|Year : 2013 | Volume
| Issue : 4 | Page : 341-344
A comparison of results by sequential and concurrent chemo radiotherapy in locally advanced carcinoma esophagus
V Bhandari1, KL Gupta1, R Taran2
1 Department of Radiation Oncology, Sri Aurobindo Institute of Medical Sciences, Indore, Madhya Pradesh, India
2 Department of Medical Oncology, Sri Aurobindo Institute of Medical Sciences, Indore, Madhya Pradesh, India
|Date of Web Publication||24-Dec-2013|
Department of Radiation Oncology, Sri Aurobindo Institute of Medical Sciences, Indore, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Aim: Many Trials using sequential and concurrent chemo radiotherapy have been done so far and has established the role of concurrent chemo radiotherapy in treatment of inoperable carcinoma esophagus. In this study, we have compared the results of concurrent chemo radiotherapy with sequential chemo radiotherapy. We have treated inoperable carcinoma esophagus in both the settings and present here the comparison of results in the two settings.
Materials and Methods: There were 26 patients of carcinoma esophagus in sequential and 31 in concurrent chemo radiotherapy arm. In sequential arm methotrexate and Cisplatin followed by radiotherapy was given whereas in concurrent arm, Cisplatin was given once weekly along with radiotherapy. Results: The 2 year survival was 38% in sequential and35.5% in the concurrent setting and the median survival was 19.5 and 18 months respectively in the two arms.The toxicities in both the arms were comparable. P value of 0.4774 with confidence interval of 95% was obtained, which is not significant. Dysphagia was improved earlier in sequential than in the concurrent arm. Conclusion: As the results and toxicities in both the arms are almost similar with better symptom control, so larger randomized trials are required to assess the response and the use of methotrexate in sequential chemo radiotherapy can be further explored.
Keywords: Chemo radiation, comparison, esophagus, sequential and concurrent
|How to cite this article:|
Bhandari V, Gupta K L, Taran R. A comparison of results by sequential and concurrent chemo radiotherapy in locally advanced carcinoma esophagus. Indian J Cancer 2013;50:341-4
|How to cite this URL:|
Bhandari V, Gupta K L, Taran R. A comparison of results by sequential and concurrent chemo radiotherapy in locally advanced carcinoma esophagus. Indian J Cancer [serial online] 2013 [cited 2020 Mar 31];50:341-4. Available from: http://www.indianjcancer.com/text.asp?2013/50/4/341/123624
| » Introduction|| |
Treatment of esophageal carcinoma is still not satisfactory, and most of the patients die due to local or distant tumor effects. The efficacy of conventional treatment with surgery and radiation for cancer of the esophagus is limited. The median survival is less than 10 months, and less than 10% of patients survive for 5 years.  Recent studies have suggested that combined chemotherapy and radiation therapy may result in improved survival. Currently, the standard treatment for inoperable esophageal cancer is concurrent chemotherapy and radiotherapy with results comparable to best surgical series, though head to head comparison is difficult due to lack of randomized study. Sequential chemotherapy and radiotherapy also has given modest improvement. Al-Sarraf et al. has shown that the median survival duration was 14.1 months and the 5 years survival rate was 27% in the combination treatment arm, while the median survival was 9.3 months with no patients alive at 5 years in the radiotherapy alone group.  We were treating patients of inoperable esophageal cancers with sequential chemo radiotherapy for sometimes but seeing better results of concurrent chemo radiotherapy in the literature we switched on to this method of treatment with a hope to further improve the results, but we found the results to be comparable. Here we present the comparison of both to know, which sequencing of chemotherapy and radiotherapy gives better results and is well tolerated.
| » Materials and Methods|| |
A retrospective analysis of two studies done from 2004 to 2009 was compared to know the effect of sequential versus concurrent chemotherapy along with radiotherapy. The drugs used in both were almost the same but in different settings. In both the series only locally advanced inoperable cases of carcinoma esophagus with clinical stage III and Kornofsky score of more than 80 were included. The male to female ratio was 1.3:1 and age ranging from 39 years to 73 years with a mean age of 52.6 years and 52.96 years in sequential and concurrent arms respectively. All the patients were of squamous cell carcinoma of middle third esophagus which was inoperable. Twenty six such patients were there in sequential group whereas 31 patients were there in the concurrent group. In all patients, routine hematological and radiological investigations were done before starting the treatment.
In sequential chemo radiotherapy group on day 1 methotrexate 40 mg/m 2 was given as a 8 h infusion and from day 2 to day 5, inj Cisplatin 30 mg/ m 2 was given with proper premedication's, hydration and diuresis. Radiotherapy was started immediately on day 6. In the concurrent chemo radiotherapy group Cisplatin 30 mg/m 2 was given once in a week with proper hydration and diuresis. Radiotherapyin both the groups was given on Theratron 780-C telecobalt unit using gamma rays, as Linear Accelerator with newer technologies was not available at our centre. A total dose of 40 Gy/20 fractions in 4 weeks to whole length of esophagus with anterio-posterior portals and then fields were localized to tumor with 5 cm margins and spinal cord was spared using three fields and a boost dose of 20 Gy/10 fractions in 2 weeks was given totaling to 60 Gy in 30 fractions in 6 weeks.
| » Results|| |
Twenty six patients were treated in sequential group and 31 in the concurrent group. One patient in the concurrent group did not complete the treatment and was lost to follow-up and on telephonic conversation it was found that he had partial improvement in swallowing and is not ready to continue the treatment due to some familial reasons. Rest of the patients completed and tolerated the treatment well. In both groups, there was no hematological and nephro toxicity seen [Table 1]. Improvement in dysphagia was seen on day 4-5 of start of treatment in sequential group whereas it was seen during the 2 nd or 3 rd week in the concurrent group. All 76.9% and 74.1% the patients in sequential and concurrent arm respectively had Grade II esophagitis as per the National Cancer Institutes Common Terminology Criteria for Adverse Events version 3 (NCI CTCAE v3.0) during radiotherapy which affected the swallowing, but it improved after completion of treatment as the esophagitis healed. There was no gap in treatment due to esophagitis in both groups.
The local control rate at 1 year was 76.15 in the sequential arm where as it was 83.87 in the concurrent arm. Six patients in sequential group developed local recurrence and three patients developed distant metastasis whereas in the concurrent group five patients developed local recurrence and five developed nodal or distant metastasis after 1 year of treatment. Local and distant metastasis was seen simultaneously in some. It was observed that patients with local recurrence had a history of both alcohol and tobacco use and all patients were males. Delayedradiation reactions were also seen in both the groups. Esophageal stricture was seen in three patients in sequential group and four patients in the concurrent group in patients with ulcerative disease and required esophageal dilatation.
The 1 and 2 year survival was 73% and 38.46% in the sequential group whereas it was 80% and 35.5% respectively in the concurrent group. The median survival was 19.5 months and 18 months in sequential and concurrent group respectively [Figure 1]. When unpaired t-test was applied a P value of 0.4774 with confidence interval of 95% was obtained and by conventional criterion, this value is not significant, meaning thereby that the local control and median survival in both the groups is similar without any benefit. Even the toxicity profile and recurrence rates are similar.
Only difference observed is that the patients symptom of dysphagia was relieved very early in sequential than in concurrent arm.
| » Discussion|| |
The treatment of choice for patients with carcinoma esophagus remains controversial. Surgery has long been the standard of care; however, its role has been challenged due to the poor outcome in locally advanced disease.  A survey of community care practice patterns from 1988 to 1993 revealed an increase in use of chemo radiotherapy relative to surgery as a primary management of esophageal cancer in the United States.  Radiation alone also has an established role but the overall survival after radiation alone is approximately 18% at 1 year and 6% at 5 years.  Many trials have shown good results with concurrent chemo radiotherapy and hence we are using this combination routinely in our practice. We could not find any literature comparing the sequential and concurrent chemo radiotherapy.
Thirteen randomized trials were included in the Cochrane database analysis.  There were eight concomitant and five sequential radiotherapy and chemotherapy (RTCT) studies. The studies were analyzed separately due to observed heterogeneity across all the studies and biological considerations. Concomitant RTCT provided significant overall reduction in mortality at 1 and 2 years. The mortality in the control arms was 67% and 86% respectively. Combined RTCT provided an absolute reduction of mortality by 9% and 8% respectively. There was a reduction in the overall local recurrence rate. The local recurrence rate for the control arms was in the order of 69%. Combined RTCT provided an absolute reduction of local recurrence rate of 5%. With the sensitivity analysis, there was a suggestion that Cisplatin and 5-fluorouracil (5-Fu) based chemotherapy studies were reasonable regimens to employ when using this strategy. The results from the sequential RTCT studies were heterogeneous and could not be pooled. Examining the results individually, there was no data to support the clinical benefit. 
In review 2010 in Cochrane analysis it has been concluded that when a non-operative approach is selected for treatment, then concomitant radio chemotherapy is superior to radiotherapy alone for patients with localized esophageal cancer but with significant toxicities. Hence in patients in good general condition concurrent chemo radiotherapy should be considered for the management of esophageal cancer compared to radiotherapy alone. The results of sequential chemo radiotherapy studies show no significant benefit or local control but significant toxicities.  In our study we found that this regimen was better tolerated with equivalent results and lower toxicity rates. A Phase II study of sequential chemotherapy with 5-Fu and Cisplatin followed by radiotherapy by Sharma showed only one (8%) complete response and 11 (85%) partial responses. Median survival was 39 weeks (range: 6-208+). Chemotherapy alone or its use sequentially with radiotherapy is inadequate, and newer approaches are needed to improve survival.  In our sequential arm the 2 year survival was 38.46, which is better than the two trials, may be as we have not given any gap between chemotherapy and radiotherapy and we have used methotrexate instead of 5-Fu, which is very effective in squamous cell carcinoma and combination of Cisplatin and methotrexate may have given good survival rates. Methotrexate being an antifolate has good results in squamous cell carcinoma and its toxicity is different from Cisplatin, which acts by forming cross linkage with DNA, hence a combination of two was used thinking to give better results in squamous cell carcinomas.
Given the poor results of radiation alone in treatment of esophageal carcinoma, concurrent use of chemo radiation has been tried in two most important multicenter trials, the Radiation Therapy Oncology Group (RTOG 85-01 study) , and the Eastern Cooperative Oncology Groupstudy  which have shown superiority of chemo radiation over radiotherapy alone in improvement of survival in esophageal cancer. In the RTOG trial 5 year overall survival in concurrent chemo radiation (Cisplatin and 5-Fu with radiation) group was 26% as compared to 0% in radiation alone group, although a higher radiation dose of 64 Gy in 32 fractions was used in radiation alone group as compared to Chemo radiation group (50Gy in 25 fraction). Similar results are seen in our concurrent chemo radiation arm using Cisplatin alone with lesser toxicity.
In the ECOG study in which 5-Fu and Mitomycin-c was used along with radiotherapy 2 and 5 years survivals were 12% and 7% in radiation alone arm and 27% and 9% in chemo radiation arm. Patients treated in the chemo radiation arm had a longer median survival of 14.8 months versus 9.2 months in radiation alone group. This difference was statistically significant.
There were no trials seen comparing the sequential or concurrent use of chemo radiation in the literature.In other trials, sequential chemo radiotherapy did not show positive results. However, in our sequential trial we did not gave a gap during the treatment between chemotherapy and radiotherapy andas has been seen in other trials, which might have given equivalent results as concurrent chemo radiation. In our comparable study, we see almost no difference in the results and tolerance in both the arms and hence chemo radiation can be given in any way without any gap to disallow proliferation of the tumor cells and take the radiobiological benefit during radiotherapy. Hence further more randomized trials using chemotherapy and radiotherapy without any gap in between are required to further assess the response and improve the results.
| » Conclusion|| |
Sequential and concurrent chemo radiotherapy gives similar survival rates (P = 0.4774) with a confidence interval of 95% in locally advanced inoperable carcinoma esophagus and the toxicity is also comparable hence both arms are comparable and chemo radiation can be used in any setting. Using methotrexate and Cisplatin together sequentially with radiotherapy without any gap in the two treatments gives equivalent control and survival results to concurrent chemo radiotherapy with similar side effects and early symptom relief. So, methotrexate should be tried in larger randomized trials in order to further assess the response.
| » References|| |
|1.||Sharma D, Krasnow SH, Davis EB, Lunzer S, Hussain MA, Wadleigh RG. Sequential chemotherapy and radiotherapy for squamous cell esophageal carcinoma. Am J ClinOncol1997;20:151-3. |
|2.||Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, Al-Sarraf M, et al. Chemoradiotherapy of locally advanced esophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999;281:1623-7. |
|3.||Schrump DS, Altorki NK, Forastiere AA, Minsky BD. Cancer of the Esophagus. In: DeVita VT, Hellman S, Rosenberg SA, editors. Principles and Practice of Oncology. 6 th ed. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 1051-91. |
|4.||Daly JM, Karnell LH, Menck HR. National cancer data base report on esophageal carcinoma. Cancer 1996;78:1820-8. |
|5.||Clifford Chao KS, Perez CA, Brady LW. Esophagus, Radiation Oncology Management Decisions. 2 nd ed. Philadelphia: Lippincott Williams and Wilkins; 2002. p. 333-44. |
|6.||Wong R, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. Cochrane Database Syst Rev 2001; (2): CD002092. |
|7.||Al-Sarraf M, Martz K, Herskovic A, Leichman L, Brindle JS, Vaitkevicius VK, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: An intergroup study.J ClinOncol1997;15:277-84. |
|8.||Smith TJ, Ryan LM, Douglass HO Jr, Haller DG, Dayal Y, Kirkwood J, et al. Combined chemoradiotherapy vs. radiotherapy alone for early stage squamous cell carcinoma of the esophagus: A study of the Eastern Cooperative Oncology Group. Int J Radiat Oncol Biol Phys1998;42:269-76. |
|This article has been cited by|
||Concurrent versus Sequential Chemoradiotherapy for Esophageal Cancer among Chinese Population: A Meta-Analysis
| ||Fang Li,Tao Li,Li Liu,Jiahua Lv,Yanqiong Song,Churong Li,Peng Diao |
| ||Tumori Journal. 2015; 101(4): 353 |
|[Pubmed] | [DOI]|