Role of Radiotherapy in the Management of Breast Cancer P. P. Kumar, MD Washington, D.C.
There is no subject as controversial as the treatment of early breast cancer in spite of 90,000 new cases per year and more than 30,000 deaths per year in the USA alone. Radical mastectomy has been in practice for over 80 years. Radiotherapy, alone, was used 50 years ago. Today, however, we are unable to state which is the method of choice in the management of early breast cancer. Radiotherapy did not become popular as the primary treatment modality during the radium and orthovoltage era because of technical problems. These technical problems have been overcome during the afterloading and supervoltage era. Unfortunately, we do not have a large series in radiotherapy to compare with those of 80 years of radical mastectomies. Until such time, radiotherapy will play an adjuvant and palliative role in the management of breast cancer patients. Breast cancer was known and treated surgically in ancient Greece and Rome. Velpeau (1795-1867),Professor of Clinical Surgery at the Paris Faculty, wrote his great treatise on Diseases of the Breast in 1854. Halsted (1852-1922), Professor of Surgery at Johns Hopkins, introduced radical mastectomy for breast cancer in 1889, based on the knowledge of the lymphatic drainage of the breast.1 After it became evident that long-term survivals were not improved by radical, loco-regional surgery, except in patients with little or no regional node involvement, McWhirter, in 1945, introduced simple mastectomy, followed by radiotherapy to the regional nodes.2 Since then, hundreds of papers were published and volumes of books written on various aspects of breast cancer. The end result is that the age-adjusted death rate of women with breast cancer has not improved appreciably over the last 20 years.3 This is based on the following premise.
Requests for reprints should be addressed to Dr. P. P. Kumar, Department of Radiotherapy, Howard University Hospital, Washington, D.C. 20060.
If the time required for a tumor to double its diameter during a known period of time is taken as a measure of growth rate, one can calculate by extrapolation that for two-thirds of its duration, breast cancer remains undetectable by the patient or physician. Long before a breast cancer can be detected clinically, metastatic spread may occur, as it does in most cases. It is clearly shown by Haagenson4 that the survival rates drastically fall as the upper groups of axillary nodes are involved, despite radical surgery. So, what we achieve by doing radical surgery in breast cancer seems to be better surgical staging rather than actual improvement in survival rates. As long as the tumor is confined to the breast and is small, it can be totally irradicated by other methods and radical surgery does not seem to be necessary. Therefore, the key to improving survival rates in breast cancer patients is to detect the disease before its regional or distant spread, that is, in its early local stage. To achieve this we need harmless, highly accurate diagnostic techniques which can be made easily available to the entire female population. Until then, how we should
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
treat this disease is the problem. It is becoming more evident that high cure rates in early breast cancer can be achieved by combining conservative surgery and radiotherapy5 or by radiotherapy alone.6 But, before these methods can replace standard radical breast surgery, which has been in practice for more than 80 years, we need more clinical trials and experience. Until this is achieved, radical surgery will continue to exist and radiotherapy will play an adjuvant role in the treatment of early breast cancer. The role of radiotherapy, in the treatment of breast cancer, can be divided into (1) as an adjuvant to surgery; (2) for palliation in advanced cancer; (3) for ovarian ablation in advanced breast cancer; and (4) as the primary method of treatment of early breast cancer.
Adjuvant Long-term follow-up of breast cancer patients following radical mastectomy clearly shows that (1) more than 50 percent die ultimately of distant disease7 but not from locoregional recurrence and (2) that adjuvant locoregional radiotherapy following radical mastectomy does not alter their survival rates.8 However, locoregional recurrence following radical mastectomy increases morbidity and causes tremendous psychological trauma to patients who were previously traumatized by the radical surgery. The incidence of locoregional recurrence, with and without axillary node involvement following radical surgery alone and radical surgery plus locoregional irradiation, shows a significant reduction in the locoregional recurrence rate when irradiation is used as an adjuvant to radical surgery.9 This drop in locoregional recurrence justi787
fies the use of adjuvant post-operative irradiation in the treatment of breast cancer despite insignificant sporadic reports that state that adjuvant radiotherapy treatment suppresses the host immunity and increases the frequency of distant metastasis and mortality.10 The most frequent site of locoregional recurrence is in the chest wall, where two types occur. (1) Locally
..
,
....a
_
widespread disease (Figure 1). This type usually appears within one year following the radical surgery, is fulminating, and response to radiotherapy is poor. Though many believe that locoregional recurrence does not alter survival, it is my observation that patients who develop this type of disease within one year after radical surgery have a very poor prognosis in
7.
r
Figure 1. Extensive local
/
recurrence one year after radical mastectomy alone for
11 disease. Patient did not respond to local irradiation and died in six months.
Stage
addition to severe morbidity. (2) The second type is a solitary nodule that usually occurs within the scar and appears many years after surgery (Figure 2). These lesions respond very well to local radiotherapy11 and patients continue to maintain good health for many years. This type does not alter survival, and causes little morbidity. It does not increase mortality. However, these patients who have overcome the psychological trauma of the disease will be subjected to similar trauma again. The sites of regional recurrence are the supraclavicular nodes and parasternal regions (internal mammary nodes).1 2 A review of pathology reports in many radical mastectomy specimens shows that the number of axillary lymph nodes removed varies widely. Therefore, in some cases the axilla (axillary nodes) is a potential site for regional recurrence. The growth of occult disease in these regional nodes causes local enlargement and pain from pressure on the brachial plexus by the supraclavicular nodes and by direct bone erosion when the internal mammary nodes are involved. This responds to irradiation and patients have good relief of pain.1 1 Studies show that locoregional recurrence does not alter the survival rates in breast cancer patients.8 If a patient does not have distant spread at the time of surgery and subsequently develops locoregional disease, the disease can spread to distant organs from these sites. Radiobiological studies also show that the smaller the number of cells, the less the dose needed to achieve total cell kill. Therefore, it is much easier to eradicate microscopic disease than macroscopic disease with a given dose. These clinical, biological, and logical observations clearly indicate that prophylactic adjuvant, locoregional irradiation, is of immense value in the treatment of operable breast cancer.
ot.,¢. . Ck,1|f!i1~, ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~...~.. ~ *~~~~~
~ ~~~~~~
...s....
Figure 2. Local recurrence in the mastectomy scar seven years following radical mastectomy alone for Stage disease. The recurrent tumor responded well to interstitial irradiation. The patient is alive and free of disease.
788
Palliative The palliative role of radiotherapy in advanced carcinoma of the breast is of two types: (1) palliation of locally advanced cancer, and (2) palliation of widespread cancer. Evaluation of the management of breast cancer is made
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
Figure 3. Locally advanced breast cancer with extensive ulceration and foul smelling discharge.
Figure 4. The lesion shown in Figure 3 after external irradiation, showing complete healing of the ulcer.
elusive by the natural history of the disease. This is the only malignant disease about which there are welldocumented data on long survivals in untreated patients. 1 3 -1 5 More than 20 percent of untreated breast cancer patients survive for five years with either advanced local or widespread disease. Therefore, it is important to achieve good palliation in these patients and keep them comfortable. One might think that with all the public education we have, it is not possible to see patients with locally advanced breast cancer. On the contrary, because of the enormous number of women developing breast cancer and the hesitancy of some women to see a doctor when they notice a lump in their breast, we still see patients with locally advanced disease. (Figure 3). The major problem in locally advanced
breast cancer is ulceration and foul smelling serosanguineous discharge. (Figure 3). These lesions cannot be operated on because of wide area of involvement. Local irradiation of these lesions is the only available method of treatment which gives gratifying results (Figure 4). More than 50 percent of breast cancer patients ultimately die of distant metastases, after definitive treatment of the primary.7 The leading sites of metastases are1 6 the distant lymph nodes 64 percent, lung 57 percent, red bone marrow 55 percent, liver 51 percent, bone 49 percent, adrenals 34 percent, and brain 10 percent. The pattern of dissemination is predominantly hematogenous. Most gratifying responses are seen when the bone and brain metastatic lesions are irradiated. The subjective response is
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
almost 100 percent in both these areas. According to Staley,l 7 39 to 53 percent of all skeletal metastases from carcinoma of the breast are located in the spine. Therefore, Eisen et all 8 suggested that the entire spine should be treated, even if these is evidence of only local involvement of the spine. This is to avoid overlapping of fields and possible transverse myelitis when other areas of the spine need irradiation subsequently. I do not feel that this is necessary because (1) most breast cancer patients with bone disease will be anemic and total spine irradiation further aggravates the anemia; (2) most patients are now given chemotherapy which is also myelosuppressive; and (3) in good radiotherapy departments matching of the spinal fields should not be a problem. However, if there is involvement of the 789
...................t.' '1'..:.
..
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_
_~~~~~~~~~~~~~~~~~~~....
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......
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.........
Figure 7. Beam film of regional nodal irradiation which includes the internal mammary, supraclavicular, and axillary nodes.
.';
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....... _~~~~~~~~~~~~~~~~~~~~~~~~~~. ....: ..
entire spine initially, the whole spine should be treated, unless the patient is severely anemic, in which case the symptomatic areas alone can be treated first. Clinically and radiologically, brain metastasis may appear solitary. However, autopsy studies by Richards and McKissockt9 showed that more than 80 percent of the metastatic lesions were multicentric. When the brain is irradiated segmentally, the matching of fields during subsequent local irradiation is more complex than in segmental irradiation of the spine because the matching of the fields is three dimensional in the brain and two dimensional in the spine. For these reasons, total brain irradiation should be done for metastatic brain disease. If there is evidence of increased intracranial pressure at initiation of total brain irradiation, medical decompression should be achieved prior to irradiation to prevent aggravation of symptoms from radiation brain edema.
Ablative McWhirter 20 reported a series of 790
275 operable breast cancer patients treated by simple mastectomy, post-op radiotherapy, and ovarian irradiation. In another series, 492 patients were treated similarly but prophylactic ovarian irradiation was not given.20 The end results in both groups were identical. Kennedy et al,2 1 after a retrospective study of 296 patients who had prophylactic or therapeutic castration, concluded that prophylactic castration tended to lengthen the disease-free interval from mastectomy to metastasis and therapeutic castration prolonged the interval from metastasis to death. But the overall survival time from initial breast cancer therapy to death was not significantly different in the two groups. It is clear that regardless of the type of endocrine therapy employed, objective tumor regression occurs in only 20 to 40 percent of breast cancer patients. These patients can be identified by performing estrogen receptor studies. Cytoplasmic estrogen receptor (ER) is found in approximately 60 to 70 percent of breast tumors. If ER is absent, the chance of a patient responding to endocrine therapy is less
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
Figure 8. Interstitial removable afterloading implant following external radiotherapy to boost the dose to the tumor which was not removed. (Diagnosed by needle biopsy)
Figure 9. Same patient shown in Figure 8 after completion of external and interstitial irradiation. The treated right breast is slightly pigmented and smaller than the normal left breast.
than 10 percent, but if it is present, a 60 percent response rate is usually found. It is also evident that progesterone receptor (PgR) can be readily measured in human breast tumors and there is clear evidence, in experimental breast tumor model systems, that PgR is under acute estrogen control. PgR is rarely found in ER negative breast tumor but is present in approximately 65 percent of ER positive breast tumors. Preliminary clinical studies show that the response rate is significantly higher if the tumor contains both ER and PgR than if the tumor contains ER alone. With the present knowledge of breast cancer responsiveness to endo-
crine therapy and availability of assays which can determine those breast cancer patients who will or will not respond to endocrine therapy, ovarian ablation is used mostly as a therapeutic, rather than a prophylactic tool. Therapeutic castration can be performed either surgically or by ovarian irradiation, with ovarian irradiation results being perhaps more variable and less striking than those performed by ovarian ablation. Urinary hormone assays and vaginal cytograms indicate that adequate ovarian irradiation is equal to surgical castration in decreasing measurable estrogenic activity. Therefore, ovarian irradiation for therapeutic castration is an effective al-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
ternative to exterpative ovarian surgery. A minimum of 1200-rad ovary dosage in four days or 2200-rad ovary dosage in two weeks is given through fields adequate to encompass the entire true pelvis. Percentage-wise, the overall response to castration is the same in patients castrated with irradiation as in those castrated by surgery. However, the advantages of surgical castration are: (1) During surgical castration one can directly examine the abdominal viscera for metastatic disease. (2) There is no chance of missing the ovaries. This can happen with irradiation due to an abnormal anatomical location which leads to inadequate dose or geographical miss. 791
(3) The response of the disease is earlier to surgical than to radiation castration.
Definitive In no other field of medicine is there as much controversy as the treatment of breast cancer. In spite of 90,000 new cases per year and more than 30,000 cases dying from it, no one method of treatment has been determined to be significantly superior to the other. So the debate on which is the best way of treating cancer of the breast has itself become cancerous. The first systematic attempt to treat operable cases of mammary cancer by interstitial radium and teleradium was made by Geoffrey Keynes at St. Bartholomew's Hospital in 1924.22 He developed the interstitial method of radium treatment and multiple field teleradium treatment. He used it either alone or in combination with conservative surgery, and obtained results which entirely justified the adoption of these methods. Keynes advocated and practiced local removal of the tumor or simple mastectomy, prior to interstitial or external beam therapy except in selected cases where surgery is contrairndicated. However, radiotherapy did not become popular as the primary modality of treatment of breast cancer because of the high exposure problems while working with the radium needles and the high incidence of skin reactions while using the orthovoltage equipment without skin sparing advantage. These two technical problems do not exist today with the afterloading interstitial implantation techniques and supervoltage teletherapy equipment. With these two technical barriers removed, one has to ask the question, can radiation alone effectively eradicate cancer in the breast as well as in the regional nodes? In the supervoltage era it has been repeatedly shown that simple mastectomy, followed by post-op radiotherapy,5 lumpectomy followed by post-op radiotherapy,23 and radiotherapy alone after needle biopsy6 are effective in treating early breast cancer. 792
With present data if one comes to the conclusion that radiotherapy can be used as effectively as radical surgery in treating early breast cancer, the question remains whether it should be used alone or in combination with conservative surgery. Radiobiological studies show that the larger the number of cells the higher the dose required to achieve total cell kill. In other words, the smaller the number of tumor cells the higher the chance to achieve total cell kill with a given dose. So it is clear that debulking is necessary to achieve good tumor control with radiotherapy. The type of debulking, lumpectomy or simple mastectomy, should be decided on an individual basis. Effective external irradiation to the whole breast following lumpectomy (Figure 5) or to the chest wall following simple mastectomy (Figure 6) and the regional lymph nodes (Figure 7), can be given without morbidity with modern equipment. If conservative surgical procedures are contraindicated, the external beam dose to the tumor can be boosted with an afterloading interstitial implant (Figure 8). There is less anatomical and psychological trauma to the patient (Figure 9) after radical radiotherapy combined with conservative surgery, especially in lumpectomy.
Summary Locoregional recurrence after radical mastectomy increases morbidity and mortality and causes tremendous psychological trauma. Adjuvant radio-
therapy markedly reduces locoregional recurrence with no increased morbidity or mortality. Radiotherapy plays a major role in the palliation of locally advanced breast cancer as well as distant metastatic disease, especially in the bones and brain. Radiotherapy is an effective alternative method of castration in patients with estrogen receptors, even though the response is slow. Present clinical data indicate that early breast cancer can be cured with effective external irradiation alone or
in combination with conservative surgery and/or interstitial irradiation.
Literature Cited 1. Halsted WS: The results of radical operation for the cure of cancer of the breast. Ann Surg 46!80, 1907 2. McWhirter B: Cancer of the breast. Am J Roentgenol Radium Ther Nucl Med 62:335, 1949 3. Cutler SJ, Myers MH, Green SB: Trends in survival rates of patients with cancer. N Engl J Med 293:122-124, 1975 4. Haagensen CD: Diseases of the breast, ed 2. Philadelphia, WB Saunders Co, 1971, p 380 5. Forrest AP, Roberts MM, Cant E, et al: Simple mastectQmy and pectoral node biopsy. Br J Surg 63:569-575, 1976 6. Levene MB, Harris JR, Hellman S: Treatment of carcinoma of the breast by radiation therapy. Cancer 39:2840-2845, 1977 7. Adair F, Berg J, Joubert L, et al: Long-term follow-lJp of breast cancer patients: The 30 year report. Cancer 33:1145-1150, 1974 8. Fisher B, Slack NH, Cavanaugh PJ, et al: Postoperative radiotherapy in the treatment of breast cancer. Ann Surg
172:711-720, 1970 9. Esson EC: Post operative radiotherapy in breast cancer. In Forest AP, Kunkler PB (eds): Prognostic factors in breast cancer. London, E.S. Livingstone, Ltd, 1968, p 118 10. Stjernsward J: Decreased survivals related to irradiation postoperatively in early operable breast cancer. Lancet
2:1285-1286, 1974 11. Chu FC, Lin FJ, Kim JH, et al: Locally recurrent carcinoma of the breast. Cancer 37:2677-2681, 1976 12. De Schryver A: The Stockholm breast cancer trial: Preliminary report on a randomized study concerning the value of preoperative or postoperative radiotherapy in operable disease. IntJ Radiat Biol 1:601, 1976 13. Bloom HJ, Richardson WW, Harnes EJ: Natural history of untreated breast cancer (1805-1933). Br Med J 2:213-221, 1962 14. Greenwood M: Report on the natural duration of cancer. Report on Public Health and Medical Subjects. 33, London Ministry of Health, 1926 15. Mathanson IT, Welch CE: Life expectancy and incidence of malignant disease: Carcinoma of the breast. Am J Cancer 28:40-53, 1936 16. Meissner NA, Warren S: Sites of metastases at autopsy. In Anderson WA (ed): Pathology, vol 1. St. Louis, CV Mosby Co, 1971 p 538 17. Staley CJ: Skeletal metastases in cancer of the breast. Surg Gynecol Obstet 102:683-688, 1956 18. Eisen HM, Bosworth JL, Ghossein MA: The rationale of whole spine irradiation in metastatic breast cancer. Radiology 108:417-418, 1973 19. Richards P, McKissock W: Intracranial metastases. Br Med J 1:15-18, 1963 20. McWhirter R: Some factors influencing prognosis in breast cancer. Clin Radiol 8:220-234, 1957 21. Kennedy BJ, Mielke PW, Fortuny IE: Therapeutic castration versus prophylactic castration in breast cancer. Surg Gynecol Obstet 118:524-540, 1964 22. Keynes G: Radiation treatrnent of primary carcinoma of the breast. Lancet 2:108-111, 1928 23. Rissanen PM: A comparison of conservative aned radical surgery combined with radiotherapy in the treatment of Stage carcinoma of the breast: Br I Radiol 42: 423-426, 1969
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
There is no subject as controversial as the treatment of early breast cancer in spite of 90,000 new cases per year and more than 30,000 deaths per year in the USA alone. Radical mastectomy has been in practice for over 80 years. Radiotherapy, alone, was used 50 years ago. Today, however, we are unable to state which is the method of choice in the management of early breast cancer. Radiotherapy did not become popular as the primary treatment modality during the radium and orthovoltage era because of technical problems. These technical problems have been overcome during the afterloading and supervoltage era. Unfortunately, we do not have a large series in radiotherapy to compare with those of 80 years of radical mastectomies. Until such time, radiotherapy will play an adjuvant and palliative role in the management of breast cancer patients. Breast cancer was known and treated surgically in ancient Greece and Rome. Velpeau (1795-1867),Professor of Clinical Surgery at the Paris Faculty, wrote his great treatise on Diseases of the Breast in 1854. Halsted (1852-1922), Professor of Surgery at Johns Hopkins, introduced radical mastectomy for breast cancer in 1889, based on the knowledge of the lymphatic drainage of the breast.1 After it became evident that long-term survivals were not improved by radical, loco-regional surgery, except in patients with little or no regional node involvement, McWhirter, in 1945, introduced simple mastectomy, followed by radiotherapy to the regional nodes.2 Since then, hundreds of papers were published and volumes of books written on various aspects of breast cancer. The end result is that the age-adjusted death rate of women with breast cancer has not improved appreciably over the last 20 years.3 This is based on the following premise.
Requests for reprints should be addressed to Dr. P. P. Kumar, Department of Radiotherapy, Howard University Hospital, Washington, D.C. 20060.
If the time required for a tumor to double its diameter during a known period of time is taken as a measure of growth rate, one can calculate by extrapolation that for two-thirds of its duration, breast cancer remains undetectable by the patient or physician. Long before a breast cancer can be detected clinically, metastatic spread may occur, as it does in most cases. It is clearly shown by Haagenson4 that the survival rates drastically fall as the upper groups of axillary nodes are involved, despite radical surgery. So, what we achieve by doing radical surgery in breast cancer seems to be better surgical staging rather than actual improvement in survival rates. As long as the tumor is confined to the breast and is small, it can be totally irradicated by other methods and radical surgery does not seem to be necessary. Therefore, the key to improving survival rates in breast cancer patients is to detect the disease before its regional or distant spread, that is, in its early local stage. To achieve this we need harmless, highly accurate diagnostic techniques which can be made easily available to the entire female population. Until then, how we should
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
treat this disease is the problem. It is becoming more evident that high cure rates in early breast cancer can be achieved by combining conservative surgery and radiotherapy5 or by radiotherapy alone.6 But, before these methods can replace standard radical breast surgery, which has been in practice for more than 80 years, we need more clinical trials and experience. Until this is achieved, radical surgery will continue to exist and radiotherapy will play an adjuvant role in the treatment of early breast cancer. The role of radiotherapy, in the treatment of breast cancer, can be divided into (1) as an adjuvant to surgery; (2) for palliation in advanced cancer; (3) for ovarian ablation in advanced breast cancer; and (4) as the primary method of treatment of early breast cancer.
Adjuvant Long-term follow-up of breast cancer patients following radical mastectomy clearly shows that (1) more than 50 percent die ultimately of distant disease7 but not from locoregional recurrence and (2) that adjuvant locoregional radiotherapy following radical mastectomy does not alter their survival rates.8 However, locoregional recurrence following radical mastectomy increases morbidity and causes tremendous psychological trauma to patients who were previously traumatized by the radical surgery. The incidence of locoregional recurrence, with and without axillary node involvement following radical surgery alone and radical surgery plus locoregional irradiation, shows a significant reduction in the locoregional recurrence rate when irradiation is used as an adjuvant to radical surgery.9 This drop in locoregional recurrence justi787
fies the use of adjuvant post-operative irradiation in the treatment of breast cancer despite insignificant sporadic reports that state that adjuvant radiotherapy treatment suppresses the host immunity and increases the frequency of distant metastasis and mortality.10 The most frequent site of locoregional recurrence is in the chest wall, where two types occur. (1) Locally
..
,
....a
_
widespread disease (Figure 1). This type usually appears within one year following the radical surgery, is fulminating, and response to radiotherapy is poor. Though many believe that locoregional recurrence does not alter survival, it is my observation that patients who develop this type of disease within one year after radical surgery have a very poor prognosis in
7.
r
Figure 1. Extensive local
/
recurrence one year after radical mastectomy alone for
11 disease. Patient did not respond to local irradiation and died in six months.
Stage
addition to severe morbidity. (2) The second type is a solitary nodule that usually occurs within the scar and appears many years after surgery (Figure 2). These lesions respond very well to local radiotherapy11 and patients continue to maintain good health for many years. This type does not alter survival, and causes little morbidity. It does not increase mortality. However, these patients who have overcome the psychological trauma of the disease will be subjected to similar trauma again. The sites of regional recurrence are the supraclavicular nodes and parasternal regions (internal mammary nodes).1 2 A review of pathology reports in many radical mastectomy specimens shows that the number of axillary lymph nodes removed varies widely. Therefore, in some cases the axilla (axillary nodes) is a potential site for regional recurrence. The growth of occult disease in these regional nodes causes local enlargement and pain from pressure on the brachial plexus by the supraclavicular nodes and by direct bone erosion when the internal mammary nodes are involved. This responds to irradiation and patients have good relief of pain.1 1 Studies show that locoregional recurrence does not alter the survival rates in breast cancer patients.8 If a patient does not have distant spread at the time of surgery and subsequently develops locoregional disease, the disease can spread to distant organs from these sites. Radiobiological studies also show that the smaller the number of cells, the less the dose needed to achieve total cell kill. Therefore, it is much easier to eradicate microscopic disease than macroscopic disease with a given dose. These clinical, biological, and logical observations clearly indicate that prophylactic adjuvant, locoregional irradiation, is of immense value in the treatment of operable breast cancer.
ot.,¢. . Ck,1|f!i1~, ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~...~.. ~ *~~~~~
~ ~~~~~~
...s....
Figure 2. Local recurrence in the mastectomy scar seven years following radical mastectomy alone for Stage disease. The recurrent tumor responded well to interstitial irradiation. The patient is alive and free of disease.
788
Palliative The palliative role of radiotherapy in advanced carcinoma of the breast is of two types: (1) palliation of locally advanced cancer, and (2) palliation of widespread cancer. Evaluation of the management of breast cancer is made
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
Figure 3. Locally advanced breast cancer with extensive ulceration and foul smelling discharge.
Figure 4. The lesion shown in Figure 3 after external irradiation, showing complete healing of the ulcer.
elusive by the natural history of the disease. This is the only malignant disease about which there are welldocumented data on long survivals in untreated patients. 1 3 -1 5 More than 20 percent of untreated breast cancer patients survive for five years with either advanced local or widespread disease. Therefore, it is important to achieve good palliation in these patients and keep them comfortable. One might think that with all the public education we have, it is not possible to see patients with locally advanced breast cancer. On the contrary, because of the enormous number of women developing breast cancer and the hesitancy of some women to see a doctor when they notice a lump in their breast, we still see patients with locally advanced disease. (Figure 3). The major problem in locally advanced
breast cancer is ulceration and foul smelling serosanguineous discharge. (Figure 3). These lesions cannot be operated on because of wide area of involvement. Local irradiation of these lesions is the only available method of treatment which gives gratifying results (Figure 4). More than 50 percent of breast cancer patients ultimately die of distant metastases, after definitive treatment of the primary.7 The leading sites of metastases are1 6 the distant lymph nodes 64 percent, lung 57 percent, red bone marrow 55 percent, liver 51 percent, bone 49 percent, adrenals 34 percent, and brain 10 percent. The pattern of dissemination is predominantly hematogenous. Most gratifying responses are seen when the bone and brain metastatic lesions are irradiated. The subjective response is
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
almost 100 percent in both these areas. According to Staley,l 7 39 to 53 percent of all skeletal metastases from carcinoma of the breast are located in the spine. Therefore, Eisen et all 8 suggested that the entire spine should be treated, even if these is evidence of only local involvement of the spine. This is to avoid overlapping of fields and possible transverse myelitis when other areas of the spine need irradiation subsequently. I do not feel that this is necessary because (1) most breast cancer patients with bone disease will be anemic and total spine irradiation further aggravates the anemia; (2) most patients are now given chemotherapy which is also myelosuppressive; and (3) in good radiotherapy departments matching of the spinal fields should not be a problem. However, if there is involvement of the 789
...................t.' '1'..:.
..
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_
_~~~~~~~~~~~~~~~~~~~....
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..
......
.:V
'':.....
.........
Figure 7. Beam film of regional nodal irradiation which includes the internal mammary, supraclavicular, and axillary nodes.
.';
.. .s..t ....... ............... ........
_ ,,, z,, >r r ,~~~~~~~~~~~~~........'2....:..
....... _~~~~~~~~~~~~~~~~~~~~~~~~~~. ....: ..
entire spine initially, the whole spine should be treated, unless the patient is severely anemic, in which case the symptomatic areas alone can be treated first. Clinically and radiologically, brain metastasis may appear solitary. However, autopsy studies by Richards and McKissockt9 showed that more than 80 percent of the metastatic lesions were multicentric. When the brain is irradiated segmentally, the matching of fields during subsequent local irradiation is more complex than in segmental irradiation of the spine because the matching of the fields is three dimensional in the brain and two dimensional in the spine. For these reasons, total brain irradiation should be done for metastatic brain disease. If there is evidence of increased intracranial pressure at initiation of total brain irradiation, medical decompression should be achieved prior to irradiation to prevent aggravation of symptoms from radiation brain edema.
Ablative McWhirter 20 reported a series of 790
275 operable breast cancer patients treated by simple mastectomy, post-op radiotherapy, and ovarian irradiation. In another series, 492 patients were treated similarly but prophylactic ovarian irradiation was not given.20 The end results in both groups were identical. Kennedy et al,2 1 after a retrospective study of 296 patients who had prophylactic or therapeutic castration, concluded that prophylactic castration tended to lengthen the disease-free interval from mastectomy to metastasis and therapeutic castration prolonged the interval from metastasis to death. But the overall survival time from initial breast cancer therapy to death was not significantly different in the two groups. It is clear that regardless of the type of endocrine therapy employed, objective tumor regression occurs in only 20 to 40 percent of breast cancer patients. These patients can be identified by performing estrogen receptor studies. Cytoplasmic estrogen receptor (ER) is found in approximately 60 to 70 percent of breast tumors. If ER is absent, the chance of a patient responding to endocrine therapy is less
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
Figure 8. Interstitial removable afterloading implant following external radiotherapy to boost the dose to the tumor which was not removed. (Diagnosed by needle biopsy)
Figure 9. Same patient shown in Figure 8 after completion of external and interstitial irradiation. The treated right breast is slightly pigmented and smaller than the normal left breast.
than 10 percent, but if it is present, a 60 percent response rate is usually found. It is also evident that progesterone receptor (PgR) can be readily measured in human breast tumors and there is clear evidence, in experimental breast tumor model systems, that PgR is under acute estrogen control. PgR is rarely found in ER negative breast tumor but is present in approximately 65 percent of ER positive breast tumors. Preliminary clinical studies show that the response rate is significantly higher if the tumor contains both ER and PgR than if the tumor contains ER alone. With the present knowledge of breast cancer responsiveness to endo-
crine therapy and availability of assays which can determine those breast cancer patients who will or will not respond to endocrine therapy, ovarian ablation is used mostly as a therapeutic, rather than a prophylactic tool. Therapeutic castration can be performed either surgically or by ovarian irradiation, with ovarian irradiation results being perhaps more variable and less striking than those performed by ovarian ablation. Urinary hormone assays and vaginal cytograms indicate that adequate ovarian irradiation is equal to surgical castration in decreasing measurable estrogenic activity. Therefore, ovarian irradiation for therapeutic castration is an effective al-
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 69, NO. 11, 1977
ternative to exterpative ovarian surgery. A minimum of 1200-rad ovary dosage in four days or 2200-rad ovary dosage in two weeks is given through fields adequate to encompass the entire true pelvis. Percentage-wise, the overall response to castration is the same in patients castrated with irradiation as in those castrated by surgery. However, the advantages of surgical castration are: (1) During surgical castration one can directly examine the abdominal viscera for metastatic disease. (2) There is no chance of missing the ovaries. This can happen with irradiation due to an abnormal anatomical location which leads to inadequate dose or geographical miss. 791
(3) The response of the disease is earlier to surgical than to radiation castration.
Definitive In no other field of medicine is there as much controversy as the treatment of breast cancer. In spite of 90,000 new cases per year and more than 30,000 cases dying from it, no one method of treatment has been determined to be significantly superior to the other. So the debate on which is the best way of treating cancer of the breast has itself become cancerous. The first systematic attempt to treat operable cases of mammary cancer by interstitial radium and teleradium was made by Geoffrey Keynes at St. Bartholomew's Hospital in 1924.22 He developed the interstitial method of radium treatment and multiple field teleradium treatment. He used it either alone or in combination with conservative surgery, and obtained results which entirely justified the adoption of these methods. Keynes advocated and practiced local removal of the tumor or simple mastectomy, prior to interstitial or external beam therapy except in selected cases where surgery is contrairndicated. However, radiotherapy did not become popular as the primary modality of treatment of breast cancer because of the high exposure problems while working with the radium needles and the high incidence of skin reactions while using the orthovoltage equipment without skin sparing advantage. These two technical problems do not exist today with the afterloading interstitial implantation techniques and supervoltage teletherapy equipment. With these two technical barriers removed, one has to ask the question, can radiation alone effectively eradicate cancer in the breast as well as in the regional nodes? In the supervoltage era it has been repeatedly shown that simple mastectomy, followed by post-op radiotherapy,5 lumpectomy followed by post-op radiotherapy,23 and radiotherapy alone after needle biopsy6 are effective in treating early breast cancer. 792
With present data if one comes to the conclusion that radiotherapy can be used as effectively as radical surgery in treating early breast cancer, the question remains whether it should be used alone or in combination with conservative surgery. Radiobiological studies show that the larger the number of cells the higher the dose required to achieve total cell kill. In other words, the smaller the number of tumor cells the higher the chance to achieve total cell kill with a given dose. So it is clear that debulking is necessary to achieve good tumor control with radiotherapy. The type of debulking, lumpectomy or simple mastectomy, should be decided on an individual basis. Effective external irradiation to the whole breast following lumpectomy (Figure 5) or to the chest wall following simple mastectomy (Figure 6) and the regional lymph nodes (Figure 7), can be given without morbidity with modern equipment. If conservative surgical procedures are contraindicated, the external beam dose to the tumor can be boosted with an afterloading interstitial implant (Figure 8). There is less anatomical and psychological trauma to the patient (Figure 9) after radical radiotherapy combined with conservative surgery, especially in lumpectomy.
Summary Locoregional recurrence after radical mastectomy increases morbidity and mortality and causes tremendous psychological trauma. Adjuvant radio-
therapy markedly reduces locoregional recurrence with no increased morbidity or mortality. Radiotherapy plays a major role in the palliation of locally advanced breast cancer as well as distant metastatic disease, especially in the bones and brain. Radiotherapy is an effective alternative method of castration in patients with estrogen receptors, even though the response is slow. Present clinical data indicate that early breast cancer can be cured with effective external irradiation alone or
in combination with conservative surgery and/or interstitial irradiation.
Literature Cited 1. Halsted WS: The results of radical operation for the cure of cancer of the breast. Ann Surg 46!80, 1907 2. McWhirter B: Cancer of the breast. Am J Roentgenol Radium Ther Nucl Med 62:335, 1949 3. Cutler SJ, Myers MH, Green SB: Trends in survival rates of patients with cancer. N Engl J Med 293:122-124, 1975 4. Haagensen CD: Diseases of the breast, ed 2. Philadelphia, WB Saunders Co, 1971, p 380 5. Forrest AP, Roberts MM, Cant E, et al: Simple mastectQmy and pectoral node biopsy. Br J Surg 63:569-575, 1976 6. Levene MB, Harris JR, Hellman S: Treatment of carcinoma of the breast by radiation therapy. Cancer 39:2840-2845, 1977 7. Adair F, Berg J, Joubert L, et al: Long-term follow-lJp of breast cancer patients: The 30 year report. Cancer 33:1145-1150, 1974 8. Fisher B, Slack NH, Cavanaugh PJ, et al: Postoperative radiotherapy in the treatment of breast cancer. Ann Surg
172:711-720, 1970 9. Esson EC: Post operative radiotherapy in breast cancer. In Forest AP, Kunkler PB (eds): Prognostic factors in breast cancer. London, E.S. Livingstone, Ltd, 1968, p 118 10. Stjernsward J: Decreased survivals related to irradiation postoperatively in early operable breast cancer. Lancet
2:1285-1286, 1974 11. Chu FC, Lin FJ, Kim JH, et al: Locally recurrent carcinoma of the breast. Cancer 37:2677-2681, 1976 12. De Schryver A: The Stockholm breast cancer trial: Preliminary report on a randomized study concerning the value of preoperative or postoperative radiotherapy in operable disease. IntJ Radiat Biol 1:601, 1976 13. Bloom HJ, Richardson WW, Harnes EJ: Natural history of untreated breast cancer (1805-1933). Br Med J 2:213-221, 1962 14. Greenwood M: Report on the natural duration of cancer. Report on Public Health and Medical Subjects. 33, London Ministry of Health, 1926 15. Mathanson IT, Welch CE: Life expectancy and incidence of malignant disease: Carcinoma of the breast. Am J Cancer 28:40-53, 1936 16. Meissner NA, Warren S: Sites of metastases at autopsy. In Anderson WA (ed): Pathology, vol 1. St. Louis, CV Mosby Co, 1971 p 538 17. Staley CJ: Skeletal metastases in cancer of the breast. Surg Gynecol Obstet 102:683-688, 1956 18. Eisen HM, Bosworth JL, Ghossein MA: The rationale of whole spine irradiation in metastatic breast cancer. Radiology 108:417-418, 1973 19. Richards P, McKissock W: Intracranial metastases. Br Med J 1:15-18, 1963 20. McWhirter R: Some factors influencing prognosis in breast cancer. Clin Radiol 8:220-234, 1957 21. Kennedy BJ, Mielke PW, Fortuny IE: Therapeutic castration versus prophylactic castration in breast cancer. Surg Gynecol Obstet 118:524-540, 1964 22. Keynes G: Radiation treatrnent of primary carcinoma of the breast. Lancet 2:108-111, 1928 23. Rissanen PM: A comparison of conservative aned radical surgery combined with radiotherapy in the treatment of Stage carcinoma of the breast: Br I Radiol 42: 423-426, 1969
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