Correspondence

Treatment of Ovarian Cancer with Intraperitoneal Cisplatin

N Engl J Med 1997; 336:1674-1675June 5, 1997

Article

To the Editor:

In their report on intraperitoneal versus intravenous cisplatin for stage III ovarian cancer, Alberts et al. (Dec. 26 issue)1 suggest that among the patients with microscopical disease (no gross residual disease), the rates of complete pathological responses differed in the intravenous and intraperitoneal groups (complete-response rate, 56 and 80 percent, respectively) because “the penetration of intraperitoneal cisplatin is limited to a depth of 0.1 to 1 mm from the surface of the peritoneal tumor,” and they cite a report by Los et al.2 However, there were no significant differences in survival between this subgroup of patients and the subgroup with minimal residual disease (<0.5 cm), a finding that runs contrary to the authors' hypothesis.

The authors' conclusions were based on overall survival, but disease-free survival was never mentioned. In addition, second-line treatments, which may influence overall survival, were not described. Therefore, the longer median survival in the intraperitoneal group, which was related to the treatment, according to the authors, could have been influenced by other factors.

In addition, to eliminate uncertainty about whether there was bias in the selection of eligible patients, information should be provided about the treatment assignments of the 54 patients who were ineligible because of inadequate surgery and the 81 who did not complete chemotherapy and did not subsequently undergo a second-look laparotomy. For a better understanding of the study, information on the initial stage (IIIA, IIIB, or IIIC) before debulking would be appreciated.

Miguel Beltran, M.D., Ph.D.
Hospital Universitario “Josep Trueta”, 17007 Girona, Spain

Rafael Fuentes, M.D., Ph.D.
Angel Izquierdo, M.D.
Hospital “Santa Caterina”, 17001 Girona, Spain

2 References

1
Alberts DS, Liu PY, Hanningan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950-1955
Full Text | Web of Science | Medline

2
Los G, Mutsaers PH, van der Vijgh WJ, Baldew GS, de Graaf PW, McVie JG. Direct diffusion of cis-diamminedichloroplatinum (II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. Cancer Res 1989;49:3380-3384
Web of Science | Medline

To the Editor:

The excellent article by Alberts et al. will probably become an important reference in the literature on ovarian cancer. However, the authors do not explain how intraperitoneal cisplatin was delivered, particularly if the patients had catheters. Moreover, they give insufficient data about the subgroup of patients with microscopical residual disease (who had a survival rate of over 40 percent). Was there a difference in survival between those who received intravenous cisplatin and those who received intraperitoneal cisplatin in this subgroup? We would also like to know whether there was a relation between survival and the rate of a complete response or between survival and the total dose of cisplatin in either group. Finally, information is not provided about second-line therapy received by patients with relapses.

E. Espinosa, M.D.
P. Zamora, M.D.
Hospital La Paz, 28046 Madrid, Spain

To the Editor:

Alberts et al. state, “There were no significant differences between the study groups with respect to important prognostic factors,” but they do not mention whether ascites was present at the time of the initial laparotomy, a factor that can affect survival.1-4 Did Alberts et al. consider ascites as a prognostic factor in their study?

Oren Fruchter, M.D.
29 Greenbaum St., Haifa 34987, Israel

4 References

1
Puls LE, Duniho T, Hunter JE, Kryscio R, Blackhurst D, Gallion H. The prognostic implication of ascites in advanced-stage ovarian cancer. Gynecol Oncol 1996;61:109-112
CrossRef | Web of Science | Medline

2
Makar AP, Baekelandt M, Trope CG, Kristensen GB. The prognostic significance of residual disease, FIGO substage, tumor histology, and grade in patients with FIGO stage III ovarian cancer. Gynecol Oncol 1995;56:175-180
CrossRef | Web of Science | Medline

3
Roszkowski P, Wronkowski Z, Szamborski J, Romejko M. Evaluation of selected prognostic factors in ovarian cancer. Eur J Gynaecol Oncol 1993;14:Suppl:140-145
Medline

4
Kosary CL. FIGO stage, histology, histologic grade, age and race as prognostic factors in determining survival for cancers of the female gynecological system: an analysis of 1973-87 SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina. Semin Surg Oncol 1994;10:31-46
CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Alberts replies:

To the Editor: The study of intraperitoneal cisplatin was designed specifically to detect a survival difference with the use of standard intention-to-treat analytic methods. A subgroup analysis was not performed because it would have been fraught with both statistical and biologic problems.

Disease-free survival was not an end point of our study, because of the requirement for second-look surgery, which strongly biases the interpretation of this end point.

The study was designed as a large phase 3 trial, specifically to minimize any bias related to randomization. Analyses performed after the completion of the trial revealed no imbalance between the two randomized groups with respect to any prognostic factors that are known to be important, including the presence of ascites at the time of the diagnosis. There is no reason to postulate that the improved survival in the intraperitoneal group was due to differences between the two groups in the treatment of recurrent disease.

Intraperitoneal cisplatin was administered in 2 liters of saline, warmed to body temperature, and instilled into the peritoneal cavity as rapidly as possible (i.e., in 30 to 60 minutes). If the flow rate was slow, a blood-pressure cuff was placed on the fluid bag containing the drugs and inflated to 100 mm Hg to speed the flow. The patients were then placed in four positions for 15 minutes each (total time, 1 hour): right side down, left side down, Trendelenburg's position, and reverse Trendelenburg's position. No attempt was made to remove the instilled fluid.

David S. Alberts, M.D.
Arizona Cancer Center, Tucson, AZ 85724-5024