Correspondence

Interval Cytoreduction in Ovarian Cancer

N Engl J Med 1995; 333:254-255July 27, 1995

Article

To the Editor:

The article by van der Burg et al. (March 9 issue)1 on debulking surgery after induction chemotherapy raises some important issues. The authors state that the morbidity associated with a second operation was similar to that associated with a primary surgical procedure. This means a doubling of morbidity in those assigned to this arm of the study, and the impact on quality of life (and cost effectiveness) must be balanced against the six-month improvement in median survival rates. It will be interesting to learn the actual five-year survival rate in both arms, and we hope the authors will supply this information in the future.

The authors claim that the value of primary cytoreductive surgery for ovarian cancer is beyond doubt. We would suggest otherwise. The basis of present practice derives from a small retrospective series of patients2 and a prospective study involving 26 patients.3 If such information were proposed as a justification for the introduction of a new chemotherapeutic agent, it is doubtful that it would be accepted. There is agreement that clearance of all macroscopic tumor in early-stage disease is curative for many patients, though in advanced disease the effect of cytoreductive surgery is not beyond doubt, since to date this practice has never been examined in a prospective study. A recent meta-analysis has indicated that primary cytoreductive surgery has a minimal, if any, effect on survival rates in advanced ovarian cancer.4 Until a study comparing the impact of radical surgery and chemotherapy with that of chemotherapy in patients with advanced disease is completed, patients may be inappropriately subjected to radical operations without enhancing their life expectancy.

Sean Kehoe, M.R.C.O.G., D.C.H.
Mahmood Shafi, M.R.C.O.G.
David Luesley, M.D.
City Hospital Trust, Birmingham B18 7QH, United Kingdom

4 References

1
van der Burg MEL, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629-634
Full Text | Web of Science | Medline

2
Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. In: Symposium on ovarian carcinoma. National Cancer Institute monograph 42. Washington, D.C.: Government Printing Office, 1975:101-4. (DHEW publication no. 75-901.)

3
Griffiths CT, Fuller AF. Intensive surgical and chemotherapeutic management of advanced ovarian cancer. Surg Clin North Am 1978;58:131-142
Web of Science | Medline

4
Hunter RW, Alexander ND, Soutter WP. Meta-analysis of surgery in advanced ovarian carcinoma: is maximum cytoreductive surgery an independent determinant of prognosis? Am J Obstet Gynecol 1992;166:504-511
Web of Science | Medline

To the Editor:

In the study by van der Burg et al. the patient population was not well defined, thus making the conclusions about the role of surgery after induction chemotherapy uncertain.

The entry criteria allowed two groups of patients to be enrolled in the study: first, patients who had not had any cytoreductive surgery at the initial laparotomy, having been referred to one of the European Organization for Research and Treatment of Cancer institutions after an “open and close” operation with a biopsy only to confirm the diagnosis; and second, patients who had undergone a serious but suboptimal attempt at primary cytoreduction, leaving residual tumor masses of more than 1 cm in diameter. It is reasonable to assume that the results of cytoreduction after three cycles of chemotherapy will be meaningfully different in these two groups.1 Removal of tumor is more likely to be feasible and to enhance survival in the first group than in the second. How many patients from both groups have been enrolled, and what have been the results of interval debulking in these two groups?

For clinical practice it is relevant to ask whether the patients in the second group benefited from surgery performed after chemotherapy and by the same surgeon. These questions are not addressed by the authors. The study also does not prove that it is wise to treat all patients with ovarian cancer with chemotherapy first and surgery afterward. The conclusion to be drawn from this study is that surgery can alter the outlook in ovarian cancer and that initial primary cytoreductive surgery remains the gold standard in the management of this disease.

J.P. Neijt, M.D., Ph.D.
Utrecht University Hospital, 3508 GA Utrecht, the Netherlands

1 References

1
Berek JS. Interval debulking of ovarian cancer -- an interim measure. N Engl J Med 1995;332:675-677
Full Text | Web of Science | Medline

To the Editor:

Although van der Burg et al. report a positive study, I find it difficult to be reassured that interval cytoreduction is appropriate for most patients with bulky residual ovarian cancer at diagnosis. Figure 2 of the article shows that patients in the interval-cytoreduction group had a six-month improvement in median survival, but it is likely that this effect was due primarily to the fact that 37 of 127 patients (29 percent) had optimal cytoreduction (residual lesions less than 1 cm in diameter) (as shown in Figure 5 of the article). It appears that the remaining 90 patients did not benefit from this procedure because either chemotherapy alone resulted in minimal residual disease (n = 44) or interval cytoreduction did not result in minimal residual disease (n = 46). Therefore, the authors' inability to identify preoperative factors that could be used to predict the success of interval cytoreduction should not be taken to imply that all patients potentially benefit from this procedure. In this regard, it would be interesting to know whether a minimal response to the first three cycles of chemotherapy (i.e., stable disease) was predictive of an inability to perform adequate interval cytoreduction.

The actual curative potential of interval cytoreduction for ovarian cancer appears to be small, and it is very possible that the survival curves for the two groups shown in Figure 2 will converge with longer follow-up. Does a possible palliative benefit for 29 percent of the population justify subjecting all patients to another operation?

What is the cost of interval cytoreduction, and is there an improvement in the quality of life of patients who undergo it? Does time spent worrying about the operation or dealing with problems related to postoperative convalescence reduce the patients' quality of life to the point where the small survival benefits (enjoyed by only a subgroup of patients) are negated? Unless this kind of information is acquired and analyzed with the same vigor as are survival data, it is difficult to know how best to incorporate the results of this “positive” study into clinical practice.

Stephen A. Cannistra, M.D.
Dana–Farber Cancer Institute, Boston, MA 02115

Author/Editor Response

The authors reply:

To the Editor: Our randomized study demonstrates that interval debulking surgery is an independent prognostic factor for survival. As stressed by Dr. Neijt, our results do not imply that interval surgery can or should replace primary debulking surgery. Rather, our data favor primary debulking surgery because the likelihood of developing drug-resistant clones is a function of tumor size and time.1 It is regrettable, as stated by Kehoe et al., that primary debulking surgery has never been submitted to a rigorous randomized evaluation, but the meta-analysis by Hunter et al.2 provides an extremely weak basis to refute its value. This meta-analysis suffers from grave methodologic problems; the most serious one is that comparing the survival of patients treated with optimal cytoreduction with the survival of those treated with suboptimal cytoreduction is hampered by the unavoidable and serious bias inherent in any comparison of patients with different prognostic factors.

All patients with residual lesions more than 1 cm in diameter after primary tumor debulking were eligible for our study. There may have been differences between the participating centers with respect to the extent of primary debulking surgery, but not between the randomized groups in the same center. Randomization was stratified according to center; therefore, the possibility of accidental bias was minimized. Moreover, the reduction in the risk of death due to interval debulking surgery remained qualitatively unchanged after adjustment for center or any other known prognostic factor. Therefore, the concern of Dr. Neijt that the positive effect of interval debulking surgery was primarily seen in patients who had not had cytoreduction at primary surgery seems unfounded. Likewise, we cannot agree with Dr. Cannistra that the 37 patients with optimal cytoreduction at interval debulking surgery were the only ones to benefit. The fact that our study identified an overall survival benefit in spite of the heterogeneity of patients' characteristics and surgical outcomes suggests that interval debulking surgery may have a benefit in larger patient populations than those referred to by our colleagues.

Finally, the increase in progression-free and overall survival may not seem impressive, but it is similar to what has been achieved with cisplatin. Such a symptom-free survival benefit may outweigh the morbidity of surgery, which is brief. A decision about interval debulking surgery will, of course, have to be individualized for each patient, but it may now be based on hard facts rather than mere speculation.

Maria E.L. van der Burg, M.D., Ph.D.
Daniel den Hoed Kliniek, 3075 EA Rotterdam, the Netherlands

Marc Buyse, Sc.D
International Institute for Drug Development, B-1050 Brussels, Belgium

Sergio Pecorelli, M.D., Ph.D.
European Institute of Oncology, 20141 Milan, Italy

2 References

1
Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727-1733
Medline

2
Hunter RW, Alexander ND, Soutter WP. Meta-analysis of surgery in advanced ovarian carcinoma: is maximum cytoreductive surgery an independent determinant of prognosis? Am J Obstet Gynecol 1992;166:504-511
Web of Science | Medline

Citing Articles (4)

Citing Articles

1
Siriwan Tangjitgamol, Sumonmal Manusirivithaya, Malinee Laopaiboon, Pisake Lumbiganon, Andrew Bryant, Siriwan Tangjitgamol. 2010. Interval debulking surgery for advanced epithelial ovarian cancer. .
CrossRef
2
Siriwan Tangjitgamol, Sumonmal Manusirivithaya, Malinee Laopaiboon, Pisake Lumbiganon, Siriwan Tangjitgamol. 2009. Interval debulking surgery for advanced epithelial ovarian cancer. .
CrossRef
3
June Y Hou, Peter E Schwartz. (2007) Neoadjuvant chemotherapy in the management of advanced epithelial ovarian cancer. Expert Review of Obstetrics & Gynecology 2:3, 321-329
CrossRef
4
P.O. VAN TRAPPEN, B.D. RUFFORD, T.D. MILLS, S.A. SOHAIB, J.A.W. WEBB, A. SAHDEV, M.J. CARROLL, K.E. BRITTON, R.H. REZNEK, I.J. JACOBS. (2007) Differential diagnosis of adnexal masses: risk of malignancy index, ultrasonography, magnetic resonance imaging, and radioimmunoscintigraphy. International Journal of Gynecological Cancer 17:1, 61-67
CrossRef