PhaseⅠ And Ⅱ Clinical Trial Of Concurrent Chemoradiotherapy Of Cisplatin With 5-Fluorouracil And Its Short-Term Effect On Quality Of Life Of Concurrent Chemoradiotherapy In Chinese Patients With Esophageal Cancer

Esophageal cancer is the eighth most common cancer worldwide, responsible for 462,000 new cases and the sixth most common cause of death from cancer, with 386,000 deaths in 2002. The age-standardized incidence rate in China was the highest in the world, 27.4/100,000 in men and 12.0/100,000 in women. Mortality rate ranks the fourth place in malignant neoplasm in China.Until now, esophageal cancer was still an aggressive, malignant neoplasm with dismal prognosis. Surgery alone is one of standard therapies. Patients undergoing surgery alone had a survival rate about 20%. The 5-year survival rate with conventional fraction of radiation alone is 0 % to 10 %. It was reported that 4.3%-16.4% of the 5-year survival rates had been achieved in Chinese clinical studies which recruited more than 1,000 cases. When esophageal cancer is diagnosed clinically, a fair part of them could not be resected radically because of extended disease. Effect of chemotherapy alone is limited to esophageal cancer with total response rate from 35%-55% and the duration less than six months. Hence chemotherapy is usually combined with surgery or radiotherapy.Radiobiology indicated Tpot (potential doubling time) of esophageal cancer was similar to that of head and neck cancer. The stem cell of esophageal cancer might repopulate during the latter half course of conventional radiotherapy. The Tumor Hospital of the Fudan University carried the prospective late course accelerated hyperfractionation radiotherapy (LACH) study in esophageal cancer for the first time in 1989. After Shi et al reported the preliminary outcome of LACH in 1994, LACH has been widely used during the past two decades. The outcomes were encouraging with the 5-year survival rates around 30%. LACH was considered to outweigh conventional radiotherapy (RT) in esophageal cancer.However, different strategies for esophageal cancer have been adopted between China and Western countries due to different cultures and economies. Concurrent chemoradiotherapy is the standard regimen for local advanced esophageal cancer.At least 6 randomized clinical trials had compared concurrent chemoradiotherapy and radiotherapy alone. Only one trial prescribed enough intensive doses: CDDP 75 mg/m2, d1, 5-Fu 1000mg/m2/d, d1-d4,in week 1 and week 5, with concurrent radiation of 50Gy/25frations/5weeks, followed by 2 cycle chemotherapy. The 5-year survival rate and 8-year survival rate were 27% and 22%, respectively. The survival outcome established the role of concurrent chemoradiotherapy in esophageal cancer.Although chemoradiotherapy was also explored in China for at least two decades, the outcomes were controversial. In 1994 Wang et al reported a long-term results: 5-year survival rate was significantly better in chemoradiotheapy than that in radiotherapy alone, 30% and 9.4%,P<0.05. However the outcome in the sequent studies achieved controversial survival results. The possible reasons were as follows: First, different recruited standard led to different demographic characteristics. Second, because it is difficult to stage the disease with non-surgery methods, many studies provided only tumor length without clinical stage. However clinical stage is the one of most important prognosis factors. Thus it could not guarantee the comparable stage between observed group and control group. Third, different radiation technology was used, including 60Co in early reports. Conventional radiotherapy and 3-dimensions conformal radiotherapy were used in different studies. Fourth, different does and fractionations were given. Radiation doses ranged from 42Gy to 75Gy. Conventional fraction, LACH and continuous hyperfractionation radiotherapy were adopted. Fifth, different chemotherapy drugs and does were prescribed, including cisplatin, carboplatin, 5-fluorouracil, mitomycin, pingyangmycin and paclitaxel. Cispatin and 5-fluorouracil were given form 20mg and 500mg per week to 20mg/m~2 and 5-Fu 500mg/m~2 d1-d4 per week.At present there is no standard chemoradiotherpy regimen in esophageal cancer in China.With the society developing and improving standard of living, the quality of life (QOL) in cancer patients are being emphasized continually. American Food and Drug Administration has made improved QOL and better survival as the two identical important standards in the course of new drugs permission in 1996. Many studies have been focused on QOL in patients with head and neck cancer, prostate cancer and breast cancer abroad. Only a few trials reported QOL in esophageal cancer. No systemic studies have been made on QOL in esophageal cancer because there are no special QOL questionnaires for esophageal cancer in China.Our study aimed to investigate a suitable chemoradiotherapy regimen for Chinese patients with esophageal cancer and to observe the actue and late toxicities. The side effect of the regimen was also evaluated in viewpoint of QOL. The study was divided into three parts.Part 1: PhaseⅠtrial of escalating-dose cisplatin with 5-fluorouracil and concurrent radiotherapy in Chinese patients with esophageal cancerObjective: To define the maximum-tolerated dose (MTD) of chemoradiotherapy (cisplatin (CDDP) with 5-fluorouracil (5-Fu) and concurrent radiotherapy) for Chinese patients with esophageal cancer.Methods: Twenty-one previously untreated patients with primary esophageal cancer entered into this study. Escalating doses of CDDP with 5-Fu were administered a modified Fibonacci sequence, with concurrent conventional fractionation radiotherapy (CFR) of 60 Gy or 50 Gy (for the last 6 enrolled patients). The starting doses were CDDP 37.5 mg/m~2 on day 1, and 5-Fu 500 mg/m~2 on days 1-5, respectively. The regimen was repeated four times every 28 days. The escalation doses were CDDP 7.5 mg/m2 and 5-Fu 100 mg/m2. Every cohort contained at least 3 patients. If no dose-limiting toxicity (DLT) was observed, the next dose level was opened for enrollment. The procedures were repeated until DLT appeared. MTD was declared as 1 dose level below the level at which DLT appeared.Results: DLT was grade 3 radiation-induced esophagitis at a dose level of CDDP 60 mg/m~2 with 5-Fu 700 mg/m~2 and concurrent 60 Gy CFR. MTD was defined as CDDP 52.5 mg/m~2 with 5-FU 700 mg/m~2 and concurrent 50 Gy CFR. The major side effects were radiation-induced esophagitis, leucopenia, nausea, vomiting, and anorexia.Conclusion: MTD of CDDP with 5-Fu and in concurrent chemoradio- therapy for Chinese patients with esophageal cancer are CDDP 52.5 mg/m~2 on day 1, 5-Fu 700 mg/m~2 on days 1-5, repeated 4 times every 28 days and concurrent 50 Gy CFR. Further evaluation of this regimen in a prospective phaseⅡtrial is ongoing.Part 2: PhaseⅡtrial of cisplatin plus 5-flurouracil concurrent chemoradiotherapy of maximum-tolerated doses in Chinese patients with esophageal cancerObjective: To estimate the effect of cisplatin plus 5-flurouracil concurrent chemoradiotherapy of maximum-tolerated doses in Chinese patients with esophageal cancer and to observe the acute and late toxicities.Methods: Forty-four patients with esophageal squamous carcinoma were randomized into two groups with delamination block randomized method: 22 cases in concurrent chemoradiotherapy (CRT) and 22 cases in late course accelerated hyperfractionation radiotherapy (LCAH). Radiotherapy in CRT group was performed with conventional fractionation on the first day of week 1. Patients were treated with five daily fractions of 2.0 Gy per week over a 5-week period. The total radiation dose was 60 Gy. Chemotherapy was prescribed on the first day of week 1 with the maximum-tolerated dose of Chinese patients: CDDP 52.5 mg/m2 on day 1, 5-Fu 700 mg/m~2 on days 1-5, repeated 4 times every 28 days. Total dose in LCAH was 60Gy in which the first half course follows the same radiation schema as used in CRT. The latter half course was prescribed in hyperfractionation radiotherapy: 1.5Gy of twice daily fractions with a interval at least six hours, 20 fractions in two weeks.Results: In CRT group 95.5%(21/22)patients completed the radiation schema. The reasons of unfinished schema were as follows: one case only completed one cycle chemotherapy and 32Gy radiation due to therapy-induced esophag-mediastinal fistula; one case could not receive the fourth cycle chemotherapy because of fatigue and gastricintestinal toxicities; one case only completed one cycle chemotherapy because of disease progression; two cases refused to continue the sequential chemotherapy because of personal reasons. Only one case received 57Gy in LACF because of personal reason instead of therapy-induced toxicity. The response rates in CRT group and LCAH group were 90.5% and 86.4%, respectively. The difference was not significant, P=0.607.The 1-year local control rate, 1-year non-metastasis rate and 1-year survival rate in CRT group and LCAH group were 92.2%,66.5%,70.4% and 54.2%,69.6%,60.2%, respectively. P values were 0.014, 0.937 and 0.181, respectively. Only the 1-year local control rate of CRT group was significantly better than that of LCAH group. The major acute toxicities in CRT group were radiation-induced esophagitis, radiation-induced pneumonia, myelosuppression, nausea and vomiting and anorexia. Most of them were slight to moderate and manageable. The late toxicities of esophagus and lung were rare and slight exception of one case late radiation-induced gradeⅤtoxicity of esophagus.Conclusion: CRT improved the local control rate significantly and showed the improved tendency of survival rate compared with LCAH. The non-metastasis rate was not improved significantly. The acute and late toxicities of CRT were manageable. The regimen of CRT was warranted to phaseⅢtrial.Part 3: The effect on the short-term quality of life in patients with primary esophageal carcinoma received concurrent chemoradiotherapy: A prospective randomized control study. Objective: To assess the effect on the short-term quality of life (QOL) in patients with primary esophageal carcinoma.Methods: QOL was assessed by the European Organization for Research and Treatment of Caner quality of life questionnaire Version 3.0(EORTC QLQ-C30) Chinese edition and the module for esophageal cancer-EORTC QLQ-OES18 Chinese edition in 32 patients who were randomly assigned to receive either concurrent chemoradiotherapy (CRT) or late course accelerated hyperfractionation radiotherapy (LCAH). The questionnaires were given before therapy and at the 4th week during therapy, the completion of therapy, 1 and 3 months after the completion of therapy.Results: Although CRT deteriorated scores of global health status, physical functioning, role functioning, emotional functioning, social functioning, nausea and vomiting, fatigue and appetite loss during the therapy, most QOL scores rapidly recovered to the baseline level post therapy. However improved tendency in most domains scores of QOL appeared only in patients received CRT. At three months post therapy global health status domain was improved, the tendency was nearly significant, the difference of mean scores was7.290±2.226,P=0.058. However at three months post therapy declined tendency in some domains scores of QOL were seen in patients received LCAH. Some additional useful information could be reflected from the esophageal cancer module OES18 that could not be achieved from the core questionnaire C30. The toxicity of CRT was much heavier during therapy course than that of LCAH. Compared with LACH, CRT deteriorated some special syndrome of esophageal cancer: dysphagia, deglutition, eating, pain and dysgeusia. Eating, pain and dysgeusia got significantly worse, The difference of scores were 19.271±5.177,16.667±4.421 and 20.833±5.510,and P values were 0.019, 0.019 and 0.011, respectively. However the above syndromes recovered rapidly after the competition of concurrent chemoradiotherapy. Inaddition dysphagia, deglutition, eating and reflux scale were improved significantly three months after the competition of concurrent chemoradiotherapy. The difference of scores were -20.833±5.450, -20.833±4.167, -14.583±2.580,and -22.917±5.667,and P values were 0.017,0.002,<0.001 and 0.011,respectively. No significant improvement was observed in LACH group exception of reflux scale three months after radiotherapy.Conclusion: Most scales of QOL in CRT group were improved three months after the competition of concurrent chemoradiotherapy. Special syndrome of esophageal cancer including dysphasia, deglutition, eating and reflux were improved significantly. In viewpoint of QOL, CRT was a feasible modality for esophageal cancer. The effects on long term of QOL in patients with esophageal carcinoma received CRT still need further observation.Conclusion1. MTD of CDDP with 5-Fu and in concurrent chemoradiotherapy for Chinese patients with esophageal cancer were CDDP 52.5 mg/m2 on day 1, 5-Fu 700 mg/m2 on days 1-5, repeated 4 times every 28 days and concurrent 50 Gy CFR.2. The major side effects of MTD of CDDP with 5-Fu and in concurrent chemoradiotherapy for Chinese patients with esophageal cancer were radiation-induced esophagitis, leucopenia, nausea, vomiting, anorexia and fatigue. The toxicities were manageable and the schema was feasible clinically.3. The late effect of MTD of CDDP with 5-Fu and in concurrent chemoradiotherapy for Chinese patients with esophageal cancer were rare and slight to moderate. Major late effects were esophagus stricture and radiation-induced lung injury.4. CRT significantly improved 1-year local control rate and showed the tendency of improving 1-year survival rate, but failed to reduce 1-year non-metastasis rate compared with LACH.5. CRT significantly deteriorated some domains of QOL. In viewpoint of QOL toxicities of CRT were more severe than LACH duting therapy course.6. At three months after the competition of concurrent chemoradiotherapy CRT showed the improving tendency of general health status in QOL. In addition CRT significantly improved special syndrome of esophageal cancer including dysphagia, deglutition, eating and reflux.7. The effects on long-term of QOL in patients with esophageal carcinoma received CRT still need further observation because of the late effect of CRT.