EDITORIAL

Inflammatory Breast Issue

C. Norman Coleman, Paul E. Wallner, Jeffrey S. Abrams

Affiliation of authors: C. N. Coleman, P. E. Wallner (Radiation Research Program), J. S. Abrams (Cancer Therapy Evaluation Program), Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.

Correspondence to: C. Norman Coleman, MD, Radiation Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bldg. 10, Rm. B3B69, MSC 1002, Bethesda, MD 20892 (e-mail: ccoleman{at}mail.nih.gov).

When we were invited to write an editorial on the emerging use of partial-breast irradiation and accelerated partial-breast irradiation, the following questions arose:

  1. When should and do new treatment approaches enter routine clinical use?
  2. When are phase II and pilot data from single institutions ready for general applicability?
  3. Does the approval of a new device by the U.S. Food and Drug Administration imply it is ready for general clinical applicability?
  4. How can innovative approaches that require long-term data to judge equivalency be made available in the short and medium term?
  5. What are the roles of professional societies, research institutions, oversight bodies, and the National Cancer Institute in the introduction of new treatments?
  6. How might overly cautious interpretation of pilot data inappropriately delay implementation of novel and/or breakthrough treatments?
  7. How might overly enthusiastic interpretation of pilot data inappropriately promote implementation of novel treatments?
  8. How does one ensure proper quality assurance as new technologies are implemented?
  9. Does the Journal have an "Editorial Witness Protection Program"?

In this issue of the Journal, Vicini et al. (1) report on a study entitled "Limited-Field Radiation Therapy in the Management of Early-Stage Breast Cancer." This article is from a group of researchers who have a strong history of carefully developing, implementing, documenting, and reporting technologic innovations in radiation oncology (25). The conclusion in their article is that "Limited-field radiation therapy administered to the region of the tumor bed has comparable 5-year local control rates to whole-breast radiation therapy in selected patients." The question that intuitively arises from this conclusion is: What are the practitioner, investigator, regulator and, most of all, the patient meant to do with this information?

A single correct answer to this question does not exist. At the National Cancer Institute, we bring expert investigators to a workshop; focus the discussion on science and not economic issues, which are addressed apart from the science; provide a venue for interchange of conflicting ideas and a vehicle for presenting them to the public in an unbiased way; support clinical trials that address key questions; cajole and implore investigators to collaborate when a large trial is needed; work with statisticians to design an "equivalency" trial that will be cost-, time-, and person-effective; ensure quality assurance in the clinical trials; and remain impartial but enthusiastic observers.

Provocative data from the 1960s on the equivalence of breast-conserving surgery plus radiation therapy to mastectomy from single institutions were initially met with a good deal of skepticism. Those of us who lived through this era remember that as more and more reports of such data emerged from single institutions, it became clear that this was an approach that would not go away. The advocates of breast-conserving therapy (BCT) demonstrated its value in reports of "their experience." Often, the introduction of BCT into clinical practice required physicians to directly address women’s groups and to present their information in the nonscientific literature, a practice now made all too easy by the Internet. Ultimately, randomized trials demonstrated equivalency in outcome for patients treated with BCT and mastectomy for early-stage breast cancer, and the proper indications and contra-indications refined the use of whole-breast irradiation for BCT (6,7). Geographic differences still persist in the use of BCT for patients with early-stage breast cancer, indicating that, even after confirmatory data from randomized trials are available, acceptance of new treatment approaches depends on physician and patient interpretation of the same sets of data (810).

Currently, a number of reports from single institutions, some with follow-up data out to 5 years or more, indicate that local control rates with partial-breast irradiation are equivalent to that of the more standard whole-breast irradiation. The techniques currently being used include brachytherapy (high- and low-dose rate) (1,1115); the Mammosite device (16,17), which was approved by the U.S. Food and Drug Administration in early 2002; intraoperative radiotherapy (18,19); and external beam radiation approaches using standard techniques or intensity-modulated radiation (3), which is now becoming widely available. Partial-breast irradiation reduces the volume of tissue irradiated, whereas accelerated partial-breast irradiation uses a more rapid treatment schedule so that treatment can be completed in about a week, which is much more convenient than the usual 5–7 weeks of conventional external beam radiation therapy.

What might partial-breast irradiation accomplish? In terms of cancer treatment, partial-breast irradiation would ideally sterilize the treated segment of breast tissue. It would, of course, not treat the ipsilateral breast tissue outside of the target volume; hence, patient selection should be limited to those patients who are not likely to have a recurrence outside the radiation field. Therefore, the extent of the radiation field, the radiation dose, and tumor characteristics need to be well-defined. Small premalignant lesions outside the treatment volume would be missed; however, in predicting the outcome for the patient treated with partial-breast irradiation, it is known that many of these premalignant lesions never become cancerous. Moreover, the risk of harboring a new cancer or premalignant lesion in the contralateral breast is similar to that in the ipsilateral breast, and yet this breast is left untreated with whole-breast irradiation. In terms of normal tissue toxicity, partial-breast irradiation might help spare normal tissues, such as the lung, heart, and axillary contents from exposure to the radiation field. In addition to the target volume, the choice of radiation fractionation scheme and treatment volume would also be determining factors in toxicity.

What might a shortened radiation schedule accomplish? It might make BCT more appealing to women who do not wish to spend 5–7 weeks in treatment. Accelerated whole-breast irradiation is an alternative (20), although this strategy is still 2 weeks longer in duration than accelerated partial-breast irradiation. In addition, for people who do not have easy access to radiation therapy—often patients in rural or health disparity areas—accelerated partial-breast irradiation might make BCT a more viable option.

It is encouraging that the article by Vicini et al. (1) and others (1115,19,21) indicate that, to date, partial-breast irradiation and accelerated partial-breast irradiation appear to be equivalent to BCT with whole-breast irradiation. Although 5-year efficacy data are more useful than 1–2 (or fewer) (16,17) years of toxicity data, they only tell us the early- to mid-term results of treatment. Late recurrences in treated tissue, metachronous tumors in untreated ipsilateral tissue, and late normal tissue toxicity may require up to 10 years or more to occur. Adding adjuvant therapy such as tamoxifen, which was used in 70% of the patients in the Vicini et al. study (1), may delay local recurrence (2224) so that extended follow-up time may be needed before the data can be fully analyzed. Proper patient selection (i.e., age, stage, and pathology) and proper use of the new techniques (i.e., dose, volume, field, and source placement) may provide local control rates that remain this good over a longer period. Because many local recurrences in an irradiated breast may be successfully salvaged, even a small increase in local recurrence from the use of partial-breast irradiation may not lead to a statistically significant difference in overall survival.

Therefore, the endpoints of interest are small differences in local control after extended follow-up and very small, if any, differences in overall survival. Study of these endpoints requires an equivalency design to resolve very small differences in long-term outcome. Typically, such studies require thousands of patients. Whether such a study is affordable or even feasible, given the current healthcare environment and marketplace, depends on the difference in outcomes that one is willing to accept to be able to call the treatments "equivalent" and the willingness of physicians and patients to participate in such a clinical trial. Whatever endpoint is chosen, long-term follow-up data will take time to develop. Even putting 10 000 patients on study today would still take 7 years to generate 7-year follow-up data.

In December 2002, the National Cancer Institute’s Radiation Research Program conducted a workshop, the results of which will soon be published in an article that discusses in greater detail many of the issues we have raised here. Among the issues discussed at that workshop was the need for a clinical trial on the equivalency of partial-breast irradiation and accelerated partial-breast irradiation with conventional BCT. The Cancer Therapy Evaluation Program is now working with the Cooperative Clinical Trials Groups to initiate an intergroup study that has reasonable statistical endpoints. Dr. Vicini, along with other pioneers of partial-breast and accelerated partial-breast irradiation, is currently developing appropriate quality-assurance measures for a multi-institutional trial to ensure that partial-breast irradiation techniques are performed correctly. The lack of long-term follow-up data places a major responsibility on the single institutions conducting pilot studies to update and report their outcome data frequently, probably annually, given that many have patients who were treated up to 7 years ago. Manufacturers who market partial-breast irradiation devices have a similar responsibility to report outcomes. Physicians and patients who choose partial-breast irradiation techniques must be made aware of the limitation of the current data but should also realize that other advances in the treatment of cancers have entered into clinical trial or clinical application before the full extent of their outcome is known. For patients who find that partial-breast irradiation is their only chance of BCT, the risk that this technique is harmful appears to be very low at this time.

For many medical conditions, decision making about treatment options includes factors other than outcome statistics; now, partial-breast irradiation is one of those treatment options. Physicians who are new to this technique should avail themselves of the training and education needed to administer this treatment properly. Quality-assurance standards as practiced in clinical trials, along with the available education and training, will help ensure that good treatment practices are maintained. Radiation oncologists are trained to bring new advances in treatment to patients in their practice, so it is fair to say that community practitioners can develop the necessary skill set. Many of the partial-breast irradiation techniques are similar to the whole-breast radiation techniques now in use. Pathologists will play a critical role in helping the surgeons and radiation oncologists select patients potentially eligible for partial-breast irradiation treatment. Indeed, it is the pathologic criteria for patient selection that are at least as important as the treatment delivery.

Meanwhile, the National Cancer Institute’s goal is to facilitate the design and conduct of a national trial that will be widely available throughout the United States and Canada. Thus, women will have the potential to receive this new and exciting treatment in the clinical trial setting and to be properly informed about what is known regarding the technique. At the same time, physicians can practice the technique in a controlled setting. Only by successfully completing a clinical trial on the equivalency of partial-breast irradiation with whole-breast irradiation can we provide definitive answers for those physicians and patients yet to face the decision about treatment options for early-stage breast cancer. Moreover, a trial such as the one under development by the Cooperative Groups and the Cancer Therapy Evaluation Program could provide balm to an inflammatory breast issue.

REFERENCES

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