|Year : 2014 | Volume
| Issue : 1 | Page : 11-14
Role of concurrent chemoradiation in inoperable carcinoma esophagus: A prospective study
Department of Radiation Oncology, Sri Aurobindo Institute of Medical Sciences, Medical College, Indore, Madhya Pradesh, India
|Date of Web Publication||23-Apr-2014|
401, Samyak Towers, 16/3 Old Palasia
Source of Support: None, Conflict of Interest: None
Introduction: The treatment of choice in cancer esophagus is controversial. Radiation therapy oncology group, Eastern cooperative oncology group and Cochrane studies have shown superiority of concurrent chemoradiation in inoperable carcinoma esophagus. In these studies full dose cisplatin was given every 3 weeks along with radiotherapy and hence had some toxicity. So, we started treating inoperable carcinoma esophagus patients with low dose weekly cisplatin given concurrently with radiotherapy aiming at low toxicity and similar results.
Materials and Methods: A total of 31 cases of inoperable cases of carcinoma esophagus were treated with once weekly cisplatin 30 mg/m 2 along with radiotherapy 60 Gy in 30 fractions in 6 weeks on Telecobalt/Linear accelerator.
Results : w0 e could achieve lower toxicity with 80%, 35% and 19% with 1, 2, and 3 year's survival with a median survival of 18 months. So, we conclude that this regimen is better than 3 weekly chemotherapy regimen as is better tolerated with less toxicity and similar outcome.
Keywords: Carcinoma Esophagus, concurrent chemoradiation, low dose cisplatin
|How to cite this article:|
Bhandari V. Role of concurrent chemoradiation in inoperable carcinoma esophagus: A prospective study. J Can Res Ther 2014;10:11-4
| > Introduction|| |
Despite all advances, treatment of esophageal carcinoma is still unsatisfactory 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 non-surgical treatment of 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 a randomized study. We started radiotherapy at this center in late 2007 and started treating inoperable cancer esophagus with concurrent chemoradiation and here we present our data which is comparable to any other study. As per Indian Cancer Registry cancer esophagus occurs in 8/100,000 population and is the third common gastrointestinal malignancy mainly caused due to alcohol and tobacco usage.
| > Materials and Methods|| |
From January 2007 to December 2011, carcinoma esophagus was 6.10% of all cancers registered in our hospital. There were 9.2% cases of upper third, 61.1% middle third and 29.6% of the lower esophagus and most were locally advanced inoperable patients. Male to female ratio was 1.3:1 and the mean age of presentation is 45.9 ranging from 29 years to 81 years. The main presenting complaints were dysphagia, chest pain, and hoarseness, pain in interscapular region, weight loss and hemetemesis. One patient presented with a cough that was found to have to fistula and was treated conservatively. Out of all esophageal cancers 31 (24.8%) patients were taken up for concurrent chemoradiotherapy. The main histology was squamous cell carcinoma except two who had adenocarcinoma. Nearly, 90% of the patients in this study were involving middle, 9.1% lower and 0.8 upper third esophagus. All the patients were investigated with computed tomography scan, Sonography of the abdomen, and routine blood investigations before starting treatment with concurrent chemoradiotherapy. Nearly, 32.25% patients were in stage IIb and 67.75% patients were in stage III with a Kornofsky score of more than 80. Radiotherapy was given on Telecobalt/Linear accelerator to the total dose of 40 Gy/20 fractions in 4 weeks to the whole length of the esophagus with anterioposterior portals and then the 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. Only one patient was given Intraluminal brachytherapy after 50 Gy of external radiotherapy. A dose of 1800 CGy in 3 weekly fractions on High Dose Rate microselectron using Iridium source was given. Chemotherapy with cisplatin 30 mg/m 2 alone was given once in a week for a minimum 5-6 times concurrently with radiation. All the patients completed the chemotherapy schedule along with radiotherapy within time and none of the patients required dose reductions due to toxicity. Proper nutrition was maintained during treatment either through Ryles tube feeding or orally or by intravenous route by parenteral nutrition given during chemotherapy. Patients were admitted only for 1 day every week for chemotherapy. During the treatment a close observation was kept on the hematological, renal and nutritional status of the patients and other toxicities were also noted.
| > Results|| |
A total of 31 patients were treated as per the chemoradiation protocol. One patient left the treatment in between, rest completed the treatment and was available for follow-up. The immediate results were encouraging and all the patients had improvement in dysphagia during the early phase of treatment [Figure 1] and [Figure 2]. Toxicity grading was carried out as per National Cancer Institute Common Terminology Criteria for Adverse Events version 3 (NCI CTCAE v3.0). In few it worsened during the later-half of treatment due to moderate esophagitis and later improved again after completion of treatment and improvement in esophagitis. There was mild to moderate esophagitis and none of the patients developed neutropenia or renal toxicity [Table 1]. Esophagitis was treated conservatively and none of the patients required parenteral nutrition or gap during treatment.
|Figure 2: Two year post-treatment. No lesion seen and the patient is with normal esophageal lumen|
Click here to view
During the follow-up period, five patients developed local recurrence, two patients developed celiac lymph nodes and one each developed bone, brain, and adrenal metastasis after 1 year of treatment, which was treated accordingly.
There were delayed radiation reactions seen. 4 patients developed esophageal stricture and all of these patients had an ulcerative lesion primarily. All patients with stricture had loco regional disease in control and were treated with endoscopic dilatation. 2 patients developed trachea oesophageal fistula within 1 year and one was treated with covered stent, but he died within 2 months of stenting. The patient who received Intraluminal brachytherapy developed local necrosis and succumbed.
The 1, 2, and 3 year survival in this study of chemoradiation was 80%, 35.5% and 19.5% respectively with a median survival of 18 months [Figure 3]. Most of the patients surviving are able to take solid diet without difficulty and only one patient requires endoscopic dilatation off and on.
| > Discussion|| |
The treatment of choice for patients with carcinoma esophagus is 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 chemoradiotherapy relative to surgery as 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.  Similar results of radiation alone 8.4% at 2 years were seen by Haddad at Tehran university hospital. 
Given the poor results of radiation alone in treatment of esophageal carcinoma, concurrent use of chemoradiation has been tried in two most important multicenter trials, the Radiation therapy Oncology Group (RTOG 85-01 study) , and the Eastern Cooperative
Oncology group (ECOG) study,  which have shown superiority of chemoradiation over radiotherapy alone in improvement of survival in esophageal cancer. In the RTOG trial 5 year overall survival in concurrent chemoradiation (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 Chemoradiation group (50 Gy in 25 fraction).
In the ECOG study in which 5-Fu and Mitomycin-c was used along with radiotherapy 2 and 5 year survivals were 12% and 7% in radiation alone arm and 27% and 9% in chemoradiation arm. Patients treated in the chemoradiation arm had a longer median survival of 14.8 months versus 9.2 months in radiation alone group. This difference was statistically significant. Similar statistically significant (P - 0.0004) were seen in concurrent chemoradiation arm then in radiotherapy alone arm by Haddad at Tehran University Hospital.  Seeing good results of concurrent chemoradiation we started the use of low dose weekly cisplatin alone with radiotherapy aiming at lower toxicity and similar response outcome.
In the Cochrane database review also it was seen that Concomitant Radiotherapy and Chemotherapy 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% (95% Confidence Interval 2-17%) and 8% (95% CI 1-17%) respectively. 
In another study Arnold  also found 50% and 38% one and two year survival with concurrent chemoradiation (cisplatin and 5-Fu) compared to 33% and 10% with radiation alone (P < 0.001) confirming the role of concurrent chemoradiation in treatment of carcinoma esophagus.
Anderson et al.  used 5-Fu and Mitomycin-c in concurrent chemoradiation group and found a median overall survival of 35 months and a two year survival of 64%. Sischy et al.  treated 135 patients with 5-FU and mitomycin C and 40 Gy radiotherapy or radiotherapy alone. The median survival for the multimodality group was significantly longer at 14 months than 9 months for radiotherapy alone. Herskovic et al.  randomized 121 potentially curable patients to 64 Gy radiation alone or 50 Gy concurrent with two courses of cisplatin and 5-FU. Long-term follow-up confirms a 3-year survival of 30% versus 0% favoring multimodal therapy.  These trials support concurrent chemotherapy and radiotherapy over radiotherapy alone.
We could not find any literature comparing weekly and three weekly use of cisplatin for carcinoma esophagus. However, in carcinoma cervix Chumworathayi et al.  concluded that concurrent chemo radiation receiving three weekly cisplatin has a higher rate of incomplete and delayed treatments then in patients receiving weekly cisplatin (P < 0.001 and 0.0236 respectively) due to higher toxicity three weekly regimen. In another trials in the head and neck cancers three weekly cisplatin at a dose of 100 mg/m 2 concurrently with radiotherapy was considered standard of care, but it is associated with significant acute and late toxicities. ,,, Only 63-85% of patients could complete the three planned chemotherapy cycles due to increased toxicity and there was a delay in radiotherapy due to gaps. None of our patient required gap during treatment or had grade III toxicities to hold up the treatment of require parenteral nutrition. Hence, weekly cisplatin use is better tolerated.
Our study also shows 35.5% and 19.5% two and three year survival with a median survival of 18 months, when cisplatin alone was used once weekly in a concurrent setting with lesser toxicities as compared to all other studies. Delayed toxicity like stricture was found in patients with ulcerative growth involving more than half of the circumference, which could be treated with esophageal dilatation. Comparing our study with all others in the literature, we found lower toxicity and almost similar control and mean survival rates. Further, studies with a large number of patients are required to establish that low dose cisplatin alone used once weekly along with radiotherapy can give similar results with less toxicities and can be well-tolerated by the patients.
| > Conclusion|| |
Combined modality therapy plays a significant role in the treatment of patients with carcinoma esophagus. Concurrent chemotherapy with weekly cisplatin alone gives similar results to cisplatin and 5-Fu or 5-Fu and Mitomycin-c as used in other studies with lesser toxicities.
Concurrent chemo radiation is a superior treatment in inoperable carcinoma esophagus in terms of local control and survival both and hence should be the standard of care as has been seen in our study also. Even for patients with localized esophageal cancer, the percentage of patients alive 5 years after treatment with chemotherapy and radiotherapy was 27% which was comparable to that achieved with surgery alone.  This implies that surgical and non-surgical therapy may be equivalent, especially considering that patients treated with combined modality therapy generally have more advanced disease and are less medically fit than patients who are treated with surgery alone. Hence, concurrent chemo radiation can also be tried in early cases and surgical morbidity survival and quality of life can be improved.
| > References|| |
|1.||Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer 1996;78:1820-8. |
|2.||Clifford Chao KS, Perez CA, Brady LW. Radiation Oncology Management Decisions. 2 nd ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 333-44. |
|3.||Haddad P, Amouzgar Hashemi F, Merati MM, Sajjadi SM. Concurrent chemoradiation for esophageal carcinoma Priliminary results. Acta Med Iran 2004;42:163-7. |
|4.||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. |
|5.||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 Clin Oncol 1997;15:277-84. |
|6.||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 Phys 1998;42:269-76. |
|7.||Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593-8. |
|8.||Arnold Herskovic, Karen Martz, MuhyiAl Sarraf, Lawrence Leichman, Jeffrey Brindle, Vainutis Vaikevius et al . Combined Chemotherapy and Radiotherapy compared with radiotherapy alone in Patients with cancer of the esophagus. N Eng J Med 1992; 326: 1593-1598. |
|9.||Anderson SE, Minsky BD, Bains M, Hummer A, Kelsen D, Ilson DH. Combined modality chemoradiation in elderly oesophageal cancer patients. Br J Cancer 2007;96:1823-7. |
|10.||Sischy B, Ryan L, Haller D. Interim report of EST 1282 phase III protocol for the evaluation of combined modalities in the treatment of patients with carcinoma of the esophagus, stage I and II. Proc Am Soc Clin Oncol 1990;9:105. |
|11.||Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593-8. |
|12.||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. |
|13.||Chumworathayi B, Suprasert P, Charoenkwan K, Srisomboon J, Phongnarisorn C, Siriaree S, et al. Weekly versus three-weekly cisplatin as an adjunct to radiation therapy in high-risk stage I-IIA cervical cancer after surgery: A randomized comparison of treatment compliance. J Med Assoc Thai 2005;88:1483-92. |
|14.||Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349:2091-8. |
|15.||Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92-8. |
|16.||Machtay M, Moughan J, Trotti A, Garden AS, Weber RS, Cooper JS, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: An RTOG analysis. J Clin Oncol 2008;26:3582-9. |
|17.||Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 1998;16:1310-7. |
|18.||Willett CG. Radiation dose escalation in combined-modality therapy for esophageal cancer. J Clin Oncol 2002;20:1151-3. |
[Figure 1], [Figure 2], [Figure 3]