Intensity-modulated radiation therapy versus three-dimensional conformal radiation therapy with concurrent nedaplatin-based chemotherapy after radical hysterectomy for uterine cervical cancer: comparison of outcomes, complications, and dose-volume histogram parameters

This study provides a comparison of the outcomes of patients with uterine cervical cancer treated with postoperative IMRT versus postoperative 3DCRT concurrent with weekly nedaplatin. There were no significant differences in OS, LRC and PFS between the cohorts, but IMRT reduced acute and chronic GI complications compared with 3DCRT. Previous reports have suggested a potential role for IMRT in adjuvant treatment of cervical cancer with adverse risk factors [12, 13]. Our retrospective data support the benefit of IMRT in reducing GI complications in postoperative chemoradiation for cervical cancer. A randomized phase III trial of postoperative treatment of endometrial and cervical cancer (RTOG1203) is ongoing for comparison of outcomes and complications between IMRT and 3DCRT, with a focus on acute GI complications.

We used nedaplatin as concurrent chemotherapy with RT. Nedaplatin (cis-diammine-glycoplatinum), a derivative of cisplatin, was developed by Shionogi Pharmaceutical Company in Japan, with the aim of reduced renal and gastrointestinal toxicity, but similar effectiveness, compared to cisplatin [14]. Nedaplatin has a particularly favorable efficacy postoperatively [5, 15] and in locally advanced cervical cancer [16]. Therefore, we considered that substitution of nedaplatin for cisplatin in concurrent chemotherapy may be beneficial for patients with cervical cancer.

We previously reported that V15-V45 of the small bowel loops has high accuracy for prediction of chronic GI complications and that V40 of the small bowel loops >340 mL is an independent risk factor for chronic GI complications in patients treated with adjuvant whole-pelvic RT using conventional 2D or 3DCRT [4]. However, dose patterns differ considerably between conventional 2D or 3DCRT and IMRT, and this raises the question of whether our previous findings for predictors apply in IMRT. In the current study, patients with grade 2 or higher chronic GI complications had significantly greater V15-V45 of the small bowel loops and the 3-year cumulative incidences of these complications were 3 and 45 % in patients with V40 values of ≤340 mL and >340 mL, respectively (p < .001). Therefore, our previous findings for predictors of chronic GI complications after 2D or 3DCRT are also useful in IMRT.

Chopra et al. found that V15 of the small bowel loops and large bowel loop are independent predictors of chronic grade 3 or higher complications [17], and recommended risk cut-off values of <275 mL and <250 mL, respectively. The difference in cut-off values in Chopra et al. and the current study may be due to treatment with or without brachytherapy, different endpoints (grade 2 or 3), different chemotherapy regimens (nedaplatin or cisplatin), and the higher DVH parameters of the small bowel loops and large bowel loop in our study (Table 3). In fact, only 9 of our patients (15 %) had V15 of the small bowel loops <275 mL. Therefore, the difference in DVH parameters might be due to differences in the physical characteristics of the patients in the two studies. There were many thin patients in our study (41/62 patients had BMI <22). However, a further study is required to determine the correlation between physical characteristics and bowel volume, and to seek better predictors of chronic GI complications.

A predictive model of acute GI complications is described in the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) guidelines [18]. QUANTEC indicated that V15 of the small bowel loops should be <125 mL or V45 of the bowel bag should be <195 mL to reduce the grade 3 complication rate to <10 %. However, in the current study the mean volumes of V15 of the small bowel loops for 3DCRT and IMRT were 428 and 411 mL, respectively, and the mean volumes of V45 of the bowel bag for 3DCRT and IMRT were 891 and 489 mL, respectively (Table 3). Therefore, the volumes of the small bowel loops or bowel bag were in excess of the QUANTEC volumes to reduce grade 3 complications to <10 % in both IMRT and 3DCRT. Consequently, a high rate of grade 3 acute GI complications of 20 % occurred in the IMRT group, but this was still less than the rate of acute GI complications after 3DCRT.

We previously reported that the small bowel loops may be better predictors of chronic GI complications compared to the bowel bag in 2D and 3DCRT [4]. However, in this study using 3DCRT and IMRT, patients with grade 2 or higher chronic GI complications had significantly greater V15-V45 volumes in the small bowel loops and bowel bag (Fig. 4a, b); and patients with grade 3 acute GI complications had significantly greater V40 and V45 volumes in the small bowel loops and bowel bag (Fig. 4c, d). The grades of acute GI complications also increased in a volume-dependent manner using V40 and V45 of the small bowel loops or bowel bag, although the relationship was not significant. Wedlake et al. found that cumulative acute GI symptoms measured by questionnaire are associated with consequential late symptoms [19]. Additionally, QUANTEC predicted that chronic GI complications are likely to be related to maximum dose or volume threshold parameters that are qualitatively similar to those related to the risk of acute GI complications [18]. Collectively, these findings indicate that bowel bag parameters are useful predictors of chronic and acute GI complications in 3DCRT and IMRT.

Patients treated with IMRT, for which the pelvic bone was not used as a planning constraint, showed a greater incidence of grade 3 or higher acute HT complications (p < .05). Klopp et al. found that V40 of the pelvic bone predicted development of HT complications in the RTOG 0418 prospective trial [20]. Therefore, in our study, the cause of the significant increase in HT complications in IMRT may have been a significantly greater V40 of the pelvic bone, compared to patients who received 3DCRT (Fig. 2 and Table 4). These data indicate that bone marrow sparing IMRT is useful because IMRT is particularly effective at reducing the volume receiving a relatively high dose. Conversely, Mell et al. and Albuquerque et al. found that V10 and V20 of the pelvic bone more accurately predicted HT complications, compared to V30 or V40 [11, 21]. However, patients in our study who received IMRT had a greater incidence of HT complications and a significantly reduced V20 of the pelvic bone compared to patients who received 3DCRT (Table 4). These data indicate that the relationship between HT complications and DVH parameters of the pelvic bone is complicated. Therefore, future studies are required to examine the clinical benefit of IMRT in reducing HT complications and to validate the critical DVH predictors of these complications.

The findings in this study should be interpreted with an understanding of the following limitations. First, the heterogeneity in the treatment planning approach over the periods of the study (3DCRT and IMRT); the low number of events, especially in IMRT; and the lack of a pre-specified model or protocol are important limitations of the data and analysis. Second, we used weekly nedaplatin as concurrent chemotherapy, whereas chemoradiation therapy with 40 mg/m² weekly cisplatin is now accepted as the standard first-line treatment. Therefore, we cannot exclude the possibility that the DVH parameter predictors found in this study may be chemotherapy-type specific, particularly as Bazan et al. showed that DVH predictors for acute HT complications in patients receiving IMRT are dependent on the type of chemotherapy [22].