Despite these concerns, it must be concluded that the expansive findings from the various overviews seem to indicate that the use of radiation therapy markedly reduced the incidence of local recurrence and somewhat, but not substantially, improved overall survival. That conclusion is reinforced by the Plain Language Summary that appears in The Cochrane Collaboration, which indicates that, “Radiotherapy following surgery for early breast cancer substantially reduces the chances of a cancer recurrence but the effects on long term survival seem small.” It is also stated in that report that, “Radiotherapy regimens able to produce the two-thirds reduction in local recurrence seen in these trials, but without long-term hazard, would be expected to produce an absolute increase in 20-year survival of approximately 2% to 4% (except for women at particularly low risk of local recurrence).”

Those findings provide further support for our original thesis that variations in locoregional therapy are unlikely to substantially affect survival. Moreover, they clearly indicate that the impression created in the Rabinovitch and Kavanagh editorial that there has been a “substantial” reduction in mortality after radiation therapy is not in keeping with what was found after a detailed examination of those authors’ sources of information.

The final “provocative observation” that Rabinovitch and Kavanagh cite in support of their claim that the “Fisher hypothesis be re-evaluated and that Halsted be brought back into view” is the following:

In numerous trials and meta-analyses, improved regional control with postmastectomy radiotherapy was associated with improved survival.”

That statement relates to information obtained from two randomized trials, 82 b & c, that were conducted by the Danish Breast Cancer Study Group. As previously noted, of the 40 trials included in the year 2000 EBCTCG overview, only the Danish studies demonstrated a significant difference in annual death rates between the radiotherapy and control groups. In a report of the findings, it was concluded that, “The survival benefit after postmastectomy RT [radiation therapy] was substantial and similar in patients with 1-3 and 4+ positive lymph nodes.” Those findings were obtained from “Only high-risk patients…, defined as patients who were node positive and/or [had] a T3 or T4 tumor and/or skin or deep fascia invasion.” Although most of the women failed to have a complete axillary dissection, almost half had four or more positive lymph nodes, two thirds of the tumors were more than 2.0 cm, and two thirds were grades 2 and 3. Thus the women, when first seen by their physicians, were at increased risk for distant disease and death because they already had disseminated tumor cells. Those were the patients who would seem to have been most unlikely to have had a reduction in mortality as a consequence of their receiving postoperative radiation therapy.

The radiation therapy used in the Danish studies was targeted to the chest wall and supraclavicular, axillary, and parasternal lymph nodes and avoided the heart. According to Overgaard et al, a major effort was made to optimize the radiation treatment so that no radiation-related excess of nonbreast cancer deaths or unacceptable toxicity was found. Those investigators concluded that, “Avoiding such negative effect of radiotherapy in the Danish trials is probably one of the reasons for the positive outcome…, “; ie, there was no increase in nonbreast cancer–related deaths as a result of radiation therapy. In view of the improvement in the radiation therapy techniques used by the investigators in the Danish trials, the authors’ conclusion seems plausible.

Because the Danish studies have played an important role in validating the premise that a survival benefit from radiation therapy exists when that modality is given with systemic therapy, providing further information from those trials would seem to be appropriate. In women with one to three positive nodes, locoregional recurrences at 15 years were substantially reduced from 27% to 4%, a decrease of 23%, and the overall survival was improved by 9% (from 48% to 57%). In women with four or more positive nodes, there was an even greater reduction in locoregional recurrence, from 51% to 10%, a decrease of 41%, and the survival, as in women who had fewer positive nodes, increased by 9% from 12% to 21%. Because in each of the nodal groups, the survival of irradiated and nonirradiated women was so poor, such a survival increase can hardly be viewed as noteworthy.

In the Danish trials, a large number of premenopausal and postmenopausal women received cyclophosphamide, methotrexate, and fluorouracil with or without radiation therapy. Almost half of those who were postmenopausal were randomly assigned to receive tamoxifen with or without radiation therapy. Because such therapy unequivocally reduces the incidence of breast tumor recurrence, and because the addition of chemotherapy and tamoxifen further diminishes such recurrence and also improves survival, it may be speculated as to what degree, if any, radiation, a locoregional therapy, played when it was used in conjunction with systemic therapy in the reduction of mortality in those high-risk women.

Overgaard has addressed that issue and provides an explanation that supports our alternative hypothesis. In that report, Overgaard stated the following:

“The aim of radiotherapy is to secure loco-regional control and to improve survival. Radiotherapy can eradicate residual loco-regional tumor deposits after surgery with adjuvant systemic therapy, and thereby improve local control and reduce the risk of secondary dissemination from these deposits. But only patients who have not yet developed distant metastases or patients who will have their limited occult distant metastases controlled by adjuvant systemic therapy can obtain additional survival benefit from irradiation. Other patients may only benefit in terms of loco-regional tumor control. ... in patients who have many nodes involved, the likelihood of developing distant metastases is very large, and, therefore, only a limited proportion of these patients can obtain survival benefit, despite their possibly obtaining a large reduction in loco-regional failures. ... Thus, the improvement in survival may not directly be linked and proportionate to the improvement in loco-regional control.”

Unfortunately, Rabinovitch failed to mention this aspect of the Overgaard report, which emphasizes what has been our view for decades, ie, that when a patient is diagnosed with breast cancer, every effort must be made to control locoregional disease to prevent further tumor cell dissemination. And, to do so does matter. However, tumor and host factors that are in play before the diagnosis and treatment of cancer are of primary importance with regard to determining survival.