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High-Dose Chemotherapy for Breast Cancer: "How Do You Know?"

Patients often ask me, "How do I protect myself from unfounded medical recommendations?" My advice to them is to respond to any opinion, from any healer, no matter how seemingly reliable, with the simple questions, "How do you know? What is the basis for your opinion?" I tell them to listen carefully to the answer, because distinguishing hopeful surmise on the part of their advisor from acceptable hard fact might make all the difference to their health and well being.

In fact, the proper response to "how do you know" is a meaningful, developing issue in modern medicine. The scholastics of medieval Europe settled scientific arguments not by experiment or detailed observation but rather by reference to Aristotle or other classical experts, whose opinions were thought to be indisputable. In most respects, our current world is the consequence of the abandonment of such dogma. We now favor what we all know as the scientific method, an advancing spiral of observation, hypothesis generation, experiment, analysis, replication, new hypothesis generation, and so on. Yet the scientific art of health care has lagged behind its sibling disciplines—the basic sciences–in that we are just now emerging from the tyranny of "expert opinion." Our increasing emphasis on evidence-based medicine will properly replace conjecture with knowledge, tradition with rationality, and subjective experience with objective data.

In clinical oncology, the tool we depend upon to accomplish this revolution is, ultimately, the randomized, prospective clinical trial. It is obvious that for clinical trials to be useful they must be reliable, which means they must be of high quality: well designed, unbiased, adequately sized, well executed, thoroughly analyzed, properly reported, and, above all, honest. The American Society of Clinical Oncology (ASCO) and the Journal of Clinical Oncology have dedicated themselves not only to promoting the performance of clinical trials in cancer but to doing all that they can to assure patients and physicians of their excellence in all of these particulars.

In this regard, Dr Weiss et al in this issue of the Journal have done a great service.¹ They offer us unequivocal evidence that Dr Werner Bezwoda’s critical study² in high-dose chemotherapy for advanced breast cancer is fake and completely inadmissible information regarding the safety and efficacy of such treatment. This work was previously and wrongly reported as positive at ASCO’s 1992 Annual Meeting,³ in the Journal in 1995,² and in multiple subsequent publications.^4-9 A previous audit, also led by Dr Weiss,¹⁰ concluded that Bezwoda’s paper regarding high-dose chemotherapy for high-risk breast cancer presented at our 1999 Annual Meeting was similarly deceitful.¹¹ Auditing is a crucial addition to the scientific method in medicine, since attempts to replicate misreported regimens may result in patient harm. That the original publication,² now being retracted by the Journal, has influenced major thinkers in this field and may have put patients in danger raises the stakes as we consider how we can improve the process to make sure that this never happens again.

The ASCO Annual Meeting is more than an opportunity to present peer-reviewed, competitively selected reports. It is an opportunity to scrutinize those reports, debate them in public, and uncover inconsistencies and incompatibilities that trigger reviews and audits such as the one published in this issue. ASCO’s policies now call for the authors of abstracts to attest to an institutional overview of the study being reported as well as complete disclosure regarding financial or other potential conflicts of interest. Similarly, the Journal adheres to the strictest standards of peer review, using multiple reviewers, several levels of editorial oversight, and opportunities for querying the lead author. We respect the attestation of the lead author, and may soon require attestation from all authors, regarding the veracity of the reported information and the adherence of the reported work to accepted standards of clinical trials, including informed consent and institutional review board oversight.

No procedure can totally protect against fraudulent statements and omissions. However, ASCO is committed to making the process as fail-safe as possible. Largely for this purpose, in May 2000 a Task Force on Oversight of Clinical Research was charged to consider issues related to the structure, function, and operation of institutional review boards and to the complex topic of conflict of interest as it concerns oncologic studies with human subjects. What should we work toward? We would all reap benefits from international guidelines on these topics, with universal adherence and acceptance of responsibility. The generation and dissemination of standardized informed consent procedures, following major strides in this direction by the National Cancer Institute (NCI), could be a significant advance. Training programs in protection of subjects from research risks, already started on the national level for NCI-sponsored trials, could be expanded to medical schools, continuing medical education activities, and even other nations. The impact of well-designed curricula in this regard on the actions of licensing bodies and specialty boards will need to be assessed. And the audit, already a standard procedure in NCI-sponsored cooperative group activities, should assume its proper, most-respected role in clinical trials everywhere. It behooves us as a community to act favorably on any and all recommendations that will safeguard the integrity of clinical science, regardless of the consequences of our actions in terms of convenience or cost.

So, when our patients ask us, "How do you know?" we will answer with assurance that clinical trials have shown us the way and that we have confidence in the process from concept to conclusion. That, and not our technology, our authority, or our prominence, will distinguish us from practitioners of questionable trustworthiness or effectiveness. It is not a matter of medical methodology but one of medical ethics, which remains at the core of our being as clinical oncologists.

NOTES

Memorial Sloan-Kettering Cancer Center New York, NY

REFERENCES

1. Weiss RB, Gill GG, Hudis CA: An on-site audit of the South African trial of high-dose chemotherapy for metastatic breast cancer and associated publications. J Clin Oncol 19: 2771-2777, 2001[Abstract/Free Full Text]

2. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 13: 2483-2489, 1995[Abstract]

3. Bezwoda WR, Seymour L, Vorobiof DA: High dose cyclophosphamide, mitoxantrone, and VP-16 (HD-CNV) as first-line treatment for metastatic breast cancer. Proc Am Soc Clin Oncol 11: 64, 1992 (abstr 81)

4. Bezwoda WR, Dansey R, Seymour L, et al: Non-cryopreserved, limited number (1 or 2) peripheral blood progenitor cell (PBPC) collections following GCSF administration provide adequate hematologic support for high dose chemotherapy. Hematol Oncol 12: 101-110, 1994[Medline]

5. Bezwoda WR: In vivo purging of peripheral stem cell products by high-dose CNVp: Results from a randomised study comparing conventional dose chemotherapy (CNV) with double high-dose CNVp chemotherapy. Proc Am Soc Clin Oncol 16: 115a, 1997 (abstr 404)

6. Bezwoda WR: High-dose chemotherapy with hematopoietic rescue in breast cancer: From theory to practice. Cancer Chemother Pharmacol 40: S79-S87, 1997 (suppl)

7. Bezwoda WR: High-dose chemotherapy with haematopoietic rescue: Application to primary management of metastatic breast cancer. Eur J Cancer Care 6: 10-15, 1997 (suppl 1)

8. Bezwoda WR: Primary high dose chemotherapy for metastatic breast cancer: Update and analysis of prognostic factors. Proc Am Soc Clin Oncol 17: 115a, 1998 (abstr 443)

9. Bezwoda WR: High dose chemotherapy with haematopoietic rescue in breast cancer. Hematol Cell Ther 41: 58-65, 1999[Medline]

10. Weiss RB, Rifkin RM, Stewart FM, et al: High-dose chemotherapy for high-risk primary breast cancer: An on-site review of the Bezwoda study. Lancet 355: 999-1003, 2000[Medline]

11. Bezwoda WR: Randomised, controlled trial of high dose chemotherapy (HD-CNVp) versus standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer. Proc Am Soc Clin Oncol 18: 2a, 1999 (abstr 4)

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