Acta Oncologica ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: https://www.tandfonline.com/loi/ionc20 Breast Cancer Lars Erik Rutqvist To cite this article: Lars Erik Rutqvist (1996) Breast Cancer, Acta Oncologica, 35:sup7, 54-63, DOI: 10.3109/02841869609101663 To link to this article: https://doi.org/10.3109/02841869609101663 Published online: 08 Jul 2009. Submit your article to this journal Article views: 98 View related articles Citing articles: 4 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ionc20 zyxwvu Section 6 zyxwvutsrq zyxwvu zyxwvuts BREAST CANCER Summary and Conclusions This synthesis of the literature on radiotherapy for breast cancer is based on 97 scientific articles, including 5 meta-analyses, 38 randomized studies, and 27 retrospective studies. These studies involve 387 634 patients. - - - - Radiotherapy is the most effective method for preventing locoregional recurrence following primary surgery for invasive breast cancer, and radiotherapy is currently more effective than adjuvant chemotherapy after either mastectomy or breast-conserving surgery (1, 2). Radiotherapy in patients at high risk for locoregional recurrence, eg, patients with spread to the axillary lymph nodes, leads to a significant increase in relapsefree survival (eg, 1, 3). Meta-analyses have shown that radiotherapy in these subgroups of patients can reduce the risk for distant metastasis and reduce the risk for cancer death (4, 5). These analyses have not statistically confirmed an improvement in total survival, probably because reduced mortality from breast cancer has been offset by increased mortality from cardiovascular disease. However, the results have successively improved, and survival gains are significantly greater in recent studies using modern treatment methods ( 5 ) . It is probable that survival gains from radiotherapy do not exceed those that can be achieved by other adjuvant treatment of breast cancer such as chemotherapy or hormones, ie, a reduction in mortality by 20% to 30%, leading to an increased total survival after, eg, 10 years of 5% to 10% (4, 6). The heart is the most important organ at risk during radiotherapy for breast cancer. Minimizing radiation doses to the heart muscle and the coronary arteries is necessary for avoiding later effects of ischemic cardiovascular disease. These side effects were particularly prominent in early treatment studies that used older radiotherapy methods (7-9). Radiotherapy in conjunction with breast-conserving surgery for invasive breast cancer significantly reduces the recurrence frequency in the breast (10- 13). Clinical studies are under way that aim at further defining the role of radiotherapy as an element in a breast-conserving treatment strategy, eg, determining the value of boost, and identifying prognostic/predictive factors for breast recurrence. Improved knowledge about such fac- 54 tors should eventually permit identification of patient groups at such low risk for breast recurrence that routine radiotherapy is unnecessary, or at such high risk-even with radiotherapy-that alternatives to breast conserving surgery should be considered. - Radiotherapy also reduces the risk for recurrence in the breast following breast-conserving surgery of DCIS (14). Controlled trials are under way that aim at more closely defining the roles of surgical methods and radiotherapy for various subgroups of patients, eg, regarding different histopathologic types of DCIS. - Radiotherapy has a substantial palliative value to patients who cannot be cured. It can reduce, prevent, or delay unpleasant symptoms from advanced disease, eg, pain, cancer lesions, fractures, neurologic symptoms, etc (15-21). Introduction zyxw zyxwv In Sweden, as in most Western countries, breast cancer is the most common cancer type. Sweden reported 5 264 new cases of breast cancer in 1992, corresponding to 13.2% of all cancer cases and 26.670 of all cancers in females. Breast cancer may also affect males, although the percentage is low, approximately 0.5%. The median age of patients with newly diagnosed breast cancer was 60 through 64 years (11). In 1992, 1 530 deaths from breast cancer were reported (111). Histologically, breast cancer is comprised mainly of epithelial tumors originating in tissue of the mammary gland. A small percentage ( < 1% to 2%) consists of soft tissue tumors in the connective tissue of the breast, eg, cystosarcoma phylloides, malignant non-Hodgkin’s lymphoma, or skin tumors (squamous cell carcinoma, malignant melanoma). This literature review is limited to primary tumors of the mammary gland in women. Several histopathologic classification systems exist for breast cancer. From a clinical perspective it is important to distinguish invasive breast cancers from the non-invasive types (cancer in situ). Non-invasive breast cancer is usually classified as ductal (DCIS) or lobular (LCIS) carcinoma in situ (22-27). DCIS is most frequently detected by mammography since it causes radiologically detectable changes such as microcalcifications. Retrospective studies have estimated the risk zy zy zyxwvuts zyxwvutsr 55 for local recurrence in the breast following breast conserving surgery of DCIS at 40% to 50% after 5 t o 10 years of followup (22-27). The frequency of lymph node metastases and/or distant metastases is low for both LClS and DCIS, less than 1% to 2%, and nearly all treated patients are cured. Among the invasive breast cancers, a minor proportion can be identified as having particular histopathological characteristics, eg, medullary, lobular, mucinous, papillary, or tubular cancer. Most of the invasive cancers are ductal carcinomas. The histopathological classification of invasive breast cancer and the grade of tumor differentiation may carry some prognostic importance, although other factors such as clinical or histopathological staging are more important (28). N o clinical data suggest that the sensitivity of radiotherapy varies by histopathological classification. Studies addressing the value of radiotherapy usually have not specified the results by group. Staging, prognostic factors. Clinical judgment concerning local tumor involvement is unreliable, and therefore it is becoming increasingly common to base staging on histopathological examination (pTNM) I (XI). Breast canccr is categorized, often in detail, by the number of lymph node metastases involved and tumor size since axillary status and tumor size are both important, independent prognostic factors. As prognostic factors, the histopathologic classification and the degree of tumor differentiation are less meaningful than staging (28). Numerous presumptive, prognostic factors relating to breast cancer have been studied in recent years. The main search has focused on factors that can separate patients without lymph node metastases into those who are at high-risk versus low-risk for relapse (29-31). A more active treatment approach appears to be motivated in high-risk patients. Currently, there is no consensus concerning which factors can best differentiate high- and low-risk patients in this group. Survival. In patients diagnosed during the 1980s. total survival a t 5 years and 10 years was approximately 70% and 50% respectively. If these figures are adjusted for the expected, “normal” mortality, then survival ( ie, relative survival) would be 80‘%,and 70% respectively ( X X ) . Breast cancer differs from many other cancers by virtue of the late recurrence of disease. ie. after 10 to 15 years. However, most relapse occurs within the first 5 to 10 years following primary diagnosis (32). Previously, age was considered an important prognostic factor. Young patients were thought to have biologically more aggressive tumors and thereby poorer survival than older patients. This traditional view is. however, erroneous. The prognosis is similar in both younger and older patients (28-31). Since the expected survival of younger patients is longer, late recurrence is a greater problem in these patients than in older patients. zyxwvutsrq zyxwvutsrqp Treatment, General Radiotherapy, like surgery. is a local treatment method. The purpose of curative treatment is to achieve local control of the disease and thereby improve relapse-free survival. However, the usual cause of death from breast cancer is not uncontrolled local disease, but distant metastasis. Whether o r not greater local control reduces the frequency of distant metastases. and thereby lowers the mortality risk from the disease, is disputed (33-35). Traditionally, surgery has been the basic treatment for breast cancer in Sweden. Radiotherapy is most effective against small tumors. Higher doses are required for local tumor control of palpable tumors compared to subclinical disease (36-39). Therefore, radiotherapy for breast cancer is usually combined with surgical excision of the local tumor, Combined treatment of this type has driven the past decade’s trend toward greater use of breast conserving surgery. zyxwvutsrqp zyxwvutsrqpo ‘ TNM class~ficutionof breast cancer: clinical staging T primary tumor Tis Cancer in situ TI Tumor < 2 cm, with fixation to T2 Tumor > 2 cm, T 3 Tumor > S cm, T4 Tumor fixed to a =without and b = muscle or muscle fascia < S cm, a and b at TI a and b at TI chest wall o r skin N regional lymph nodes NO No palpable axillary lymph nodes NI Palpable movable axillary lymph nodes N? Axillary lymph nodes fixed to one another o r other structures N3 Lymh nodes supra- o r infraclavivular M distant metastasis MO No distant metastasis MI Distant metastasis T N M classi~carionof’breast cuncer: histoputliologic srcrgin~(p T N M ) T Primary tumor Tis Cancer in situ TI Tumor < 2 cm, a =without and b = with fixation to muscle or muscle fascia. Further catagorized: i ~ 0 . cm. 5 ii >0.5 cm < 1 cm, and iii > 1 cm < 2 cm. T 2 Tumor > 2 cm, < 5 cm, a and b as TI T3 Tumor > 5 cm, a and b at TI T 4 Tumor fixed to chest wall or skin N NO NI Regional lymph nodes N o axillary lymph node metastasis Axillary lymph node metastasis. a = micrometastasis 1 0 . 2 cm and b = visible metastasis depending on size i - iv. N 2 Axillary lymph nodes lixed to one another or other structures N 3 Lymph nodes supra- or infraclavicular M Distant metastasis MO N o distant metastask MI Distant metastasis zyxwvutsr 56 Surgical treatment consists of either mastectomy (removal of the entire breast), or breast conserving surgery (removal of a smaller portion of the breast). Mastectomy may involve either simple mastectomy (only the breast is removed) or modified radical mastectomy (the entire breast and axillary lymph nodes are removed). Until the 1960s radical mastectomy, involving removal of the pectoralis major muscle, was routinely performed at many centers. In breast conserving surgery, lumpectomy refers to removal of only the tumor and some margin, sector resection represents a somewhat larger intervention, and in quadrant resection approximately one fourth of the breast is removed. Both procedures are associated with removal of axillary lymph nodes. The clinical situations in which curative radiotherapy is mainly used in Sweden include pre-or postoperative radiotherapy in conjunction with mastectomy (due to invasive cancer or excision of locoregional residuals), and treatment following breast conserving surgery (due to invasive or noninvasive cancer). These situations are discussed separately below. In other countries, curative radiotherapy has been used as the only treatment for operable disease, and in addition to simple mastectomy to replace modified radical mastectomy. These indications have not been used to any great extent in Sweden, and consequently will not be discussed further in this overview. Pre- and postoperative radiotherapy for mastectomy Postoperative radiotherapy following mastectomy was the treatment method for breast cancer first studied within the framework of a prospective, controlled clinical trial. The first of the so-called Manchester trials began in 1949 (40). Since then, several randomized studies have been conducted on adjuvant radiotherapy in which the treatment groups differed only in respect to the addition of radiotherapy. From 1949 to 1985, over 20 such studies involving approximately 18 000 patients were initiated ( I , 3, 7, 10-13, 40-61). The exact number of studies is somewhat arbitrary since some studies included several patient and treatment groups (eg, both patients with and without lymph node metastasis, patients treated with different techniques/irradiation qualities, etc) which sometimes were considered as separate studies, but in other contexts were reported as a single, unified study. Early studies used treatment techniques which would be unacceptable today, eg, conventional x-rays (7, 40). Some of the randomization methods were unacceptable according to modern criteria, eg, the Manchester trials assigned treatment alternatives according to birth dates (40). This may have introduced systematic errors (34, 35). The studies initiated in the late 1970s and 1980s consistently used zyx zyxw high-voltage methods and were designed according to modern biostatistical principles. A finding consistent across all studies, even the older trials, is that the frequency of locoregional recurrence is substantially lower in the radiotherapy group (1, 3, 7, 10- 13, 40-61). Modem radiotherapy with high-voltage technology reduces the frequency of locoregional recurrence after mastectomy to approximately one fourth that of surgery alone. Among, eg, patients with lymph node metastasis, the rate of local recurrence falls from between 30% and 40% to less than 5% to 10%. In patients randomized to primary surgery alone, two studies revealed an increased frequency of patients who, after relapse, developed uncontrolled local disease even though relapse treatment often included radiotherapy (41, 42). These studies illustrate the difficulty in achieving lasting local cure in cases of clinically manifest, locoregional recurrence. In most patients, uncontrolled local disease leads to extensive suffering that considerably reduces the quality of life, eg, pain, maloderous cancer lesions, lymphoedema in the arm, etc. Preoperative radiotherapy was compared with postoperative treatment in one study with 960 patients. The study found no difference in locoregional tumor control (I). Survival; relapse-free and total Several studies have demonstrated significantly better relapse-free survival after radiotherapy compared to surgery alone (eg, 3, 41). Most studies have been unable to individually show that radiotherapy has a significant effect on overall survival. Some authors claim this supports the hypothesis that breast cancer is a systemic disease where tumor metastasis prior to the primary diagnosis determines whether or not patients will survive (33). According to this hypothesis, involvement of the regional lymph nodes and locoregional recurrence are only indicators of simultaneous distant metastases of the disease. This hypothesis has been criticized, in part referring to the results from some prospective studies and retrospective data which suggest that patients with locoregional involvement of the disease do not always develop distant metastases (1, 32, 34, 35). One reason why many prospective studies have been unable to demonstrate effects on survival from radiotherapy has been that they include too few patients to achieve adequate statistical power (34, 35). This has stimulated the interest in metaanalyses, three of which were published on studies where the treatment arms differed only with respect to the addition of radiotherapy (4, 5, 62, 63). One objective of metaanalyses is to increase statistical power by basing the analysis on a larger number of patients. One of the metaanalyses was recently updated (5). The first meta-analysis was based on ten studies comprised of all available radiotherapy studies initiated dur- zyxwvutsrqp zyxwvut zyxwvutsrqpo zyxwvutsrqp zyxwv zyxwv ing 1949 through 1975 (63). Approximately 8 000 patients were included. No difference in survival was observed between irradiated and non-irradiated patients during the first 10 to 15 years. After 15 years, a significant increase in mortality was observed in the irradiated group. This result was based mainly on older studies since followup time in the newer studies was limited. An updated analysis found no significant differences in survival among the treatment groups (5). The treatment gains with radiotherapy were significantly better in the later studies. The studies initiated during the 1970s showed a significant reduction in mortality from breast cancer among radiotherapy patients, which offset an increase in cardiovascular mortality that was observed mainly in the older studies. The relative reduction in breast cancer mortality with radiotherapy in studies initiated during the 1970s varied substantially among studies: 6% to 61'1/0. It may be assumed that this variation reflects both random and systematic differences (eg, differences concerning selection of patients and different treatment methods) among the studies. A more detailed analysis of two of these studies. which used high-voltage methods exclusively (Stockholm and Oslo It), observed a significant relationship between the rate of lymph node metastasis and treatment effects (4). The analysis involved 1 185 patients. Improved distantmetastasis-free survival and a trend toward increased total survival were observed in patients with lymph node metastasis, while corresponding treatment gains were not observed in patients without lymph node metastasis. The difficulty in determining the effects of radiotherapy on overall survival stem somewhat from the late effects on the heart muscle caused by treatment in several studies (particularly those which use older treatment techniques). In some analyses, this resulted in an increased overall mortality in subgroups of patients. particularly those with left-side tumors which, for anatomical reasons, received higher doses to the heart than patients with right-side tumors (7-9, 64-66). Studies using modern radiotherapy technology that avoids excessive irradiation dosage have, as mentioned previously, demonstrated a significant reduction in distant metastases and reduced mortality rates from breast cancer (4, 5). Studies that address ihe ilalue of pre- or postoperuiire radiotherapy for eurly ininsice hreusi cuncer M C 1 =High 2 = Moderate 3 = Low - 3*/11 394 813 525 612 183 12/12 424 - * based on original data collected for each individual patient. The literature review shows - - - that radiotherapy substantially reduces the rate of locoregional recurrence following mastectomy ( I , 3, 7. 46-61), that available data from meta-analyses suggest that radiotherapy based on modern technology can reduce the risk of death from the disease (4, 5). that increased total survival has not been documented by available studies. probably because of increased cardiovascular mortality in patients who received radiotherapy with older technology (4. 5. 62). zyxwvutsrqp Radiotherapy and breast conserving surgery for invasive cancer The role of radiotherapy in breast conserving surgery was studied in randomized trials involving approximately 6000 patients (10-13, 67-71). The studies were of two principally different types. Either different methods of modified radical mastectomy were compared with breast conserving surgery (lumpectomy, sector resection, quadrantectomy) plus radiotherapy (67-71), o r the studies compared different types of breast conserving surgery with or without the addition of radiotherapy (10- 13). These studies mainly included patients with limited local tumor involvement (TI. T2, NO). Some studies routinely offered additional systemic adjuvant therapy to patients where histopathological examination revealed axillary lymph node involvement (eg, 10. 13, 71). The results have shown a similar frequency of local recurrence, recurrence-free survival, and overall survival among the groups treated with mastectomy and those treated with breast conserving surgery plus radiotherapy (67-71 ). The four studies which specifically examined the role of radiotherapy all showed a reduced rate of recurrence in the breast in those receiving radiotherapy (10- 13). The rate of breast recurrence in the group receiving surgery alone varied substantially among the studies: 9% to 43% This variation presumably reflects systematic differences in, eg, patient selection, surgical methods, and followup time. The lowest frequency (9%) was observed in a study with a median followup of 3 years where patients received quadrant resection (13). while the highest frequency was ob- zyxwvutsrqpon zyxwvuts Studies that address the value of combining radiothorripj* with surgery for early hreast cuncer 1 =High 2 = Moderate M - C 19/18 793 3*/1 I 394 11/4 321 3 = Low - 612 183 * based on original data collected for each individual patient. zyxwvutsrqp 58 served among lymph-node-positive patients after a median followup time of 8 years in a study with less invasive surgery (lumpectomy) (10). This study found no statistically significant differences in total survival among treatment groups. One study compared radiotherapy of the breast versus adjuvant chemotherapy (2). The rate of recurrence in the breast was substantially lower in the group receiving radiotherapy. Some centers delivered a boost to the breast area from which the tumor originated. Theoretically, such a boost should further reduce the risk for recurrence in the breast (72). The value of adding a boost is being tested within the framework of a European, randomized multicenter trial, but no results have yet been published from a randomized study. An argument against routine radiotherapy in conjunction with breast conserving surgery is that many patients receive unnecessary treatment since recurrence would not develop in the breast even without radiotherapy (1 I). This has focused interest on the factors which precede the risk for recurrence (73-75). No study has yet identified a subgroup of patients in whom the risk for breast recurrence without radiotherapy is low enough ( < 5 % to 10%) to deny prophylactic radiotherapy (10- 13). Recurrence in the breast often leads to mastectomy and sometimes to uncontrolled local disease. I =High 2 = Moderate - - 413 948 - M C 2 = Moderate Studies that address the value of postoperative radiotherapy after breast conserving surgery for DCIS 3 = Low M C Studies that address the value of postoperative radiotherapy afier breast conserving surgery for early invasive breast cancer 1 = High Mastectomy has long been the only accepted treatment for non-invasive breast cancer. This treatment method fully cures the disease in nearly all patients. On the other hand, this treatment alternative probably represents overtreatment since many patients with DCIS have locally limited disease in the breast, where a less invasive surgical procedure may be sufficient (22-27). Since DCIS appears to have a tendency for local recurrence following breast conserving surgery, it has been common to irradiate the breast in an attempt to reduce the relapse rate. Retrospective studies of DCIS patients who were treated with breast conserving surgery with or without radiotherapy suggest a reduced rate of recurrence with radiotherapy (27). Only one randomized study involving 8 18 patients has been published (14). This study observed that after an average followup of 3.5 years the rate of recurrence in the breast had declined significantly (from 21% to 10%) among patients randomized to radiotherapy. The value of radiotherapy for DCIS is being studied in several European randomized trials. Some of these also include a randomized comparison of the treatment value of tamoxifen, an antiestrogen drug. Radiotherapy has not been considered as a relevant primary treatment for patients with LCIS, and therefore no randomized studies have been conducted. zyxwvutsrqp zyxw zyxwvutsrqp zyxwvutsr zyxwvutsr Studies that address the value of postoperatiue radiotherapy after breast conserving surgery for early invasive breast cancer M C Radiotherapy and breast conserving surgery of non-invasive breast cancer 3 = Low - - - 211 603 31796 - The literature review shows that radiotherapy following breast conserving surgery reduces the risk for breast recurrence (10-13); - that a scientific basis is currently lacking for distinguishing patients with a sufficiently low risk for breast recurrence that radiotherapy can be avoided; - that local recurrence following breast conserving surgery often leads to removal of the breast, and sometimes to uncontrolled local disease. 1 = High 2 = Moderate 3 = LOW - - - 11818 - - The literature review shows: - that routine therapy for DCIS has been mastectomy, but that many patients should probably be treated with breast conserving surgery; that one study showed adjuvant radiotherapy following breast conserving surgery for DCIS reduces the local recurrence rate from 21% to 10%; that radiotherapy has no role to play as primary treatment for LCIS. - Radiotherapy methods The target volume for external radiotherapy following breast conserving surgery for stage I invasive breast cancer or DCIS is usually defined as the breast parenchyma itself. Treatment in conjunction with surgery of more locally advanced cancer usually also involves the regional lymph nodes. Due to the irregular three-dimensional scope of the 59 target volume, it is often technically difficult to deliver an equal and adequate dose to the entire target while minimizing the dose t o the surrounding organs at risk (eg, lungs and heart). The need for different radiation qualities (electrons, photons) and different energy levels can, eg. lead to problems along the borders between radiation fields. These circumstances make common radiotherapy one of the more technically complicated and challenging treatments in clinical practice. New techniques for radiotherapy of breast cancer reflect the technical advancements which have occurred in radiotherapy in recent years. The knowledge about the effects of radiotherapy obtained from controlled clinical trials with prolonged followup, obviously addresses the technologies which were available more than 10 to 15 years ago. Since earlier technology has been upgraded-eg, with three-dimensional dose planning-it is clear that the radiotherapy methods used in earlier controlled clinical trials were often inadequate (8, 9). The most common fractionation has been 1.75 to 2.00 G y per day, 5 days per week up to a total dose of 45 to 55 Gy. For radiotherapy following breast conserving surgery, or for local recurrence, a boost has sometimes been delivered to the tumor area up to a total dose of 55 to 65 Gy. also a risk for an increased rate of contralateral breast cancer or other solid tumors following radiotherapy. Studies of the risks for irradiation-induced breast cancer, eg, in atomic bomb survivors or in patients exposed to ionizing radiation of the breast for diagnosis/treatment of benign disease, show that this risk declines markedly the older the woman is when exposed to radiation (87-97). Women who are treated at ages above 40 to 50 years-eg, the ages where breast cancer is most common-have a substantially lower risk than younger women. This situation has presumably contributed to no single clinical study having revealed an increase in the risk for contralateral breast cancer among treated patients. zyxwvutsrq Side effects Utilization trends for different treatments Traditionally, most centers have used surgery with or without radiotherapy as the primary treatment for most patients with operable disease. The use of breast conserving surgery in combination with postoperative radiotherapy is now an established treatment alternative for selected patients ( 10- 13, 67 -7 I ). Due to increased mammography screening and the Favorable results of preoperative (neoadjuvant) chemotherapy, the number of patients in whom breast conserving surgery is appropriate can be expected to increase. It is possible that better knowledge about factors that predict the risk for recurrence in the breast will allow definition of patient groups in whom the risk is so low that radiotherapy is unmotivated. N o randomized studies have yet identified such a group (10- 13). Several large randomized studies have demonstrated that combining systemic medical treatment with chemotherapy and/or antiestrogen therapy ( oophorectomy, tamoxifen) significantly reduces the risk for recurrence, and thereby extends survival (6). Chemotherapy however has shown to be less effective in preventing locoregional recurrence ( I , 2). Radiotherapy continues to be the most effective method. There is an increasing tendency to offer patients combined radiotherapy and systemic treatment (eg, 3, 44). Thus far, no unfavorable interaction has been shown between radiotherapy and endocrine treatment. On the other hand, the biological effects of radiotherapy increase when chemotherapy is delivered simultaneously. Concurrent chemotherapy has, eg, adversely affected cosmetic results following radiotherapy after breast conserving surgery due to an increased fibrosis tendency in the breast (77. 80-83). zyxwvuts zyxwv Radiotherapy for breast cancer can lead to acute and/or late side effects in nearby organs a t risk, eg, the heart, lungs, and brachial plexus (9, 64, 66, 76-78). As mentioned above, earlier studies have shown that excessive radiation doses to the heart led to increased cardiovascular mortality in treated patients, particularly those with leftside tumors (7-9). Besides the high dose volume in the myocardium, it appears that the use of high, single fractions ( > 2.5 Gy) predisposes patients for late cardiovascular effects (4). High single fractions have also shown to increase the risk for late effects in the brachial plexus (76). The risk for radiation pneumonitis has shown to correlate to the dose volume in lung tissue (79). Late effects in the soft tissues can lead to poorer cosmetic results. eg, following breast conserving surgery (77, 80-83). Radiotherapy of the axilla can lead to an increased tendency toward lymph node edema in the arm (84). Side effects of radiotherapy can be expected to increase when chemotherapy is administered concurrently (83). Ionizing radiation is a potential carcinogen. This situation has been a starting point for studies of cancer risks, particularly the risk for leukemia in breast cancer patients who have received radiotherapy (85, 86). These results suggest some increase in the relative risk although it is less pronounced than for patients who have received chemotherapy. Since acute leukemia is an unusual disease, these results are based on a few observed cases in clinical data covering thousands of patients. Theoretically, there is Palliative treatment Previous sections have dealt only with the role of radiotherapy in patients with primary, operable disease where treatment is intended to be curative. However, radiotherapy is also used extensively as a palliative (symptom relieving) treatment. Experiences concerning the value of 60 palliative radiotherapy for breast cancer have been closely associated with the development of radiotherapy as a means of cancer treatment, and date back to the early 1900s. Since we are dealing with treatment effects which can be directly measured in patients, eg, reduced tumor size, less pain, healing of lytic bone metastases, reduced neurological symptoms, etc, randomized studies have naturally played a limited role in contributing toward the knowledge in this field. Documentation on the palliative effects of radiotherapy date back several decades. This section briefly summarizes the field, and does not represent a comprehensive review of all the literature published during the 1900s. Approximately 5% to 10% of all new breast cancer patients have an inoperable tumor. Half of these patients have tumors that have advanced locally to the extent that surgery is unable to make these patients clinically tumorfree. The remainder of the patients with inoperable disease present clinically with distant metastases even on primary diagnosis. In patients receiving curative treatment, some experience relapse after varying followup periods. The most common recurrence sites are locoregional, on the chest wall/breast, lymph nodes in the axilla and neck, bone, lung/pleura, liver, and brain. Uncontrolled primary tumors or uncontrolled recurrence usually result in substantial suffering for patients, eg, pain, malodorous cancer lesions, fractures, paralysis. etc. In patients with locally advanced, inoperable primary cancer, radiotherapy often leads to tumor regression ( 15). Local control is achieved in approximately 60% of patients with T3 and T4 tumors by using doses between 60 Gy and 70 Gy, and in 75% to 80% of cases by using higher doses (15). In many cases, tumor regression is so pronounced that cases which initially are technically inoperable become operable (16-18). In local recurrence on the chest wall following mastectomy, o r in the regional lymph nodes, there is a substantial risk for new recurrence after surgical excision alone ( 1 9). Adding radiotherapy reduces the risk for recurrence, similar to pre- or postoperative radiotherapy in conjunction with primary surgical intervention (19). Irradiation of bone metastases often reduces pain and the risk for pathological fractures (20). Pain is reduced in approximately 70% to 80% of the patients (20). (See Section 16 on bone metastases). The symptoms of brain metastases include headache, personality change, and cranial-nerve-related changes, eg, reduced field of vision, reduced sensation, dizziness, etc. Metastases in the spinal canal can create pressure on the spinal cord or on nerves exiting the spinal cord, possibly resulting in paraplegia. Radiotherapy may prevent or delay the development of these symptoms, and in symptomatic cases, radiotherapy alone improves neurological status in 50% to 70% of the patients (21). However, radiotherapy is often combined with other strategies, eg, neurosurgical intervention and medical treatment. The literature review shows: - - that in patients with locally advanced, inoperable disease, radiotherapy can lead to sufficient tumor regression for patients to become operable and potentially curable (15-18); that, in a major percentage of patients, radiotherapy for advanced disease can alleviate tumor symptoms, eg, pain, and can prevent the development of cancer lesions, fractures, paralysis, etc, (20, 21); that radiotherapy has a substantial palliative value in breast cancer. zyxwvutsrqpo zyxwvutsrq zyxwv zyxw - Literature The articles that appear in the reference list were classified and graded as follows: (Number of studieslNumber of patients) 1 = High 2 = Moderate M 1/74 652 C 20124 120 1217 309 P - - R 171247 945 L 0 16 3 Total 571346 717 3 = Low 4/27 000 - 612 183 ~ Total 5/101 652 38/33 612 - 1/1 461 27/252 370 5 3 - 21 6 33/37 273 713 644 971387 634 912 964 The value of radiotherapy for the most common indications has been tested within the framework of numerous prospective randomized studies and meta-analyses. Because of the relatively high availability of randomized studies, this literature review does not include retrospective, nonrandomized studies. Such studies are methodologically weak and of uncertain or limited value for judging the effects of curative treatment. The section on palliative indications is based largely on studies without randomized controls. Randomized studies have played a limited role in contributing knowledge in this field since the effects of palliative treatment can be directly measured in patients, eg, reduced tumor size, reduced pain, healing of lytic bone metastases. zyxwvutsrq REFERENCES I . Rutqvist LE, Cedermark B, Glas U, et al. Radiotherapy, chemotherapy and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomized trials. Int J Radiation Oncol Biol Phys 1989; 16: 629-639. (C1/1666, 2 trials) 2. Stewart HJ. Prescott RJ, Forrest PA. Conservation therapy of breast cancer. Lancet 1989; 2: 168-169. (C2/556) 3. Overgaard M, Juul Christensen J, Johansen H, et al. Postmastectomy irradiation in high-risk breast cancer patients. Present status of the Danish Breast Cancer Cooperative Group trials. Acta Oncologica 1988; 27: 707-714. (C1/2342, 2 trials) zyxwvutsrqpo zy zyxwvutsrq zyxwvuts 61 4. Auquier A. Rutqvist LE, Host H, Rotstein S, Arriagada R. Post-mastectomy megavoltage radiation: the Oslo and Stockholm trials. Eur J Cancer 1992; 28: 433-437. (M2/1185) 5. Cuzick J, Stewart H , Rutqvist LE, et al. Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 1994; 12: 447- 453. (M217941) 6. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic. or immune therapy, 133 randomised trials involving 31 000 recurrences and 24000 deaths among 75000 women. Lancet 1992: 339: 1-15, 71-85. (M1/74652) 7. Host H, Brennhovd 1, Loeb M. 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