4-year overall survival of patients with carcinoma of the uterine cervix and involved paraaortic lymph nodes is 30%," Dr. De Los Santos said. "The Radiation Therapy Oncology Group [RTOG] 92-10 trial investigated dose-escalation with hyperfractionated radiotherapy but reported unacceptable acute and late toxicities, notably 50% grade 4 acute gastrointestinal [GI] toxicity and a cumulative incidence of late grade 3 and grade 4 toxicities of 34% at 36 months." Several trials have shown that it is possible to set IMRT to deliver doses as high as 50.4 Gy to the para-aortic nodes while sparing the small bowel and rectum. Dr. De Los Santos also said that research in Japan recently documented the feasibility of delivering dynamic arc conformal therapy, a simple form of IMRT, in 29 patients with isolated para-aortic nodal recurrences, to doses of 50 to 63.4 Gy (median, 60 Gy).[1] "Two-year infield recurrence-free survival was 58%, with acute grade 1 and 2 GI toxicities occurring in 31% and 17% of patients, respectively. There were no grade 3 complications, either acute or late," she reported. Adding Cytoprotection
Because amifostine has been associated with a reduction in acute grade 2 or 3 bladder and lower GI tract toxicities in patients being treated with definitive or postoperative radiation for pelvic malignancies, Dr. De Los Santos and colleagues decided to test this cytoprotective drug with IMRT in cervical cancer patients who had para-aortic metastases. "The primary objective will be to determine the maximum tolerated dose of external-beam radiation therapy [EBRT] to the paraaortic nodes when using IMRT and amifostine. Secondary endpoints will be local-regional control, overall survival, and acute and late toxicity," she said. The trial will enroll patients who have had no prior therapy other than cervix biopsy with or without endoscopic resection of enlarged pelvic nodes. They must have positive para-aortic nodes, defined as nodes at least 1.5 cm or less than 1.5 cm that are biopsy- or PETscan positive, and no other evidence of distant metastasis. Study Design
Treatment will include EBRT to 45 Gy in 25 fractions to pelvic and para-aortic fields, with concurrent cisplatin at 40 mg/m2/wk for 6 weeks. Two low-dose radiation or five high-dose radiation insertions will be done over 2 to 2.5 weeks to deliver an equivalent of 85 to 90 Gy within 56 days, and parametrial and pelvic nodal boosts will occur in the interval between brachytherapy treatments. IMRT para-aortic nodal boosts will be given at the same time as the parametrial/pelvic nodal boosts. "Amifostine 500 mg SC will be administered 30 to 45 minutes prior to each EBRT treatment except on the days of cisplatin infusion," Dr. De Los Santos said. "Amifostine 500 mg SC will be administered prior to each dose of platinum chemotherapy." The radiation technique will be a standard four-field box of the pelvis with the isocenter placed at the L5/S1 interspace, matched to a para-aortic IMRT chimney, she said. IMRT fields will treat all microscopic disease in the para-aortic chain from the T11/12 interspace to the L5/S1 interspace, and a sequential boost to the involved para-aortic nodes with reduced IMRT fields will be delivered at the time of the parametrial/pelvic nodal boost. The trial is a phase I doseescalation study to determine the maximum tolerated dose of radiation in patients treated with IMRT and amifostine. The dose is stratified by tumor volume in the paraaortic region, so that larger volumes will initially receive slightly lower doses (see Table 1) to avoid overdosing critical structures (eg, bowel, kidney, spinal cord, etc).


1. Aoki T, Nagata Y, Mizowaki T, et al: Clinical evaluation of dynamic arc conformal radiotherapy for paraaortic lymph node metastasis. Radiother Oncol 67(1):113-118, 2003.
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