- © 2005 by American Society of Clinical Oncology
Continuation of Trastuzumab Beyond Disease Progression
To the Editor:
A few retrospective analyses show that, in patients with HER-2 positive advanced breast cancer progressing on trastuzumab-containing therapy, continuing trastuzumab alone or combined with other cytostatic drugs is feasible and safe.1-3 Moreover, despite the main issue addressed (safety of trastuzumab for long periods), some of these articles report encouraging tumor response and survival data.2,3 Preclinical observations indicating that trastuzumab might be beneficial, even in the presence of disease progression, by slowing down tumor growth, lend support to the “continuation” hypothesis. As a consequence, despite the absence of results from randomized trials, many physicians throughout the world consider continuing trastuzumab beyond disease progression a reasonable approach in the current clinical practice. However, because of severe selection biases, retrospective analyses need to be considered with extreme caution. For example, patients with rapidly progressing disease after an initial trastuzumab-based treatment are not likely to have been included in these analyses. On the other hand, patients whose disease progresses at a rate at which additional treatment is possible may fare equally well with chemotherapy or endocrine therapy without trastuzumab. We published a phase II multi-institutional trial in 42 patients with HER2-positive (Dako HercepTest 2+ or 3+; Dako, Carpinteria, CA) advanced breast cancer who received six cycles of docetaxel (75 mg/m2 every 3 weeks) and weekly trastuzumab.4 Patients responding or showing disease stabilization received weekly trastuzumab until disease progression or unacceptable toxicity. The postprogression treatment was left to the discretion of the treating physician. We recently updated the follow-up information for all the patients registered in our study (median follow-up, 28 months; range, 17 to 53 months) and analyzed postprogression treatments and clinical outcome. During the protocol, three patients stopped treatment because of toxicity, and one patient, who had achieved a partial remission (PR), refused to continue the treatment after the fourth cycle. At the time of the current analysis, of the remaining patients enrolled on the trial, three are still alive and without signs of tumor progression, 35 have progressed, and 23 have died of disease progression. Of the 35 progressing patients, six continued trastuzumab with or without chemotherapy; six with rapidly progressing disease received supportive care alone or with palliative radiation therapy; and 23 received chemotherapy (up to three regimens) and/or endocrine therapy, without trastuzumab. In these 23 patients, one achieved a complete remission, and three, a PR to the first postprogression therapy, for an overall response rate of 17%. The clinical benefit rate to the first postprogression therapy (percentage of patients achieving complete remission, PR, or disease stabilization for ≥ 6 months) was 50%, but tumor responses or stabilizations were also seen during further lines of treatment. The median overall survival was 29.3 months (range, 11 to 53+ months) from the date of the first on-protocol administration of trastuzumab, and 19.0 months (range, 3 to 33.7+ months) from the date of the initiation of postprogression treatment. Median survival from the date of on-protocol progression was 1.9 months for the six patients who experienced rapidly progressing disease, and 20 months for the six patients who continued trastuzumab beyond disease progression. Our findings in patients not continuing trastuzumab beyond disease progression but who could be treated with chemotherapy or hormone therapy, are in the range of what has been reported in retrospective analyses of patients receiving trastuzumab beyond disease progression.
In a time when careful usage of healthcare resources is crucial even in the most developed countries, continuing trastuzumab beyond disease progression in the absence of data from randomized trials is at least debatable. In our opinion, it is significant that the only phase III trial designed by colleagues at The M.D. Anderson Cancer Center to evaluate the worth of continuing trastuzumab beyond disease progression had to be closed because of lack of accrual (G.N. Hortobagyi, personal communication).
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Other Remuneration: Filippo Montemurro, Roche SPA. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
Acknowledgments
The authors whish to acknowledge Dr Gabriel N. Hortobagyi for reviewing this letter.
