Normal Tissue Complication Probability Analysis of Acute Gastrointestinal Toxicity in Cervical Cancer Patients Undergoing Intensity Modulated Radiation Therapy and Concurrent Cisplatin

Abstract

Purpose/Objective(s): There have been over 19 randomized trials and three meta-analyses addressing the issue of concomitant chemoradiotherapy (CRT) in carcinoma cervix. The benefit was largely limited to early stage and in post-operative settings (FIGO IIIB accounting for \30%). In developing countries, advanced disease at presentation, poor nutrition including anemia, low tolerability and poor compliance, inadequate supportive therapy and financial constraints pose a major challenge for CRT practice. To evaluate the role of cisplatin based CRT in carcinoma cervix stage IIIB in our setting, we carried out this phase III randomized study. Materials/Methods: Patients with histologically proven FIGO IIIB carcinoma cervix (Sq Ca only) after obtaining written inform consent are randomized to radical radiation therapy (RT: standard arm) or CRT (study arm) with weekly cisplatin (40 mg/m 2 ). With a hypothesis of improvement in absolute survival by 10% with CRT, a-error of 0.05, power of detection of 80% and 10% patients more for attrition a total of 800 patients will be randomized and evaluated. Results: Until March 2010, 727 patients have been randomized. This is a report of first 631 patients treated until December 2008. Out of 631, 316 pts received RT while 315 received CRT. Mean (+ SD) overall treatment time for the whole group was 39 (+7) days. In CRT arm, 83% pts received $ 4 cycles of weekly CT while 17% did not complete planned CT. The treatment related acute grade II/III toxicities in the form of Gastrointestinal (14% vs. 17%), genitourinary (3% vs. 5%), anemia (1.5% vs. 7%), neutropenia (0.5% vs. 16%) and thrombocytopenia (1% vs. 10%) were higher in CRT and required active support more often than RT arm. There were two cisplatin related grade IV ototoxicity and two toxicity related deaths in CRT. With a median follow-up of 36 months (mean 39 months; 12-76), 129 (126 deaths) patients in RT while 110 (105 deaths) patients in CRT had failures. The patterns of failures were comparable. The DFS at 3 years is 52% in RT as compared to 60% in CRT arm (p = 0.051). Late rectal Grade II and III are 10 (2%) vs. 15 (3%) and 8 (0.6%) vs. 4 (0.8%) patients. Conclusions: CRT although feasible appears to be associated with higher incidence of hematological and gastrointestinal toxicities requiring active support. Disease outcome and late sequelae are comparable so far. Completion of accrual and final outcome analysis is essential to evaluate further the exact role of concurrent chemo-radiation in advance carcinoma cervix.Purpose/Objective(s): The ability to assess each tumor voxel with dynamic contrast-enhanced (DCE) MRI provides unique opportunity to characterize functional heterogeneity of tumors, including low-DCE tumor subregions that are likely hypoxic and therapy-resistant. However, quantitative assessment of these high-risk subvolumes has not been incorporated into outcome prediction. This study intended to functionally quantify the functional risk volume (FRV), the absolute subvolume characterized by low DCE, within th...

Phase 2 Multicenter Clinical Trial of Bone Marrow–Sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin for Stage IB-IVA Cervical Cancer

“…Multiple previous retrospective and prospective studies have found that the use of IMRT is associated with reduced normal tissue dose and toxicity compared with conventional radiation techniques (ie, either anteroposterior/posteroanterior or 4-field box methods) (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(26)(27)(28)(29). However, IMRT has not been widely tested in multicenter trials of cervical cancer, in particular, for the large international population of patients undergoing definitive CRT.…”

“…The IMRT plans consisted of 7 to 9 coplanar fields or 2 to 3 coplanar arcs and were designed to optimize bowel and pelvic bone marrow sparing and maintain PTV coverage. The key organ dosimetric constraints were the bowel volume receiving !45 Gy (V 45 ) <200 cm 3 and pelvic bone marrow V 10 and V 20 <90% and <75%, respectively, according to validated normal tissue complication probability models (16,18). The "bowel" was contoured beginning from the axial slice situated 1 cm superior to the superior-most slice containing the PTV and continuing to its most inferior extent in the pelvis, with the outermost extent of the small and large bowel loops outlined on each axial CT slice, as described previously (16).…”

“…Previous studies have found that IMRT reduces the dose to pelvic organs, maintains acceptable target coverage (10), and is associated with reduced toxicity and favorable outcomes in cervical cancer (11)(12)(13)(14)(15). In addition, modeling studies have indicated that optimized IMRT plans can decrease toxicity by approximately twofold (16)(17)(18)(19). Recent evidence has also raised the possibility that positronemission tomography (PET) could further augment the advantages of IMRT (20)(21)(22).…”

A dosimetric analysis of volumetric-modulated arc radiotherapy with jaw width restrictionvs7 field intensity-modulated radiotherapy for definitive treatment of cervical cancer

“…The small intestine is an organ that could develop acute gastrointestinal (GI) toxicity after radiation. Roeske et al 25 and Simpson et al 26 reported that the increasing bowel V45 was correlated with increased GI toxicity in patients with cervical cancer who are undergoing IMRT. Another investigation clearly showed that Grade 2 or more severe acute bowel toxicity was highly correlated with the intestinal cavity receiving 40-50 Gy.…”

Tolerance of combined radiochemotherapy in cervical cancer patients

“…26 Similarly, Simpson et al proved such a dependency for the volume of intestine receiving the dose above 45Gy and the intensification of post radiation reaction. 27 Erpolat et al proved, however, that post-radiation reaction in G ≥ 2 degree in 3D technique compared with IMRT technique related to anemia was present respectively in 2% and 27% of the patients, as for leukopenia respectively in 41.5% and 53%, as for neutropenia respectively in 12% and 24.5% of the patients and as for thrombocytopenia respectively in 0 and 4.5%. The values of V10, 20, 30, 40 were better in IMRT technique, but they did not relate to the diminished post-radiation reactions.…”