A Randomized Controlled Trial Comparing Clinical Outcomes and Toxicity of Lobaplatin- Versus Cisplatin-Based Concurrent Chemotherapy Plus Radiotherapy and High-Dose-Rate Brachytherapy for FIGO Stage II and III Cervical Cancer

Background: We designed this randomized controlled trial (RCT) to assess whether lobaplatin-based concurrent chemotherapy might be superior to cisplatin-based concurrent chemotherapy for FIGO stage II and III cervical cancer in terms of efficacy and safety. Materials and Methods: This prospective, open-label RCT aims to enroll 180 patients with FIGO stage II and III cervical cancer, randomly allocated to one of the three treatment groups (cisplatin 15mg/m 2 , cisplatin 20mg/m 2 and lobaplatin 35mg/m 2 ), with 60 patients in each group. All patients will receive external beam irradiation (EBRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT). Patients in cisplatin 15mg/m 2 and 20mg/m 2 groups will be administered four cycles of 15mg/m 2 or 20mg/m 2 cisplatin intravenously once weekly from the second week to the fifth week during EBRT, while patients inthe lobaplatin 35mg/m 2 group will be administered two cycles of 35mg/m 2 lobaplatin intravenously in the second and fifth week respectively during pelvic EBRT. All participants will be followed up for at least 12 months. Complete remission rate and progression-free survival (PFS) will be the primary endpoints. Overall survival (OS), incidence of adverse events (AEs), and quality of life will be the secondary endpoints. Results: Between March 2013 and March 2014, a total of 61 patients with FIGO stage II and III cervical cancer were randomly assigned to cisplatin 15mg/m 2 group (n=21), cisplatin 20mg/m 2 group (n=21) and lobaplatin 35mg/m 2 group (n=19). We conducted a preliminary analysis of the results. Similar rates of complete remission and grades 3-4 gastrointestinal reactions were observed for the three treatment groups (P=0.801 and 0.793, respectively). Grade 3-4 hematologic toxicity was more frequent in the lobaplatin group than the cisplatin group. Conclusions: This proposed study will be the first RCT to evaluate whether lobaplatin-based chemoraiotherapy will have beneficial effects, compared with cisplatin-based chemoradiotherapy, on complete remission rate, PFS, OS, AEs and quality of life for FIGO stage II and III cervical cancer.


A Randomized Controlled Trial Comparing Clinical Outcomes and Toxicity of Lobaplatin-Versus Cisplatin-Based Concurrent Chemotherapy Plus Radiotherapy and High-Dose-Rate Brachytherapy for FIGO Stage II and III Cervical Cancer
Ji-Quan Wang, Tao Wang, Fan Shi, Yun-Yi Yang, Jin Su, Yan-Lan Chai, Zi Liu* and nephrotoxicity. This has led to the development of second-and third-generation platinum analogues, such as lobaplatin, with reduced toxicity and a better therapeutic index.
Lobaplatin (D-19466; 1, 2-diammino-methylcyclobutaneplatinum (II)-lactate) is a representative of the third-generation platinum compounds delivered as a diastereomeric mixture of S, S and R, R configurations of the carrier ligand, complex with DNA alkylating activity . It can obstruct the process of DNA replication and transcription by forming Pt-GG and Pt-AG intrachain cross-linking so as to interfere the running of tumor cell cycles (Eliopoulos et al., 1995). Compared with cisplatin, lobaplatin is considered to be less toxic, more soluble and stable in water and shows incomplete cross-resistance to cisplatin (McKeage et al., 2001;Deng et al., 2013). It has been approved in China for the treatment of chronic myelogenous leukaemia (CML), inoperable metastatic breast and small cell lung cancer. In addition, many clinical trials also suggest the effectiveness of lobaplatin in the treatment for various cancers, including esophageal, gastric, testicular and ovarian cancers (Harstrick et al., 1993). Now we conduct this randomized controlled trial (RCT) to compare clinical outcomes and toxicity of concomitant cisplatin versus lobaplatin plus radiotherapy and high-dose-rate intracavitary brachytherapy (HDR-ICBT) for FIGO stage II and III cervical cancer. This paper describes the trial design and analyzes the preliminary results. Based on the primary results, appropriate adjustments will be made for ongoing trials.

Study design
The aim of this study is to observe clinical outcomes and toxicity of concomitant cisplatin versus lobaplatin plus radiotherapy and HDR-ICBT for FIGO stage II and III cervical cancer. It was approved by the Ethics Committee of The First Affiliated Hospital of Xi'an Jiaotong University. All study participants provided written informed consent before participation.
This clinical trial was a prospective open-label RCT at The First Affiliated Hospital of Xi'an Jiaotong University. It aimed to enroll 180 patients with FIGO stage II and III cervical cancer who meet the study criteria below. Using a random-number table (Center of Evidence-Based Medicine and Clinical Epidemiology, The First Affiliated Hospital of Xi'an Jiaotong University), patients would be randomly assigned in a 1:1:1 ratio to either the group1 ,2 or 3 ( Figure 1). The primary endpoint with respect to efficacy is complete remission rate and progression-free survival (PFS). Secondary endpoints are overall survival (OS), incidence of adverse events, and quality of life (QOL).
Patient registration began on March 2013 and is to continue for three years or until 180 individuals have been randomly assigned. When all the patients will have been followed up for at least 12 months, the full study is expected to be finished.

Patients
Inclusion criteria included (1) hospitalized patients, age 65years; (2) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; (3) pathological diagnosis of cervical cancer, FIGO stage II and Ⅲ disease by pelvic examinations; (3) no previous treatment with chemotherapy or radiotherapy for cancer; (4) hematology, liver and kidney function are normal; (5) Good understanding and compliance by patients with the pilot program, and provision of informed consent.
Baseline examinations included physical status, physical examination (height, weight, body surface area, pelvic examinations and palpation of superficial lymph nodes), computed tomography (CT) of the chest and abdomen, magnetic resonance imaging (MRI) of the pelvis, electrocardiography (ECG), complete blood count and biochemistry panels.

Treatment
Radiotherapy: All the patients received platinum-based chemoradiotherapy. Radiotherapy included external beam irradiation (EBRT) and HDR-ICBT. EBRT was implanted by a linear accelerator of three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT). According to Radiation Therapy Oncology Group (RTOG) guidelines (Small et al., 2008), the clinical target volume (CTV) included the common, external, and internal iliac lymph node regions and the upper 3.0 cm of the vagina. The superior margin of the external radiation field was located at the abdominal aortic bifurcation, went down along 7mm outside the iliac vessels and the inferior border was determined by the degree of vaginal violations. External irradiation was delivered to the whole pelvis (2 Gy per fraction), with five fractions administered per week for a total of 25 fractions and 50 Gy. After completing external irradiation, gynecological examinations were performed to determine the appropriate ICBT program and dose. ICBT was performed using the Fletcher-Suit-Delclos set with a microSelectron HDR (Nucletron, Veenendaal, Netherlands). The total planned dose to point A for HDR-ICBT was 24 Gy in four fractions.

Chemotherapy
Patients in group 1 were administered four cycles of 15 mg/m 2 cisplatin intravenously once weekly from the second week to the fifth week during EBRT. Those in group 2 received four cycles of 20mg/m 2 cisplatin intravenously once weekly from the second to fifth week during EBRT. Patients in group 3 were administered two cycles of 35 mg/m 2 lobaplatin intravenously in the second and fifth week respectively during pelvic EBRT. All patients were administered antiemetic drugs prior to chemotherapy. Physical status and routine blood should be performed weekly during the treatment. If bone marrow suppression Figure 1 occurred, appropriate and timely interventions should be taken. The patients with III-IV grade thrombocytopenia or leukopenia should be treated with recombinant human interleukin-11 or recombinant human granulocyte colonystimulating factor. The treatment would be stopped if disease progression or unacceptable toxicity or withdrawal of patient's consent occurs.

Follow-up
Follow-up will consist of a telephone survey and a visit to the clinic for re-examination. Patients were re-examined every three months for the first year, every six months the second through fifth years, and annually thereafter. Gynecologic examination and supraclavicular lymph node palpation were performed at each appointment. Chest x-rays were obtained one year after treatment. Suspected cases of persistent or recurrent disease were confirmed by biopsy whenever possible. For these cases, chest CT and abdomino-pelvic CT or MRI were obtained to detect the site of failure.

Definition of early outcomes and toxicity
Tumor evaluations were performed at entry and after treatment by pelvic examinations according to Response Evaluation Criteria in Solid Tumors (RECIST)/WHO evaluation criteria (Tsuchida et al., 2001). A complete response (CR) was defined as a disappearance of all evidence of the tumor and no development of new lesions for at least 4 weeks. A partial response (PR) was defined as a decrease of at least 50% in the sum of the products of the largest perpendicular diameters of all measurable lesions. The severity of the complications associated with chemotherapy was classified according to the National Cancer Institute Common Toxicity Criteria (NCI-CTCv2.0) (Hughes et al., 2008).

Statistical analysis
Differences between the two treatment groups were assessed using a χ 2 test or Fisher's exact test for categorical variables. An independent sample t-test was used for continuous variables. A P-value less than 0.05 were considered statistically significant. Statistical Package for Social Scientists (SPSS, version 18.0, IL) was used for all analyses.

Trial status
As of March 2014, 61 patients have been enrolled and randomized for this trial, and recruitment is ongoing. Now we conduct a preliminary analysis of the results.

Patient characteristics
Between March 2013 and March 2014, sixty-one patients were randomly allocated to group 1, 2 and 3. No patients withdraw from the trail and all 61 patients entered a preliminary analysis of results. Of the 61 eligible patients, 21, 21 and 19 cases were randomly assigned to group 1, 2 and 3. Baseline characteristics turned out to be well balanced between the two groups with no significant imbalances in age, maximum tumor diameter, FIGO stage, pathological grading and ERBT methods. Baseline characteristics are shown in Table 1.

Efficacy
Complete remission rate was 52.38%, 47.62%and 42.11% for group 1, 2 and 3 (Table 2), which did not significantly differ between the three treatment groups (P=0.801). No distant metastases occurred in any patient when we evaluated for efficacy.

Adverse effects
All patients were evaluable for toxicity assessments. The most common grades 3-4 adverse events (AEs) are summarized in Table 3.

Treatment duration
Treatment duration of the three groups is 48.04, 47.66 and 50.05 days, respectively, with no significant difference (p=0.115).

Discussion
This study is the first randomized control trial to investigate the efficacy and toxicity of lobaplatin combined with concurrent radical radiation for cervical cancer. Although cisplatin-based chemoradiotherapy is a promising option for FIGO stage II and III disease, 15-30% patients will relapse and metastasis. Lobaplatin, characterized by no crossing drug resistance with other platinum-based drugs, good water solubility, broad anti-tumor spectrum, strong anti-tumor activity and low toxicity, exerts definite effects in the treatment of various tumors, such as breast cancer (Engel et al., 2012;Deng et al., 2013), lung cancer (Xie et al., 2012), esophageal carcinoma, gastrointestinal cancer Zhao et al., 2014) and malignant pleural effusion and ascites . In terms of cervical cancer, the in-vitro experimental studies have demonstrated that lobaplatin inhibits cell proliferations in human cervical cancer CaSki cells by inducing apoptosis, cell cycle arrest and changing many kinds of protein molecule expression level . The dose-limiting toxicity of lobaplatin is thrombocytopenia, with incidence ranging from 14.5% to 26% and a nadir at approximately 2 weeks after drug administration (Degardin et al., 1995;Welink et al., 1999;Zhao et al., 2014). Leukopenia is less severe than thrombocytopenia, and the drug does not induce nephrotoxicity, neurotoxicity, or ototoxicity (Welink et al., 1999).
The primary outcome of our RCT indicates that complete remission rate was comparable between cisplatinand lobaplatin-based chemoradiotherapy for FIGO stage II and III cervical cancer, ranging from 42.11% to 52.38%.
The adverse reactions mainly include thrombocytopenia, leukopenia and gastrointestinal toxicity. The incidence of thrombocytopenia and leukopenia in lobaplatin-based chemoradiotherapy group is significantly higher than that in cisplatin-based chemoradiotherapy group. Even so, treatment duration of lobaplatin-based chemoradiotherapy group was similar to cisplatin-based chemoradiotherapy group. There is no standard dose for lobaplatin combined with radical radiotherapy for cervical cancer. Climbing test should be implemented in order to seek the optimal dose. Based on our preliminary results, the dose of lobaplatin will be reduced to 30 mg/m 2 . Efficacy and side effects are comparable between cisplatin 15 mg/m 2 group and 20 mg/ m 2 group, which indicate 15 mg/m 2 is the optimal dose of cisplatin combined with radical radiotherapy for cervical cancer.
In conclusion, efficacy of lobaplatin-and cisplatinbased chemoradiotherapy is comparable while thrombocytopenia and leucopenia of lobaplatin-based chemoradiotherapy are higher than cisplatin-based chemoradiotherapy according to preliminary results of our RCT. The final results and long-term efficacy need to be further observed and analyzed.