Originally published as JCO Early Release 10.1200/JCO.2009.23.6653 on August 24 2009

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Maintenance Therapy for Ovarian Cancer: Of Helsinki and Hippocrates

Harry and Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center, Baltimore, MD

In this issue of Journal of Clinical Oncology (JCO), an Italian consortium presents the results of a randomized, phase III trial¹ in ovarian cancer that addresses the potential value of continued therapy (ie, maintenance therapy) after attainment of a clinical or pathologic complete response to primary treatment. They conclude that six additional every-3-week cycles of paclitaxel monotherapy do not alter the important end points of progression-free or overall survival. Though there are some criticisms that can be leveled at the conduct of the trial, the negative results are not surprising in the context of the preponderance of data in ovarian cancer—as well as in other solid tumors—that fail to show convincingly that such a strategy is effective. One fault with this study is that 15% of patients in the control arm received some maintenance paclitaxel, 6% of the patients in the maintenance arm received no paclitaxel, and an additional 3% in the maintenance arm discontinued therapy early because of withdrawal of consent. However, in both the intent-to-treat analysis and the per-protocol analysis, no differences emerged in outcomes as a function of providing or withholding maintenance therapy. These data are in concert with multiple negative studies that have used the phase III, randomized trial design to test high-dose chemotherapy with stem-cell rescue, intravenous topotecan, intravenous epirubicin, intravenous monoclonal antibody directed at CA-125 (ie, oregovomab), subcutaneous interferon alfa, intraperitoneal yttrium-90–labeled monoclonal antibody directed against the MUC-1 antigen, intraperitoneal phosphorus-32 chromic phosphate, and whole-abdomen radiation therapy. In every instance, additional treatment has failed to alter progression or survival in patients who have no clinical evidence of disease after standard therapy with surgery and chemotherapy. These studies are referenced in the article by Pecorelli et al¹ in this issue of JCO for those readers unfamiliar with the specifics of each study.

So why, you might wonder, is this editorial even being written? There remains a single randomized, phase III trial that came to the opposite conclusion from the study by Pecorelli et al¹ in this issue of JCO. That divergent study of 277 patients, published by the Southwest Oncology Group and Gynecologic Oncology Group (SWOG/GOG) in 2003,² found a statistically significant, 7-month difference in median progression-free survival (28 v 21 months) for either 12 or three additional cycles, respectively, of paclitaxel monotherapy in patients with advanced disease who had attained a clinical complete response with primary therapy. This difference led the Data Monitoring Committee to suspend the protocol and to eventually close the study when approximately half the proposed accrual had occurred. A survival advantage never emerged. Proponents of maintenance therapy have cited the underpowered design of the study after early closure as one reason that a survival benefit was not seen; others have confessed that many of the patients who remained disease free and who were randomly assigned to three cycles of maintenance were given additional maintenance treatment when the data were made public. This latter decision certainly is consistent with the strictest interpretation of ethical conduct in clinical research, as outlined in the Declaration of Helsinki, which has undergone six revisions since its inception in 1964 and which remains open to interpretation. The National Institutes of Health have summarized the Declaration of Helsinki and have stated that "physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results."³ Most experienced investigators would argue that a lengthening of progression-free survival does not necessarily translate into improved quality of life, nor does it guarantee improved overall survival. Cannistra⁴ has appropriately argued that only improved overall survival or quality of life should be the gold standard for adoption of a new therapy and that early closure of studies that do not meet one or the other of these end points should not qualify for early stopping. The study presented here was underway before the SWOG/GOG study was reported, and the Italian investigators had no ethical or legal dictate to close this trial with the publication of the SWOG/GOG study. In addition, even GOG has initiated a protocol of its own to additionally evaluate maintenance therapy; that study, GOG212, contains a no-maintenance treatment arm.

How can one explain the differences in outcome of two trials, each conducted in multiple hospitals so as to avoid the bias often inherent in single-institution trials? First, it is important to note that the SWOG/GOG data have been updated multiple times since the original report.^5–7 Second, subsequent analyses have continued to show no survival benefit for the 12 cycles of therapy, and the median progression-free survival times have declined to 22 and 14 months for 12 cycles and three cycles, respectively. Finally, subset analysis has suggested that the association between improved progression-free survival and additional maintenance therapy appears confined to those patients who have the lowest tumor markers at study entry (< 11 units), which is felt to correlate with the lowest volume of disease. One area of concern with the updated SWOG/GOG data is the short median progression-free survival for the entire cohort who received three cycles of maintenance therapy. Compare the median progression-free survival for the short maintenance therapy of 14 months in the SWOG/GOG study to the Italian study of 30 months in the no-maintenance arm. This wide variation can be explained partially by the pathologic verification of complete response in few, if any, of the patients in the SWOG/GOG study; conversely, in the trial reported here, more than half the patients experienced pathologic complete response. These are presumably the patients likely to have the lowest CA-125 values at study entry and are the patients most likely to benefit, according to the subset analysis of the SWOG/GOG experience. In the SWOG/GOG study, the published subset analysis in the patients with low CA125 demonstrated a median progression-free survival of 24 months and a significant survival benefit for 12 cycles of maintenance therapy (P = .03). Yet, in the Italian study, this best-patient subset (ie, those with no macroscopic residual disease after debulking surgery and presentation at a stage less than IIIC) had not yet reached a median progression-free survival at the time of publication (which exceeded 36 months of observation). Thus, we are left with opposing conclusions regarding the effect of maintenance paclitaxel on progression-free survival in patients with complete response after primary therapy. Neither study, however, meets the criteria for proof of benefit, because there is no appreciable effect on overall survival and because quality of life was not formally assessed.

It is appropriate, then, that we should turn our attention to the toxicity of this therapy, because we are cautioned by Hippocrates to do no harm. In the absence of treatment-related deaths—of which there were none in either study—it is peripheral neurotoxicity that is of paramount importance, because it is not always reversible and may adversely affect activities of daily living. The SWOG/GOG study reports no motor toxicity in either group and only a 4% difference in grades 2 and 3 sensory neurotoxicity between the two groups; this difference favored the three cycles (15% v 23%). Notably, however, the dose of paclitaxel in the SWOG/GOG study was reduced from 175 mg/m² to 135 mg/m² during the conduct of the study, apparently to abrogate excessive neurotoxicity. In the Italian study, the incidences of grades 2 and 3 sensory neurotoxicity were 21% and 7%, respectively, and those of motor neurotoxicity were 8% and 3%, respectively. One assumes that all the neurotoxicity was in the treated group and that none was in the control group, although this is not categorically stated in the manuscript. Creation of a significant, treatment-related symptom in approximately 25% of patients is not trivial and needs to be balanced by some obvious, real benefit of that therapy. As noted in this article, benefit has not been shown in either study.

With this conundrum before us, what is our responsibility to the patient who has just completed primary chemotherapy and is, by all measures, disease free? If we follow the recommendation of Markman⁸ or a strict interpretation of the Declaration of Helsinki, then we are compelled to tell this patient the results of the SWOG/GOG study and possibly to offer or even recommend 12 additional cycles of paclitaxel. But should we not also be compelled to mention the 25% chance of significant neurotoxicity or the lack of apparent long-term benefit (ie, improved cure rate or improved quality of life)? At least the Italian study, with some of the similar flaws as the original SWOG/GOG study, gives the practicing physician the alternate argument. Should the physicians simply evaluate the opposing data sets and decide for the patients what to recommend, or should we fully disclose and possibly fully confuse the average patient with all the data? That would appear to be a personal decision for each practitioner. GOG feels this is still an open question. The current GOG protocol for patients in clinical complete remission after primary therapy randomly assigns them to no additional therapy or to 12 months of either paclitaxel or polyglumex, a paclitaxel congener, that may or may not have less toxicity than the parent compound. Although this study would serve possibly to resolve the conflict generated by the Italian study and the previous SWOG/GOG study, its accrual has been slow, and it may not definitively resolve an important question facing patients and their physicians about what is best to recommend for the patient with ovarian cancer in complete remission. Do you follow Hippocrates or Helsinki? (or both...they're not in opposition).

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

Acknowledgment

I thank Stephen A. Cannistra, MD, for his helpful comments during the preparation of this manuscript.

REFERENCES

1. Pecorelli S, Favalii G, Gaducci A, et al: Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: Final results of the After-6 Protocol 1. J Clin Oncol 27:4642–4648, 2009.[Abstract/Free Full Text]

2. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460–2465, 2003.[Abstract/Free Full Text]

3. National Institutes of Health: Office of Human Subjects Research. Regulations and ethical guidelines: World Medical Association Declaration of Helsinki. http://ohsr.od.nih.gov/guidelines/helsinki.html.

4. Cannistra SA: The ethics of early stopping rules: Who is protecting whom? J Clin Oncol 22:1542–1545, 2004.[Free Full Text]

5. Markman M, Liu PY, Rothenberg ML, et al: Pretreatment CA-125 and risk of relapse in advanced ovarian cancer. J Clin Oncol 24:1454–1458, 2006.[Abstract/Free Full Text]

6. Liu PY, Alberts DS, Monk BJ, et al: An early signal of CA-125 progression for ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy. J Clin Oncol 25:3615–3620, 2007.[Abstract/Free Full Text]

7. Markman M: Maintenance chemotherapy in advanced ovarian cancer: The US experience. Int J Gynecol Cancer 18:40–43, 2008 (suppl 1.[CrossRef][Medline]

8. Markman M: Ethical conflict in providing informed consent for clinical trials: A problematic example from the gynecologic cancer research community. Oncologist 9:3–7, 2004.[Abstract/Free Full Text]

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