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A Comparison of Chemotherapy and Radiotherapy as Adjuvant Treatment to Surgery for Esophageal Carcinoma
A Comparison of Chemotherapy and Radiotherapy as Adjuvant Treatment to Surgery for Esophageal Carcinoma* japanese Esophageal Oncology Group A cooperative, prospective randomized study to compare radiotherapy (50 Gy) or 2 courses of combination chemotherapy consisting of cispIatin (SO mglmS) and vindesine (3 mglmS) following curative resection was performed in 258 patients at 9 institutions between August 1985 and August 1987. In the two groups, no difference was present in the background factors such as sex, age, and the location and length of the tumor. Also, there was no difference of
distribution of pT, pN, pM or p stage by the revised TNM classi6cation of 1987. There was no signi6cant difference in survival up to 5 years in the 2 groups. Concerning the side effects, the decrease in white blood cell and platelet counts was similar in the two groups, but elevation of blood urea nitrogen and creatinine concentrations was more marked in the group receiving chemotherapy than in the group with radiotherapy. (Chat 1993; 104:203-07)
In the treatment of esophageal carcinoma, radiotherapy has long been used as an adjuvant to surgery, in the form of preoperative and postoperative treatment. Since the introduction by Cliffton et al' and Nakayama," preoperative radiotherapy has been performed routinely in Japan. Recently, our comparison between preoperative and postoperative radiotherapy by a prospective randomized trial showed that postoperative radiotherapy is superior in terms of survival. 3 The 3-year survival rate for preoperative radiotherapy was 24 percent, and that for postoperative was 38 percent. During the last 10 years, chemotherapy for esophageal carcinoma has improved significantly. Kelserr' accumulated data from the world literature and described response rates to single agents for esophageal cancer as 22 percent (16173) for cisplatin and 28.6 percent (28191) for vindesine. In Japan, Nishihira and Abo" reported that cisplatin had a response rate of 21 percent (10/47) in a phase 2 study, and we6 reported a phase 2 study of vindesine with a response rate of 13 percent (6145). Kelsen et al? reported combination chemotherapy with cisplatin, vindesine, and bleomycin with a response rate of 53 percent in 68 patients with esophageal carcinoma. The present investigation attempted to determine whether radiotherapy or chemotherapy is better for postoperative treatment of esophageal cancer by a prospective randomized study in cooperation with nine institutions. Kelsen et al8 reported the results of preoperative chemotherapy with two cycles of cisplatin, vindesine, and bleomycin, but we wanted to study postoperative methods in this study, because postoperative radiotherapy had shown a higher survival rate
than preoperative radiotherapy reported in our previous study" We plan to examine the effect of preoperative chemotherapy in a future study. A combination of cisplatin and vindesine was selected, removing bleomycin from the regimen reported by Kelsen et aI,7 because bleomycin had significantly higher operative mortality due to pulmonary complications than tegafur, when administered combined with preoperative radiotherapy in our previous study" The concentration of chemotherapeutic agents was set at levels currently employed in japan." The dose of radiation was set at 50 Gy based on our previous study.3
*Supported by a grant-in-aid for Cancer Research (59 S-l) from the Ministry of Health and Welfare of Japan. Manuscript received July 15, 1991; revision accepted November 6, 1992 Reprint requests: Dr. 1bshifumi lizuka, National Oft Hospital, 1756 Akabanedai 4-chome, J(jta-ku, Tolqp 115, japan
MATERIALS AND METHODS
Patients who bad undergone curative resection, which includes complete removal of the main tumor and dissection of regional lymph nodes, were entered into this stud~ Regional lymph nodes include not only mediastinal but also perigastric nodes, which were classified according to the new TNM classiflcation revised in 1987. 10 Such patients constituted 40 percent (2581643) of all esophageal patients who underwent resection at the group's institutions during the same period. Postoperative treatments were divided into two arms, radiotherapy (group A) and chemotherapy (group B), which were started within 2 to 4 weeks following surgery. Selection for group A or B was performed by block randomization before starting postoperative treatment. In group A, 50 Gy of radiotherapy was given to the supraclavicular area and the upper mediastinum in doses of 2 Gy/day 5 times per week for 5 weeks. If myelosuppression was noticed during radiotherapy, radiotherapy was halted until recovery, but all radiotherapy had to be terminated within 7 weeks. In group B, cisplatin (50 mglml ) was given by slow drip infusion and vindesine (3 mglml ) by intravenous bolus infusion on the first day Chemotherapy was to be repeated twice at intervals of 3 weeks. The dose of vindesine was decreased to 50 percent in cases where a WBC count of 2,5OOImm3 to 4,()()QImm3 , or a platelet count of 5O,OOOImm3 to lOO,OOOImm3 were noted. Therapy with vindesine was halted for a WBC count of less than 2,5OOImm3 or a platelet count of less than 5O,()()QImm3 • Cisplatin was halted in the case of a serum creatinine level over 2.0 mg/ml or creatinine clearance of less than 40 mVmin. Patients entered into this study were selected according to the CHEST I 104 I 1 I JUL~ 1993
203
following criteria for eligibility: (1) age under 75 years; (2) nonnal values on clinical laboratory examinations (WBCs >4,()()(lImm3 ; platelets >100,OOOImm3 ; hemoglobin >10 mgldl; bilirubin, glutamie-oxaloacetic transaminase [GOT], and glutamic-pyruvic transaminase [GPT], normal value; creatinine <1.2 mgldl; creatinine clearance >60 mVmin; PaO. >70 mm Hg); and (3) informed consent was obtained from all patients before treatment. The extent of disease was described according to the new TNM classiflcation'? revised in 1987. Patients who were not given any treatment were considered ineligible, and only those who received treatment were eligible. Only patients who completed the scheduled regimen were regarded as complete cases, and patients given 49 Gy or less of radiotherapy or only 1 administration of chemotherapy were considered as incomplete. The results were compared among eligible patients including incomplete cases. The prognoses of all patients were evaluated on August 31, 1990; the survival rate in each I-year interval was calculated by the life table method, and a survival curve was plotted using the survival rate by Kaplan-Meyer's method. Comparison of the two survival rates was conducted by standard error in each year and by log rank and the Wdcoxon test for the total period using the LIFETEST procedure of the SAS program package software. l l Registered patients were examined to identify any favorable differences in the distribution ofbaclcground factors and side effects between the two groups by the y; test using the FREQ procedure of SAS. u All calculations were done on a mainframe computer of the National Cancer Center, Tokyo.
During the period from August 1, 1985 to August 31, 1987, there were 258 patients entered into this study; 128 patients in group A and 130 patients in group B, as seen in Table 1. There were 5 ineligible patients (2 percent), 1 in group A and 4 in group B, 2 of whom did not receive postoperative therapy due to pneumonia, 1 due to cardiac infarction, 1 due to wound infection, and 1 due to refusal of further therapy There were 18 patients who were not able to complete postoperative treatment due to side effects, 7 of whom were in group A, who underwent less than 50 Gy of irradiation, and 1 in group B, who underwent Table 1-ChtJrtJCteriaticB ofEligible PatientI Characteristic
Group A
GroupB
Entered Eligible Ineligible Cause of ineligibility Pneumonia Cardiac infarction Wound infection Refusal of further therapy Sex Male Female Age, yr <50 51-60 61-70
128 127 1
130 126 4
0 1 0 0
2 0 1 1
110 17
113 13
11
14 46 55 11
204
Classification
Group A
GroupB
1 10 70 47
2 8 69 51
40 49 25 14
30 49 35 16
13 31 75 8
20
Location of tumor Cervical Upper thoracic Mid-thoracic Lower thoracic Length of tumor, cm <5 5-7 7-9 >9 pT pTI pT2 pT3 pT4 pN p-NO p-Nl p stage p stage I p stage IIA p stage lIB p stage III p stage IV
18 79 9
34 93
37
2 28 27 55 15
5 30
89
25
51 15
• As revised in 1987. 10
RESULTS
~71
Table 2- TNM ClaaijictJtion of Eligible PatientI*
39
52 25
only 1 course of chemotherapy Therefore, there were 235 cases (91 percent) who completed the treatment. There was no statistical difference in either the male/female ratio or in the age distribution, as seen in Table 1. As seen in Table 2, there was no statistically significant difference between the two groups in terms of the distribution of the location of the tumor or the length of the tumor. Also, there was no significant difference in pT, pN, pM, and p stage classification in the two groups. Because there is no bias in terms of background factors relating to the prognosis of the patients, it is reasonable to compare the survival rates of the two groups. The survival rate of group A was 80 percent at 1 year, 61 percent at 2 years, and 51 percent at 3 years, as seen in Table 3. Group B had a survival rate of 90 percent at 1 year, 60 percent at 2 years, and 52 percent at 3 years. Group B had a better survival rate at 1 year, but there was no significant difference in the total survival rate by log rank (p=0.8061) and the Wilcoxon test (p = 0.6545). The survival curve is shown Table 3-CumulaOOe Suroiool Bate (%) (± SE) by life Table Method for Eligible PatientI* Cumulative Survival Rate, %
Group A GroupB Test
No.
1st yr
2ndyr
3rdyr
4thyr
5thyr
127 127
80±4 9O±3 p
61±4 6O±4 NS
51±4 52±4 NS
46±5 47±5 NS
44±5 42±5 NS
*NS, Not statistically significant at level ofO.OS. Therapy Adjuvantto Surgeryfor EsophagealCarcinoma (Toshlfumi lizuke)
SURVIVAL CURVE GRO'UPA
vs
B
1.0
S 0.9
U R 0.8
Y0.7
V 0.6
A L 0.5
R 0.4 ~ 0.3 E 0.2
0.1
0. 0 ~-.----r---.----.---,.......-....--......-......--.....--....--r--.-----.~~.....-...---,..-~-r--r--,--r--...---.-~---r---r---....-,.-.,..
e
12
48
24
FIGURE 1. Survival curves in two groups. Solid line, group A (radiotherapy); and broken line, group B (chemotherapy).
in Figure 1, and there was no difference between the
2 groups.
The sites of recurrence were classified as local and distant recurrences and others, as seen in Table 4. There were more patients who died of local recurrence in the group receiving chemotherapy than in the group with radiotherapy, but the difference was not statistically significant. The rates of recurrence up to 3 years were 55 percent for group A and 56 percent for group B. There was no significant difference in the time to recurrence
between the 2 groups by log rank (p = 0.9265) and the Wilcoxon test (p=0.9326). Side effects after the postoperative treatment were classified according to the criteria of the World Health Organization." As seen in Table 5, there was no difference in the distribution of side effects in the WBC count, platelet count, blood urea nitrogen (BUN) level, and creatinine level before the treatment. After the treatment, a grade 4 side effect was seen in the WBC and platelet counts and none in the BUN and creatinine levels. For the WBC count, more cases with
Table 4-DiBtribution of¤t Sitea Between Group. A and B Group A
Table 5-Side EJfecta Pretreatment Grade *
Local Bronchus Esophagus Mediastinum Pleural membrane Neck Distant Kidney Liver Lung Abdominal lymph node Bone Brain Others No cancer Unknown * *Cause of death was unknown.
Posttreatment
GroupB
2 0 17 4
0 1 23 1
5
8
1 9 11 5 3 3 13 54
1
5 11 6 2 2 11
55
Grade·
~
Grade WBCcount Group A GroupB Platelets Group A Group B BUN Group A GroupB Creatinine Group A GroupB
0
1
2
3
4
x't
63
45
16 10
3 10
0 2
p=O.026
1 2
1 1
1 0
0 1
NS
116 100
11 24
0 2
0 0
0 0
p=0.018
118
9 21
0
5
0 1
0 0
p=O.OO6
0
1
x1t
125
123
2 3
NS
125 126
2 0
NS
124 122
122 125
5 1
NS
116 117
11 9
NS
74 30
99
*Grade of side effect was expressed in terms of criteria of WHO. 13 tNS, Not significant. CHEST I 104 I 1 I JUL'f, 1993
205
grade 3 and 4 side effects were seen in the group receiving chemotherapy, with a p value of 0.026; however, there was no significant difference in the platelet count. On the contrary, significant differences were observed in the BUN (p=0.018) and creatinine (p = 0.006) levels between the 2 groups. One patient was considered to be a chemotherapyrelated death. This 49-year-old man had received esophagectomy and intrathoracic anastomosis for cancer of the middle thoracic esophagus on May 6, 1987. Chemotherapy, consisting of 75 mg of cisplatin and 4.5 mg of vindesine, was given twice, on the 30th and 56th postoperative days. After the second administration, the platelet count decreased to 32,OOO/mm;3 on the third day after chemotherapy, the WBC count dropped to 6OO/mm3, and the BUN level was 60 midI the ninth day after chemotherapy. On the tenth day the WBC count was 200/mm 3, the platelet count was 3,OOO/mm3, and the BUN and creatinine levels became 196 mg/dl and 3.5 mg/dl, respectively. The patient died of sepsis and multiple organ failure on the 11th day after chemotherapy DISCUSSION
During a period of 25 months, 258 patients were entered into this study Of these, 235 (91 percent) could be adquately evaluated. There was no difference between the two groups in sex, age, the location and length of the tumor, or pT, pN, or p stage of the TNM classification. There was no statistically significant difference in the survival rates of the two groups by either log rank or Wilcoxon tests. Based on these data, we concluded that the chemotherapy with cisplatin combined with vindesine has an effect on survival equivalent to 50 Gy of radiotherapy as a postoperative adjuvant treatment. In our previous study," survival rates after surgery in the group receiving postoperative radiotherapy were 38 percent at 3 years, 35 percent at 4 years, and 30 percent at 5 years. In this new series, the patients with postoperative radiotherapy had the same criteria for eligibility and same dose of radiation as in the previous study, but more favorable results were obtained, with the 5-year survival rate being 44 percent. This improvement in survival may be attributable to the advancement of both the operative technique and perioperative management. To prevent the possibility of chemotherapy-related death, we emphasize careful checking of the blood cell count and creatinine clearance before the second administration of chemotherapy. Although these results suggest that the chemotherapy used in group B seems to have an effect potentially equivalent to postoperative irradiation on survival, it can be interpreted differentl~ ie, neither postopera206
tive adjuvant treatment has an impact on the survival when compared to surgery alone. Recent results of the phase 2 trials of cisplatin and vindesine on patients with advanced esophageal carcinoma'! suggest that the chemotherapy used in this study has only a modest effect. In this study, there were five PRs among 31 cases, and the response rate was 16 percent (95 percent confidence limit, 6 to 40 percent). While the concentrations of chemotherapy were low by Western standards, the concentrations were at a level consistent with general policy in Japan when the study was carried out." The fact that there was one treatment-related death shows that the level employed did cause toxic effects, yet future trials should nevertheless employ more aggressive chemotherapy. Based on these results, it has become necessary for us to study whether adjuvant chemotherapy following surgery has an impact on survival or not in patients with esophageal carcinoma. Therefore, we initiated a prospective randomized trial in which surgery alone was compared with postoperative chemotherapy using cisplatin and vindesine. Based on the report by Kelsen et al," we plan to examine the effect of preoperative chemotherapy in our next study ACKNOWLEDGMENTS: The Japanese Esophageal Oncology Group consists of 1bshifumi Iizu~, M.D., F.C.C.~, Department of Surgery, National Cancer Center Hospital, Tokyo, (present address: National Oji Hospital, Tokyo; Teruo Kakegawa, M.D., F.C.C.~, Department of Surgery, Faculty of Medicine, Kurume University, Kurume; Hiroko Ide, M.D., Department of Surgery, Tokyo Women's Medical College, Tokyo; Nobutoshi Ando, M.D., Department of Surgery, Faculty of Medicine, Keio University, TolCYo; Hiroshi Watanabe, M.D., F.C.C.~, Department of Surgery, National Cancer Center Hospital, Tolcvo; Koichi Sasaki, M.D., Department of Surgery, Faculty of Medicine, Niigata University, Niigata; Iwao Takagi, M.D., Department of Surgery, Aichi Cancer Center Hospital, Nagoya; Masanori Fukushima, M.D., Department of Internal Medicine, Aichi Cancer Center Hospital, Nagoya; Atsushi Nashimoto, M.D., Department of Surgery, Niigata Cancer Center Hospital, Niigata; Show Mori, M.D., Department of Surgery, Iwate Medical College, Morioka; (present address: Department of Surgery, Faculty of Medicine, Tohoku University, Sendai); Kaoru Ishida, M.D., Department of Surgery, Iwate Medical College, Morioka; Masaki Arimori, M.D., Department of Surgery, Tokyo Second National Hospital, Tokyo, and Shoichiro Tsugane, M.D., Epidemiology Division, National Cancer Center Research Institute, Tokyo. We thank Professor J. Patrie Barron of Tokyo Medical College for his review of the manuscript. REFERENCES
1 Cliffton EE, Goodner JT, Bronstein EL. Preoperative irradiation for cancer of the esophagus. Cancer 1960; 13:37-45 2 Nakayama K. Preoperative radiotherapy for esophageal carcinoma. Jpn J Radioll961; 21:435-39 3 Iizuka T, Ide H, Kakegawa T, Sasaki K, Takagi I, Ando N, et al. Preoperative radioactive therapy for esophageal carcinoma. Chest 1988; 93: 1054-58 4 Kelsen D. Chemotherapy of esophageal cancer. Semin Oneol 1984; 11:159-68 5 Nishihira T, Abo S. Phase II study of cisplatin for esophageal cancer. Gan to Kagakuryoho 1986; 13:2939-46 6 Iizuka T, Kakegawa T, Ide H. A phase II study of vindesine in the treatment of esophageal cancer. Jpn J Clin Oneol 1989; 19:380-83 Therapy Adjuvant to Surgeryfor EsophagealCarcinoma (Toshifumi lizuka)
7 Kelsen D~ Hilaris B, Coonley C. Cisplatin, vindesine, and bleomycin chemotherapy of local regional and advanced esophageal carcinoma. Am J Med 1983; 75:645-52 8 Kelsen D~ Minsky B, Smith M, Beitler J, Niedzwiecki D, Chapman D, et ale Preoperative therapy for esophageal cancer: a randomized comparison of chemotherapy versus radiation therapy J Coo Oncoll990; 8:1352-61 9 Cooperative clinical study group for esophageal carcinoma. Multi-discipOOary treabnent for esophageal carcinoma. Jpn J Clin Oncoll983; 13:417-24 10 International Union Against Cancer. TNM classification of
11 12 13 14
malignant tumours. 4th fully revised ed. Berlin: Springer-Verlag, 1987 Delong DM. The LIFETEST procedure, SAS user's guide: statistics. Cary, NC: SAS Institute, 1985; 539-57 The FREQ procedure, SAS user's guide: statistics, version 5 edition. Cary NC: SAS Institute, 1985; 403-32 Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47:207-14 Iizuka T, Kakegawa T, Ide H, Ando N, Watanabe H. Phase II study of cisplatin and vindesine in the treatment of esophageal carcinoma. Jpn J Clin Oncoll991; 21:176-79
18th International Conference on Lung Sounds This 18th conference will be held August 25-27 at Lake Louise, Alberta, Canada. For information, contact Dr. Raymond L. H. Murphy Jr, MD, Attn: Barbara Keith, Faulkner Hospital, 1153 Centre Street, Boston 02130 (617:522-5800).
CHEST I 104 I 1 I JUL'( 1993
207
distribution of pT, pN, pM or p stage by the revised TNM classi6cation of 1987. There was no signi6cant difference in survival up to 5 years in the 2 groups. Concerning the side effects, the decrease in white blood cell and platelet counts was similar in the two groups, but elevation of blood urea nitrogen and creatinine concentrations was more marked in the group receiving chemotherapy than in the group with radiotherapy. (Chat 1993; 104:203-07)
In the treatment of esophageal carcinoma, radiotherapy has long been used as an adjuvant to surgery, in the form of preoperative and postoperative treatment. Since the introduction by Cliffton et al' and Nakayama," preoperative radiotherapy has been performed routinely in Japan. Recently, our comparison between preoperative and postoperative radiotherapy by a prospective randomized trial showed that postoperative radiotherapy is superior in terms of survival. 3 The 3-year survival rate for preoperative radiotherapy was 24 percent, and that for postoperative was 38 percent. During the last 10 years, chemotherapy for esophageal carcinoma has improved significantly. Kelserr' accumulated data from the world literature and described response rates to single agents for esophageal cancer as 22 percent (16173) for cisplatin and 28.6 percent (28191) for vindesine. In Japan, Nishihira and Abo" reported that cisplatin had a response rate of 21 percent (10/47) in a phase 2 study, and we6 reported a phase 2 study of vindesine with a response rate of 13 percent (6145). Kelsen et al? reported combination chemotherapy with cisplatin, vindesine, and bleomycin with a response rate of 53 percent in 68 patients with esophageal carcinoma. The present investigation attempted to determine whether radiotherapy or chemotherapy is better for postoperative treatment of esophageal cancer by a prospective randomized study in cooperation with nine institutions. Kelsen et al8 reported the results of preoperative chemotherapy with two cycles of cisplatin, vindesine, and bleomycin, but we wanted to study postoperative methods in this study, because postoperative radiotherapy had shown a higher survival rate
than preoperative radiotherapy reported in our previous study" We plan to examine the effect of preoperative chemotherapy in a future study. A combination of cisplatin and vindesine was selected, removing bleomycin from the regimen reported by Kelsen et aI,7 because bleomycin had significantly higher operative mortality due to pulmonary complications than tegafur, when administered combined with preoperative radiotherapy in our previous study" The concentration of chemotherapeutic agents was set at levels currently employed in japan." The dose of radiation was set at 50 Gy based on our previous study.3
*Supported by a grant-in-aid for Cancer Research (59 S-l) from the Ministry of Health and Welfare of Japan. Manuscript received July 15, 1991; revision accepted November 6, 1992 Reprint requests: Dr. 1bshifumi lizuka, National Oft Hospital, 1756 Akabanedai 4-chome, J(jta-ku, Tolqp 115, japan
MATERIALS AND METHODS
Patients who bad undergone curative resection, which includes complete removal of the main tumor and dissection of regional lymph nodes, were entered into this stud~ Regional lymph nodes include not only mediastinal but also perigastric nodes, which were classified according to the new TNM classiflcation revised in 1987. 10 Such patients constituted 40 percent (2581643) of all esophageal patients who underwent resection at the group's institutions during the same period. Postoperative treatments were divided into two arms, radiotherapy (group A) and chemotherapy (group B), which were started within 2 to 4 weeks following surgery. Selection for group A or B was performed by block randomization before starting postoperative treatment. In group A, 50 Gy of radiotherapy was given to the supraclavicular area and the upper mediastinum in doses of 2 Gy/day 5 times per week for 5 weeks. If myelosuppression was noticed during radiotherapy, radiotherapy was halted until recovery, but all radiotherapy had to be terminated within 7 weeks. In group B, cisplatin (50 mglml ) was given by slow drip infusion and vindesine (3 mglml ) by intravenous bolus infusion on the first day Chemotherapy was to be repeated twice at intervals of 3 weeks. The dose of vindesine was decreased to 50 percent in cases where a WBC count of 2,5OOImm3 to 4,()()QImm3 , or a platelet count of 5O,OOOImm3 to lOO,OOOImm3 were noted. Therapy with vindesine was halted for a WBC count of less than 2,5OOImm3 or a platelet count of less than 5O,()()QImm3 • Cisplatin was halted in the case of a serum creatinine level over 2.0 mg/ml or creatinine clearance of less than 40 mVmin. Patients entered into this study were selected according to the CHEST I 104 I 1 I JUL~ 1993
203
following criteria for eligibility: (1) age under 75 years; (2) nonnal values on clinical laboratory examinations (WBCs >4,()()(lImm3 ; platelets >100,OOOImm3 ; hemoglobin >10 mgldl; bilirubin, glutamie-oxaloacetic transaminase [GOT], and glutamic-pyruvic transaminase [GPT], normal value; creatinine <1.2 mgldl; creatinine clearance >60 mVmin; PaO. >70 mm Hg); and (3) informed consent was obtained from all patients before treatment. The extent of disease was described according to the new TNM classiflcation'? revised in 1987. Patients who were not given any treatment were considered ineligible, and only those who received treatment were eligible. Only patients who completed the scheduled regimen were regarded as complete cases, and patients given 49 Gy or less of radiotherapy or only 1 administration of chemotherapy were considered as incomplete. The results were compared among eligible patients including incomplete cases. The prognoses of all patients were evaluated on August 31, 1990; the survival rate in each I-year interval was calculated by the life table method, and a survival curve was plotted using the survival rate by Kaplan-Meyer's method. Comparison of the two survival rates was conducted by standard error in each year and by log rank and the Wdcoxon test for the total period using the LIFETEST procedure of the SAS program package software. l l Registered patients were examined to identify any favorable differences in the distribution ofbaclcground factors and side effects between the two groups by the y; test using the FREQ procedure of SAS. u All calculations were done on a mainframe computer of the National Cancer Center, Tokyo.
During the period from August 1, 1985 to August 31, 1987, there were 258 patients entered into this study; 128 patients in group A and 130 patients in group B, as seen in Table 1. There were 5 ineligible patients (2 percent), 1 in group A and 4 in group B, 2 of whom did not receive postoperative therapy due to pneumonia, 1 due to cardiac infarction, 1 due to wound infection, and 1 due to refusal of further therapy There were 18 patients who were not able to complete postoperative treatment due to side effects, 7 of whom were in group A, who underwent less than 50 Gy of irradiation, and 1 in group B, who underwent Table 1-ChtJrtJCteriaticB ofEligible PatientI Characteristic
Group A
GroupB
Entered Eligible Ineligible Cause of ineligibility Pneumonia Cardiac infarction Wound infection Refusal of further therapy Sex Male Female Age, yr <50 51-60 61-70
128 127 1
130 126 4
0 1 0 0
2 0 1 1
110 17
113 13
11
14 46 55 11
204
Classification
Group A
GroupB
1 10 70 47
2 8 69 51
40 49 25 14
30 49 35 16
13 31 75 8
20
Location of tumor Cervical Upper thoracic Mid-thoracic Lower thoracic Length of tumor, cm <5 5-7 7-9 >9 pT pTI pT2 pT3 pT4 pN p-NO p-Nl p stage p stage I p stage IIA p stage lIB p stage III p stage IV
18 79 9
34 93
37
2 28 27 55 15
5 30
89
25
51 15
• As revised in 1987. 10
RESULTS
~71
Table 2- TNM ClaaijictJtion of Eligible PatientI*
39
52 25
only 1 course of chemotherapy Therefore, there were 235 cases (91 percent) who completed the treatment. There was no statistical difference in either the male/female ratio or in the age distribution, as seen in Table 1. As seen in Table 2, there was no statistically significant difference between the two groups in terms of the distribution of the location of the tumor or the length of the tumor. Also, there was no significant difference in pT, pN, pM, and p stage classification in the two groups. Because there is no bias in terms of background factors relating to the prognosis of the patients, it is reasonable to compare the survival rates of the two groups. The survival rate of group A was 80 percent at 1 year, 61 percent at 2 years, and 51 percent at 3 years, as seen in Table 3. Group B had a survival rate of 90 percent at 1 year, 60 percent at 2 years, and 52 percent at 3 years. Group B had a better survival rate at 1 year, but there was no significant difference in the total survival rate by log rank (p=0.8061) and the Wilcoxon test (p = 0.6545). The survival curve is shown Table 3-CumulaOOe Suroiool Bate (%) (± SE) by life Table Method for Eligible PatientI* Cumulative Survival Rate, %
Group A GroupB Test
No.
1st yr
2ndyr
3rdyr
4thyr
5thyr
127 127
80±4 9O±3 p
61±4 6O±4 NS
51±4 52±4 NS
46±5 47±5 NS
44±5 42±5 NS
*NS, Not statistically significant at level ofO.OS. Therapy Adjuvantto Surgeryfor EsophagealCarcinoma (Toshlfumi lizuke)
SURVIVAL CURVE GRO'UPA
vs
B
1.0
S 0.9
U R 0.8
Y0.7
V 0.6
A L 0.5
R 0.4 ~ 0.3 E 0.2
0.1
0. 0 ~-.----r---.----.---,.......-....--......-......--.....--....--r--.-----.~~.....-...---,..-~-r--r--,--r--...---.-~---r---r---....-,.-.,..
e
12
48
24
FIGURE 1. Survival curves in two groups. Solid line, group A (radiotherapy); and broken line, group B (chemotherapy).
in Figure 1, and there was no difference between the
2 groups.
The sites of recurrence were classified as local and distant recurrences and others, as seen in Table 4. There were more patients who died of local recurrence in the group receiving chemotherapy than in the group with radiotherapy, but the difference was not statistically significant. The rates of recurrence up to 3 years were 55 percent for group A and 56 percent for group B. There was no significant difference in the time to recurrence
between the 2 groups by log rank (p = 0.9265) and the Wilcoxon test (p=0.9326). Side effects after the postoperative treatment were classified according to the criteria of the World Health Organization." As seen in Table 5, there was no difference in the distribution of side effects in the WBC count, platelet count, blood urea nitrogen (BUN) level, and creatinine level before the treatment. After the treatment, a grade 4 side effect was seen in the WBC and platelet counts and none in the BUN and creatinine levels. For the WBC count, more cases with
Table 4-DiBtribution of¤t Sitea Between Group. A and B Group A
Table 5-Side EJfecta Pretreatment Grade *
Local Bronchus Esophagus Mediastinum Pleural membrane Neck Distant Kidney Liver Lung Abdominal lymph node Bone Brain Others No cancer Unknown * *Cause of death was unknown.
Posttreatment
GroupB
2 0 17 4
0 1 23 1
5
8
1 9 11 5 3 3 13 54
1
5 11 6 2 2 11
55
Grade·
~
Grade WBCcount Group A GroupB Platelets Group A Group B BUN Group A GroupB Creatinine Group A GroupB
0
1
2
3
4
x't
63
45
16 10
3 10
0 2
p=O.026
1 2
1 1
1 0
0 1
NS
116 100
11 24
0 2
0 0
0 0
p=0.018
118
9 21
0
5
0 1
0 0
p=O.OO6
0
1
x1t
125
123
2 3
NS
125 126
2 0
NS
124 122
122 125
5 1
NS
116 117
11 9
NS
74 30
99
*Grade of side effect was expressed in terms of criteria of WHO. 13 tNS, Not significant. CHEST I 104 I 1 I JUL'f, 1993
205
grade 3 and 4 side effects were seen in the group receiving chemotherapy, with a p value of 0.026; however, there was no significant difference in the platelet count. On the contrary, significant differences were observed in the BUN (p=0.018) and creatinine (p = 0.006) levels between the 2 groups. One patient was considered to be a chemotherapyrelated death. This 49-year-old man had received esophagectomy and intrathoracic anastomosis for cancer of the middle thoracic esophagus on May 6, 1987. Chemotherapy, consisting of 75 mg of cisplatin and 4.5 mg of vindesine, was given twice, on the 30th and 56th postoperative days. After the second administration, the platelet count decreased to 32,OOO/mm;3 on the third day after chemotherapy, the WBC count dropped to 6OO/mm3, and the BUN level was 60 midI the ninth day after chemotherapy. On the tenth day the WBC count was 200/mm 3, the platelet count was 3,OOO/mm3, and the BUN and creatinine levels became 196 mg/dl and 3.5 mg/dl, respectively. The patient died of sepsis and multiple organ failure on the 11th day after chemotherapy DISCUSSION
During a period of 25 months, 258 patients were entered into this study Of these, 235 (91 percent) could be adquately evaluated. There was no difference between the two groups in sex, age, the location and length of the tumor, or pT, pN, or p stage of the TNM classification. There was no statistically significant difference in the survival rates of the two groups by either log rank or Wilcoxon tests. Based on these data, we concluded that the chemotherapy with cisplatin combined with vindesine has an effect on survival equivalent to 50 Gy of radiotherapy as a postoperative adjuvant treatment. In our previous study," survival rates after surgery in the group receiving postoperative radiotherapy were 38 percent at 3 years, 35 percent at 4 years, and 30 percent at 5 years. In this new series, the patients with postoperative radiotherapy had the same criteria for eligibility and same dose of radiation as in the previous study, but more favorable results were obtained, with the 5-year survival rate being 44 percent. This improvement in survival may be attributable to the advancement of both the operative technique and perioperative management. To prevent the possibility of chemotherapy-related death, we emphasize careful checking of the blood cell count and creatinine clearance before the second administration of chemotherapy. Although these results suggest that the chemotherapy used in group B seems to have an effect potentially equivalent to postoperative irradiation on survival, it can be interpreted differentl~ ie, neither postopera206
tive adjuvant treatment has an impact on the survival when compared to surgery alone. Recent results of the phase 2 trials of cisplatin and vindesine on patients with advanced esophageal carcinoma'! suggest that the chemotherapy used in this study has only a modest effect. In this study, there were five PRs among 31 cases, and the response rate was 16 percent (95 percent confidence limit, 6 to 40 percent). While the concentrations of chemotherapy were low by Western standards, the concentrations were at a level consistent with general policy in Japan when the study was carried out." The fact that there was one treatment-related death shows that the level employed did cause toxic effects, yet future trials should nevertheless employ more aggressive chemotherapy. Based on these results, it has become necessary for us to study whether adjuvant chemotherapy following surgery has an impact on survival or not in patients with esophageal carcinoma. Therefore, we initiated a prospective randomized trial in which surgery alone was compared with postoperative chemotherapy using cisplatin and vindesine. Based on the report by Kelsen et al," we plan to examine the effect of preoperative chemotherapy in our next study ACKNOWLEDGMENTS: The Japanese Esophageal Oncology Group consists of 1bshifumi Iizu~, M.D., F.C.C.~, Department of Surgery, National Cancer Center Hospital, Tokyo, (present address: National Oji Hospital, Tokyo; Teruo Kakegawa, M.D., F.C.C.~, Department of Surgery, Faculty of Medicine, Kurume University, Kurume; Hiroko Ide, M.D., Department of Surgery, Tokyo Women's Medical College, Tokyo; Nobutoshi Ando, M.D., Department of Surgery, Faculty of Medicine, Keio University, TolCYo; Hiroshi Watanabe, M.D., F.C.C.~, Department of Surgery, National Cancer Center Hospital, Tolcvo; Koichi Sasaki, M.D., Department of Surgery, Faculty of Medicine, Niigata University, Niigata; Iwao Takagi, M.D., Department of Surgery, Aichi Cancer Center Hospital, Nagoya; Masanori Fukushima, M.D., Department of Internal Medicine, Aichi Cancer Center Hospital, Nagoya; Atsushi Nashimoto, M.D., Department of Surgery, Niigata Cancer Center Hospital, Niigata; Show Mori, M.D., Department of Surgery, Iwate Medical College, Morioka; (present address: Department of Surgery, Faculty of Medicine, Tohoku University, Sendai); Kaoru Ishida, M.D., Department of Surgery, Iwate Medical College, Morioka; Masaki Arimori, M.D., Department of Surgery, Tokyo Second National Hospital, Tokyo, and Shoichiro Tsugane, M.D., Epidemiology Division, National Cancer Center Research Institute, Tokyo. We thank Professor J. Patrie Barron of Tokyo Medical College for his review of the manuscript. REFERENCES
1 Cliffton EE, Goodner JT, Bronstein EL. Preoperative irradiation for cancer of the esophagus. Cancer 1960; 13:37-45 2 Nakayama K. Preoperative radiotherapy for esophageal carcinoma. Jpn J Radioll961; 21:435-39 3 Iizuka T, Ide H, Kakegawa T, Sasaki K, Takagi I, Ando N, et al. Preoperative radioactive therapy for esophageal carcinoma. Chest 1988; 93: 1054-58 4 Kelsen D. Chemotherapy of esophageal cancer. Semin Oneol 1984; 11:159-68 5 Nishihira T, Abo S. Phase II study of cisplatin for esophageal cancer. Gan to Kagakuryoho 1986; 13:2939-46 6 Iizuka T, Kakegawa T, Ide H. A phase II study of vindesine in the treatment of esophageal cancer. Jpn J Clin Oneol 1989; 19:380-83 Therapy Adjuvant to Surgeryfor EsophagealCarcinoma (Toshifumi lizuka)
7 Kelsen D~ Hilaris B, Coonley C. Cisplatin, vindesine, and bleomycin chemotherapy of local regional and advanced esophageal carcinoma. Am J Med 1983; 75:645-52 8 Kelsen D~ Minsky B, Smith M, Beitler J, Niedzwiecki D, Chapman D, et ale Preoperative therapy for esophageal cancer: a randomized comparison of chemotherapy versus radiation therapy J Coo Oncoll990; 8:1352-61 9 Cooperative clinical study group for esophageal carcinoma. Multi-discipOOary treabnent for esophageal carcinoma. Jpn J Clin Oncoll983; 13:417-24 10 International Union Against Cancer. TNM classification of
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malignant tumours. 4th fully revised ed. Berlin: Springer-Verlag, 1987 Delong DM. The LIFETEST procedure, SAS user's guide: statistics. Cary, NC: SAS Institute, 1985; 539-57 The FREQ procedure, SAS user's guide: statistics, version 5 edition. Cary NC: SAS Institute, 1985; 403-32 Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47:207-14 Iizuka T, Kakegawa T, Ide H, Ando N, Watanabe H. Phase II study of cisplatin and vindesine in the treatment of esophageal carcinoma. Jpn J Clin Oncoll991; 21:176-79
18th International Conference on Lung Sounds This 18th conference will be held August 25-27 at Lake Louise, Alberta, Canada. For information, contact Dr. Raymond L. H. Murphy Jr, MD, Attn: Barbara Keith, Faulkner Hospital, 1153 Centre Street, Boston 02130 (617:522-5800).
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