Therapy in Stage I ovarian cancer

Volume 141 Number 2

Correspondence 231

Iabus that pmvided necessary information for the history and gyn<~cologic examination was developed at the . University of Louisville. Fourth, the program was organized with two instructors working with four medical students. Each instructor first role-played a patient to help the student acquire gynecologic history-taking skills. The instructor allowed two students (in sequence) to perform a pelvic examination on the CTA. The second instructor, along with the other three students, provided additional critique for the "on" student during the role playing, and pelvic examination. Each session frequently required 3Y2 hours for a group of four students. The program was incorporated into the physical diagnosis course for second-year medical students. Close association with physicians conducting courses in obstetrics and gynecology as well as physical diagnosis was recommended. The total cost of the program in 1980 was $6,412 for an entire medical school class of 142 students. Each CTA was paid $15 per hour. This included orientation as well as actual student instructor sessions. Sources of funding for the second-year program stemmed from the medical school curriculum budget. The cost should decrease if fewer new instructors are required each year to continue the services. The results of the program as revealed by student evaluations uniformly reinforced the fact that this program was an excellent method of acquiring skills in the history and physical examination. Students felt more comfortable eliciting a gynecologic history and performing a pelvic examination. In addition, they had a better definition of their own limitations. Subsequent clinical rotations were approached in a more meaningful manner. This program has been expanded and currently includes first-year residents in obstetrics and gynecology. as well as family practice. joseph S. Sanfilippo, M.D. Nancy Gottlieb Barbara]. Berman Walter M. Wolfe, M.D. University of Louisville Department of Obstetrics and Gynecology 550 South jackson Street Louisville, Kentucky 40202

Therapy in Stage I ovarian cancer To the Editors:

The conclusions drawn by the authors concerning the relative merits of the three tested therapies in Stage I ovarian cancer are not supported by the data they presented (Hreshchyshyn, M. M., et al.: AM. J. 0BSTET. GYNECOL. 138:1.39, 1980). There are several reasons for this, mostly :related to the handling of the statistical data. First, 49% (82/ 168) of the patients entered into the study were removed from the analysis. Two m;:Uor objectives of the randomization process are to ensure that the treatment groups being compared will not differ

systematically with respect to any prognostic variables and that bias is eliminated from the selection of treatment. However, these expectations were dearly not fulfilled. Patients were withdrawn from the study after randomization according to their treatment preference or that of their physician's, thus introducing bias. Furthermore, there are 48% more patients in the melphalan group than in the pelvic irradiation group (34 versus 23), an imbalance indicative of an ineffective randomization process. The maldistribution of prognostic factors between patients in each of the groups, as commented upon by the authors, is, therefore, to be expected. As a consequence, the usual assumptions in regard to the significance level of the alpha p value at 0.05 are rendered meaningless when the treatment methods are compared. This significance level only applies to the treatment variable when like is compared with like. The wholesale exclusion of cases does not permit the authors to present this study as a randomized trial, with all its connotations of strict control. The validity of any analysis conducted under these circumstances is questionable. Second, and notwithstanding the above, in concluding that an advantage was demonstrated for the melphalan arm, the authors have chosen to ignore the results obtained in the control arm. [The following p values were calculated from their data with use of the twosided Fisher exact test. In a situation in which a tested therapy might be worse than the control, a two-sided test must be employed. We were unsure whether the p values reported were for variation among the three treatment arms, or a maximum contrast between two treatment arms, or two treatment arms combined versus the third; or whether the p value was derived from a comparison of crude proportions (the only data presented) rather than the more preferable actuarial rates for measuring risk of relapse.] There was no significant difference in the total number of relapses between the melphalan arm and the control arm groups (2/34 versus 5/29, p = 0.30) or in relapses beyond the pelvis ( l/34 versus 4/29, p = 0.26). Although there are several statements in the text in regard to a "trend" favoring the melphalan-treated patients, the current standard is to assume that an observed difference where the p value exceeds 0.05 is one that could have occurred by chance. Thus, this study did not demonstrate that melphalan-treated patients had a lower relapse rate than patients who received no postoperative therapy. Nor did it demonstrate that patients treated with pelvic irradiation fared differently from control patients with respect to total proportion of relapses (7/23 versus 5/29, p = 0.43) or relapses beyond the pelvis (6/23 versus 4/29, p = 0.44). Therefore, the most likely explanation for the observed differences between the melphalan and pelvic irradiation groups with respect to total relapses (2/34 versus 7/23, p 0.034) and extrapelvic relapses ( l/34 versus 6/23, p = 0.028) is that these differences were due to factors other than the treatment administered, namely, a thwarted random-

232 Correspondence

ization process that resulted in patient populations which were dissimilar with respect to prognostic factors. If melphalan were better treatment than pelvic irradiation, it should also be better than no treatment at alL It is not acceptable to compare the proportion of relapses in the melphalan arm with that in the other two arms combined, since this was not the study design (2/34 versus 12/52: p == 0.061, not significant at any rate). There are several other disturbing aspects to this report that cannot here be commented upon in detail: for example, the complete lack of any mention of survival data, which is the most meaningful endpoint in a phase III study; the arbitrary decision to analyze results with regard to some prognostic factors (substage, grade, pathology) and not others (adherence, thoroughness of staging procedure, patient age); the failure to apply appropriate multivariate statistical maneuvers to correct for the imbalance in all prognostic variables; the heterogeneity of a study population of 86 patients derived from more than 20 institutions over a 7 year period; and the fact that for some Stage I patients (e.g., serous well-differentiated) the risk of death from melphalan (through leukemogenesis) probably exceeds the benefits of this therapy. We have reported a study which failed to demonstrate that pelvic irradiation was of benefit to patients with Stage I ovarian cancer.' Data from the present report support the same conclusion for the use of melphalan in this situation. At best, the authors can suggest that their failure to show a significant benefit for adjuvant melphalan therapy exemplifies a type II error. Alon J. Dembo, M.B. Raymond S. Bush, M.D. Gm·it De Boer, Ph.D. The Princess Margaret Hospital 500 Sherbourne Street Toronto, M4X I K9 Canada

REFERENCE L Dembo, A. J., Bush, R. S., Beale, F. A., Bean, H. A., Pringle, J. F., and Sturgeon, J. F. G.: The Princess Margaret Hospital Study of Ovarian Cancer: Stages I, II, and asymptomatic III presentations, Cancer Treat. Rep. 63: 249, 1979.

Reply to Drs. Dembo, Bush, and De Boer To the Editors: The group of radiation therapists from the Ontario Cancer Institute have criticized the results and conclusions presented in our article on 'The role of adjuvant therapy in Stage I ovarian cancer." Their concern revolves mainly around randomization and the· large number of patients withdrawn from the study and the resulting possibility of investigator bias. Although the number of exclusions is large by current Gynecologic Oncology Group standards, these exclusions do not reflect investigator bias.

Sept.ember 15. 1981 Am.J. Obstet. GynecoL

As noted in the manuscript, there are two areas in which the patients were removed-those who were ineligible and those who were inevaluable. Of the former group, 38 patients were excluded for pathologic reasons-low malignant potential (30), benign (five), secondary primary (two), and wrong histology (one). Seven of the cases excluded as inevaluable had inadequate slides for pathology review, and four were improperly randomized. All of these exclusions were totally without regard to randomized therapy. Eleven cases were excluded as major protocol violations. Such cases would not presently be excluded under our current procedures, but rather would be included in the analysis. Nonetheless, the issue of investigator bias is easily negated when one "reinstates" the eight such .::ases with relevant follow-up data. In that instance the percentage of recurrences for the no-treatment arm is 17.2%, whereas that for radiotherapy is 41.7%. compared to 5.4% for melphalan. Thus, the exclusion of these cases can by no means be construed as investigator bias favoring melphalan. With regard to those cases removed by investigator, all were on the radiotherapy arm. The stated reason was that radiation therapists thought that inadequate treatment was given to a large number of patients receiving radiation therapy. Their comments in regard to tests of hypothesis and associated p values have varying degrees of accuracy. At the time the study was designed, it was designed as a one-sided test since it was deemed unlikely that either modality would prove to be inferior to the control. Next, the comparisons that the Ontario Group state as inappropriate were not made in the first place, that is, a comparison of melphalan versus the other two arms combined was never performed or published. The majority of the comparisons and associated p values they made are tangentiaL The "most likely explanation" suggested is not based upon a scientific line of reasoning but rather a combination of unrelated p values and intuition. The "several other disturbing aspects" which the questionnaires state but do not amplify upon is a shopping list of which the article addressed many, i.e., survival-opposite of recurrence in ovarian cancer. other prognostic factors, and risk of melphalan in the subsequent development ofleukemia, to mention a few. Their last paragraph refers to their data stating that pelvic irradiation had no benefit in patients with Stage I ovarian cancer and implying that the same was true for melphalan in our article. Actually, their article referred only to Stage IA patients. Although not statistically significant, it should be noted that all four Stage IB patients treated with radiation therapy in our study had recurrence whereas all six Stage IB patients treated \vith melphalan are alive without evidence of disease. It is recognized by all imestigators that the surgical exploration and operation required by this protocol by