939
CORRESPONDENCE a surgically documented CR. CR has been only rarely observed with other regimens.' Ten of 14 partial responders with unresectable disease at first laparotomy were surgically resectable and rendered disease-free at second laparotomy. 2 The median relapse-free survival was 10 months and overall survival 22 months for this group. However, the median survival of all partial responders was 91/2 months, and for all patients in the study it was 9 months. This is comparable to the experience with FAM and FU/RT. Therefore, the patients who benefited from EAP were those who achieved a CR, and possibly those with locally advanced unresectable disease who had a partial response (PR) and underwent second-look laparotomy. Other studies using similar but not identical schedules of 3 EAP have been published. CR occurred in 12% of patients in one study,' but none occurred in two other studies.5 6' If the results of these studies are pooled, CR occurred in three of 70 patients (4%). The differences in outcome of these studies may be due to changes in the drug schedule or patient selection. In our study, etoposide was given orally instead of intravenously in a bioequivalent and equitoxic dose in 13 of 24 treatment cycles.5 In two other studies, the dose of etoposide was reduced 17% in both,6 '7 and the schedule was 7 slightly modified in one. In our study, seven of 10 patients had localized or nodal disease. The sites of disease were not outlined in the other studies. EAP is clearly more toxic than other conventional treatments for gastric cancer, and is associated with a significant risk of death. Although 12% of patients developed "serious infections" in the study by Preusser et al,' it was not stated what percentage of courses were complicated by fever and neutropenia requiring hospitalization. In our experience, neutropenia and fever occurred in 13 of 24 (53%) courses and in eight of 10 patients. Only one of 10 patients had a documented bacterial infection. The mean neutrophil count was 404/mm3 and 222/m' in the group administered oral and intravenous etoposide, respectively. In addition, four of 10 5 patients required platelet transfusions. Serious myelotoxicity and death were observed by other groups, and appear to be greater than that observed with FAM or FU/RT (Table 1). In summary, EAP may be an advance in the treatment of a select group of patients with locally advanced unresectable gastric cancer in a setting where optimal supportive care can be provided. Other trials using EAP are warranted to confirm the encouraging CR rate initially observed. Future attempts at studying EAP should consider restricting treatment to patients with advanced regional disease, identifying other prognostic factors that may predict outcome (eg, flow cytometry"t), or comparing EAP to no therapy in the adjuvant therapy of high-risk patients. It would also be a suitable regimen to study in combination with recombinant hematopoietic growth factors. Joseph A. Sparano Peter H. Wiernik Montefiore Medical Center Bronx, NY REFERENCES 1. Preusser P, Wilke H, Achterrath W, et al: Phase II study with the combination of etoposide, doxorubicin, and cisplatin in advanced measurable cancer. J Clin Oncol 7:1310-1317, 1989
2. Wilke H, Preusser P, Fink U, et al: Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: A phase II study with etoposide, doxorubicin, and cisplatin. J Clin Oncol 7:1318-1326, 1989 3. Sparano J, Schwartz EL, Wiernik PH, et al: Pharmacokinetic study of oral and intravenous etoposide in patients with prior gastrectomy. Proc Am Assoc Can Res 29:201, 1988 (abstr) 4. Sparano J, Schwartz E, Salva M, et al: Sever myelotoxicity associted with etoposide, Adriamycin, and cisplatin in the treatment of gastric cancer. Proc Am Assoc Can Res 30:257, 1989 (abstr) 5. Sparano JA, Schwartz EL, Salva KM, et al: Phase II trial of etoposide, doxorubicin, and cisplatin in advanced gastric cancer. Am J Clin Oncol (in press) 6. Taguchi T: Combination chemotherapy with etoposide, Adriamycin, and cisplatin for advanced gastric cancer. Proc Am Soc Clin Oncol 8:108, 1989 (abstr) 7. Katz A, Gansl R, Simon S, et al: Phase II trial of VP-16, Adriamycin, and cisplatinum in patients with advanced gastric cancer. Proc Am Soc Clin Oncol 8:98, 1989 (abstr) 8. Macdonald JS, Schein PS, Woolley PV, et al: 5fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 93:533-536, 1980 9. Moertel CG, Childs DS, Reitemeier RJ, et al: Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2:865867, 1969 10. Nanus DM, Kelsen DP, Niedzwiecki D, et al: Flow cytometry as a predictive indicator in patients with operable gastric cancer. J Clin Oncol 7:1105-1112, 1989 EAP in Advanced Gastric Cancer To the Editor: In their recent report Preusser et al' described impressive results of a combination of etoposide, Adriamycin (doxorubicin, Adria Laboratories, Columbus, OH), and cisplatin (EAP) in advanced gastric cancer: 23 partial responses (PRs) and eight complete responses (CRs) in 55 patients giving a response rate of 51%. Similar findings were reported in abstract form by Katz et al2 and Taguchi.3 Our clinical impression, however, is very different. We have updated our prospective phase II study using the same EAP regimen in advanced measurable gastric cancer. Twentysix consecutive patients were entered into the protocol between March 1987 and October 1989: 21 men and five women; median age, 52 years (range, 25 to 66). Evaluation after two cycles of chemotherapy was one CR, three PRs, seven no changes, three early progressions, nine progressions, and three toxic deaths (renal failure, septicemia, and hemorrhage). The overall response rate was four of 26 (15%). The patient with complete remission is still alive after 20 months without evidence of disease. The main toxicity was bone marrow depression comparable to that reported by Preusser 2 et al.' The other investigators " used a mitigated dose from the very start to avoid severe side effects. However, they still reported two treatment-related deaths out of 29 patients. Preusser et al reported no toxic deaths. How can we explain our disappointing results in such a promising EAP scheme? By variations in dose/time schedule
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
940
CORRESPONDENCE Table 1. Patient Characteristics
General factors Male + female Age Localization Cordia Stomach Histology Poorly differentiated Signet cell WHO performance Grade 0 Grade 1 Grade 2 Prognostic factors Locally advanced Metastatic + primary Metastatic, primary resected Metastatic site Lung Liver Peritoneal
Preusser et al' (n = 67)
Taal et al (n = 26)
49 + 18 51 (18-65)
21 + 5 52 (25-66)
? ?
7 19
? ?
14 7
1 19 47
9 14 3
12 45 10
7 14 5
4 26 14
1 7 6
of the drug combination? By response evaluating? By prognostic factors or by patient selection? The administration of the cytostatic scheme was the same as described by Preusser et al.' Response evaluation was done in the same way, according to World Health Organization criteria. The significant prognostic factors of metastatic disease, resection status of the primary tumor, and metastatic site (peritoneum), as reported in an abstract by the same German groups, 4 showed no major differences (Table 1). The only question that remains difficult to answer is that of patient selection. Since our hospital is a cancer institute, it could be that there is a particular selection of patients referred here, but it would be difficult to say whether this was advantageous or the opposite. However, consecutive patients were treated with EAP, and there were hardly any refusals. In conclusion, EAP appears to be a disappointing and toxic regimen in our hands and is no longer recommended in our institution. Before this regimen is accepted for widespread use, it is essential to elucidate why there should be such a large discrepancy between our results and those of Preusser et al. B.G. Taal W.W. ten Bokkel Huinink H. Franklin S. Rodenhuis The Netherlands Cancer Institute Amsterdam, The Netherlands
REFERENCES 1. Preusser P, Wilke H, Achterrath W, et al: Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7:1310-1317, 1989
2. Katz A, Gansl R, Simon S, et al: Phase II trial of VP16, Adriamycin and cisplatin in patients with gastric cancer. Proc Am Soc Clin Oncol 8:98 1989 (abstr) 3. Taguchi T: Combination chemotherapy with etoposide, Adriamycin and cisplatin for advanced gastric cancer. Proc Am Soc Clin Oncol 8:108, 1989 (abstr) 4. Wilke H, Preusser P, Fink H, et al: Etoposide/ Adriamycin/cisplatin (EAP) in advanced gastric cancer: Analysis of prognostic factors in 145 patients. Proc Am Soc Clin Oncol 8:128, 1989 (abstr)
Reply To the Editor: We agree with Drs Sparano and Wiernik that etoposide, doxorubicin, and cisplatin (EAP) is an intensive regimen that might induce World Health Organization (WHO) grade 4 myelosuppression in approximately 20% of the patients, but the duration is short with a median time to recovery at day 22 after start of treatment. Because of its side effects, EAP should be used only in younger patients (5 65 years) with good performance status (_s 2 on the WHO scale) and no prior chemotherapy. Some comments about their letters are, however, necessary. Randomized trials comparing EAP versus fluorouracil, doxorubicin, and mitomycin (FAM) or fluorouracil, doxorubicin, and methotrexate with leucovorin rescue have not been published yet. The reported phase II trials with EAP'-5 differ from our studies6 7' as follows: inclusion of patients with WHO performance status 31''s and/or older than 65 years4' 5 and inclusion of patients with prior chemotherapy. 2 These differences in patient selection are of important influence on 8 response and toxicity in several studies. A retrospective comparison of the summarized results of phase II studies with EAP'-4,6,7 and FAM 9 shows 11% complete remissions and 53% overall remissions with a median survival time of 7 to 9 months for EAP and 29% overall remissions including 1% complete remissions with a median survival time of approximately 6 months for FAM. The direct comparison of our EAP trial6 with the original FAM study"' is difficult, since prognostic factors and the assessment of response were different. The median survival time for all patients in our EAP study is 9 months compared with 5.5 months in the original FAM study. 6"t° In the EAP trials,6 7 the worst hematologic toxicities per patient after all cycles of chemotherapy are reported. In the cited FAM study,'0 the hematologic toxicity after the first cycle is stated. The comparison of fluorouracil/radiotherapy (FU/RT)" to EAP in locally advanced disease7 seems even less permissible. In the EAP trial, all patients had surgically confirmed unresectable tumors. It is well known that clinical staging of gastric cancer is misleading in approximately 30% to 50% of the cases. None of the patients in the FU/RT trial had an exploratory laparotomy.' Taking into account that all patients in the trial with preoperative EAP had bulky disease, their median survival time of 18 months compares favorably with the FU/RT trial (13 months). The long-term survival rate with FU/RT is not reported. In our preoperative EAP study, the 2- and 3-year survival rate is 26% and 18%, respectively. For patients with no evidence of disease the median survival time is 24 months.7 From our point of view the analysis by Sparano and
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
941
CORRESPONDENCE Wiernik is based on studies not directly comparable to our studies. The Netherlands Cancer Institute achieved four remissions (15%) with EAP in 26 patients, and there were three drug-related deaths, one due to renal failure and two related to myelosuppression. These results are difficult to explain, especially since no data on pretreatment are stipulated. Since Taal et al are working in a cancer institute we could imagine that the "particular selection" of patients referred to includes pretreated patients. Acute renal failure with toxic death is an exception to the rule after cisplatin at the administered dosage, and after adequate hydration. It did not occur in our study, in which vigorous hydration was routinely applied. We also routinely instituted platelet transfusions in patients achieving grade IV thrombocytopenia. We indeed observed a high incidence of severe myelosuppression but no toxic deaths in our experience with EAP, which involved 150 patients. A 12% fatal toxicity is therefore exceptionally high. The response rate of 15% in the Dutch study is even more difficult to explain and is comparable to the response to 9 single-agent cisplatin in pretreated patients. 'g In any case, the response rate in the study reported by Taal et al is by far the lowest and the toxicity the highest of all other trials who have sought to reproduce our data. Peter Preusser Hansjoachim Wilke Klinik und Poliklinikfiir Allgemeine Chirurgie Miinster, West Germany REFERENCES 1. Kim SY, Song MH, Park CS, et al: Etoposide, Adriamycin, and cisplatin (EAP) combination chemotherapy for advanced gastric cancer. Blut 59:257, 1989 (abstr 51) 2. Kutz A, Gansl R, Simon S, et al: Phase II trial of VP-16 (V), Adriamycin (A) and cisplatin (C) in patients (PTS) with advanced gastric cancer (AGC). Proc Am Soc Clin Oncol 8:98, 1987 (abstr 378) 3. Tagushi T: Combination chemotherapy with etoposide (E), Adriamycin (A), and cisplatin (P) (EAP) for advanced gastric cancer. Proc Am Soc Clin Oncol 8:108, 1987 (abstr 420) 4. Flechtner H, Roeth U, Selbach J, et al: Etoposide, Adriamycin, cisplatinum (EAP) combination for advanced gastric cancer. Proc Eur Soc Med Oncol C:106, 1988 (abstr, 422) 5. Sparano J, Schwartz E, Salva M, et al: Severe myelotoxicity associated with etoposide, Adriamycin, and cisplatin in the treatment of gastric cancer. Proc Am Assoc Cancer Res 8:108, 1989 6. Preusser P, Wilke H, Achterrath W, et al: Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7:1310-1317, 1989 7. Wilke H, Preusser P, Fink U, et al: Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: A phase II study with etoposide, Adriamycin plus cisplatin. J Clin Oncol 7:1318-1326, 1989 8. Wilke H, Preusser P, Fink U, et al: Etoposide/ Adriamycin/cisplatin (EAP) in advanced gastric cancer
(GC)-Analysis of prognostic factors in 145 pts. Proc Am Soc Clin Oncol 8:128, 1989 (abstr 499) 9. Preusser P, Achterrath W, Wilke H, et al: Chemotherapy of gastric cancer. Cancer Treat Rev 15:257-277, 1988 10. Macdonald JS, Schein PS, Woolley PV, et al: 5fluoruracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 93:533-536, 1980 11. Moertel CG, Childs DS, Reitermeier RJ, et al: Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2:865867, 1969 12. Lacave AJ, Wils J, Diaz-Rubio E, et al: Cisplatin as a second line chemotherapy in advanced gastric cancer. A phase II study of the EORTC Gastrointestinal Tract Cooperative Group. Eur J Cancer Clin Oncol 21:1321-1324, 1985 To Lap or Not to Lap To the Editor: The meticulous review by Mauch et al' of staging laparotomy in Hodgkin's disease provides a major update of the Harvard Joint Center Experience. 2 In spite of their own plan to continue surgical staging, the authors may leave many readers tempted to avoid surgical staging in several favorable groups-which occurs not uncommonly in the community currently. For example, those subsets with less than 10% found to have positive laparotomies include the following: (1) female patients with clinical staging IA (CS 1A), (2) male patients with CS IA and high neck disease, and (3) male patients with CS 1A and lymphocyte predominance histology. With so many potential subgroups for comparison, lymphologists need a healthy disrespect for decisions based on simple P values.3 Regarding decision-making based on histologic subtype, for example, some have had difficulty in documenting the reproducibility in histologic classification of Hodgkin's disease.4 Also, for a decade there has been the disconcerting fact that the Harvard group (Table 6 of article) finds right neck disease more frequently upstaged, while Stanford showed dramatically opposite results.' Likewise, these institutions differ in whether the number of sites above the diaphragm predict for disease control. 6' 7 With the low complication rates for staging cited in this series, laparotomy continues to offer staging clarity that would be forever blurred by CS alone, permits eliminating in selected patients 4 weeks of irradiation, which would require inclusion of the spleen and at least part of the left kidney, and offers those patients found with extensive disease a chance at better survival with either the addition or substitution of chemotherapy. Laparotomy, while seeming like too much treatment for some, actually remains the most logical way at the present time to customize treatment to individual patient requirements, based on the anatomy of presentation. Other approaches will either enhance morbidity or yield greater rates of relapse, only half of which will be "salvaged." Thomas E. Goffman Eli Glatstein National CancerInstitute Bethesda, MD
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
CORRESPONDENCE a surgically documented CR. CR has been only rarely observed with other regimens.' Ten of 14 partial responders with unresectable disease at first laparotomy were surgically resectable and rendered disease-free at second laparotomy. 2 The median relapse-free survival was 10 months and overall survival 22 months for this group. However, the median survival of all partial responders was 91/2 months, and for all patients in the study it was 9 months. This is comparable to the experience with FAM and FU/RT. Therefore, the patients who benefited from EAP were those who achieved a CR, and possibly those with locally advanced unresectable disease who had a partial response (PR) and underwent second-look laparotomy. Other studies using similar but not identical schedules of 3 EAP have been published. CR occurred in 12% of patients in one study,' but none occurred in two other studies.5 6' If the results of these studies are pooled, CR occurred in three of 70 patients (4%). The differences in outcome of these studies may be due to changes in the drug schedule or patient selection. In our study, etoposide was given orally instead of intravenously in a bioequivalent and equitoxic dose in 13 of 24 treatment cycles.5 In two other studies, the dose of etoposide was reduced 17% in both,6 '7 and the schedule was 7 slightly modified in one. In our study, seven of 10 patients had localized or nodal disease. The sites of disease were not outlined in the other studies. EAP is clearly more toxic than other conventional treatments for gastric cancer, and is associated with a significant risk of death. Although 12% of patients developed "serious infections" in the study by Preusser et al,' it was not stated what percentage of courses were complicated by fever and neutropenia requiring hospitalization. In our experience, neutropenia and fever occurred in 13 of 24 (53%) courses and in eight of 10 patients. Only one of 10 patients had a documented bacterial infection. The mean neutrophil count was 404/mm3 and 222/m' in the group administered oral and intravenous etoposide, respectively. In addition, four of 10 5 patients required platelet transfusions. Serious myelotoxicity and death were observed by other groups, and appear to be greater than that observed with FAM or FU/RT (Table 1). In summary, EAP may be an advance in the treatment of a select group of patients with locally advanced unresectable gastric cancer in a setting where optimal supportive care can be provided. Other trials using EAP are warranted to confirm the encouraging CR rate initially observed. Future attempts at studying EAP should consider restricting treatment to patients with advanced regional disease, identifying other prognostic factors that may predict outcome (eg, flow cytometry"t), or comparing EAP to no therapy in the adjuvant therapy of high-risk patients. It would also be a suitable regimen to study in combination with recombinant hematopoietic growth factors. Joseph A. Sparano Peter H. Wiernik Montefiore Medical Center Bronx, NY REFERENCES 1. Preusser P, Wilke H, Achterrath W, et al: Phase II study with the combination of etoposide, doxorubicin, and cisplatin in advanced measurable cancer. J Clin Oncol 7:1310-1317, 1989
2. Wilke H, Preusser P, Fink U, et al: Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: A phase II study with etoposide, doxorubicin, and cisplatin. J Clin Oncol 7:1318-1326, 1989 3. Sparano J, Schwartz EL, Wiernik PH, et al: Pharmacokinetic study of oral and intravenous etoposide in patients with prior gastrectomy. Proc Am Assoc Can Res 29:201, 1988 (abstr) 4. Sparano J, Schwartz E, Salva M, et al: Sever myelotoxicity associted with etoposide, Adriamycin, and cisplatin in the treatment of gastric cancer. Proc Am Assoc Can Res 30:257, 1989 (abstr) 5. Sparano JA, Schwartz EL, Salva KM, et al: Phase II trial of etoposide, doxorubicin, and cisplatin in advanced gastric cancer. Am J Clin Oncol (in press) 6. Taguchi T: Combination chemotherapy with etoposide, Adriamycin, and cisplatin for advanced gastric cancer. Proc Am Soc Clin Oncol 8:108, 1989 (abstr) 7. Katz A, Gansl R, Simon S, et al: Phase II trial of VP-16, Adriamycin, and cisplatinum in patients with advanced gastric cancer. Proc Am Soc Clin Oncol 8:98, 1989 (abstr) 8. Macdonald JS, Schein PS, Woolley PV, et al: 5fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 93:533-536, 1980 9. Moertel CG, Childs DS, Reitemeier RJ, et al: Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2:865867, 1969 10. Nanus DM, Kelsen DP, Niedzwiecki D, et al: Flow cytometry as a predictive indicator in patients with operable gastric cancer. J Clin Oncol 7:1105-1112, 1989 EAP in Advanced Gastric Cancer To the Editor: In their recent report Preusser et al' described impressive results of a combination of etoposide, Adriamycin (doxorubicin, Adria Laboratories, Columbus, OH), and cisplatin (EAP) in advanced gastric cancer: 23 partial responses (PRs) and eight complete responses (CRs) in 55 patients giving a response rate of 51%. Similar findings were reported in abstract form by Katz et al2 and Taguchi.3 Our clinical impression, however, is very different. We have updated our prospective phase II study using the same EAP regimen in advanced measurable gastric cancer. Twentysix consecutive patients were entered into the protocol between March 1987 and October 1989: 21 men and five women; median age, 52 years (range, 25 to 66). Evaluation after two cycles of chemotherapy was one CR, three PRs, seven no changes, three early progressions, nine progressions, and three toxic deaths (renal failure, septicemia, and hemorrhage). The overall response rate was four of 26 (15%). The patient with complete remission is still alive after 20 months without evidence of disease. The main toxicity was bone marrow depression comparable to that reported by Preusser 2 et al.' The other investigators " used a mitigated dose from the very start to avoid severe side effects. However, they still reported two treatment-related deaths out of 29 patients. Preusser et al reported no toxic deaths. How can we explain our disappointing results in such a promising EAP scheme? By variations in dose/time schedule
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
940
CORRESPONDENCE Table 1. Patient Characteristics
General factors Male + female Age Localization Cordia Stomach Histology Poorly differentiated Signet cell WHO performance Grade 0 Grade 1 Grade 2 Prognostic factors Locally advanced Metastatic + primary Metastatic, primary resected Metastatic site Lung Liver Peritoneal
Preusser et al' (n = 67)
Taal et al (n = 26)
49 + 18 51 (18-65)
21 + 5 52 (25-66)
? ?
7 19
? ?
14 7
1 19 47
9 14 3
12 45 10
7 14 5
4 26 14
1 7 6
of the drug combination? By response evaluating? By prognostic factors or by patient selection? The administration of the cytostatic scheme was the same as described by Preusser et al.' Response evaluation was done in the same way, according to World Health Organization criteria. The significant prognostic factors of metastatic disease, resection status of the primary tumor, and metastatic site (peritoneum), as reported in an abstract by the same German groups, 4 showed no major differences (Table 1). The only question that remains difficult to answer is that of patient selection. Since our hospital is a cancer institute, it could be that there is a particular selection of patients referred here, but it would be difficult to say whether this was advantageous or the opposite. However, consecutive patients were treated with EAP, and there were hardly any refusals. In conclusion, EAP appears to be a disappointing and toxic regimen in our hands and is no longer recommended in our institution. Before this regimen is accepted for widespread use, it is essential to elucidate why there should be such a large discrepancy between our results and those of Preusser et al. B.G. Taal W.W. ten Bokkel Huinink H. Franklin S. Rodenhuis The Netherlands Cancer Institute Amsterdam, The Netherlands
REFERENCES 1. Preusser P, Wilke H, Achterrath W, et al: Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7:1310-1317, 1989
2. Katz A, Gansl R, Simon S, et al: Phase II trial of VP16, Adriamycin and cisplatin in patients with gastric cancer. Proc Am Soc Clin Oncol 8:98 1989 (abstr) 3. Taguchi T: Combination chemotherapy with etoposide, Adriamycin and cisplatin for advanced gastric cancer. Proc Am Soc Clin Oncol 8:108, 1989 (abstr) 4. Wilke H, Preusser P, Fink H, et al: Etoposide/ Adriamycin/cisplatin (EAP) in advanced gastric cancer: Analysis of prognostic factors in 145 patients. Proc Am Soc Clin Oncol 8:128, 1989 (abstr)
Reply To the Editor: We agree with Drs Sparano and Wiernik that etoposide, doxorubicin, and cisplatin (EAP) is an intensive regimen that might induce World Health Organization (WHO) grade 4 myelosuppression in approximately 20% of the patients, but the duration is short with a median time to recovery at day 22 after start of treatment. Because of its side effects, EAP should be used only in younger patients (5 65 years) with good performance status (_s 2 on the WHO scale) and no prior chemotherapy. Some comments about their letters are, however, necessary. Randomized trials comparing EAP versus fluorouracil, doxorubicin, and mitomycin (FAM) or fluorouracil, doxorubicin, and methotrexate with leucovorin rescue have not been published yet. The reported phase II trials with EAP'-5 differ from our studies6 7' as follows: inclusion of patients with WHO performance status 31''s and/or older than 65 years4' 5 and inclusion of patients with prior chemotherapy. 2 These differences in patient selection are of important influence on 8 response and toxicity in several studies. A retrospective comparison of the summarized results of phase II studies with EAP'-4,6,7 and FAM 9 shows 11% complete remissions and 53% overall remissions with a median survival time of 7 to 9 months for EAP and 29% overall remissions including 1% complete remissions with a median survival time of approximately 6 months for FAM. The direct comparison of our EAP trial6 with the original FAM study"' is difficult, since prognostic factors and the assessment of response were different. The median survival time for all patients in our EAP study is 9 months compared with 5.5 months in the original FAM study. 6"t° In the EAP trials,6 7 the worst hematologic toxicities per patient after all cycles of chemotherapy are reported. In the cited FAM study,'0 the hematologic toxicity after the first cycle is stated. The comparison of fluorouracil/radiotherapy (FU/RT)" to EAP in locally advanced disease7 seems even less permissible. In the EAP trial, all patients had surgically confirmed unresectable tumors. It is well known that clinical staging of gastric cancer is misleading in approximately 30% to 50% of the cases. None of the patients in the FU/RT trial had an exploratory laparotomy.' Taking into account that all patients in the trial with preoperative EAP had bulky disease, their median survival time of 18 months compares favorably with the FU/RT trial (13 months). The long-term survival rate with FU/RT is not reported. In our preoperative EAP study, the 2- and 3-year survival rate is 26% and 18%, respectively. For patients with no evidence of disease the median survival time is 24 months.7 From our point of view the analysis by Sparano and
Downloaded from ascopubs.org by UNIVERSITY LIVERPOOL on April 22, 2019 from 154.059.124.102 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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CORRESPONDENCE Wiernik is based on studies not directly comparable to our studies. The Netherlands Cancer Institute achieved four remissions (15%) with EAP in 26 patients, and there were three drug-related deaths, one due to renal failure and two related to myelosuppression. These results are difficult to explain, especially since no data on pretreatment are stipulated. Since Taal et al are working in a cancer institute we could imagine that the "particular selection" of patients referred to includes pretreated patients. Acute renal failure with toxic death is an exception to the rule after cisplatin at the administered dosage, and after adequate hydration. It did not occur in our study, in which vigorous hydration was routinely applied. We also routinely instituted platelet transfusions in patients achieving grade IV thrombocytopenia. We indeed observed a high incidence of severe myelosuppression but no toxic deaths in our experience with EAP, which involved 150 patients. A 12% fatal toxicity is therefore exceptionally high. The response rate of 15% in the Dutch study is even more difficult to explain and is comparable to the response to 9 single-agent cisplatin in pretreated patients. 'g In any case, the response rate in the study reported by Taal et al is by far the lowest and the toxicity the highest of all other trials who have sought to reproduce our data. Peter Preusser Hansjoachim Wilke Klinik und Poliklinikfiir Allgemeine Chirurgie Miinster, West Germany REFERENCES 1. Kim SY, Song MH, Park CS, et al: Etoposide, Adriamycin, and cisplatin (EAP) combination chemotherapy for advanced gastric cancer. Blut 59:257, 1989 (abstr 51) 2. Kutz A, Gansl R, Simon S, et al: Phase II trial of VP-16 (V), Adriamycin (A) and cisplatin (C) in patients (PTS) with advanced gastric cancer (AGC). Proc Am Soc Clin Oncol 8:98, 1987 (abstr 378) 3. Tagushi T: Combination chemotherapy with etoposide (E), Adriamycin (A), and cisplatin (P) (EAP) for advanced gastric cancer. Proc Am Soc Clin Oncol 8:108, 1987 (abstr 420) 4. Flechtner H, Roeth U, Selbach J, et al: Etoposide, Adriamycin, cisplatinum (EAP) combination for advanced gastric cancer. Proc Eur Soc Med Oncol C:106, 1988 (abstr, 422) 5. Sparano J, Schwartz E, Salva M, et al: Severe myelotoxicity associated with etoposide, Adriamycin, and cisplatin in the treatment of gastric cancer. Proc Am Assoc Cancer Res 8:108, 1989 6. Preusser P, Wilke H, Achterrath W, et al: Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 7:1310-1317, 1989 7. Wilke H, Preusser P, Fink U, et al: Preoperative chemotherapy in locally advanced and nonresectable gastric cancer: A phase II study with etoposide, Adriamycin plus cisplatin. J Clin Oncol 7:1318-1326, 1989 8. Wilke H, Preusser P, Fink U, et al: Etoposide/ Adriamycin/cisplatin (EAP) in advanced gastric cancer
(GC)-Analysis of prognostic factors in 145 pts. Proc Am Soc Clin Oncol 8:128, 1989 (abstr 499) 9. Preusser P, Achterrath W, Wilke H, et al: Chemotherapy of gastric cancer. Cancer Treat Rev 15:257-277, 1988 10. Macdonald JS, Schein PS, Woolley PV, et al: 5fluoruracil, doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 93:533-536, 1980 11. Moertel CG, Childs DS, Reitermeier RJ, et al: Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2:865867, 1969 12. Lacave AJ, Wils J, Diaz-Rubio E, et al: Cisplatin as a second line chemotherapy in advanced gastric cancer. A phase II study of the EORTC Gastrointestinal Tract Cooperative Group. Eur J Cancer Clin Oncol 21:1321-1324, 1985 To Lap or Not to Lap To the Editor: The meticulous review by Mauch et al' of staging laparotomy in Hodgkin's disease provides a major update of the Harvard Joint Center Experience. 2 In spite of their own plan to continue surgical staging, the authors may leave many readers tempted to avoid surgical staging in several favorable groups-which occurs not uncommonly in the community currently. For example, those subsets with less than 10% found to have positive laparotomies include the following: (1) female patients with clinical staging IA (CS 1A), (2) male patients with CS IA and high neck disease, and (3) male patients with CS 1A and lymphocyte predominance histology. With so many potential subgroups for comparison, lymphologists need a healthy disrespect for decisions based on simple P values.3 Regarding decision-making based on histologic subtype, for example, some have had difficulty in documenting the reproducibility in histologic classification of Hodgkin's disease.4 Also, for a decade there has been the disconcerting fact that the Harvard group (Table 6 of article) finds right neck disease more frequently upstaged, while Stanford showed dramatically opposite results.' Likewise, these institutions differ in whether the number of sites above the diaphragm predict for disease control. 6' 7 With the low complication rates for staging cited in this series, laparotomy continues to offer staging clarity that would be forever blurred by CS alone, permits eliminating in selected patients 4 weeks of irradiation, which would require inclusion of the spleen and at least part of the left kidney, and offers those patients found with extensive disease a chance at better survival with either the addition or substitution of chemotherapy. Laparotomy, while seeming like too much treatment for some, actually remains the most logical way at the present time to customize treatment to individual patient requirements, based on the anatomy of presentation. Other approaches will either enhance morbidity or yield greater rates of relapse, only half of which will be "salvaged." Thomas E. Goffman Eli Glatstein National CancerInstitute Bethesda, MD
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