NDP injection (trade name, Jiebaishu, 10 mL) was provided by Simcere Pharmaceutical (Nanjing, China).

Sixty-eight patients who were pathologically proven to have locally advanced esophageal squamous cell carcinoma by gastroesophagoscopy from March 2007 to September 2009 in Department of Radiation Oncology of the Nanjing General Hospital of Nanjing Military Region and had evaluable tumor lesions were included in the study. There were 38 males and 30 females, and their median age was 54 years (range, 26 to 72 years). According to the 1997 Union for International Cancer Control esophageal cancer staging system, 29 patients had stage II disease and 39 had stage III disease. The patients were randomly divided into either a NDP group (n = 34) or a DDP group (n = 34) to receive NDP + leucovorin (CF) + 5-FU and DDP + CF + 5-FU, respectively. In the NDP group, 14 patients had stage II disease and 20 had stage III disease. In the DDP group, 15 patients had stage II disease and 19 had stage III disease. The average age of patients in the NDP and DDP groups was 55 and 53 years old, and the median age was 54 and 53 years old, respectively. Clinical data for patients in both groups are shown in Table 1.

Inclusion criteria are (1) previously untreated, histologically or pathologically proven locally advanced esophageal carcinoma, with at least one measurable lesion (≥ 2 cm); (2) Eastern Cooperative Oncology Group performance status score ≤ 2; (3) expected survival for three months or more; (4) age between 26 and 72 years; (5) basically normal heart, lung, liver, kidney functions; (6) no previous thoracic radiotherapy or chemotherapy, and no significant chemotherapy contraindications; (7) no other malignancy; or (8) willing to provide signed informed consent.

Exclusion criteria included (1) participation in other drug trial or receiving anti-tumor therapy within 4 wk; (2) other serious complications that made the patient not to fit to the study; (3) pregnant or lactating women; and (5) allergy to the test drug.

Withdrawal criteria included (1) serious adverse reactions during treatment, such as life-threatening bleeding due to thrombocytopenia, life-threatening infections for leukopenia, and grade III or more liver and kidney adverse reactions; (2) not being able to complete the treatment; (3) not willing to continue the trial; or (4) disease progression during treatment.

The NDP group received NDP 80-100 mg/m²iv on day 1 + CF 100 mg/m²iv on days 1-5 + 5-FU 500 mg/m²iv on days 1-5. The DDP group received DDP 30 mg/m²iv on days 1-3 + CF 100 mg/m² on days 1-5 + 5-FU 500 mg/m²iv on days 1-5. The treatment was repeated every 4 wk in both groups. Before chemotherapy, prophylactic antiemetic therapy with 5-HT3 receptor antagonist was given. Granulocyte colony-stimulating factor (G-CSF) was administered when grade 3/4 neutropenia occurred. When anemia and grade 3/4 thrombocytopenia occurred, erythropoietin (EPO) and recombinant human interleukin-11 (IL-11) or therapeutic plateletpheresis were given, and the dose of main chemotherapy drugs was reduced by 25% in the next cycle or the interval between two cycles was extended. Concurrent radiotherapy was given during chemotherapy in both groups.

Three-dimensional conformal radiotherapy (3D-CRT) was adopted, with high-energy X-ray beams (6 MV) produced by a linear accelerator. Gross tumor volume (GTV) boundaries were determined by esophageal X-ray, barium meal, CT, and esophagoscopy. The upper and lower boundaries for clinical target volume (CTV) were defined as upper and lower boundaries for GTV plus 3 cm. The lateral boundaries for CTV were defined as the lateral boundaries for tumors plus 0.8 cm. Planning target volume (PTV) was defined as CTV plus 0.5 cm.

Efficacy was evaluated using the 2000 RECIST criteria based on physical examination and imaging data (X-ray, barium meal, chest CT). Imaging data were assessed independently by two professional radiologists. Patients were rated as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). The response rate (RR) was defined as (number of cases with CR + number of cases with PR)/total number of cases (n). Acute radiation injury was assessed using the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity criteria (grades 0 to 4). Chemotherapy-associated adverse reactions were assessed using the U.S. National Cancer Institute common toxicity criteria (NCI-CTC), version 3.0 (grades 0-4).

Statistical analyses were performed using SPSS 13.0 software. Rates or percentages between two groups were compared using the chi-square test and Fisher exact test. Survival was analyzed using the Kaplan-Meier method. Survival curves were compared using the Log-rank significance test. Survival was defined as the period from the date of diagnosis to death. Two-tailed P-values <0.05 were considered statistically significant.

In the NDP group, 33 of 34 patients completed two or more cycles of treatment and were evaluable for efficacy and toxicity. In the DDP group, 32 patients completed two or more cycles of chemotherapy and can be evaluated for efficacy and toxicity, and the remaining two cases discontinued the treatment after one cycle of chemotherapy (one for intolerable side effects and the other for poor incompliance) but can be evaluated for toxicity. Short-term responses in the two groups are shown in Table 2.

The 1-year overall survival rate was 75.8% (25/33) for the NDP group and 68.8% (22/32) for the DDP group, and the 2-year overall survival rate was 57.6% (19/33) and 50.0% (16/32), respectively. Although the overall survival rate was higher in the NDP group than in the DDP group, the difference was not statistically significant (χ² = 0.375, P = 0.504).

During the follow-up period, 19 patients survived and 14 died in the NDP group. Of 14 dead patients, 9 died of distant metastasis, 3 of local control failure, and 2 of distant metastasis plus local control failure. Of 16 dead patients in the DDP group, 4 died of local control failure, 7 of local control failure plus distant metastasis, and 5 of distant metastasis. These findings suggest that distant metastasis was the main cause of death in both groups. The percentage of patients who died of distant metastasis showed no significant difference between the NDP group and DDP group (78.6% vs 75.0%, χ² = 0.053, P = 0.818) (Figure 1).

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Figure 1 Survival curves for the two groups. NDP: Nedaplatin; DDP: Cisplatin.

Toxicity could be evaluated in all cases. In the NDP group, grades I-IV decreased hemoglobin developed in 20 patients (58.8%), grades I-IV leukopenia in 21 patients (61.8%), and grades I-IV thrombocytopenia in 19 patients (55.9%); the corresponding figures in the DDP group were 18 (52.9%), 19 (55.9%) and 14 cases (41.2%). The incidences of decreased hemoglobin, leukopenia and thrombocytopenia showed no significant differences between the two groups (P = 0.990, 0.805, 0.540). Although the incidence of hepatic dysfunction did not differ significantly between the two groups (P = 0.565), the incidence of renal toxicity was significantly higher in the DDP group (38.2% vs 8.8%, P = 0.039). The incidences of nausea and vomiting were significantly lower in the NDP group than in the DDP group (17.6% vs 50.0%, 11.8% vs 47.1%, P = 0.031, 0.016) (Table 3).

Late grade 4 esophageal toxicity was noted in one patient in the DDP group, but no patient developed late grade 3 or more esophageal toxicity in the NDP group. The incidences of late esophageal and lung toxicities showed no significant difference between the two groups (P > 0.05 for both). Serious late radiation toxicities such as radiation-induced myelitis and pericarditis were not observed (Table 4).

Radiotherapy given concurrently with chemotherapy can improve the efficacy of radiotherapy in esophageal carcinoma. Concurrent chemoradiotherapy has been recommended as the standard treatment for locally advanced esophageal carcinoma, and conventional fractionated radiotherapy plus cisplatin (DDP) and 5-fluorouracil (5-FU) has been advocated as a standard regimen for this malignancy. However, the risk of gastrointestinal and renal toxicity associated with DDP-based PF regimen (DDP + 5-FU) limits its use.

In the present study, the authors designed a randomized controlled phase II trial to compare the efficacy, acute adverse reactions and late toxicity of three-dimensional conformal radiotherapy plus nedaplatin (NDP) and 5-FU vs plus the PF regimen in the treatment of locally advanced esophageal carcinoma, with an aim to find a regimen that has fewer adverse reactions and better efficacy than the PF regimen.

The survival and local control as well as the side effects during follow-up were analyzed by comparing with cisplatin. The authors found NDP-based concurrent chemoradiotherapy is effective and well-tolerated. Compared with DDP, NDP-based concurrent chemoradiotherapy exhibits favorable efficacy with lower toxicity.

The study results suggest that NDP-based concurrent chemoradiotherapy is a potential therapeutic regimen that could be used in locally advanced esophageal carcinoma.

Cisplatin, a common chemotherapeutic drug, has been one of doctors’ first lines of defense against tumors, especially those of the lung, ovary, testes and locally advanced esophageal carcinoma. Nedaplatin is a new platinum derivative, selected from a series of platinum analogues based on its pronounced preclinical antitumor activity against various solid tumors with lower nephrotoxicity and gastrointestinal reactions.

This is a good clinical study in which the authors evaluated the efficacy and safety of three-dimensional conformal radiotherapy plus NDP and 5-FU versus plus the PF regimen in the treatment of locally advanced esophageal carcinoma. The results suggest that NDP-based concurrent chemoradiotherapy exhibits favorable efficacy with lower toxicity.