Based on the five randomized controlled trials, concurrent cisplatin-based chemoradiotherapy has become the standard treatment for locally advanced cervical cancer[12-16]. Several studies have demonstrated that the addition of concurrent chemotherapy to postoperative radiation may improve pelvic control and survival rate for patients with high- or intermediate-risk factors[10-12, 26, 27]. Although the benefit of postoperative RT combined with chemotherapy is obvious, treatment of the pelvic nodal regions carries inherent side effects. In fact, a generic GI dysfunction, urinary frequency, diarrhea, bleeding, and obstruction, have been described as major toxic consequences of surgery combined with adjuvant radiotherapy for gynecologic malignancy. Based on the results of a previous clinical trial, cisplatin or cisplatin-fluorouracil with radiotherapy failed to control distant occult micrometastases very well[12, 18]. To reduce the risk of sequelae of postoperative radiotherapy and decrease distant occult micrometastases, we explored the use of IMRT with concurrent cisplatin and docetaxel chemotherapy in our cervical cancer patients after hysterectomy (type III).
To our best knowledge, the cisplatin and docetaxel combined regimen has not been tested previously in the adjuvant setting for uterine cervical carcinoma. However, there is no standard dosing schedule of concurrent RT with cisplatin-docetaxel chemotherapy. Alvarez et al. reported the results of the phase I study with RT and weekly doses of docetaxel, starting at 20 mg/m2 and escalating by 10 mg/m2. The maximum tolerated doses in this study were weekly 40 mg/m2 docetaxel for 4–6 cycles. Rue et al. showed that triweekly cisplatin 75 mg/m2 chemotherapy concurrent with radiotherapy is more effective and feasible than the conventional weekly cisplatin 40 mg/m2 regimen in patients with locally advanced cervical cancer.
We believe this study is the first to report that triweekly cisplatin 75 mg/m2 and docetaxel 75 mg/m2 chemotherapy concurrent with radiotherapy is feasible and has better survival outcome than reported in previous studies [10, 12, 36]. In the present study, we found that the 3-year OS rate was 98.7%. Postoperative pelvic IMRT with concurrent cisplatin and docetaxel chemotherapy was effective in preventing local recurrence. Although distant sites are the most common sites of failure, the distant relapse control rate was good. Only four patients (5.3%) developed local recurrence, and four patients (5.2%) had distant recurrence. This result is better than those of previous studies[25, 29, 32]. A possible explanation of our results is that the high peak concentration of cisplatin and docetaxel may be more effective not only in enhancing the synergy of chemoradiation but also in eliminating micrometastases, with resulting decrease of local failure and distant metastasis and eventual improvement in survival.
A retrospective planning study conducted a dosimetric comparison of pelvic IMRT and conventional pelvic radiotherapy plans for gynecologic cancer and demonstrated that IMRT can improve target coverage and reduce the dose to critical structures in gynecologic patients. Hsselle et al. showed that IMRT shows a reduced incidence of acute toxicities in patients with cervical cancer. Kim et al. have reported grade 3 to 4 acute GI toxicity and GU toxicity in 3% and 11% of patients, respectively. In comparison, our study showed acute grade 3 GI toxicity in 1% of the patients, and there was no grade 3 GU toxicity. These results are very similar to those reported in previous studies that used pelvic IMRT and concurrent cisplatin chemotherapy[25, 36]. The use of IMRT greatly assisted in the conformality of dose distribution, confined the high-dose portions of radiation fields, and reduced the absorbed dose and volume of critical organs, resulting in reduced overall toxicity. Grade 1-2 GI and GU toxicities occurred more frequently in our study than in the one by Chen. However, these were easily managed and did not cause delay in therapy.
To reduce myelotoxicity, we used the bone marrow-sparing IMRT approach. This technique has been shown to dosimetrically reduce the volume of bone marrow irradiated. In our study, the volume of marrow receiving 20 Gy was reduced to <80%, and the volume receiving 35 Gy was reduced to <45%. Acute grade 3 hematologic toxicity was seen in 7% of our patients. This finding is similar to the hematologic toxicity reported by Chen (6%) and is superior to the results reported by Kim et al. (30%) and Shih et al.(32.3%). This difference may be related to the use of triweekly cisplatin and docetaxel chemotherapy. In addition, other risk factors may account for these differences in toxicity, including low body mass index, smoking, and other causes of microvascular disease.
Mundt et al. suggested that definitive pelvic IMRT is associated with less chronic GI toxicity than conventional pelvic RT (11% vs. 50%). Shih et al. reported that no patients who underwent postoperative pelvic IMRT and concurrent chemotherapy experienced grade 3 or higher late toxicities. However, as there has been no randomized controlled clinical study yet, it is not clear whether concurrent chemotherapy increases the incidence of late toxicity in the setting of adjuvant therapy. Our result showed 1.3% of patients had grade 3 late toxicity, which is similar to a previous study’s results with a grade 3 late toxicity rate of 1.8%, despite our follow-up being relatively limited. In this study, the addition of concurrent triweekly cisplatin and docetaxel chemotherapy to pelvic IMRT did not increase late GI and GU toxicities.
We further evaluated the feasibility of IMRT to retain ovarian function. The degree and persistence of ovarian damage and suppression of ovarian function is related to the patient’s age and the dose of radiation delivered to the ovaries. The importance of the radiation dose is clear because a low dose can save many follicles and repair the damage induced in some of them. For over three decades, ovarian function has been maintained by transposing the ovaries out of the field of irradiation, which reduces ovarian exposure. Bidzinski et al. confirmed that ovarian function was preserved when the ovaries were transposed at least 3 cm from the upper border of the field. In our study, 17 patients underwent ovarian transposition to a position as high or as lateral as possible during radical surgery procedure before radiotherapy. Fourteen (82%) patients retained ovarian function; 11 of these patients had ovarian transposition at 3–3.5 cm from the upper border of the pelvic field (above the iliac crest), while the remaining three patients had ovarian transposition to 1.5 cm from the radiation field edge. We used a dose-volume limitation with <50% of the ovarian volume receiving 7 Gy for IMRT. The median ovarian dose was 3 (2.5–3.4) Gy. Three (18%) patients experienced ovarian failure; one of them was 42 years old with ovarian transposition at 1.5 cm from the radiation field edge and the other two were 44 and 47 years old with ovarian transposition at 3–3.5 cm from the upper border of the field. As previously described in the literature, ovarian transposition is of limited value in patients who are older than 40 years, because they have an intrinsically reduced fertilization potential as well as a much higher risk of ovarian failure despite transposition than younger women.