Introduction
Cervical cancer is a significant worldwide health problem, particularly in developing countries. Globally, cervical cancer accounted for the third most commonly diagnosed type of cancer and the fourth leading cause of cancer-related mortality in women in 2008 (1). Patients in the early stages of cervical cancer typically exhibit no symptoms, whereas various symptoms, such as abnormal vaginal bleeding, pelvic pain and pain during sexual intercourse, are observed in the advanced stages (2,3). Cancer screening with the Papanicolaou smear test has been demonstrated to markedly reduce the occurrence of advanced cervical cancer and mortality (2,3). However, treatment of cervical cancer varies significantly; for example, the early stages of the disease are treated with surgery, while the later stages of the disease are treated only with chemotherapy and/or radiotherapy. Generally, cervical cancer is radiosensitive; thus, radiation may be used in all stages of disease, including when surgery is not an option for a patient in the early stages of disease (3). Concurrent cisplatin-based chemoradiotherapy is the standard treatment for locally advanced cervical cancer. Cervical cancer patients with enlarged para-aortic nodes (PAN) may be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy, whereas larger early stage tumors may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy with adjuvant radiation therapy, or cisplatin chemotherapy followed by hysterectomy (3,4). By contrast, advanced stages of cervical cancer (stages IIB-IVA) are typically treated with radiation therapy and cisplatin-based chemotherapy (3,4). However, cervical cancer with metastasis to the PAN has a poor prognosis (5,6). In such cases, concurrent cisplatin-based chemotherapy with extended-field radiotherapy (EFRT) is the standard treatment strategy. Previous studies have demonstrated an improvement in disease control using EFRT and concurrent chemotherapy, and have shown a positive effect on overall survival (OS) compared with radiotherapy alone (7–10). However, the high levels of acute and chronic toxicities associated with EFRT are still potential barriers. In addition to decreasing patient quality of life, acute toxicity leads to premature termination of chemotherapy, and the number of chemotherapy cycles is an independent predictor of survival (11). Therefore, there is an urgent need to evaluate novel treatment strategies to reduce toxicity and improve treatment efficacy. A previous study discussed the benefits of intensity-modulated radiotherapy (IMRT), which provides more conformal dose distribution into the tumor lesion. Furthermore, IMRT reduces the absorbed dose and the volume of the organ at risk (OAR), thus leading to reduced acute and late toxicity (12). Nedaplatin is an analog of cisplatin that exhibits less nephrotoxicity, neurotoxicity and gastrointestinal (GI) toxicity than cisplatin (13). Thus, the present study assessed the efficacy and toxicity of extended field-IMRT (EF-IMRT) with concurrent nedaplatin treatment in cervical cancer.
Discussion
In the present study, patients with cervical cancer were treated with EF-IMRT plus concurrent nedaplatin therapy for ≤8 weeks. All patients responded to this treatment regimen, although 24/48 (45%) patients experienced grade 3 or 4 neutropenia and thrombocytopenia. However, this treatment regimen featured a low rate of high-grade GI toxicity. The 12-month OS and DFS were 87.5 and 75.8%, respectively, and the 24-month OS and DFS were 69.7 and 49.7%, respectively. Thus, the present study indicates that EF-IMRT plus concurrent nedaplatin treatment in cervical patients is a safe and highly effective treatment strategy.
EFRT causes known side-effects on the bone marrow and small bowel, and the addition of concurrent chemotherapy to EFRT only exacerbates its toxicity. Previously, a prospective phase II cooperative group clinical trial, in which para-aortic lymph nodes were treated with 4,500 cGy, reported grade 3–4 acute GI toxicity in 18.6% of patients. Furthermore, a late morbidity actuarial risk of 14% at 4 years primarily involved the rectum in cervical cancer patients treated with concurrent chemotherapy and EFRT (7). However, the use of the IMRT significantly reduced doses to the OAR, and decreased GI and hematological toxicities (12). Consensus guidelines for delineation of the CTV have been published (15,16). The theoretical drawbacks of IMRT treatment include dose inhomogeneity within target volumes, longer treatment times than conventional radiotherapy and the uncertainty of organ motion. However, previous studies demonstrated the advantages of IMRT over EFRT delivered by three-dimensional conformal radiotherapy for extended field treatments (19–21). For example, Portelance et al (19) performed a dosimetric analysis to determine the feasibility of pelvic and para-aortic IMRT in 10 patients who underwent CT simulation from T2 to the ischial tuberosities with conventional 2- and 4-field plans versus 4-, 7- and 9-fields IMRT plans. IMRT resulted in a statistically significant reduction (P<0.05) in the volume of small bowel irradiation, demonstrating 11, 15 and 13.6% reduction in the 4-, 7- and 9-field IMRT, respectively. By contrast, 35 and 34% reduction occurred in the conventional 2- and 4-field plans, respectively. The rectal dose was significantly lower with IMRT (P<0.001) (19). Furthermore, Gerszten et al demonstrated a significant reduction in critical organ irradiation with EF-IMRT, and proposed that the treatment may reduce both acute and late treatment-associated side-effects (20). Salama et al reported the preliminary outcome and toxicity of EF-IMRT for gynecological malignancies, in which 13 women with gynecologic malignancies tolerated EF-IMRT and only 2 patients experienced grade 3 or higher acute toxicity (21). By contrast, Jensen et al demonstrated high toxicity rates in patients with cervical cancer that underwent EF-IMRT and concurrent cisplatin treatment; acute grade 3 or higher GI toxicity was 19.0% and acute grade 3 or higher hematological toxicity was 57.1% (22). In the current study, 20/48 patients (41.7%) exhibited grade 3 or higher neutropenia, 4 patients (8.4%) had grade 3 or higher thrombocytopenia and 2 patients (4.2%) developed grade 3 diarrhea. This further indicates that the hematological toxicity was significant, however, the majority of patients tolerated the side effects, with >90% of patients able to complete the treatment regime.
Nedaplatin is an analog of cisplatin that exhibits less nephrotoxicity, neurotoxicity and GI toxicity than cisplatin itself. A previous phase I study determined that the recommended weekly dose of nedaplatin was 30 mg/m2, administered for >5 cycles and ≤8 cycles if possible. Weekly administration of nedaplatin may be more tolerable and less toxic than weekly administration of cisplatin (23). Furthermore, a phase II study confirmed that concurrent chemoradiotherapy using weekly nedaplatin (30 mg/m2) is safe and effective (24). No grade 3 vomiting was observed in the present study, and the total high-grade GI toxicity was 4.2%, which is considerably lower than reported in a previous study by Jensen et al (22).
The impact of total length of radiation treatment is critical for determining OS rate. Walker et al reported that delays in treatment were predominantly a result of dehydration due to diarrhea, nausea and vomiting, which may be caused by cisplatin toxicity and increased small bowel radiation toxicity in the para-aortic field (25). With the integrated boost of involved nodes using EF-IMRT, the median treatment time from the first day of EF-IMRT to the last day of brachytherapy in the current study was 53 days (range, 48–61 days), which did not significantly prolong the length of radiation treatment compared with previous studies of chemoradiotherapy (7,25). Furthermore, regarding renal toxicity in patients treated with EFRT (3,5), the current study did not induce any acute or late renal grade 3 or higher toxicity. Jensen et al reported 18-month cumulative incidences of late grade 3 or higher genitourinary and GI toxicity were 4.8 and 0%, respectively, following EF-IMRT with concurrent cisplatin chemotherapy (22). RTOG 90–01 reported a late toxicity rate of 12% in patients treated with EFRT without concurrent chemotherapy (26). In prior studies of EFRT and concurrent chemotherapy, the reported late toxicity rates were 0–14% (7,27–30). The present study revealed that 2/48 patients (4.2%) developed grade 3 GI late toxicity. The current results are consistent with reports from these prior studies (7,27–31).
The delivery of radiation to grossly involved nodes has been limited due to its toxicity to adjacent organs and tissues (6). However, IMRT has been shown to permit delivery of ≤60 Gy to para-aortic and/or pelvic nodes, with substantially reduced doses to the bowel, bladder and bone marrow (17,32). In the current study, tumors metastasized to the para-aortic and/or pelvic nodes were treated with a total dose of 55–60 Gy in 2.0–2.4 Gy daily fractions using simultaneous integrated boost-IMRT. Following this treatment, no recurrence was observed in the para-aortic regions, and no increased acute or late GI toxicity was observed.
The present study demonstrated that concurrent treatment with nedaplatin and definitive EF-IMRT was effective in cervical cancer patients, with a low incidence of high-grade acute gastrointestinal toxicity. The results also revealed that distant metastasis was the major cause of mortality; thus, novel treatment regimens, such as multidrug concurrent chemo/radiotherapy or immunotherapy with or without radiotherapy, require investigation. The current study was not a randomized controlled trial and was limited by the small number of patients. Thus, in order to confirm the safety and efficacy of this treatment regime on patients with cervical cancer, further studies are warranted using a larger sample size and a randomized controlled trial.