- Email: [email protected]
Post-operative chemotherapy improves disease-free survival, but not overall survival in people with oesophageal squamous cell carcinoma
CANCER TREATMENT REVIEWS (2004) 30, 473–477
www.elsevierhealth.com/journals/ctrv
EVIDENCE-BASED ONCOLOGY
Post-operative chemotherapy improves disease-free survival, but not overall survival in people with oesophageal squamous cell carcinoma Abstracted from: Ando N, Iizuka T, Ide H et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study – JCOG9204. Journal of Clinical Oncology 2003;21:4592–6.
Background
Objective
(7%), middle (58%) and lower oesophagus (35%). Lymph node status was N1 for 82% and N0 for 18% of participants. Inclusion criteria: absence of microscopic residual tumour (R0); pathological disease stage of IIA (18%), IIB (29%), III (35%) or IV – positive cervical or celiac nodes (18%); an Eastern Cooperative Oncology Group performance status between 0 and 2; an otherwise normal clinical laboratory profile. Exclusion criteria: additional synchronous or metachronous cancer.
To assess whether post-operative adjuvant chemotherapy is more effective than surgery alone in people with oesophageal squamous cell carcinoma.
Intervention
Evidence to support the administration of postoperative cisplatin plus fluorouracil chemotherapy regimens in people with oesophageal squamous cell carcinoma is lacking.
Setting Seventeen institutions in Japan; recruitment from July 1992 to January 1997.
Method Multicentre randomised controlled trial.
Participants Two hundred and forty two people aged 6 75 years (mean age 59 years, range 40 to 75 years) with histologically proven oesophageal squamous cell carcinoma. Tumours were located in the upper
All participants underwent regional lymphadenectomy, right or left thoracotomy for curative resection by subtotal or total oesophagectomy before randomisation to no further treatment (surgery only group) or two courses of chemotherapy (surgery plus chemotherapy). The chemotherapy regime comprised: cisplatin (80 mg/m2 of body surface area) administered over 2 h on day 1 via slow drip infusion plus fluorouracil (800 mg/m2 of body surface area) administered via continuous infusion from days 1 to 5. A second course of chemotherapy was administered after an interval of 3 weeks. Second course doses were adjusted or suspended altogether depending on the clinical laboratory profile. Median follow-up from time of randomisation was 62.8 months. Of the people randomised to receive post-operative chemotherapy, 21 (17.5%) failed to complete two planned courses, due either to toxicity or participant
0305-7372/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2004.05.007
474 refusal, and a further 8 (6.7%) people underwent no chemotherapy.
Main outcomes Disease-free survival (from the date of randomisation to the date of first evidence of relapse or death from any cause); overall survival (from the date of surgery to the date of death or last followup) and adverse events.
Main results Surgery plus chemotherapy improved disease-free survival compared with surgery alone at 5 years (see Evidence Table 1). There was no significant difference in overall survival between groups. One person died as a result of treatment in the surgery plus chemotherapy group (see Evidence Table 2). Information regarding adverse events in the surgery alone group was not reported.
Evidence-based Oncology Allocation Not clear concealment Balanced groups
Analysis
Adequate: groups were balanced at baseline with respect to sex, age, tumour location and pathology Intention to treat; Kaplan–Meier; Cox proportional hazards model
Sources of funding: This study was supported by the Ministry of Health, Labor and Welfare of Japan and the Second Term Comprehensive 10-Year Strategy for Cancer Control. For Correspondence: Nobutoshi Ando, Department of Surgery, Tokyo Dental College, Ichikawa General Hospital, Sugano, Ichikawashi, Chiba, Japan. E-mail: [email protected]. Abstract provided by Bazian Ltd., London.
Commentary Authors’ conclusions Post-operative adjuvant chemotherapy is more effective than surgery alone at improving diseasefree survival in people with oesophageal squamous cell carcinoma.
Method notes
Power calculation
80% power with 290 people to detect an absolute risk increase in 5-year disease-free survival of 13% with surgery plus chemotherapy compared with surgery alone at a 5% level of significance using a 1-sided test. However, only 242 people were enrolled in the study, and smaller differences in response rate cannot be excluded Blinding Nature of intervention precludes blinding of participants Generation of Adequate: randomisation was allocation centrally assigned using a minisequence misation method so that institution and pathologic lymph node status would be balanced
Esophageal cancer remains one of the most challenging malignancies to treat, of all gastrointestinal (GI) tract cancers. In the United States (US), it is estimated that 14,250 new cases and 13,300 deaths due to esophageal cancer will occur in 2004.1 Surgery remains the mainstay of treatment, but as the median survival is only 12 to 16 months, there is increasing interest in the role of adjuvant and neoadjuvant therapy. To date, studies evaluating adjuvant therapy have been inconclusive with regard to benefit. The two largest trials evaluating adjuvant cisplatin and 5-fluorouracil chemotherapy in resectable esophageal cancer have demonstrated conflicting results. The American Intergroup (INT113) trial reported by Kelsen et al. randomized 440 patients to adjuvant chemotherapy plus surgery or surgery alone. The median survival for the two groups was 16.1 months and 14.9 months, respectively ðp ¼ 0:53Þ.2 In contrast, the British Medical Research Council (MRC) trial treated 802 patients in a similar fashion and demonstrated median survivals of 16.8 months and 13.3 months, respectively ðp ¼ 0:004Þ, concluding a positive benefit to post-operative chemotherapy.3 Other trials have been either small or had design flaws complicating their interpretation (Table 1). Even meta-analyses on this subject fail to agree on the relative merits of adjuvant chemotherapy.4;5
Evidence-based Oncology Evidence Table 1
Disease-free and overall survival (intention to treat analysis)
Five-year disease-free survival Five-year overall survival
Evidence Table 2 therapy
475
Surgery alone ðN ¼ 122Þ
Surgery plus chemotherapy ðN ¼ 120Þ
Significance
45% (95% CI 36 to 54%) 52% (95% CI 43 to 61%)
55% (95% CI 46 to 64%) 61% (95% CI 52 to 70%)
p ¼ 0:037 p ¼ 0:13
Mortality and serious (Grade 3 or Grade 4)a adverse events during post-operative chemoSurgery plus post-operative chemotherapy ðN ¼ 120Þ
Absolute risk for mortality Cause of death: lactic acidosis relating to thiamine deficiency Absolute risk of toxicity Granulocytes Nausea/vomiting Leucocytes Platelets Diarrhoea Haemoglobin Arrhythmia Infection Fever a
1 (0.8%)
22 10 5 3 3 2 1 1 1
(18.3%) (8.3%) (4.2%) (2.5%) (2.5%) (1.7%) (0.8%) (0.8%) (0.8%)
Classified according to WHO toxicity criteria.
The trial by Ando et al.6 assesses the role of adjuvant chemotherapy in squamous cell esophageal cancer. In 242 patients from Japan, treatment with either surgery alone or surgery plus two courses of cisplatin and 5-fluorouracil (5FU) resulted in an improved 5-year disease-free survival ðp ¼ 0:037Þ. However, there was no difference in the overall survival between the groups ðp ¼ 0:13Þ. The authors rationalized that the lack of an overall survival benefit may be due to differences in surgical technique between the groups or the more frequent use of off-protocol chemoradiotherapy for recurrence in the surgery alone arm (35%) compared to the chemotherapy arm (25%). Weaknesses of the trial include a small sample size, failure to adhere to the original statistical design, off-protocol chemoradiotherapy, and a significant number of patients lost to follow-up. Ando et al. concluded that adjuvant chemotherapy is beneficial and that it should be used as a control arm for subsequent studies. The conclusions of the trial by Ando et al. are not definitive. The relevance of this trial to the current management of esophageal cancer in the Western world is limited by a number of factors. First, the patient cohort in this trial significantly differs from patients treated in the US or Europe. All patients in the Japanese study had squamous cell carcinoma and had 5-year survivals of 61% and
52% in the two arms. In the US intergroup trial, the 3-year survival was 23% and 26%, and in the MRC trial 2-year survival was 43% and 34%, respectively, for surgery plus chemotherapy versus surgery alone. In addition, adenocarcinoma was the predominant histology in both the US and MRC trials, in contrast to the Japanese study. Second, many patients in the Ando et al. trial had locally advanced disease but, presumably in an attempt to preserve the validity of the trial, off-protocol chemoradiotherapy was restricted to patients with recurrent disease. In the US, preoperative chemoradiotherapy is the standard of care for locally advanced esophageal cancer based on a number of trials demonstrating an improvement in either disease-free or overall survival using this approach.7 Also, patients with adenocarcinoma of the gastroesophageal (GE) junction are treated with post-operative chemoradiotherapy.8 A recent pattern of care study in the US reported combined chemoradiotherapy as being the most commonly employed modality of treatment for esophageal cancer.9 Finally, lack of an overall survival benefit using post-operative cisplatin and 5FU in the Ando et al. trial does not necessarily imply that adjuvant chemotherapy is ineffective. It is possible that had a greater number of cycles of chemotherapy been delivered, more definitive benefit might have been
476
Table 1
Prospective randomized trials of neoadjuvant or adjuvant chemotherapy in esophageal cancer
Author
Year
N
Histology
Treatment
Preop/Postop
Median (months) or 3-year survival
P value
Study limitations
Roth et al.
1988
20 19
SCC
Preop + postop
9 9
NS
Small
Schlag et al.
1991
24
SCC
Surgery Cisplatin/Vindesine/ Bleomycin Surgery
Preop
10
NS
NS
Randomized + nonrandomized in the paper 2 x 2 factorial design
22 Nygaard et al.
1992
50
Cisplatin/5FU SCC
56
Surgery
10 Preop
Cisplatin/bleomycin
Maipang et al.
1994
22 24
SCC
Pouliquen et al.
1996
68
SCC
Surgery Cisplatin/Vinblastine/ Bleomycin Surgery
Ando et al.
1997
52 100
SCC
Law et al.
1997
105 73
Kok et al.
1997
74 74
Kelsen et al.
1998
Ancona et al.
2001
13% 6% 17 17
NS
Small
Postop
14
NS
Cisplatin/Vindesine Surgery
Postop
13 45%
Some patients had R2 resections
NS
Small
SCC
Cisplatin/5FU Surgery
Preop
48% 13
NS
Small
SCC
Cisplatin/5FU Surgery
Preop
17 11
0.002
Only in abstract form
74 234
Adeno/SCC
Cisplatin/Etoposide Surgery
Preop + postop
18.5 16
NS
233 47
SCC
Cisplatin/5FU Surgery
Preop
15 24
Decreased surgery in chemotherapy arm
NS
R0 resection not performed in all patients Small
47
Cisplatin/5FU
25
Wang et al.
2001
50
Adeno/SCC
Surgery
Preop
32%
<0.05
MRC
2002
50 402
Adeno/SCC
Cisplatin-based Surgery
Preop
46% 13
0.004
Ando et al.
2003
SCC
Cisplatin/5FU Surgery
Preop
17 122
Off protocol radiotherapy
NS
Off protocol chemoradiotherapy
400
Cisplatin/5FU *
120
5-year survival; SCC, squamous cell carcinoma; Adeno, adenocarcinoma; Preop, pre-operative chemotherapy; Postop, post-operative chemotherapy; NS, non-significant.
Evidence-based Oncology
Preop
Evidence-based Oncology observed. A similar trial performed today in the US or Europe in adenocarcinoma patients, as accrual for a trial of this size in squamous cell patients is likely to be difficult, would be expected to incorporate newer chemotherapy regimens, which are potentially more efficacious and usually given preoperatively to facilitate better tolerance, increase resectability rates, and treat micrometastatic disease. The use of epirubicin, cisplatin and 5FU (ECF), and docetaxel, cisplatin and 5FU (DCF) has significantly improved survival in patients with metastatic cancer of the upper GI tract, when compared to other combination chemotherapy including cisplatin/5FU. Adjuvant ECF has improved disease-free survival in patients with resected gastric and GE cancers although follow-up was too premature to detect an overall survival difference.10 Other regimens such as irinotecan and cisplatin have also shown promising response rates (57%) and await investigation in phase III trials.11 We await the outcomes of trials using these regimens in the perioperative management of esophageal cancer. Despite the limitations of the trial by Ando et al., with respect to current practice in the Western world, a clearly positive or negative result would have provided further insight on the role of adjuvant chemotherapy in esophageal cancer. Unfortunately, this trial, like its predecessors, engenders more questions than firm conclusions. Although, while probably best interpreted as a negative trial due to the lack of an overall survival benefit, supporters of adjuvant chemotherapy will be encouraged by the marginal statistically significant improvement in diseasefree survival which was the primary endpoint of the study. Current practice will not change based on the results of the study by Ando et al. but these results provide continued support for the role of chemotherapy in the multidisciplinary management of potentially resectable esophageal cancer. Future trials in esophageal cancer must focus on newer more active chemotherapy and targeted therapies with or without radiotherapy. As chemoresponsive patients have consistently been shown to have an improved survival compared to non-responders, perhaps more important is the identification of chemoresponsive patients for the selected use of adjuvant therapy. Hopefully, with better patient selection and staging we can positively impact on the challenging prognosis of this disease.
477 Quality Assessment (scale 1 ¼ fair; 4 ¼ excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
4 3 3 3 3 4
Gregory D. Leonard Eileen M. O Reilly Memorial Sloan Kettering Cancer Center New York, NY, USA
References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics. CA Cancer J Clin 2004;54:8–29. 2. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339: 1979–84. 3. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002;359:1727–33. 4. Malthaner R, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 2001;(1):CD001556. 5. Urschel JD, Vasan H, Blewett CJ. A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2002;183:274–9. 6. Ando N, Iizuka T, Ide H, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study–JCOG9204. J Clin Oncol 2003;21: 4592–6. 7. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003;185:538–43. 8. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–30. 9. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer 1996;78:1820–8. 10. Allum W, Cunningham D, Weeden S. Perioperative chemotherapy in operable gastric and lower oesophageal cancer: a randomised, controlled trial (the MAGIC trial, ISRCTN 93793971). Proc Am Soc Clin Oncol 2003;22:249 (Abstract 998). 11. Ilson DH, Saltz L, Enzinger P, et al. Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 1999;17:3270–5.
www.elsevierhealth.com/journals/ctrv
EVIDENCE-BASED ONCOLOGY
Post-operative chemotherapy improves disease-free survival, but not overall survival in people with oesophageal squamous cell carcinoma Abstracted from: Ando N, Iizuka T, Ide H et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study – JCOG9204. Journal of Clinical Oncology 2003;21:4592–6.
Background
Objective
(7%), middle (58%) and lower oesophagus (35%). Lymph node status was N1 for 82% and N0 for 18% of participants. Inclusion criteria: absence of microscopic residual tumour (R0); pathological disease stage of IIA (18%), IIB (29%), III (35%) or IV – positive cervical or celiac nodes (18%); an Eastern Cooperative Oncology Group performance status between 0 and 2; an otherwise normal clinical laboratory profile. Exclusion criteria: additional synchronous or metachronous cancer.
To assess whether post-operative adjuvant chemotherapy is more effective than surgery alone in people with oesophageal squamous cell carcinoma.
Intervention
Evidence to support the administration of postoperative cisplatin plus fluorouracil chemotherapy regimens in people with oesophageal squamous cell carcinoma is lacking.
Setting Seventeen institutions in Japan; recruitment from July 1992 to January 1997.
Method Multicentre randomised controlled trial.
Participants Two hundred and forty two people aged 6 75 years (mean age 59 years, range 40 to 75 years) with histologically proven oesophageal squamous cell carcinoma. Tumours were located in the upper
All participants underwent regional lymphadenectomy, right or left thoracotomy for curative resection by subtotal or total oesophagectomy before randomisation to no further treatment (surgery only group) or two courses of chemotherapy (surgery plus chemotherapy). The chemotherapy regime comprised: cisplatin (80 mg/m2 of body surface area) administered over 2 h on day 1 via slow drip infusion plus fluorouracil (800 mg/m2 of body surface area) administered via continuous infusion from days 1 to 5. A second course of chemotherapy was administered after an interval of 3 weeks. Second course doses were adjusted or suspended altogether depending on the clinical laboratory profile. Median follow-up from time of randomisation was 62.8 months. Of the people randomised to receive post-operative chemotherapy, 21 (17.5%) failed to complete two planned courses, due either to toxicity or participant
0305-7372/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2004.05.007
474 refusal, and a further 8 (6.7%) people underwent no chemotherapy.
Main outcomes Disease-free survival (from the date of randomisation to the date of first evidence of relapse or death from any cause); overall survival (from the date of surgery to the date of death or last followup) and adverse events.
Main results Surgery plus chemotherapy improved disease-free survival compared with surgery alone at 5 years (see Evidence Table 1). There was no significant difference in overall survival between groups. One person died as a result of treatment in the surgery plus chemotherapy group (see Evidence Table 2). Information regarding adverse events in the surgery alone group was not reported.
Evidence-based Oncology Allocation Not clear concealment Balanced groups
Analysis
Adequate: groups were balanced at baseline with respect to sex, age, tumour location and pathology Intention to treat; Kaplan–Meier; Cox proportional hazards model
Sources of funding: This study was supported by the Ministry of Health, Labor and Welfare of Japan and the Second Term Comprehensive 10-Year Strategy for Cancer Control. For Correspondence: Nobutoshi Ando, Department of Surgery, Tokyo Dental College, Ichikawa General Hospital, Sugano, Ichikawashi, Chiba, Japan. E-mail: [email protected]. Abstract provided by Bazian Ltd., London.
Commentary Authors’ conclusions Post-operative adjuvant chemotherapy is more effective than surgery alone at improving diseasefree survival in people with oesophageal squamous cell carcinoma.
Method notes
Power calculation
80% power with 290 people to detect an absolute risk increase in 5-year disease-free survival of 13% with surgery plus chemotherapy compared with surgery alone at a 5% level of significance using a 1-sided test. However, only 242 people were enrolled in the study, and smaller differences in response rate cannot be excluded Blinding Nature of intervention precludes blinding of participants Generation of Adequate: randomisation was allocation centrally assigned using a minisequence misation method so that institution and pathologic lymph node status would be balanced
Esophageal cancer remains one of the most challenging malignancies to treat, of all gastrointestinal (GI) tract cancers. In the United States (US), it is estimated that 14,250 new cases and 13,300 deaths due to esophageal cancer will occur in 2004.1 Surgery remains the mainstay of treatment, but as the median survival is only 12 to 16 months, there is increasing interest in the role of adjuvant and neoadjuvant therapy. To date, studies evaluating adjuvant therapy have been inconclusive with regard to benefit. The two largest trials evaluating adjuvant cisplatin and 5-fluorouracil chemotherapy in resectable esophageal cancer have demonstrated conflicting results. The American Intergroup (INT113) trial reported by Kelsen et al. randomized 440 patients to adjuvant chemotherapy plus surgery or surgery alone. The median survival for the two groups was 16.1 months and 14.9 months, respectively ðp ¼ 0:53Þ.2 In contrast, the British Medical Research Council (MRC) trial treated 802 patients in a similar fashion and demonstrated median survivals of 16.8 months and 13.3 months, respectively ðp ¼ 0:004Þ, concluding a positive benefit to post-operative chemotherapy.3 Other trials have been either small or had design flaws complicating their interpretation (Table 1). Even meta-analyses on this subject fail to agree on the relative merits of adjuvant chemotherapy.4;5
Evidence-based Oncology Evidence Table 1
Disease-free and overall survival (intention to treat analysis)
Five-year disease-free survival Five-year overall survival
Evidence Table 2 therapy
475
Surgery alone ðN ¼ 122Þ
Surgery plus chemotherapy ðN ¼ 120Þ
Significance
45% (95% CI 36 to 54%) 52% (95% CI 43 to 61%)
55% (95% CI 46 to 64%) 61% (95% CI 52 to 70%)
p ¼ 0:037 p ¼ 0:13
Mortality and serious (Grade 3 or Grade 4)a adverse events during post-operative chemoSurgery plus post-operative chemotherapy ðN ¼ 120Þ
Absolute risk for mortality Cause of death: lactic acidosis relating to thiamine deficiency Absolute risk of toxicity Granulocytes Nausea/vomiting Leucocytes Platelets Diarrhoea Haemoglobin Arrhythmia Infection Fever a
1 (0.8%)
22 10 5 3 3 2 1 1 1
(18.3%) (8.3%) (4.2%) (2.5%) (2.5%) (1.7%) (0.8%) (0.8%) (0.8%)
Classified according to WHO toxicity criteria.
The trial by Ando et al.6 assesses the role of adjuvant chemotherapy in squamous cell esophageal cancer. In 242 patients from Japan, treatment with either surgery alone or surgery plus two courses of cisplatin and 5-fluorouracil (5FU) resulted in an improved 5-year disease-free survival ðp ¼ 0:037Þ. However, there was no difference in the overall survival between the groups ðp ¼ 0:13Þ. The authors rationalized that the lack of an overall survival benefit may be due to differences in surgical technique between the groups or the more frequent use of off-protocol chemoradiotherapy for recurrence in the surgery alone arm (35%) compared to the chemotherapy arm (25%). Weaknesses of the trial include a small sample size, failure to adhere to the original statistical design, off-protocol chemoradiotherapy, and a significant number of patients lost to follow-up. Ando et al. concluded that adjuvant chemotherapy is beneficial and that it should be used as a control arm for subsequent studies. The conclusions of the trial by Ando et al. are not definitive. The relevance of this trial to the current management of esophageal cancer in the Western world is limited by a number of factors. First, the patient cohort in this trial significantly differs from patients treated in the US or Europe. All patients in the Japanese study had squamous cell carcinoma and had 5-year survivals of 61% and
52% in the two arms. In the US intergroup trial, the 3-year survival was 23% and 26%, and in the MRC trial 2-year survival was 43% and 34%, respectively, for surgery plus chemotherapy versus surgery alone. In addition, adenocarcinoma was the predominant histology in both the US and MRC trials, in contrast to the Japanese study. Second, many patients in the Ando et al. trial had locally advanced disease but, presumably in an attempt to preserve the validity of the trial, off-protocol chemoradiotherapy was restricted to patients with recurrent disease. In the US, preoperative chemoradiotherapy is the standard of care for locally advanced esophageal cancer based on a number of trials demonstrating an improvement in either disease-free or overall survival using this approach.7 Also, patients with adenocarcinoma of the gastroesophageal (GE) junction are treated with post-operative chemoradiotherapy.8 A recent pattern of care study in the US reported combined chemoradiotherapy as being the most commonly employed modality of treatment for esophageal cancer.9 Finally, lack of an overall survival benefit using post-operative cisplatin and 5FU in the Ando et al. trial does not necessarily imply that adjuvant chemotherapy is ineffective. It is possible that had a greater number of cycles of chemotherapy been delivered, more definitive benefit might have been
476
Table 1
Prospective randomized trials of neoadjuvant or adjuvant chemotherapy in esophageal cancer
Author
Year
N
Histology
Treatment
Preop/Postop
Median (months) or 3-year survival
P value
Study limitations
Roth et al.
1988
20 19
SCC
Preop + postop
9 9
NS
Small
Schlag et al.
1991
24
SCC
Surgery Cisplatin/Vindesine/ Bleomycin Surgery
Preop
10
NS
NS
Randomized + nonrandomized in the paper 2 x 2 factorial design
22 Nygaard et al.
1992
50
Cisplatin/5FU SCC
56
Surgery
10 Preop
Cisplatin/bleomycin
Maipang et al.
1994
22 24
SCC
Pouliquen et al.
1996
68
SCC
Surgery Cisplatin/Vinblastine/ Bleomycin Surgery
Ando et al.
1997
52 100
SCC
Law et al.
1997
105 73
Kok et al.
1997
74 74
Kelsen et al.
1998
Ancona et al.
2001
13% 6% 17 17
NS
Small
Postop
14
NS
Cisplatin/Vindesine Surgery
Postop
13 45%
Some patients had R2 resections
NS
Small
SCC
Cisplatin/5FU Surgery
Preop
48% 13
NS
Small
SCC
Cisplatin/5FU Surgery
Preop
17 11
0.002
Only in abstract form
74 234
Adeno/SCC
Cisplatin/Etoposide Surgery
Preop + postop
18.5 16
NS
233 47
SCC
Cisplatin/5FU Surgery
Preop
15 24
Decreased surgery in chemotherapy arm
NS
R0 resection not performed in all patients Small
47
Cisplatin/5FU
25
Wang et al.
2001
50
Adeno/SCC
Surgery
Preop
32%
<0.05
MRC
2002
50 402
Adeno/SCC
Cisplatin-based Surgery
Preop
46% 13
0.004
Ando et al.
2003
SCC
Cisplatin/5FU Surgery
Preop
17 122
Off protocol radiotherapy
NS
Off protocol chemoradiotherapy
400
Cisplatin/5FU *
120
5-year survival; SCC, squamous cell carcinoma; Adeno, adenocarcinoma; Preop, pre-operative chemotherapy; Postop, post-operative chemotherapy; NS, non-significant.
Evidence-based Oncology
Preop
Evidence-based Oncology observed. A similar trial performed today in the US or Europe in adenocarcinoma patients, as accrual for a trial of this size in squamous cell patients is likely to be difficult, would be expected to incorporate newer chemotherapy regimens, which are potentially more efficacious and usually given preoperatively to facilitate better tolerance, increase resectability rates, and treat micrometastatic disease. The use of epirubicin, cisplatin and 5FU (ECF), and docetaxel, cisplatin and 5FU (DCF) has significantly improved survival in patients with metastatic cancer of the upper GI tract, when compared to other combination chemotherapy including cisplatin/5FU. Adjuvant ECF has improved disease-free survival in patients with resected gastric and GE cancers although follow-up was too premature to detect an overall survival difference.10 Other regimens such as irinotecan and cisplatin have also shown promising response rates (57%) and await investigation in phase III trials.11 We await the outcomes of trials using these regimens in the perioperative management of esophageal cancer. Despite the limitations of the trial by Ando et al., with respect to current practice in the Western world, a clearly positive or negative result would have provided further insight on the role of adjuvant chemotherapy in esophageal cancer. Unfortunately, this trial, like its predecessors, engenders more questions than firm conclusions. Although, while probably best interpreted as a negative trial due to the lack of an overall survival benefit, supporters of adjuvant chemotherapy will be encouraged by the marginal statistically significant improvement in diseasefree survival which was the primary endpoint of the study. Current practice will not change based on the results of the study by Ando et al. but these results provide continued support for the role of chemotherapy in the multidisciplinary management of potentially resectable esophageal cancer. Future trials in esophageal cancer must focus on newer more active chemotherapy and targeted therapies with or without radiotherapy. As chemoresponsive patients have consistently been shown to have an improved survival compared to non-responders, perhaps more important is the identification of chemoresponsive patients for the selected use of adjuvant therapy. Hopefully, with better patient selection and staging we can positively impact on the challenging prognosis of this disease.
477 Quality Assessment (scale 1 ¼ fair; 4 ¼ excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
4 3 3 3 3 4
Gregory D. Leonard Eileen M. O Reilly Memorial Sloan Kettering Cancer Center New York, NY, USA
References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics. CA Cancer J Clin 2004;54:8–29. 2. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339: 1979–84. 3. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet 2002;359:1727–33. 4. Malthaner R, Fenlon D. Preoperative chemotherapy for resectable thoracic esophageal cancer. Cochrane Database Syst Rev 2001;(1):CD001556. 5. Urschel JD, Vasan H, Blewett CJ. A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2002;183:274–9. 6. Ando N, Iizuka T, Ide H, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study–JCOG9204. J Clin Oncol 2003;21: 4592–6. 7. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg 2003;185:538–43. 8. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–30. 9. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer 1996;78:1820–8. 10. Allum W, Cunningham D, Weeden S. Perioperative chemotherapy in operable gastric and lower oesophageal cancer: a randomised, controlled trial (the MAGIC trial, ISRCTN 93793971). Proc Am Soc Clin Oncol 2003;22:249 (Abstract 998). 11. Ilson DH, Saltz L, Enzinger P, et al. Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 1999;17:3270–5.