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Journal of Clinical Oncology, Vol 21, Issue 14 (July), 2003: 2697-2702
© 2003 American Society for Clinical Oncology

Long-Term Toxicity After Definitive Chemoradiotherapy for Squamous Cell Carcinoma of the Thoracic Esophagus

Satoshi Ishikura, Keiji Nihei, Atsushi Ohtsu, Narikazu Boku, Shuichi Hironaka, Kiyomi Mera, Manabu Muto, Takashi Ogino, Shigeaki Yoshida

From the Radiation Oncology Division and Gastrointestinal Oncology/Digestive Endoscopy Division, National Cancer Center Hospital East, Kashiwa, Japan.

Address reprint requests to Satoshi Ishikura, MD, Radiation Oncology Division, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan; email: sishikur{at}east.ncc.go.jp.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: To assess the long-term toxicity after definitive chemoradiotherapy (CRT) for squamous cell carcinoma (SCC) of the esophagus.

Patients and Methods: Patients newly diagnosed with SCC of the esophagus and treated with definitive CRT between 1992 and 1999 in our institution were recruited from our database on the basis of the following criteria: age <= 75 years, performance status (PS; based on the Eastern Cooperative Oncology Group scale) 0 to 2, and clinical tumor-node-metastasis system stage I to IVA. The CRT consisted of two cycles of cisplatin 40 mg/m2 on days 1 and 8, and continuous infusion of fluorouracil 400 mg/m2/d on days 1 to 5 and 8 to 12, repeated every 5 weeks with concurrent radiotherapy of 60 Gy in 30 fractions. For the assessment of toxicity, the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme was adopted.

Results: A total of 139 patients were recruited, and their characteristics were as follows: median age, 62 years (range, 38 to 75 years); 121 males and 18 females; 96 patients PS 0, 42 patients PS 1, and one patient PS 2; 15 patients T1, 11 patients T2, 60 patients T3, and 53 patients T4; and 101 patients M0, 38 patients M1a. With a median follow-up of 53 months, the median survival time and 5-year survival rate were 21 months and 29%, respectively. Of 78 patients with complete remission, two patients died as a result of acute myocardial infarction. Grade 2, 3, and 4 late toxicities occurred with the following incidences: pericarditis in eight patients, seven patients, and one patient, respectively; heart failure in zero, zero, and two patients; pleural effusion in seven, eight, and zero patients; and radiation pneumonitis in one patient, three patients, and zero patients, respectively.

Conclusion: Definitive CRT for SCC of the esophagus is effective with substantial toxicities. Additional investigation to minimize the normal tissue toxicities is warranted.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
CARCINOMA OF the esophagus has been a challenging disease. In contrast to Western countries, where the number of patients with adenocarcinoma has been increasing, most patients in Japan still have squamous cell carcinoma (SCC), and the mortality rate for Japanese patients with esophageal cancer was 8.0 per 100,000 (13.8 per 100,000 males, 2.4 per 100,000 females), representing 3.4% (4.8% males, 1.3% females) of all deaths by malignant neoplasms in 1999.1 In recent years, the number of patients with stage I disease has been increasing, although most patients are still diagnosed with advanced disease and have a dismal prognosis. The standard therapy in Japan for patients with resectable disease has been surgery. According to the comprehensive registry of esophageal cancer in Japan,2 10,455 of 12,794 registered patients (81.7%) underwent surgery during 1988 and 1994. The 5-year survival rates for T1, T2, and T3 diseases were 44.8% to 51.8%, 37.3%, and 28.1%, respectively. Radiotherapy alone had been indicated in unresectable or medically inoperable patients as a definitive or palliative treatment, with a 5-year survival benefit of 8.3% to 12%.3–5

During the last decade, chemoradiotherapy (CRT) for esophageal cancer has revealed promising results.6,7 After the report of a intergroup randomized controlled trial (Radiation Therapy Oncology Group 85–01), which compared CRT with radiotherapy alone, the combined-modality treatment became a standard for patients who received nonsurgical treatment for esophageal cancer.8,9

Esophageal cancer deaths often occur before the general time period when one would expect to detect the manifestation of treatment-related late toxicity. However, recent data indicate that the risk of early death from esophageal cancer is not quite as daunting for patients who achieve complete response (CR) after CRT. Therefore, a significant proportion of CR patients may have a sufficiently long survival time to allow for adequate assessment of treatment-related late toxicity. We have already reported a phase II study of cisplatin (CDDP) and fluorouracil (FU) with concurrent radiotherapy for patients with unresectable, T4, M1 lymph node (according to the International Union Against Cancer tumor-node-metastasis system, 1987) esophageal cancer, which resulted in promising survival rates.10,11 During and after the study, this regimen was adopted as a clinical practice for patients with the same stage and with potentially resectable stages but who refused surgery.

We report on the long-term toxicity after definitive CRT for SCC of the thoracic esophagus.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
Patients newly diagnosed with SCC of the thoracic esophagus and treated with definitive CRT between August 1992 and April 1999 in our institution were recruited from our database on the basis of the following criteria: age <= 75 years, performance status (Eastern Cooperative Oncology Group) 0 to 2, clinical stage I to IVA (International Union Against Cancer tumor-node-metastasis system, 1997), adequate organ functions, and no other site of carcinoma except for early stage. Informed consent was obtained from all patients. Of the patients in the previous study,11 those who were treated in our institution and met the recruitment criteria were also included in this analysis.

Pretreatment Evaluation
Pretreatment evaluation included barium swallow, endoscopy of the esophagus, and computed tomography (CT) of the neck, chest, and abdomen. Endoscopic ultrasound of the esophagus and ultrasound of the neck were optional. Bronchoscopy was performed if tracheobronchial involvement was suspected and surgical resection was under consideration. The tracheobronchial tree was judged to be involved if the tumors extended into the lumen or caused deformity of the lumen. The descending aorta was judged to be involved if the contact angle of the tumor was 90 degrees or greater on the CT scan. The T-factor in patients with less than T4 was determined by endoscopic ultrasound or endoscopy (or both). Metastatic lymph nodes were defined if they were >= 1 cm in their greatest diameter on any imaging technique.

Treatment Details
The treatment consisted of two cycles of CDDP 40 mg/m2 on days 1 and 8 and continuous infusion of FU 400 mg/m2/d on days 1 to 5 and 8 to 12, repeated every 5 weeks, with concurrent radiotherapy of 60 Gy in 30 fractions over 8 weeks, including a 2-week break. An additional two cycles of CDDP 80 mg/m2 on day 1 and continuous infusion of FU 800 mg/m2/d on days 1 to 5 every 4 weeks were administered for responders.

Radiation therapy was delivered with megavoltage equipment using anterior-posterior opposed fields up to 40 Gy, including the primary tumor, the metastatic lymph nodes, and the regional nodes. A booster dose of 20 Gy was given to the primary tumor and the metastatic lymph nodes for a total dose of 60 Gy, using bilateral oblique or multiple fields. The clinical target volume for the primary tumor was defined as the gross tumor volume plus 3 cm craniocaudally. The planning target volumes for the primary tumor and the metastatic lymph nodes were determined with 1- to 1.5-cm margins to compensate for setup variations and internal organ motion. Lung heterogeneity corrections were not used.

Toxicity Assessment
Acute toxicity, including complete blood cell count and serum chemistry profile, was assessed weekly during the CRT segment and every 2 weeks during the additional chemotherapy. Toxicity assessments for all patients were performed using the criteria defined by the Japan Clinical Oncology Group.12 These criteria were based on the National Cancer Institute common toxicity criteria (version 1.0). Late toxicity assessments for CR patients were performed using Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme. Late toxicity was defined as that occurring more than 90 days after the treatment initiation.

Follow-Up Evaluation
The following evaluations were performed until disease progression every 3 months for the first year and every 6 months thereafter: physical examination, toxicity assessment, complete blood cell count, serum chemistry profile, endoscopy of the esophagus, and CT scan of the neck, chest, and abdomen. Biopsy of the primary tumor site was routinely performed at each follow-up examination. Pulmonary function testing, ECG, and cardiac ultrasound were performed when indicated.

Response Assessment
CR for the primary tumor was defined by endoscopy when all visible tumors, including ulcerations, disappeared with negative biopsy and lasted for >= 4 weeks.

Responses of the metastatic lymph nodes were assessed using the World Health Organization response criteria for measurable diseases. In brief, CR was defined as the complete disappearance of all measurable and assessable disease for >= 4 weeks. Uncertain CR was defined as the persistence of small nodes (<= 1 cm) with no evidence of progression for >= 3 months after completion of treatment, and patients with uncertain CR were included in the analysis of those with CR.

Pattern of Treatment Failure
Patterns of treatment failure were defined as the first site of failure. Locoregional failure included the primary tumor and regional lymph nodes. Distant failure included any site beyond the primary tumor and regional lymph nodes.

Statistics
Survival analysis was performed using the Kaplan-Meier method,13 and differences between the curves were analyzed using the log-rank test.14 The time to event was calculated from the start of the treatment.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
There were 217 patients who received definitive or palliative CRT during the period: 139 patients matched the recruitment criteria, and 78 patients were excluded from the analysis. The reasons for exclusion were stage IVB (16 patients), double cancer (16 patients), recurrence after surgery (13 patients), inadequate organ function (seven patients), age more than 75 years (five patients), fistula (five patients), prior endoscopic mucosal resection (three patients), poor performance status (three patients), small-cell carcinoma (three patients), prior chemotherapy (three patients), comorbidity (two patients), and carcinoma of the cervical esophagus (two patients). The characteristics of the remaining 139 patients are listed in Table 1Go. The median age was 62 years (range, 38 to 75 years). One hundred thirty-three patients (96%) completed at least the CRT segment with a total radiation dose of 60 Gy. Sixty-six patients (47%) received two or more additional cycles of chemotherapy.


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  		Table 1. Patient Characteristics
 
Response
Of 139 patients, 78 achieved CR (56%; 95% confidence interval [CI], 47% to 65%). Patients with T4 disease showed CR of 36% (95% CI, 23% to 50%), which was worse than 69% (95% CI, 58% to 78%) in patients with non-T4 disease.

Survival and Pattern of Treatment Failure
With a median follow-up period of 53 months (range, 14 to 86 months) for surviving patients, the median survival time of the 139 patients was 21 months. Three- and 5-year overall survival rates were 38% and 29%, respectively. In a subgroup analysis, 3- and 5-year overall survival rates for patients with potentially resectable T1-3 M0 disease, and patients with unresectable T4 or M1 lymph node disease (or both T4 and M1 lymph disease) were 44 months, 55%, and 49%; and 11 months, 22%, and 13%, respectively (Fig 1Go). There was significant difference in survival benefit between the two groups (P < .0001). For 78 CR patients, 3- and 5-year survivals were 63% and 51%, whereas 3- and 5-year survivals were 6% and 2% for 61 non-CR patients (Fig 2Go), respectively. The patterns of first treatment failure were local only (15 patients), local and distant (two patients), and distant only (13 patients). Thirteen patients died without progression, and 35 patients are still alive with no evidence of disease.



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  		Fig 1. Overall survival data for all patients; T1-3 M0 patients; and T4 and/or M1 lymph node patients.

 


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  		Fig 2. Overall survival data for patients who achieved complete remission (CR) and patients who did not achieve complete remission.

 
Acute Toxicity
The worst toxicities throughout the treatment period are listed in Table 2Go. Major treatment toxicities included myelosuppression and esophagitis. Grade >= 3 toxicities of leukopenia, anemia, thrombocytopenia, and esophagitis occurred in 43%, 23%, 18%, and 10% of patients, respectively. There were three (2%) treatment-related deaths, including sepsis in one patient, pneumonitis in one patient, and renal failure in one patient. All of the three patients had unresectable disease at baseline, and no treatment-related deaths occurred in the 67 patients with potentially resectable disease.


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  		Table 2. Acute Toxicities (N = 139)*
 
Late Toxicity
Four patients suffered benign esophageal strictures and required esophageal dilatation one to three times.

Grade >= 2 late cardiopulmonary toxicities are summarized in Table 3Go. Two patients died as a result of acute myocardial infarction at 30 and 40 months, respectively, after the initiation of treatment. The median time to the onset of pericarditis from the initiation of treatment was 17 months (range, 3 to 42 months) for grade >= 2 pericarditis and 15 months (range, 10 to 36 months) for grade >= 3 pericarditis. Of eight patients with grade >= 3 pericarditis, one patient suffered grade 4 heart failure, required pericardial window placement 23 months after the initiation of treatment, and died as a result of heart failure without cancer recurrence 15 months later. Another patient also suffered grade 4 heart failure at 35 months and died without cancer recurrence. The other six patients required pericardiocentesis once and needed no further treatment. Of eight patients with grade 2 pericarditis, one patient died as a result of an unknown cause 1 month later, and the other seven patients with pericarditis were manageable with diuretics only for various periods (2 to 75+ months).


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  		Table 3. Patients With >=Grade 2 Late Cardiopulmonary Toxicities (RTOG/EORTC late radiation morbidity scoring scheme)
 
The median time to the onset of pleural effusion from the initiation of treatment was 19 months (range, 3 to 42 months) for grade >= 2 pleural effusion and 18 months (range, 5 to 39 months) for grade 3 pleural effusion. Of eight patients who required pleurocentesis, two patients suffered grade 3 pericarditis, and two patients suffered grade 3 radiation pneumonitis simultaneously. One patient without cancer recurrence died as a result of pneumonia 4 months later. One patient required frequent repeated pleurocentesis and two patients required pleurocentesis three to five times. Of seven patients with grade 2 pleural effusion, one patient suffered grade 4 heart failure and five patients suffered grade 2 pericarditis simultaneously. Six pleural effusions were manageable with only diuretics for various periods (4 to 75+ months).

Four patients required corticosteroid therapy for radiation pneumonitis. The median time to symptomatic radiation pneumonitis was 5 months (range, 4 to 7 months). Three of the four patients subsequently required oxygen support and one patient died without cancer recurrence 19 months later.

In total, eight patients died without cancer recurrence, and these causes of death may have been related to cardiopulmonary toxicity.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the last decade, the number of patients receiving definitive CRT has been increasing worldwide. However, the long-term survival and late toxicity for these patients have not been reported precisely. Although our study, including 72 patients with T4 or M1 lymph node (or both), was retrospective and may be biased, the results with 3- and 5- year survivals of 38% and 29%, respectively, were comparable with the reported trials of CRT, including RTOG 85–01 and intergroup study (INT) 0123/RTOG 94–05.15,16 The pattern of failure in the present analysis showed that local failure was still dominant. The INT 0123 study also showed a similar pattern of failure and the tumor control probability of current CRT approaches seems to have reached a plateau. We should make further efforts to improve local control, which may affect survival. The dose-escalation strategy of radiotherapy was not proven to be effective in the INT 0123 study, and we may need newer cytotoxic drugs or molecular targeted therapy in combination with radiotherapy.

Radiation-induced heart disease is one of the complications in patients who undergo thoracic radiotherapy.17,18 Pericardial disease is the most common manifestation of radiation-induced heart disease. There have been many reports of pericardial disease after thoracic radiotherapy in patients with Hodgkin’s lymphoma.19–21 According to recent observations, coronary artery disease after thoracic radiotherapy is not negligible and it should be considered in the radiotherapy treatment planning.22–24 We also observed two patients with acute myocardial infarction, although we were not sure whether these were related to the treatment. There have been few reports on pericardial disease in patients with esophageal cancer, because of the dismal prognosis.25,26 However, the number of reports will increase with the prevalence of definitive CRT and with improved survival. The incidence of grade >= 3 pericarditis in our study was 10% (eight of 78 patients) and seemed to be substantial. One cause of this, in addition to the concurrent use of chemotherapy, may be the wide elective nodal irradiation up to 40 Gy with anteroposterior-posteroanterior opposed portals. This means that more than 60% of the entire heart volume received at least 40 Gy in most patients. It is clear that a precise analysis using dose-volume histogram and normal tissue complication probability is necessary, and this will be reported elsewhere.

Treatment of pericardial effusion includes medication, pericardiocentesis, and pericardial window placement, which are thought to be manageable;17,27 however, some patients died as a result of heart failure in our study, and the obvious best treatment is prevention. Three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy have potential advantages over traditional anteroposterior-posteroanterior treatment in reducing doses to the heart, and their incorporation may thus be beneficial.

Pleural effusion after thoracic radiotherapy also has been reported, mainly in Hodgkin’s lymphoma.28,29 The main cause of benign pleural effusion after thoracic radiotherapy is thought to be lymphatic obstruction resulting from mediastinal fibrosis and, in some cases, it may be related to heart disease, such as heart failure and pericardial effusion. The incidence of grade >= BORDER="0"> 2 benign pleural effusion in our study was 19% (15 of 78 patients), and we note that patients with benign pleural effusion after definitive CRT in esophageal cancer are common. The treatment of pleural effusion after thoracic radiotherapy includes medication, pleurocentesis, and pleurodesis. This treatment may not directly affect survival, but it clearly affects the quality of life as influenced by medical intervention. We should make every effort to reduce toxicity, and conformal radiotherapy techniques may also be helpful.


   NOTES
 
This study was presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18–21, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
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1. Editorial Board of the Cancer Statistics in Japan (ed). Cancer statistics in Japan 2001: Foundation for promotion of cancer research. http://www.ncc.go.jp/en/statistics/2001/tables.html

2. Registration Committee for Esophageal Cancer (ed). Comprehensive registry of esophageal cancer in Japan: The Japan Society for Esophageal Diseases. http://plaza.umin.ac.jp/~jsed/

3. Okawa T, Kita M, Tanaka M, et al: Results of radiotherapy for inoperable locally advanced esophageal cancer. Int J Radiat Oncol Biol Phys 17:49–54, 1989[Medline]

4. Slevin NJ, Stout R: Carcinoma of the oesophagus: A review of 108 cases treated by radical radiotherapy. Clin Radiol 40:200–203, 1989[CrossRef][Medline]

5. Hyden EC, Langholz B, Tilden T, et al: External beam and intraluminal radiotherapy in the treatment of carcinoma of the esophagus. J Thorac Cardiovasc Surg 96:237–241, 1988[Abstract]

6. Coia LR: Chemoradiation as primary management of esophageal cancer. Semin Oncol 21:483–492, 1994[Medline]

7. Forastier AA, Orringer MB, Perez-Tamayo C, et al: Preoperative chemoradiation followed by transhiatal esophagectomy for carcinoma of the esophagus: Final report. J Clin Oncol 11:1118–1123, 1993[Abstract/Free Full Text]

8. Herskovic A, Martz K, Al-Sarraf M, et al: Combined chemotherapy and radiotherapy in patients with cancer of the esophagus. N Engl J Med 326:1593–1598, 1992[Abstract]

9. Al-Sarraf M, Martz K, Herskovic A, et al: Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: An intergroup study. J Clin Oncol 15:277–284, 1997[Abstract/Free Full Text]

10. Ohtsu A, Yoshida S, Boku N, et al: Concurrent chemotherapy and radiation therapy for locally advanced carcinoma of the esophagus. Jpn J Clin Oncol 25:261–266, 1995[Abstract/Free Full Text]

11. Ohtsu A, Boku N, Muro K, et al: Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus. J Clin Oncol 17:2915–2921, 1999[Abstract/Free Full Text]

12. Tobinai K, Kohno A, Shimada Y, et al: Toxicity grading criteria of the Japan Clinical Oncology Group. Jpn J Clin Oncol 23:250–257, 1993[Free Full Text]

13. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

14. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170, 1966[Medline]

15. Cooper JS, Guo MD, Herskovic A, et al: Chemoradiotherapy of locally advanced esophageal cancer: Long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA 281:1623–1627, 1999[Abstract/Free Full Text]

16. Minsky BD, Pajak TF, Ginsberg RJ, et al: INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: High-dose versus standard-dose radiation therapy. J Clin Oncol 20:1167–1174, 2002[Abstract/Free Full Text]

17. Stewart JR, Fajardo LF, Gillette SM, et al: Radiation injury to the heart. Int J Radiat Oncol Biol Phys 31:1205–1211, 1995[CrossRef][Medline]

18. Veinot JP, Edwards WD: Pathology of radiation-induced heart disease: A surgical and autopsy study of 27 cases. Hum Pathol 27:766–773, 1996[CrossRef][Medline]

19. Byhardt R, Brace K, Ruckdeschel J, et al: Dose and treatment factors in radiation-related pericardial effusion associated with the mantle technique for Hodgkin’s disease. Cancer 35:795–802, 1975[CrossRef][Medline]

20. Tötterman KJ, Pesonen E, Siltanen P: Radiation-related chronic heart disease. Chest 83:875–878, 1983[Abstract/Free Full Text]

21. Cosset JM, Henry-Amar M, Pellae-Cosset B, et al: Pericarditis and myocardial infarctions after Hodgkin’s disease therapy. Int J Radiat Oncol Biol Phys 21:447–449, 1991[Medline]

22. Boivin JF, Hutchinson GB, Lubin JH, et al: Coronary artery disease mortality in patients treated for Hodgkin’s disease. Cancer 69:1241–1247, 1992[Medline]

23. Corn BW, Trock BJ, Goodman RL: Irradiation-related ischemic heart disease. J Clin Oncol 8:741–750, 1990[Abstract]

24. Joensuu H: Acute myocardial infarction after heart irradiation in young patients with Hodgkin’s disease. Chest 95:388–390, 1989[Abstract/Free Full Text]

25. Cwikiel M, Albertsson M, Hambraeus G: Acute and delayed effects of radiotherapy in patients with oesophageal squamous cell carcinoma treated with chemotherapy, surgery and pre- and postoperative radiotherapy. Acta Oncol 33:49–53, 1994[Medline]

26. Gergel T, Proulx G, Leichman L: Diagnostic dilemmas in oncology: Case 3—Pericardial effusion after esophageal radiation. J Clin Oncol 19:4344–4345, 2001[Free Full Text]

27. Veeragandham RS, Goldin MD: Surgical management of radiation-induced heart disease. Ann Thorac Surg 65:1014–1019, 1998[Abstract/Free Full Text]

28. Rodríguez-García JL, Fraile G, Moreno MA, et al: Recurrent massive pleural effusion as a late complication of radiotherapy in Hodgkin’s disease. Chest 100:1165–1166, 1991[Abstract/Free Full Text]

29. Morrone N, Gama e Silva Volpe VL, Dourado AM, et al: Bilateral pleural effusion due to mediastinal fibrosis induced by radiotherapy. Chest 104:1276–1278, 1993[Abstract/Free Full Text]

Submitted March 10, 2003; accepted April 29, 2003.




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