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Breast cancer: Adjuvant radiotherapy revisited
0360-3016/80/030389-03$02.00/O
Inr. J. Rodiofion Onmbgy Biol. Phys.. Vol. b. pp 3X9-391 Printed in the U.S.A. 0 Pergamon Press Ltd.. 1980.
0 Editorial BREAST CANCER: ADJUVANT RADIOTHERAPY MELVIN Professor
DEUTSCH,
radiotherapy,
2 January
Health Center,
Clinical trials.
was delivered to the target areas. In the second series, radiotherapy was administered using Cobalt 60 and treated only the ipsilateral internal mammary region, supraclavicular-infraclavicular region and the apex of the axilla. The chest wall was not included. A tumor dose of 5000 rad at 3 cm. was delivered in 20 fractions. Three groups of patients comprised this study; a control group from both series (patients who had only radical mastectomy), orthovoltage irradiated patients, and Cobalt irradiated patients. This study demonstrated no apparent benefit from either cobalt or orthovoltage irradiation in Stage I patients, regardless of the location of the primary tumor. In Stage II patients, there was a “non-significant trend” toward fewer distant metastases in the cobalt irradiated patients when they were compared to the kilo-voltage irradiated patients and the nonirradiated controls. Both types of radiotherapy decreased the incidence of local-regional recurrence in Stage II patients. There was also a trend toward a survival benefit in Stage II patients with medial tumors and in patients with four or more positive axillary nodes who received post-operative Cobalt 60 radiotherapy when they were compared to controls and to kilo-voltage irradiated patients. In this issue, the Stockholm Breast Cancer Trial updated by Wallgren et al8 evaluates modified radical mastectomy alone, pre-operative radiotherapy followed by modified radical mastectomy, and modified radical mastectomy and post-operative radiotherapy. The radiotherapy was administered to the breast (chest wall in the post-operative group), axilla, supraclavicular and internal mammary node regions. Both ipsilateral and contralateral internal mammary node regions were irradiated “in about 400 patients.” This study shows a statistically significant survival advantage to pre-operative radiotherapy when it was compared to modified radical mastectomy alone. The sub-groups who gained the most benefit were those whose primary tumor size was equal to or less than 3 cm., patients with clinically uninvolved axillary
Three major prospective randomized clinical trials that evaluated adjuvant radiotherapy for operable carcinoma of the breast have been published within the past three years. (Figure 1) These ,three studies have produced conflicting results which have further fueled the controversy between those physicians who advocate adjuvant radiotherapy for carcinoma of the breast, and their antagonists who claim that adjuvant radiotherapy confers no benefit and may even be harmful. The National Surgical Adjuvant Breast Project (NSABP)’ evaluated total (simple) mastectomy and post-operative radiotherapy that was directed to the ipsilateral chest wall, axilla, internal mammary and supraclavicular node regions versus radical mastectomy alone in patients who had clinically positive axillary nodes. The same two treatment arms were compared with total mastectomy alone for patients with clinically negative axillary nodes. In this latter arm, patients who subsequently developed recurrence in the axilla as the sole manifestation of initial recurrence then underwent axillary node dissection. This extensive study that included over 1600 patients did not demonstrate an advantage to any of the treatment arms. There was a lower incidence of local chest wall recurrence in the radiotherapy arm for patients with both clinically negative and clinically positive nodes. However, survival was neither enhanced nor decreased in the groups that received post-operative radiotherapy. Host and Brennhovd’ from the Norwegian Radium Hospital evaluated post-operative radiotherapy in patients who had classical radical mastectomy. The trial was performed in two parts. In the early years of the trial (Series l), post-operative radiotherapy was given with kilo-voltage equipment. Radiotherapy was directed to the chest wall and internal malmmary node region via two opposing tangential fields. The supraclavicular fossa was treated with a separate field., an additional field was used to treat the axilla. A rather low dose that varied from 1800 to 3600 rad, with an inhomogeneous distribution, for publication
M.D.
of Radiology, Joint Radiation Oncology Center, University of Pittsburgh 3601 Fifth Avenue, Pittsburgh, PA 15213
Breast cancer, Adjwant
Accepted
REVISITED
1980. 389
390
Radiation
Oncology
0 Biology
0 Physics
March
1. NSABP Clinically Radical Mastectomy
Uninvolved
Volume 6, Number 3
B-04
Axilla
Total Mastectomy + Post-operative Radiotherapy
”
1980,
Clinically Total Mastectomy
VS
Total Mastectomy + Post-operative Radiotherapy
i Axillary dissection for recurrence 2. Norwegian
Radium
Radical Mastectomy
Series 11 Radical Mastectomy + Ovarian Irradiation
\ Post-operative Kilovoltage Irradiation
vs
\ Post-operative Co.60 lrradiation
I No further Therapy
3. Stockholm Pre-operative Radiotherapy + Modified Radical Mastectomy
vs
Hospital Trial
Series I Radical Mastectomy + Ovarian Irradiation I No further Therapy
Involved Axilla
Breast Cancer Trial.
Modified Radical Mastectomy + Post-Operative Radiotherapy
vs
Modified Radical Mastectomy
Fig. 1. Clinical trials.
nodes, and those with medially located tumors. There was a trend toward a survival benefit with post-operative radiation therapy in patients who had medially located tumors and also those with tumors that were equal to or less than 3 cm. While the NSABP study showed no apparent advantage to post-operative radiotherapy following total mastectomy, the Norwegian Radium Hospital study showed an apparent advantage to post-operative relatively high dose irradiation of the internal mammary node and supraclavicular-infraclavicular region in a subset of patients with Stage II medially located lesions and in patients with four or more positive axillary nodes. By contrast, the Stockholm Breast Cancer Trial’ indicated that there was an advantage to pre-operative radiotherapy; it was most evident in patients with clinically negative axillary nodes, patients with primary tumors less than or equal to 3 cm., and those with medially located lesions. In light of the results from the Norwegian Radium Hospital Study,5 it is difficult to explain the NSABP study results. Radiotherapy in the NSABP Trial was administered after total simple mastectomy without axillary node dissection whereas patients in the Norwegian Radium Hospital’ trial all had radical mastectomies. However, the NSABP study demonstrates that the involved axillary nodes that were not removed in patients with clinically negative nodes did not increase the incidence of treatment failures. The NSABP Radiotherapy data has been re-evaluated extensively; the lack of benefit in the radiotherapy arms cannot be explained by lack of compliance with the protocol.2 All patients in the Norwegian Radium Hospital trial nderwent ovarian irradiation. Is it possible that radioerapy to regional lymphatics combined with ovarian
irradiation produced an advantage? Patients were randomized without stratification in the Norwegian Study. Although there were no major differences between the two groups regarding age and lymph node involvement, it is questionable whether the two series of patients were indeed comparable. The authors suggest that the benefit in the cobalt irradiated patients was derived from the high dose that was administered to the internal mammary nodes; the benefit appeared precisely in those patients who were most likely to have internal mammary node involvement, viz patients with Stage II medially located lesions and patients with four or more positive axillary nodes. However, if radiation to internal mammary nodes does indeed confer an advantage, it is difficult to explain why this was not perceived in the NSABP Protocol #4, and the previous NSABP Study #2.4 The Stockholm Breast Cancer Trial is a well organized prospective randomized clinical trial. The three treatment groups certainly seem comparable. If one postulates that irradiation of the internal mammary node region is responsible for the improved survival that was seen for both the pre-operative and post-operatively irradiated patients, then it is easy to understand why the subset of patients with medially located tumor fared better. Yet it is difficult to understand why irradiation of the internal mammary nodes would confer benefit upon patients with relatively small primaries and clinical uninvolved axillary nodes-patients who are least likely to have internal mammary node involvement. Unlike the Norwegian Radium Hospital’ trial, post-operative radiotherapy in this series did not confer a survival benefit to Stage II patients. The findings of the Norwegian trial were more compatible with results of the extended radi-
Breast cancer:
Adjuvant
revisited 0 M. DEUTSCH
radiotherapy
cal mastectomy study reported by Lacour et a1,6 they demonstrated improved survival with intqrnal mammary node dissection only in the subset of patients with inner quadrant Tl and T2 tumors with involved axillary nodes, a group who are likely to have internal mammary node involvement. Thus, if pre-operative radiotherapy is indeed beneficial, some mechanism other than destruction of tumor cells within internal mammary nodes must be invoked. One might suggest, as the authors do, that pre-operative radiation destroys cells that are most likely to be disseminated by manipulation of the tumor at the time of surgery. However, .as suggested by Fisher et al,-’ breast cancer is likely to bc a “systemic disease” at the time of presentation. It is possible that irradiation of the tumor in-situ produces a therapeutic immunological response. This would probably be the most plausible explanation for a benefit conferred by pre-operative radiotherapy as opposed to post-operative radiotherapy. The data from the Stockholm Breast Cancer Trial’ indicates that a main differencme between the irradiated and
391
non-irradiated groups was the higher incidence of localregional recurrences in patients who did not receive radiotherapy. The total number of recurrences, distant and local-regional, is practically the same for the preoperative and post-operative groups. Why was there a difference in survival? The Stockholm Breast Cancer trial,* together with the Norwegian Radium Hospital Trial,’ once again raises the question of whether there is benefit to adjuvant radiotherapy combined with mastectomy for operable breast carcinoma. The debate will undoubtedly continue; proponents and antagonists of adjuvant radiotherapy will meticulously dissect the data from these studies to find support for their respective views. However, one thing appears to be fairly certain from the three reported studies on adjuvant radiotherapy; adjuvant radiotherapy, combined with mastectomy for operable breast carcinoma, does not seem to have a deleterious affect on treatment outcome.
REFERENCES 1. Fisher, B., Montague, E., Redmond, C., Barton, B., Borland, D., Fisher, E.R., Deutsch, M., Schwarz, G., Margolese, R., Donegan, W., Volk, H., Konvolinka, C., Gardner, B., Cohn, I., Lesnick, G., Cruz, A.13.. Lawrence, W., Nealon, T., Burtcher, H., Lawton, R., and Other NSABP Investigators: Comparison of radical mastectomy with alternative treatments for primary breast cancer: A first report of results from a prospective randomized clinical trial. Cancer 39: 2827-2839, 1977. 2. Fisher B., Montague, E., Redmond, C., Deutsch, M., Brown, G.R., Zauber, A., Hanson, W.F., Wong, A., and other NSABP investigators: Findings from NSABP protocol No. B-04: Comparison of radical mastectomy with alternative treatments for primary breast cancer. I. Radiation compliance and its relation to treatment outcome. Cancer. In Press. 3. Fisher, B., Redmond, C., Fisher, E.R., and Participating NSABP Investigators: The contribution of recent NSABP clinical trials of primary breast cancer therapy to an understanding of tumor biology. An overview of findings. Cancer.. In Press.
4. Fisher, B., Slack, N.H., Cavanaugh, P.J., Gardner, B., Ravdin, R.G., and Cooperating Investigators: Postoperative radiotherapy in the treatment of breast cancer. Ann. Surg. 172: 71 l-732, 1970. 5. Host, H., Brennhovd, 1.0.: The effect of post-operative radiotherapy in breast cancer. In<. J. Radial. Oncol. Biol. Phys. 2: 1061-1067, 1977. 6. Lacour, J., Bucalossi, P., Caters, E., Jacobelli, G., Koszarowski, T., Le, M., Rumeau-Rouquette, C., Veronesi, U.: Radical mastectomy versus radical mastectomy plus internal mammary dissection. Cancer 37: 206-2 14, 1976. 7. Wallgren, A., Arner, O., BergstrGm, J., Blomstedt, B., Granberg, P-O, KarnstrGm, L., Raf, L., Silfverswgrd, C: Preoperative radiotherapy in operable breast cancer. Results in the Stockholm breast cancer trial. Cancer 42: 1120-l 125, 1978. 8. Wallgren, A., Arner, O., Bergstriim, J., Blomstedt, B., Granberg, P-O, KarnstrSm, Raf, L., Silfverswgrd, C: The value of preoperative radiotherapy in operable mammary carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 6: 000-000, 1980.
Inr. J. Rodiofion Onmbgy Biol. Phys.. Vol. b. pp 3X9-391 Printed in the U.S.A. 0 Pergamon Press Ltd.. 1980.
0 Editorial BREAST CANCER: ADJUVANT RADIOTHERAPY MELVIN Professor
DEUTSCH,
radiotherapy,
2 January
Health Center,
Clinical trials.
was delivered to the target areas. In the second series, radiotherapy was administered using Cobalt 60 and treated only the ipsilateral internal mammary region, supraclavicular-infraclavicular region and the apex of the axilla. The chest wall was not included. A tumor dose of 5000 rad at 3 cm. was delivered in 20 fractions. Three groups of patients comprised this study; a control group from both series (patients who had only radical mastectomy), orthovoltage irradiated patients, and Cobalt irradiated patients. This study demonstrated no apparent benefit from either cobalt or orthovoltage irradiation in Stage I patients, regardless of the location of the primary tumor. In Stage II patients, there was a “non-significant trend” toward fewer distant metastases in the cobalt irradiated patients when they were compared to the kilo-voltage irradiated patients and the nonirradiated controls. Both types of radiotherapy decreased the incidence of local-regional recurrence in Stage II patients. There was also a trend toward a survival benefit in Stage II patients with medial tumors and in patients with four or more positive axillary nodes who received post-operative Cobalt 60 radiotherapy when they were compared to controls and to kilo-voltage irradiated patients. In this issue, the Stockholm Breast Cancer Trial updated by Wallgren et al8 evaluates modified radical mastectomy alone, pre-operative radiotherapy followed by modified radical mastectomy, and modified radical mastectomy and post-operative radiotherapy. The radiotherapy was administered to the breast (chest wall in the post-operative group), axilla, supraclavicular and internal mammary node regions. Both ipsilateral and contralateral internal mammary node regions were irradiated “in about 400 patients.” This study shows a statistically significant survival advantage to pre-operative radiotherapy when it was compared to modified radical mastectomy alone. The sub-groups who gained the most benefit were those whose primary tumor size was equal to or less than 3 cm., patients with clinically uninvolved axillary
Three major prospective randomized clinical trials that evaluated adjuvant radiotherapy for operable carcinoma of the breast have been published within the past three years. (Figure 1) These ,three studies have produced conflicting results which have further fueled the controversy between those physicians who advocate adjuvant radiotherapy for carcinoma of the breast, and their antagonists who claim that adjuvant radiotherapy confers no benefit and may even be harmful. The National Surgical Adjuvant Breast Project (NSABP)’ evaluated total (simple) mastectomy and post-operative radiotherapy that was directed to the ipsilateral chest wall, axilla, internal mammary and supraclavicular node regions versus radical mastectomy alone in patients who had clinically positive axillary nodes. The same two treatment arms were compared with total mastectomy alone for patients with clinically negative axillary nodes. In this latter arm, patients who subsequently developed recurrence in the axilla as the sole manifestation of initial recurrence then underwent axillary node dissection. This extensive study that included over 1600 patients did not demonstrate an advantage to any of the treatment arms. There was a lower incidence of local chest wall recurrence in the radiotherapy arm for patients with both clinically negative and clinically positive nodes. However, survival was neither enhanced nor decreased in the groups that received post-operative radiotherapy. Host and Brennhovd’ from the Norwegian Radium Hospital evaluated post-operative radiotherapy in patients who had classical radical mastectomy. The trial was performed in two parts. In the early years of the trial (Series l), post-operative radiotherapy was given with kilo-voltage equipment. Radiotherapy was directed to the chest wall and internal malmmary node region via two opposing tangential fields. The supraclavicular fossa was treated with a separate field., an additional field was used to treat the axilla. A rather low dose that varied from 1800 to 3600 rad, with an inhomogeneous distribution, for publication
M.D.
of Radiology, Joint Radiation Oncology Center, University of Pittsburgh 3601 Fifth Avenue, Pittsburgh, PA 15213
Breast cancer, Adjwant
Accepted
REVISITED
1980. 389
390
Radiation
Oncology
0 Biology
0 Physics
March
1. NSABP Clinically Radical Mastectomy
Uninvolved
Volume 6, Number 3
B-04
Axilla
Total Mastectomy + Post-operative Radiotherapy
”
1980,
Clinically Total Mastectomy
VS
Total Mastectomy + Post-operative Radiotherapy
i Axillary dissection for recurrence 2. Norwegian
Radium
Radical Mastectomy
Series 11 Radical Mastectomy + Ovarian Irradiation
\ Post-operative Kilovoltage Irradiation
vs
\ Post-operative Co.60 lrradiation
I No further Therapy
3. Stockholm Pre-operative Radiotherapy + Modified Radical Mastectomy
vs
Hospital Trial
Series I Radical Mastectomy + Ovarian Irradiation I No further Therapy
Involved Axilla
Breast Cancer Trial.
Modified Radical Mastectomy + Post-Operative Radiotherapy
vs
Modified Radical Mastectomy
Fig. 1. Clinical trials.
nodes, and those with medially located tumors. There was a trend toward a survival benefit with post-operative radiation therapy in patients who had medially located tumors and also those with tumors that were equal to or less than 3 cm. While the NSABP study showed no apparent advantage to post-operative radiotherapy following total mastectomy, the Norwegian Radium Hospital study showed an apparent advantage to post-operative relatively high dose irradiation of the internal mammary node and supraclavicular-infraclavicular region in a subset of patients with Stage II medially located lesions and in patients with four or more positive axillary nodes. By contrast, the Stockholm Breast Cancer Trial’ indicated that there was an advantage to pre-operative radiotherapy; it was most evident in patients with clinically negative axillary nodes, patients with primary tumors less than or equal to 3 cm., and those with medially located lesions. In light of the results from the Norwegian Radium Hospital Study,5 it is difficult to explain the NSABP study results. Radiotherapy in the NSABP Trial was administered after total simple mastectomy without axillary node dissection whereas patients in the Norwegian Radium Hospital’ trial all had radical mastectomies. However, the NSABP study demonstrates that the involved axillary nodes that were not removed in patients with clinically negative nodes did not increase the incidence of treatment failures. The NSABP Radiotherapy data has been re-evaluated extensively; the lack of benefit in the radiotherapy arms cannot be explained by lack of compliance with the protocol.2 All patients in the Norwegian Radium Hospital trial nderwent ovarian irradiation. Is it possible that radioerapy to regional lymphatics combined with ovarian
irradiation produced an advantage? Patients were randomized without stratification in the Norwegian Study. Although there were no major differences between the two groups regarding age and lymph node involvement, it is questionable whether the two series of patients were indeed comparable. The authors suggest that the benefit in the cobalt irradiated patients was derived from the high dose that was administered to the internal mammary nodes; the benefit appeared precisely in those patients who were most likely to have internal mammary node involvement, viz patients with Stage II medially located lesions and patients with four or more positive axillary nodes. However, if radiation to internal mammary nodes does indeed confer an advantage, it is difficult to explain why this was not perceived in the NSABP Protocol #4, and the previous NSABP Study #2.4 The Stockholm Breast Cancer Trial is a well organized prospective randomized clinical trial. The three treatment groups certainly seem comparable. If one postulates that irradiation of the internal mammary node region is responsible for the improved survival that was seen for both the pre-operative and post-operatively irradiated patients, then it is easy to understand why the subset of patients with medially located tumor fared better. Yet it is difficult to understand why irradiation of the internal mammary nodes would confer benefit upon patients with relatively small primaries and clinical uninvolved axillary nodes-patients who are least likely to have internal mammary node involvement. Unlike the Norwegian Radium Hospital’ trial, post-operative radiotherapy in this series did not confer a survival benefit to Stage II patients. The findings of the Norwegian trial were more compatible with results of the extended radi-
Breast cancer:
Adjuvant
revisited 0 M. DEUTSCH
radiotherapy
cal mastectomy study reported by Lacour et a1,6 they demonstrated improved survival with intqrnal mammary node dissection only in the subset of patients with inner quadrant Tl and T2 tumors with involved axillary nodes, a group who are likely to have internal mammary node involvement. Thus, if pre-operative radiotherapy is indeed beneficial, some mechanism other than destruction of tumor cells within internal mammary nodes must be invoked. One might suggest, as the authors do, that pre-operative radiation destroys cells that are most likely to be disseminated by manipulation of the tumor at the time of surgery. However, .as suggested by Fisher et al,-’ breast cancer is likely to bc a “systemic disease” at the time of presentation. It is possible that irradiation of the tumor in-situ produces a therapeutic immunological response. This would probably be the most plausible explanation for a benefit conferred by pre-operative radiotherapy as opposed to post-operative radiotherapy. The data from the Stockholm Breast Cancer Trial’ indicates that a main differencme between the irradiated and
391
non-irradiated groups was the higher incidence of localregional recurrences in patients who did not receive radiotherapy. The total number of recurrences, distant and local-regional, is practically the same for the preoperative and post-operative groups. Why was there a difference in survival? The Stockholm Breast Cancer trial,* together with the Norwegian Radium Hospital Trial,’ once again raises the question of whether there is benefit to adjuvant radiotherapy combined with mastectomy for operable breast carcinoma. The debate will undoubtedly continue; proponents and antagonists of adjuvant radiotherapy will meticulously dissect the data from these studies to find support for their respective views. However, one thing appears to be fairly certain from the three reported studies on adjuvant radiotherapy; adjuvant radiotherapy, combined with mastectomy for operable breast carcinoma, does not seem to have a deleterious affect on treatment outcome.
REFERENCES 1. Fisher, B., Montague, E., Redmond, C., Barton, B., Borland, D., Fisher, E.R., Deutsch, M., Schwarz, G., Margolese, R., Donegan, W., Volk, H., Konvolinka, C., Gardner, B., Cohn, I., Lesnick, G., Cruz, A.13.. Lawrence, W., Nealon, T., Burtcher, H., Lawton, R., and Other NSABP Investigators: Comparison of radical mastectomy with alternative treatments for primary breast cancer: A first report of results from a prospective randomized clinical trial. Cancer 39: 2827-2839, 1977. 2. Fisher B., Montague, E., Redmond, C., Deutsch, M., Brown, G.R., Zauber, A., Hanson, W.F., Wong, A., and other NSABP investigators: Findings from NSABP protocol No. B-04: Comparison of radical mastectomy with alternative treatments for primary breast cancer. I. Radiation compliance and its relation to treatment outcome. Cancer. In Press. 3. Fisher, B., Redmond, C., Fisher, E.R., and Participating NSABP Investigators: The contribution of recent NSABP clinical trials of primary breast cancer therapy to an understanding of tumor biology. An overview of findings. Cancer.. In Press.
4. Fisher, B., Slack, N.H., Cavanaugh, P.J., Gardner, B., Ravdin, R.G., and Cooperating Investigators: Postoperative radiotherapy in the treatment of breast cancer. Ann. Surg. 172: 71 l-732, 1970. 5. Host, H., Brennhovd, 1.0.: The effect of post-operative radiotherapy in breast cancer. In<. J. Radial. Oncol. Biol. Phys. 2: 1061-1067, 1977. 6. Lacour, J., Bucalossi, P., Caters, E., Jacobelli, G., Koszarowski, T., Le, M., Rumeau-Rouquette, C., Veronesi, U.: Radical mastectomy versus radical mastectomy plus internal mammary dissection. Cancer 37: 206-2 14, 1976. 7. Wallgren, A., Arner, O., BergstrGm, J., Blomstedt, B., Granberg, P-O, KarnstrGm, L., Raf, L., Silfverswgrd, C: Preoperative radiotherapy in operable breast cancer. Results in the Stockholm breast cancer trial. Cancer 42: 1120-l 125, 1978. 8. Wallgren, A., Arner, O., Bergstriim, J., Blomstedt, B., Granberg, P-O, KarnstrSm, Raf, L., Silfverswgrd, C: The value of preoperative radiotherapy in operable mammary carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 6: 000-000, 1980.