T of radiation treatment and surgical resection

Transcription

1 BREAST CANCER-PREOPERATIVE AND POSTOPERATIVE RADIATION THERAPY WILLIAM E. POWERS, MD Our goal is to develop new methods of breast cancer treatment that produce results better than those usually obtained in patients with operable breast cancer who have a radical mastectomy and patients with inoperable breast cancer who receive desultory and inadequate radiation therapy. We must examine our views operable patients are curable and inoperable patients are incurable in light of our actual results and recent changes in understanding of the mechanisms of failure to cure breast cancer by surgical treatment and the processes by which radiation therapy cures breast cancer. We must search out ways to increase the cure rate in both operable and inoperable breast cancer patients. Combinations of radiation therapy and surgical resection have been tried with varying successes However, since it is apparent that aggressive radiation therapy cures a significant proportion of patients with inoperable breast cancer,*. 9, 11, 15, 22 it seems reasonable to re-evaluate this combination therapy and reassess the benefits and failures of such combinations. HE SEARCH FOR EFFECTIVE COMBINATIONS T of radiation treatment and surgical resection in the treatment of carcinoma of the breast is directed towards an improvement in the survival of the whole population of patients who present with breast carcinoma and have no clinical evidence of systemic dissemination of tumor, rather than to seek a method which provides equivalence in survival and morbidity to radical or super radical surgical therapy. It is not sufficient to develop new adjunctive radiation therapy techniques which, when combined with either simple mastectomy or wedge resection, produce results equivalent to radical mastectomy. This has already been done. Our goal is an absolute increase in cure rate of patients with breast cancer, not the production of good statistics by careful selection of patients who can be cured by a selected technique discarding the rest of the patients to a consideration of no treatment. This goal may be accomplished either by an increase in the cure of a Presented at the First National Conference on Breast Cancer, Washington, D.C., May 8-10, Supported by USPHS (NCI) Research Grant #5 PO2 CA Professor of Radiology, The Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Mo. Address for reprints: W. E. Powers, MD, Mallinckrodt Institute of Radiology, 510 South Kingshighway, St. Louis, Mo Received for publication August 25, given operable stage or by increasing the number of patients who are operable and can be cured by surgery. To produce such improvement it is appropriate that we examine the characteristics of the tumors of the total population of patients with breast cancer and examine for the mechanisms of failures that we might preclude or modify by change in our treatment policy or technique. The total population consists of some patients that simple mastectomy might cure and some patients that no combination of therapy can cure because they have disseminated disease. There is also an indeterminate sized group of patients in whom some addition of treatment can make a difference. In the first group, the patients have a localized tumor, and either simple mastectomy, simple mastectomy plus radiation, or radical surgery will all produce cure, as all procedures have a common minimum-removal of the total tumor. In the second group of patients, there may be either clinically apparent disseminated disease or clinically occult disseminated disease. Either condition results in failure-not of the method, but of the recognition of the extent of disease. The third group of patients with intermediate extent of disease is the one which most concerns us. This is a group in which the clinically apparent disease and actual extent of the disease may be 1301

2 1302 CANCER December 1969 Vol. 24 controlled, if the patient doesn t fail because tumor cells are spread or cut across at the time of treatment and if all of the local tumor is treated. This is the population in which adjunctive therapy may be of benefit if we can develop techniques to exclude the processes of failure. The possible methods of failure ordained at the time of the surgical procedure include: a. small extensions of the tumor may be cut through; b. tumor may be disseminated by lymphatics or blood vessels at the time of the surgical procedure; or c. tumor cells may be implanted into the wound at the time of the surgical procedure. Another mechanism of failure, not due to the surgical procedure, is local and regional lymph node involvement in the internal mammary or supraclavicular nodes-extensions not resected in the conventional radical mastectomy, but resectable by extended operations. It must be repeated that benefit from either preoperative or postoperative radiation therapy can be achieved only if tumor cells left in the patient fomowing completion of the surgical resection are, or were, within the irradiation ports and are sterilized by the administered irradiation. This is true whether the radiation is administered before or after the surgical procedure and whether the dose administered is high or low. Thus, if only a few cells are disseminated systemically, failure will result even though the overwhelming preponderance of the tumor has been removed or killed. The lack of dramatic benefit from either preoperative or postoperative radiation therapy is due to the small proportion of patients with breast cancer whose clinical course can be altered by local adjunctive therapy. Thus, though we get striking local regression of the tumor, and even complete disappearance to histopathologic examination, our weak link is the extent of tumor spread at the time of onset of treatment, or the amount of spread during treatment and prior to inactivation of the cells by irradiation. Postoperative radiation therapy: Postoperative irradiation may be used as an alternative to radical surgical treatment, or as an adjunct to radical surgical effort. In all cases, the use of postoperative therapy implies the possible presence of unresected tumor-either in the operative wound or in the adjacent structures. If the remnant tumor is localized and sufficient dose is administered, cure should result. Our dependence on this form of therapy arises from our clear knowledge that even in the earliest clinical stage of breast cancer, from 10 to ZOyo of patients will fail due to regrowth of tumor, either local or distant. In more advanced breast cancer with axillary node involvement, the failure rate approaches SO%, and we seek local therapy that will reduce these failures. In the evaluation of postoperative irradiation following local resection of the breast cancer, 2 studies have been performed comparing the results of simple mastectomy plus postoperative radiation therapy with, in one study, the results of radical mastectomy and in the other the results of extended radical mastectomy.l, 12, l4 These reports clearly demonstrate that the patients having simple mastectomy and postoperative radiation therapy to the chest wall and adjacent node areasaxilla, supraclavicular, and internal mam- mary nodes-have a survival rate similar to that of patients treated by more radical surgery (Table 1). A detailed evaluation of the various mechanisms of failure occurring in TABLE 1. Comparison of Results of Radical Mastectomy vs. Simple Mastectomy or Wedge Resection plus Radical Radiation Therapy Author Radical surgery 5-year survival Lotal surgery and irradiation # % Surv. # yo Surv. Brinklcy and Haybittlel* 91 54% % Kaae and JohansenI4* % % Peters % % * Only stage I1 patients studied. Patients selected for alternate mode of treatment by random allocation.

3 No. 6 RADIATION THERAPY IN BREAST CANCER - P0711~!YS the 2 treatment groups in each of these 2 studies would be quite informative but unfortunately is not available. In another review of patients treated by wedge resection and radical postoperative radiation therapy, there has been demonstrated a 5- and 10-year survival equivalent to results of more radical surgical treatment.17 In these patients, the surgeon clearly identified that not all of the tumor-containing tissues were removed, and aggressive radiation therapy was administered to the operation site and the adjacent node areas with a curative intent (Fig. 1). The results must be interpreted to demonstrate that high dose radiation therapy administered as an alternative to radical resection has cured patients with incompletely resected breast cancer. These techniques have a lesser morbidity than radical mastectomy and preserve the axillary structures and a portion of the breast and are, therefore, valuable. As discussed earlier, we seek to discover im FIG. 2. Postoperative radiation therapy-adjacent nodes. The radiation therapy is applied to adjacent lymph node areas only, with the expectation that the primary tumor and axilla are adequately treated by the surgical resection. In this case, radiation therapy in high doses is administered to lymph nodes peripheral to the operated field. FIG. 1. Postoperative radiation therapy-wide field technique. Postoperative radiation therapy following simple mastectomy or wedge resection or aggressive postoperative radiation therapy following a radical mastectomy. Radiation therapy is delivered to the internal mammary and supraclavicular areas but, in addition, radiation therapy is administered to the entire operated area to preclude chest wall recurrences, provement in cure and while a preservation of the breast and axillary structures is a worthy goal and these results do show again the striking benefit of irradiation in producing cure of breast cancer, a more radical method that produces improved cure will be welcome and widely utilized. In patients treated prophylactically following radical mastectomy, radiation therapy is usually delivered to the supraclavicular nodes, the apex of the axilla, and to the internal mammary nodes shortly following the surgical resection (Fig. 2). When this procedure is studied, there is no clear demonstration that such therapy increases cure.3-4s 5, l8 These investigations have shown that therapy to the adjacent node areas does provide a temporary prevention of recurrence in the treated region. The deaths due to tumor are similar in number, and there is a similar distribution of lesions in patients treated prophylactically and in patients who are watched originaliy and treated only when the tumor recurred (Fig. 3). It is similar in those patients treated to the

4 1304 CANCER Dece mber 1969 Vol. 24 FIG. 3. Radical mastectomy plus postoperative radiation therapy. A comparison in the 5-year results in 2 populations of patients: a. watched, b. treated. The opposite sides of the figure indicate that the recurrence rates in various sites in the 2 groups of patients are essentially similar whether the patients are treated postoperatively (prophylactically) or alternatively are watched and only those patients with recurrence (symptomatic) exposed! chest wall, but there is no modification of the survival rates when compared with watched patients who are treated as needed when lesions occur. Thus, we are faced with yet another para. dox in breast cancer.6 Radiation therapy alone cures breast cancer in some cases and radiation plus partial surgical resection cures cancer in many cases. Rut radiation given postoperatively following radical surgical therapy does not appear to produce the expected increase in cure. Since there is some benefit from prevention of metastasis to the regional tissues and some possibility of increased cure if higher doses are delivered when both chest wall and adjacent nodes are treated and there is little morbidity, postoperative therapy is recommended if: a. preoperative therapy was not used; and b. tumor is cut through, the tumor is over 5 cm in diameter, or axillary nodes contain tumor. In these cases, high doses should be given to the chest wall and to the adjacent nodes. One should, however, not expect a great deal of benefit from even aggressive postoperative radiation therapy since only those patients who fail locally can be aided. Since postoperative radiation therapy after simple or incomplete mastectomy is no better than radical mastectomy in suitable patients, and since radical mastectomy plus postoperative therapy to either chest wall or adjacent nodes is no better than radical mastectomy alone in appropriate patients, we still must find a way to increase the cure in patients with all stages of breast cancer. Preoperative radiation therapy: Preoperative radiation therapy as an adjunct to surgical resection has been shown to be of clear and definite value in operable breast cancer cases and possibly of value to make inoperable cancer patients curable by a radical mastectomy.7~ 10, 13, 1G.22 In the case of operable breast cancer, many studies have shown an increase in survival and a decrease in local and distant recurrence in patients treated with an adequate dose of preoperative radiation therapy followed by a radical surgical procedure (Fig. 4). Such increased benefits may not be generally applicable as all such studies have consisted of selected patients rather than groups chosen by random allocation, and this selection might modify the results in favor of the patients treated by the combination therapy. In considering preoperative radiation therapy, the radiation therapy fields must include all of the structures that are going to be removed by the surgeon, and these structures should be treated to a moderately high dose. In addition, some tissue, possibly containing tumor (for example supraclavicular and internal mammary lymph nodes), will be left in the patient and thus, these areas must receive a full curative dose of radiation to produce any benefit. While a less than curative dose may be of value to the breast tissue and the axillary structures that will be removed, because of the technical difficulty of delivering the dose so that the breast and axilla (which will be resected) receive a different dose than that to the contiguous chain of

5 No. 6 RADIATION THERAPY IN BREAST CANCER nodes in the supraclavicular and internal mammary areas (which will remain), it is probably best that all these structures be treated to the high (near curative) dose of radiation. Our goal is to minimize the complications but still produce an effective modification of all of the cancer cells that might be left in the patient. The breast and chest wall structures must be treated by opposing tangential fields (Fig. 5) that reduce the dose of radiation to the lung and protect the normal structures in the shoulder joint. These efforts will prevent an excessive morbidity because of unnecessary application of the preoperative radiation to normal structures. Cobalt-60 therapy or other high energy radiation should be used to prevent skin and bone necrosis. While the protection of the skin and the superficial structures is impor- Powers 1305 FIG. 5. Preoperative radiation therapy. In this instance, because of the difficulty of varying the dose to the breast and to the supraclavicular or internal mammary structures, it is important that all of the structures receive high-dose therapy so that any nodes in the area adjacent to the surgical resection will have been sterilized and the tumor cells inactivated. It is important that the chest wall radiation be administered by tangenital fields that exclude the adjacent lung and that the shoulder joint and spinal cord be protected. I. * \ FIG. 4. Preoperative vs. postoperative therapy. Comparison of patients treated with preoperative radiation therapy and patients treated with postoperative radiation therapy. The incidence of clinically positive nodes is greater in the patients treated preoperatively although the frequency of patients with positive nodes in the surgical specimens are less in this group. This is possibly a result of the local effect of radiation therapy. The recurrence rate in the population treated preoperatively is much smaller than in those patients treated postoperatively, and the survival rate is slightly better.1 tant, if the skin or dermal lymphatics in the breast are involved, bolus material must be applied to increase the dosage to the superficial structures. Preoperative irradiation therapy has only a limited potential for improvement in cure rate and, for this reason, there is considerable reason to be especially careful in the fields and techniques utilized, as a moderate increase in complications can offset a small increase in cure. Since the doses used are high rads to 6000 rads-a delay period between the end of radiation therapy and the surgical resection must ensue to allow repopulation of the normal tissues that will be required to heal the surgical wound. With proper techniques, the morbidity of such treatment should be low.10 The use of a planned course of preoperative radiation therapy and a subsequent radical resection

6 : 1306 CANCER December 1969 Vol. 24 require a close and honest working relationship between the concerned surgeon and radiation therapist who must be aware of each other s skills but also recognize each other s limitations. The surgeon must not plan to reduce the scope of his surgical procedure just because of regression of the primary tumor. True, a number of inoperable breast cancers have been made operable and resectable, but still the radical all-encompassing surgical procedure should be employed. The presumed biological basis for preoperative irradiation is that even modest doses or radiation kills (inactivates reproductive capacity) tumor cells and normal cells. Delivery of high doses locally to the area of tumor kills tumor cells so that any cells left behind in the irradiated and operated field will be unable to reproduce and cause a recurrence. The use of treatment prior to sur- gery seems optimal as if cells are killed locally prior to surgical effort and then spread; they, too, will be unable to regrow a recurrence. Although preoperative radiation has made inoperable patients operable and curable, it is not clear that the control rate of this combined treatment in patients with extensive disease is superior to the results in patients treated by primary radiation therapy. SUMMARY The benefits of preoperative or postoperative radiation therapy of breast cancer are uncertain. At present, rational efforts are being directed at obtaining answers. Preoperative radiation therapy should be used in moderately advanced breast cancer; postoperative irradiation should be used in selected instances. REFERENCES 1. Brinkley, Diana, and Haybittle, J. L.: Treatment of stagc-i1 carcinoma of the female breast. Lancet , Butcher, H. R., Jr., Seaman, W. B., Eckert, C., and Saltzstcin, S.: An assessment of radical mastectomy and postoperative irradiation therapy in the treatment of mammaiy cancer. Cancer 17:48&485, Chu, F. C. H., Lucas, J. C., Jr.. Farrow, J. H., and Nickson, J. J.: Does prophylactic radiation therapy given for cancer of the breast predispose to metastasis? Amer. J. Roentgen. 99: , Cole, Mary P.: The place of radiotherapy in the management of early breast cancer. A report of two clinical trials. B7it. J. Surg. 51: , * -. The value of post-operative radiotherapy in the management of breast cancer. J. Int. CoZZ. Surg. 38~ , Collins, V. P., and Adams, R. M.: The paradox of breast cancer. Amer. J. Roentgen. 99: , DeLarue, N. C., Ash, C. L., Peters, Vera, and Fielden, R.: Preoperative irradiation in managcrnent of locally advanced breast cancer. Arch. Surg. 91: , Edelman, A. H., Holtz, S., and Powers, W. E.: Rapid radiotherapy for inoperable carcinoma of the breast, benefits and complications. Amer. J. Roentgen. 93~ , Fletcher, G. H., Montague, E. D., and White, E. C.: Evaluation of irradiation of the peripheral lymphatics in conjunction with radical mastectomy for cancer of the breast. Cancer 21: , Fletcher, G. H.: The advantages of preoperative irradiation. JAMA , Guttniann, Ruth J.: Role of supervoltage irradiation of regional lymph node bearing areas in breast cancer. Amer. J. Roentgen. 96: , Kaae, S.: Docs simple mastectomy followed by irradiation offer survival comparable to radical procedures? JAMA 200: , : Preoperative x-ray therapy in cancer of the breast. Bzdl. Schweiz. Akad. Med. Wiss , , and Johansen, H.: Brcast cancer: a comparison of the results of simple mastectomy with postoperative roentgen irradiation by the McWhirter method with those of extended radical mastectomy. Acta Radiol , Montague, Eleanor D.: Physical and clinical parameters in the management of advanced breast cancer with radiation therapy alone. Amer. J. Roentgen , Peters, M. Vera: Carcinoma of the breast, with particular reference to pre-operative radiation. J. Cnnad. Ass. Radiol. 4:32-39, ~ Wedge resection and irradiation, an ef- fcctive treatment in early breast cancer. JAMA 200: , Robbins, G. F., Lucas, J. C., Jr., Fracchia, A. A., Farrow, J. H., and Chu, Florence C. H.: An evaluation of postoperative prophylactic radiation therapy in breast cancer Surg. Gynec. Obstet. 122: , 1966.