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0360.3016/91 $3.00 + IMI Copyright 0 1991 Pergamon Pressplc
2 I. PP. 355-360
l Original Contribution
RADIATION PNEUMONITIS IN BREAST CANCER PATIENTS TREATED WITH CONSERVATIVE SURGERY AND RADIATION THERAPY TATIANA I. LINGOS, M.D., ABRAM RECHT, M.D., FRANK VICINI, M.D., ANTHONY ABNER, M.D., BARBARA SILVER, B.A. AND JAY R. HARRIS, M.D. Joint Center for Radiation
Therapy
and Department
of Radiation
Therapy,
Harvard Medical School. Boston, MA
The likelihood of radiation pneumonitis and factors associated with its development in breast cancer patients treated with conservative surgery and radiation therapy have not been well established. To assess these, we retrospectively reviewed 1624 patients treated between 1968 and 1985. Median follow-up for patients without local or distant failure was 77 months. Patients were treated with either tangential fields alone (n = 508) or tangents with a third field to the supraclavicular (SC) or SC-axillary (AX) region (n = 1116). Lung volume treated in the tangential fields was generally limited by keeping the perpendicular distance (demagnified) at the isocenter from the deep field edges to the posterior chest wall (CLD) to 3 cm or less. Seventeen patients with radiation pneumonitis were identified (1.0%). Radiation pneumonitis was diagnosed when patients presented with cough (15/17, 88%), fever (9/17,53%), and/or dyspnea (6/17,35%) and radiographic changes (17/17) following completion of RT. Radiographic infiltrates corresponded to treatment portals in all patients, and in 12 of the 17 patients, returned to baseline within 1-12 months. Five patients had permanent scarring on chest X ray. No patient had late or persistent pulmonary symptoms. The incidence of radiation pneumonitis was correlated with the combined use of chemotherapy (CT) and a third field. Three percent (11/328) of patients treated with a 3-field technique who received chemotherapy developed radiation pneumonitis compared to 0.5% (6 of 1296) for all other patients (p = 0.0001). When patients treated with a 3-field technique received chemotherapy concurrently with radiation therapy, the incidence ofradiation pneumonitis was 8.8% (8/92) compared with 1.3% (3/236) for those who received sequential chemotherapy and radiation therapy (p = 0.002). A case:control analysis was performed to determine if the volume of lung kradiated (as determined using central lung distance (CLD)) was related to the risk of developing radiation pneumonitis. Three control patients were matched to each case of radiation pneumonitis based on age, side of lesion, chemotherapy (including sequencing), use of a third field, and year treated. Lung volumes were similar in the radiation pneumonitis cases and controls. We conclude that radiation pneumonitis following conservative surgery and radiation therapy for breast cancer is a rare complication, and that it is more likely to occur in patients treated with both a 3-field technique and chemotherapy (particularly given concurrently with radiation therapy). Over the limited range of volumes treated, lung volume was not associated with an increased risk of radiation pneumonitis. Breast cancer, Conservative surgery, Radiation therapy, Chemotherapy, Complications.
INTRODUCTION
Radiation pneumonitis, Pulmonary effects,
As increasing numbers of women with early stage breast cancer choose breast conserving treatment, the short and long-term effects of this approach need to be elucidated. In addition, more patients are being given chemotherapy along with radiation therapy (RT), but the risk of complications resulting from combined modality therapy has not been well documented. One of the potential complications of concern is radiation pneumonitis (RP). While irradiation to the breast and draining lymph nodes is generally well tolerated, radiation pneumonitis, defined as a clinical syndrome of cough, fever, and/or shortness of
breath accompanied by radiographic changes consistent with a non-infectious infiltrate, has been described following RT for breast cancer (8, 11, 12, 18, 19, 21, 27). The risk of developing RP appears to be related to the volume of lung irradiated (8, 13, 18, 19, 20, 2 1, 22, 26, 28). Rothwell retrospectively studied 201 patients who received postoperative RT to the chest wall. Reconstructions of the inner contour of the chest wall onto the RT plan were done and the incidence of RP was shown to rise exponentially with an increase in irradiated volume. Bornstein et al. described a technique for quantitating the percent of ipsilateral lung volume in the tangential fields at the time of simulation by measuring central lung dis-
Presented at the 32nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, FL October 1990.
Reprint requests to: Tatiana 1. Lingos, M.D., Joint Center for Radiation Therapy, 50 Binney St., Boston, MA 02 115. Accepted for publication 25 January 199 1. 355
356
1. J. Radiation Oncology 0 Biology 0 Physics
tance (CLD) (1). If this technique could be used to correlate treated lung volume with a defined risk of developing RP, it would be beneficial to the radiation oncologist at the time of treatment planning. In addition, the volume of lung irradiated in a third field used to treat the supraclavicular-axillary region needs to be considered regarding the risk of developing RP. This study was undertaken to assess the incidence of RP in patients treated for early stage breast cancer, to identify women who are at highest risk for developing RP and to document the long-term consequences, if any. Our results reveal that RP is an uncommon complication, is self-limited, and is most likely to occur in patients treated with both chemotherapy (particularly when given concurrently with RT) and 3-field RT encompassing the axillary-supraclavicular lymph nodes. The treated lung volume was assessed using CLD measurements, and within the limited range of lung volumes treated in our population (CLD _( 3 cm), tangential lung volume was not associated with RP. METHODS
AND MATERIALS
Between 1968 and 1985, 1624 women were treated at the Joint Center for Radiation Therapy (JCRT) with CS and RT for unilateral Stage I-II breast cancer. The median age was 5 1 years (range, 25-93). The median follow-up was 77 months for patients without local or distant failure. Patients were treated with either tangential fields alone (n = 508) or tangents plus a third field encompassing the supraclavicular (SC) or SC-axillary (AX) region (n = 1 116) at the physician’s discretion. Internal mammary nodes, when treated, were included in the tangential fields, often guided by lymphoscintigraphy ( 16). “Hockey stick” fields were rarely used, and, if so, for only a portion of the treatment. The technique was that of the JCRT and has been described in detail elsewhere (23). The tangential fields were treated to a dose of 45-50 Gy with 1.8-2.0 Gy fractions, 5 days a week, using coplanar fields. A boost dose to the tumor bed was delivered with either an interstitial iridium implant in the earlier years of the study (58%) or, more recently, with electrons of 7- 15 MeV (37%). The median total tumor bed dose was 64.93 Gy (range, 4484 Gy). For patients who received nodal irradiation, 45 Gy was typically delivered to the SC/AX nodes with an en-face field (23). A minority of patients received boosts to the axilla via en-face photon, posterior photon, or electron fields. Adjuvant chemotherapy (CT) was determined by the medical oncologist and varied in terms of regimens, dose, and duration, The sequencing of CT and RT also varied. A total of 379 patients received some form of chemotherapy. Two hundred seventy-six patients received CMF without doxorubicin (72%) 15 (4%) received doxorubicin without CMF, 54 (14%) received both and the remainder were given other drugs. Dose modifications were made on an individual basis, determined by blood counts and
July 1991. Volume 21, Number 2
tolerance, but not by pre-determined policy. Ninety-five patients (25%) received concurrent CT and RT (defined as any amount of CT delivered during external beam RT). In patients who received concurrent CT, only doxorubicin was withheld during the RT; all others were administered, including methotrexate. Some of the women in the “concurrent” group had also received one or more cycles of CT prior to the initiation of RT. Two hundred patients (75%) did not receive the CT and RT concurrently. One hundred fifty received all CT after RT, 29 received all CT before RT, 66 got “sandwich” CT-RT-CT, 35 received CT in the interval between external beam RT and the implant (but not concurrently) and after the completion of RT, and for 4 patients the sequence was unknown. As no significant differences were found between the various sequential treatment groups, they were consequently combined and termed “sequential CT and RT” for all further analysis. Upon completion of RT, all patients were seen by the radiation oncologist in regular follow-up appointments, usually 3-4 weeks after RT, then every 3-4 months for the first l-2 years and semiannually thereafter. Followup times and time to development of RP were calculated from the first day of irradiation. RP was diagnosed when patients complained of cough, fever and/or shortness of breath accompanied by radiographic changes on X ray consistent with an acute inflammatory, non-infectious process (18, 21, 24). If infection was suspected, a trial of antibiotics was given, but this did not exclude patients from further evaluation and work-up for RP. Bronchoscopy and biopsy were not routinely performed, but were done when an infectious etiology could not be distinguished from RP. To determine whether the volume of lung irradiated was a contributing factor to the development of RP, we performed a case: control analysis. Each identified patient with RP (“case”) was matched with three “control” patients on the basis of age, side of lesion, CT (including sequencing), use of a third field, and year treated (to better insure similarity of RT technique). For both cases and controls. the volume of lung irradiated in the tangential fields was calculated using the central lung distance (CLD) method described by Bornstein et al. from the simulation and/or portal films when available (14/ 17 cases and 381 5 1 controls). The amount of lung in the supraclavicular field was fairly consistent clinically, and volume calculations were not done. Comparison between proportions was done using Fisher exact test. P values < 0.05 were considered statistically significant. RESULTS Of a total patient population of 1624, 17 women developed a clinical syndrome of radiation pneumonitis (RP) for an overall crude incidence of 1%. The median age of patients who developed RP was 58 years old. The most
Radiation pneumonitis in breast cancer 0 T. 1. LINGOS et
common presenting symptom was cough (15/17, 88%) followed by fever (9/17, 53%) and dyspnea (6/17, 35%). Chest X rays were obtained for all patients and were positive for infiltrates in the irradiated region all patients (either in the tangential fields or in the axillary-supraclavicular field, if used). Four patients underwent bronchoscopy and biopsy to rule out an infectious process. Six patients received a trial of antibiotics, although in only three patients was infection suspected. We investigated the antecedent pulmonary conditions as potential predisposing factors in the group that developed RP. Smoking history was known for only eight patients (three smokers, five non-smokers). One patient had a history of previously treated active tuberculosis as a teenager. None of the patients had been on chronic steroid therapy. The duration and severity of symptoms varied. In four patients, the symptoms began within 1 month after completion of RT, but the latent period ranged from 2-l 9 weeks following therapy (median, 7 weeks). Symptoms lasted for a median of 4.5 weeks with a range of 2-20 weeks. Abnormalities on chest X ray resolved within l12 months in 7 1% of patients ( 12117). Five patients had permanent scarring or fibrosis. No patient had any late or persistent pulmonary symptoms. Most were managed conservatively; 5 of the 17 patients were treated with steroids, but none required hospitalization. We compared the characteristics of the 17 patients who developed radiation pneumonitis with those of the rest of the population in an attempt to identify factors related to RP (Table 1). The two factors of note in this comparison were the use of chemotherapy (CT) and a third field to treat the axillary-supraclavicular region. On univariate analysis the incidence of RP was correlated with the use of chemotherapy in our patients. Eleven of 379 patients (2.9%) who received CT developed RP compared to 6/ Table 1. Potential factors contributing to the development of RP
Cases 17 No. patients Median age 58 Side of lesion (LR) 6:l I Medial/central lesions 8 (47%) Median total dose to 64 (45-69.5) primary (GY) Implant 10 (59%) Median implant dose 19 (GY) Electron boost 4 (24%) Median electron boost 16.8 dose (GY) 3rd field to treat AX/ SC area 16 (94%) 11 (65%) Chemotherapy Concurrent chemotherapy 8/l 1 (73%)
General population
al.
351
1245 (0.5%) treated with RT alone (p = 0.0003). Four of 69 patients (5.8%) who received doxorubicin-based regimens developed RP compared to 7/310 (2.3%) who received other drugs (p = 0.2). The use of a third radiation field (SC/AX) was also associated with an increased risk of developing RP on univariate analysis. Patients who were treated with tangents only had a 0.2% (l/508) incidence of RP in contrast to 1.4% ( 16/ 1116) in women who received nodal irradiation (p = 0.03). We then examined the combined effect of chemotherapy and 3-field RT. CT and 3-field RT were strongly correlated with one another (p < 0.0001). The incidence of RP among women treated with three fields was 0.6% (51 788) for those who did not receive CT and 3.3% (1 l/328) for those who did receive CT (JI = 0.001) (Table 2). In patients who were treated with two fields (tangents only), the incidence of RP was 0.2% (l/457) in those who did not receive chemotherapy and 0% (O/51) in those who did receive CT. The effect of chemotherapy was even more pronounced when sequencing of RT and CT was analyzed. Patients treated with three fields and sequential RT/ CT had a 1.3% incidence of RP (3/236) compared with 8.8% (8/92) for those given concurrent CT and RT (p = 0.002) (Table 3). To determine if the volume of lung irradiated was unusually large in patients who developed RP, we performed a case: control analysis in which each case was matched with three controls based on age, side of lesion, CT (including sequencing), use of a third field, and year treated. For the tangential fields, the central lung distance (CLD) was equal to or less than 3.0 cm in 12/14 (86%) of the patients who developed RP for whom simulation films were available compared to 37 of the 38 evaluable controls (97%) (p = 0.2). The median CLD was 2.6 cm (range = 2.0-3.7 cm) for the cases and 2.5 cm (range = I .3-3.2 cm) for the controls (p = NS). This corresponds to up to approximately 20% of the ipsilateral lung in the tangential field. The volume of lung in the third field was not quantitated, but appeared similar on portals and simulation films in both cases and controls.
p value
DISCUSSION 1607 51 776:83 1 583 (36%)
N.S. N.S. N.S.
64 (44-84) 935 (58%) N.S. 20.3 542 (34%)
N.S.
16
1100 (68%) 368 (23%)
0.03 0.0003
87/368 (24%)
0.0009
The results of this study corroborate most clinicians’ impression that RT for primary breast cancer is generally well-tolerated and is associated with a low incidence of radiation pneumonitis (RP). For the first time, we have quantified the risk of developing RP in a large patient population, taking into consideration the volume of lung in the tangential fields and assessing the contributions of chemotherapy and nodal irradiation in its evolution. Our results indicate that the risk of RP is increased in patients treated with both a 3-field technique to treat the axillarysupraclavicular region and chemotherapy (particularly when given concurrently with the RT). Radiation pneumonitis and fibrosis of the lung as a result of therapeutic irradiation were described as far back
358
I. J. Radiation Oncology 0 Biology 0 Physics Table 2.
Effect of chemotherapy development No chemotherapy
2-field 3-field
(CT) on the
of RP Chemotherapy
l/457 (0.2%) o/51 (0%) 5/788 (0.6%) c -p = O.OOl- + 1l/328 (3.3%)
as 1922 (7, 10). Physiologic, histologic, and radiographic studies have been performed to evaluate this effect following RT for breast, lung, Hodgkin’s disease, pediatric malignancies, and advanced metastatic disease (2, 5, 8, 11, 13, 21, 25, 27, 28). Certain predisposing factors in individuals have been described as contributing to the evolution of RP, such as age, cigarette smoking, collagen vascular disorders, and steroid therapy (2, 3, 8,9, 12,2 1). More recently, several authors have specifically addressed the issue of RP following RT for breast cancer. both following mastectomy and in women treated with breastconserving therapy (4, 6, 19, 22). In the current study, the timing of the clinical syndrome from 1 to several months after RT was consistent with other published studies (5, 8, 9, 12, 15, 19, 22). The location and nature of the radiographic changes (patchy infiltrates within the region of irradiation) was also in accordance with the rest of the literature (8, 9, 12, 13, 15, 18, 19, 2 1, 24). Of note, we did not perform nuclear medicine scans (9), CT scans (25), or pulmonary function tests (12), as no patient in this series had any long term clinically apparent sequelae of treatment. Our study identified two factors that were correlated with the risk of radiation pneumonitis: the use of chemotherapy and the use of a 3-field RT technique. Each factor had a positive correlation with RP on univariate analysis. However, when both factors were analyzed together, it became evident that neither alone had a significant impact on RP. Rather, it was the combination of chemotherapy and a third field that produced an increased incidence of radiation pneumonitis. This effect was exacerbated by the use of concomitant CT and RT. Pulmonary toxicity from concomitant CT and RT has been well described in patients with Hodgkin’s disease, lymphomas, and pediatric malignancies and is known to have a higher incidence in patients who receive bleomycin, methotrexate, doxorubicin, or prednisone ( 14, 18,2 1,26, 28). It has been less extensively characterized in women receiving definitive RT for breast cancer. In the current study, the incidence of RP was 8.5% with concomitant RT/CT compared with 1.1% for sequential RT/CT (p = 0.001). The association between RP and the use of CT has not been previously documented in breast cancer patients. Glick et al. published results of 96 consecutive women who received concurrent CT and RT using CMF, CMFP, or CF. Only 1 of the 96 developed symptomatic RP in relation to initial therapy. Another patient had RP at the time of relapse after being given additional CT (6). Fowble
July 1991, Volume 21, Number 2
et al. published the results in 63 “high risk” patients who received adjuvant CT and post-mastectomy RT in which 9 of the patients were given CT concurrently with RT, 32 patients had RT after CT, 1 had RT prior to CT, and 21 received “sandwich” CT. Of note, methotrexate was withheld during the course of RT in the concurrent group. In total, 3 of the 63 (5%) of patients developed RP, 1 of whom required steroids. The authors did not specify the incidence of RF in the concurrent group, but the overall incidence is similar to the results presented here (4). Weiss et al. examined 764 patients who received adjuvant CT after conservative surgery and RT or modified radical mastectomy. Patients were given CMF with or without doxorubicin which began 1 week before and continued through RT. The major focus of this paper was the tolerance to CT, however, other toxicities were addressed as well. In 208 patient charts, comment was made as to the presence or absence of radiographic changes. Only 7 of the 208 (3%) were reported to have changes on X ray and none were reported to have developed RP (29). The impact of using a third field to treat the AX/SC region on the development of RP has been debated. Rothwell and colleagues felt that the tangents had a larger effect than the nodal fields, but that apical fibrosis secondary to supraclavicular irradiation could have contributed to RP (19). Polansky et al. commented that fibrosis in the upper lung zones was less likely to cause symptoms because the lung volume in that region is small and pulmonary blood flow is lowest (15). Kaufman et al. calculated the total alveolar lung volume in one lung to be 1346 ml by computerized tomographic reconstruction, and estimated the volume of lung in the supraclavicular field to be 300 ml compared to 220 ml for the internal mammary portion and 48 ml for tangents ( 12). However, a convenient technique for quantifying the amount of lung in the AX/SC field has not yet been developed, and few, if any, patients are now being treated with nodal irradiation only. On a clinical level, physicians are now faced with the decision of whether or not to add a third field to treat nodal areas, often in a patient who will be receiving adjuvant chemotherapy. Although the risk of RP in patients receiving three-field RT and sequential RT and CT was significantly increased (3.3%), it was still uncommon. The survival and local control benefits of nodal irradiation are a matter of debate; the link between such treatment and pulmonary toxicity makes this issue even more complex. Time, dose, fraction size, and volume of lung in the high dose regions are believed to be important in the de-
Table 3. Effect of sequencing on the development Sequential CT 2-field 3-field
of CT and RT of RP Concurrent CT
Of46 (0%) o/3 (0%) 3/236 (I .3%) 4 - p = 0.002 - + 8/92 (8.8%)
Radiation pneumonitis in breast cancer 0 T. 1. LINGOSel d.
velopment of RP (8, 13, 18, 19, 20, 21, 22, 26, 28). The first three parameters are rather constant when dealing with the current treatment for breast cancer patients. Lung volume in the tangential fields is more variable as this is related to patient size and shape and whether or not the internal mammary nodes (IMN) are treated. Some have suggested that the increased risk of RP is due primarily to the placement of the tangential fields (15, 19, 29). In these studies, however, the IMN’s were generally treated with an en-face, 5-6 cm wide, hockey-stick field, thereby increasing the volume of irradiated lung even further than with tangential fields alone ( 17). In our population, even though 14 of the 17 patients with RP had internal mammary nodes treated, this was accomplished with the aid of lymphoscintigraphy to identify the position of the IMN’s and the use of tangential field irradiation which generally did not go farther than 3 cm beyond midline. The median central lung distance (CLD) was 2.6 cm ( lo20% of ipsilateral lung) in patients who developed radia-
359
tion pneumonitis, very similar to that of the control patients. Rothwell et al. found no further cases of RP once the lung area treated was limited to a mean of 17 cm 2. This was calculated using estimated chest wall thickness measurements, internal chest diameter (estimated from chest X ray) and standard chest shape to reconstruct the inner chest wall and measure the area of lung enclosed by 70% isodose line in the mid-plane of the tangential fields ( 19). Schoeppel et al. found no cases of RP in 140 patients who had less than 3.35 cm lung in the tangential fields as measured in centimeters along the central axis of the simulation film (CLD). All of their cases of RP occurred in patients who had had more than 4 cm of lung irradiated. Thus, CLD appears to be a reasonable guide to the risk of radiation pneumonitis, and for patients treated with a CLD less than or equal to 3 cm radiation pneumonitis is rare, except in patients treated with both a third field and chemotherapy, particularly when given concomitantly.
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0360.3016/91 $3.00 + IMI Copyright 0 1991 Pergamon Pressplc
2 I. PP. 355-360
l Original Contribution
RADIATION PNEUMONITIS IN BREAST CANCER PATIENTS TREATED WITH CONSERVATIVE SURGERY AND RADIATION THERAPY TATIANA I. LINGOS, M.D., ABRAM RECHT, M.D., FRANK VICINI, M.D., ANTHONY ABNER, M.D., BARBARA SILVER, B.A. AND JAY R. HARRIS, M.D. Joint Center for Radiation
Therapy
and Department
of Radiation
Therapy,
Harvard Medical School. Boston, MA
The likelihood of radiation pneumonitis and factors associated with its development in breast cancer patients treated with conservative surgery and radiation therapy have not been well established. To assess these, we retrospectively reviewed 1624 patients treated between 1968 and 1985. Median follow-up for patients without local or distant failure was 77 months. Patients were treated with either tangential fields alone (n = 508) or tangents with a third field to the supraclavicular (SC) or SC-axillary (AX) region (n = 1116). Lung volume treated in the tangential fields was generally limited by keeping the perpendicular distance (demagnified) at the isocenter from the deep field edges to the posterior chest wall (CLD) to 3 cm or less. Seventeen patients with radiation pneumonitis were identified (1.0%). Radiation pneumonitis was diagnosed when patients presented with cough (15/17, 88%), fever (9/17,53%), and/or dyspnea (6/17,35%) and radiographic changes (17/17) following completion of RT. Radiographic infiltrates corresponded to treatment portals in all patients, and in 12 of the 17 patients, returned to baseline within 1-12 months. Five patients had permanent scarring on chest X ray. No patient had late or persistent pulmonary symptoms. The incidence of radiation pneumonitis was correlated with the combined use of chemotherapy (CT) and a third field. Three percent (11/328) of patients treated with a 3-field technique who received chemotherapy developed radiation pneumonitis compared to 0.5% (6 of 1296) for all other patients (p = 0.0001). When patients treated with a 3-field technique received chemotherapy concurrently with radiation therapy, the incidence ofradiation pneumonitis was 8.8% (8/92) compared with 1.3% (3/236) for those who received sequential chemotherapy and radiation therapy (p = 0.002). A case:control analysis was performed to determine if the volume of lung kradiated (as determined using central lung distance (CLD)) was related to the risk of developing radiation pneumonitis. Three control patients were matched to each case of radiation pneumonitis based on age, side of lesion, chemotherapy (including sequencing), use of a third field, and year treated. Lung volumes were similar in the radiation pneumonitis cases and controls. We conclude that radiation pneumonitis following conservative surgery and radiation therapy for breast cancer is a rare complication, and that it is more likely to occur in patients treated with both a 3-field technique and chemotherapy (particularly given concurrently with radiation therapy). Over the limited range of volumes treated, lung volume was not associated with an increased risk of radiation pneumonitis. Breast cancer, Conservative surgery, Radiation therapy, Chemotherapy, Complications.
INTRODUCTION
Radiation pneumonitis, Pulmonary effects,
As increasing numbers of women with early stage breast cancer choose breast conserving treatment, the short and long-term effects of this approach need to be elucidated. In addition, more patients are being given chemotherapy along with radiation therapy (RT), but the risk of complications resulting from combined modality therapy has not been well documented. One of the potential complications of concern is radiation pneumonitis (RP). While irradiation to the breast and draining lymph nodes is generally well tolerated, radiation pneumonitis, defined as a clinical syndrome of cough, fever, and/or shortness of
breath accompanied by radiographic changes consistent with a non-infectious infiltrate, has been described following RT for breast cancer (8, 11, 12, 18, 19, 21, 27). The risk of developing RP appears to be related to the volume of lung irradiated (8, 13, 18, 19, 20, 2 1, 22, 26, 28). Rothwell retrospectively studied 201 patients who received postoperative RT to the chest wall. Reconstructions of the inner contour of the chest wall onto the RT plan were done and the incidence of RP was shown to rise exponentially with an increase in irradiated volume. Bornstein et al. described a technique for quantitating the percent of ipsilateral lung volume in the tangential fields at the time of simulation by measuring central lung dis-
Presented at the 32nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, FL October 1990.
Reprint requests to: Tatiana 1. Lingos, M.D., Joint Center for Radiation Therapy, 50 Binney St., Boston, MA 02 115. Accepted for publication 25 January 199 1. 355
356
1. J. Radiation Oncology 0 Biology 0 Physics
tance (CLD) (1). If this technique could be used to correlate treated lung volume with a defined risk of developing RP, it would be beneficial to the radiation oncologist at the time of treatment planning. In addition, the volume of lung irradiated in a third field used to treat the supraclavicular-axillary region needs to be considered regarding the risk of developing RP. This study was undertaken to assess the incidence of RP in patients treated for early stage breast cancer, to identify women who are at highest risk for developing RP and to document the long-term consequences, if any. Our results reveal that RP is an uncommon complication, is self-limited, and is most likely to occur in patients treated with both chemotherapy (particularly when given concurrently with RT) and 3-field RT encompassing the axillary-supraclavicular lymph nodes. The treated lung volume was assessed using CLD measurements, and within the limited range of lung volumes treated in our population (CLD _( 3 cm), tangential lung volume was not associated with RP. METHODS
AND MATERIALS
Between 1968 and 1985, 1624 women were treated at the Joint Center for Radiation Therapy (JCRT) with CS and RT for unilateral Stage I-II breast cancer. The median age was 5 1 years (range, 25-93). The median follow-up was 77 months for patients without local or distant failure. Patients were treated with either tangential fields alone (n = 508) or tangents plus a third field encompassing the supraclavicular (SC) or SC-axillary (AX) region (n = 1 116) at the physician’s discretion. Internal mammary nodes, when treated, were included in the tangential fields, often guided by lymphoscintigraphy ( 16). “Hockey stick” fields were rarely used, and, if so, for only a portion of the treatment. The technique was that of the JCRT and has been described in detail elsewhere (23). The tangential fields were treated to a dose of 45-50 Gy with 1.8-2.0 Gy fractions, 5 days a week, using coplanar fields. A boost dose to the tumor bed was delivered with either an interstitial iridium implant in the earlier years of the study (58%) or, more recently, with electrons of 7- 15 MeV (37%). The median total tumor bed dose was 64.93 Gy (range, 4484 Gy). For patients who received nodal irradiation, 45 Gy was typically delivered to the SC/AX nodes with an en-face field (23). A minority of patients received boosts to the axilla via en-face photon, posterior photon, or electron fields. Adjuvant chemotherapy (CT) was determined by the medical oncologist and varied in terms of regimens, dose, and duration, The sequencing of CT and RT also varied. A total of 379 patients received some form of chemotherapy. Two hundred seventy-six patients received CMF without doxorubicin (72%) 15 (4%) received doxorubicin without CMF, 54 (14%) received both and the remainder were given other drugs. Dose modifications were made on an individual basis, determined by blood counts and
July 1991. Volume 21, Number 2
tolerance, but not by pre-determined policy. Ninety-five patients (25%) received concurrent CT and RT (defined as any amount of CT delivered during external beam RT). In patients who received concurrent CT, only doxorubicin was withheld during the RT; all others were administered, including methotrexate. Some of the women in the “concurrent” group had also received one or more cycles of CT prior to the initiation of RT. Two hundred patients (75%) did not receive the CT and RT concurrently. One hundred fifty received all CT after RT, 29 received all CT before RT, 66 got “sandwich” CT-RT-CT, 35 received CT in the interval between external beam RT and the implant (but not concurrently) and after the completion of RT, and for 4 patients the sequence was unknown. As no significant differences were found between the various sequential treatment groups, they were consequently combined and termed “sequential CT and RT” for all further analysis. Upon completion of RT, all patients were seen by the radiation oncologist in regular follow-up appointments, usually 3-4 weeks after RT, then every 3-4 months for the first l-2 years and semiannually thereafter. Followup times and time to development of RP were calculated from the first day of irradiation. RP was diagnosed when patients complained of cough, fever and/or shortness of breath accompanied by radiographic changes on X ray consistent with an acute inflammatory, non-infectious process (18, 21, 24). If infection was suspected, a trial of antibiotics was given, but this did not exclude patients from further evaluation and work-up for RP. Bronchoscopy and biopsy were not routinely performed, but were done when an infectious etiology could not be distinguished from RP. To determine whether the volume of lung irradiated was a contributing factor to the development of RP, we performed a case: control analysis. Each identified patient with RP (“case”) was matched with three “control” patients on the basis of age, side of lesion, CT (including sequencing), use of a third field, and year treated (to better insure similarity of RT technique). For both cases and controls. the volume of lung irradiated in the tangential fields was calculated using the central lung distance (CLD) method described by Bornstein et al. from the simulation and/or portal films when available (14/ 17 cases and 381 5 1 controls). The amount of lung in the supraclavicular field was fairly consistent clinically, and volume calculations were not done. Comparison between proportions was done using Fisher exact test. P values < 0.05 were considered statistically significant. RESULTS Of a total patient population of 1624, 17 women developed a clinical syndrome of radiation pneumonitis (RP) for an overall crude incidence of 1%. The median age of patients who developed RP was 58 years old. The most
Radiation pneumonitis in breast cancer 0 T. 1. LINGOS et
common presenting symptom was cough (15/17, 88%) followed by fever (9/17, 53%) and dyspnea (6/17, 35%). Chest X rays were obtained for all patients and were positive for infiltrates in the irradiated region all patients (either in the tangential fields or in the axillary-supraclavicular field, if used). Four patients underwent bronchoscopy and biopsy to rule out an infectious process. Six patients received a trial of antibiotics, although in only three patients was infection suspected. We investigated the antecedent pulmonary conditions as potential predisposing factors in the group that developed RP. Smoking history was known for only eight patients (three smokers, five non-smokers). One patient had a history of previously treated active tuberculosis as a teenager. None of the patients had been on chronic steroid therapy. The duration and severity of symptoms varied. In four patients, the symptoms began within 1 month after completion of RT, but the latent period ranged from 2-l 9 weeks following therapy (median, 7 weeks). Symptoms lasted for a median of 4.5 weeks with a range of 2-20 weeks. Abnormalities on chest X ray resolved within l12 months in 7 1% of patients ( 12117). Five patients had permanent scarring or fibrosis. No patient had any late or persistent pulmonary symptoms. Most were managed conservatively; 5 of the 17 patients were treated with steroids, but none required hospitalization. We compared the characteristics of the 17 patients who developed radiation pneumonitis with those of the rest of the population in an attempt to identify factors related to RP (Table 1). The two factors of note in this comparison were the use of chemotherapy (CT) and a third field to treat the axillary-supraclavicular region. On univariate analysis the incidence of RP was correlated with the use of chemotherapy in our patients. Eleven of 379 patients (2.9%) who received CT developed RP compared to 6/ Table 1. Potential factors contributing to the development of RP
Cases 17 No. patients Median age 58 Side of lesion (LR) 6:l I Medial/central lesions 8 (47%) Median total dose to 64 (45-69.5) primary (GY) Implant 10 (59%) Median implant dose 19 (GY) Electron boost 4 (24%) Median electron boost 16.8 dose (GY) 3rd field to treat AX/ SC area 16 (94%) 11 (65%) Chemotherapy Concurrent chemotherapy 8/l 1 (73%)
General population
al.
351
1245 (0.5%) treated with RT alone (p = 0.0003). Four of 69 patients (5.8%) who received doxorubicin-based regimens developed RP compared to 7/310 (2.3%) who received other drugs (p = 0.2). The use of a third radiation field (SC/AX) was also associated with an increased risk of developing RP on univariate analysis. Patients who were treated with tangents only had a 0.2% (l/508) incidence of RP in contrast to 1.4% ( 16/ 1116) in women who received nodal irradiation (p = 0.03). We then examined the combined effect of chemotherapy and 3-field RT. CT and 3-field RT were strongly correlated with one another (p < 0.0001). The incidence of RP among women treated with three fields was 0.6% (51 788) for those who did not receive CT and 3.3% (1 l/328) for those who did receive CT (JI = 0.001) (Table 2). In patients who were treated with two fields (tangents only), the incidence of RP was 0.2% (l/457) in those who did not receive chemotherapy and 0% (O/51) in those who did receive CT. The effect of chemotherapy was even more pronounced when sequencing of RT and CT was analyzed. Patients treated with three fields and sequential RT/ CT had a 1.3% incidence of RP (3/236) compared with 8.8% (8/92) for those given concurrent CT and RT (p = 0.002) (Table 3). To determine if the volume of lung irradiated was unusually large in patients who developed RP, we performed a case: control analysis in which each case was matched with three controls based on age, side of lesion, CT (including sequencing), use of a third field, and year treated. For the tangential fields, the central lung distance (CLD) was equal to or less than 3.0 cm in 12/14 (86%) of the patients who developed RP for whom simulation films were available compared to 37 of the 38 evaluable controls (97%) (p = 0.2). The median CLD was 2.6 cm (range = 2.0-3.7 cm) for the cases and 2.5 cm (range = I .3-3.2 cm) for the controls (p = NS). This corresponds to up to approximately 20% of the ipsilateral lung in the tangential field. The volume of lung in the third field was not quantitated, but appeared similar on portals and simulation films in both cases and controls.
p value
DISCUSSION 1607 51 776:83 1 583 (36%)
N.S. N.S. N.S.
64 (44-84) 935 (58%) N.S. 20.3 542 (34%)
N.S.
16
1100 (68%) 368 (23%)
0.03 0.0003
87/368 (24%)
0.0009
The results of this study corroborate most clinicians’ impression that RT for primary breast cancer is generally well-tolerated and is associated with a low incidence of radiation pneumonitis (RP). For the first time, we have quantified the risk of developing RP in a large patient population, taking into consideration the volume of lung in the tangential fields and assessing the contributions of chemotherapy and nodal irradiation in its evolution. Our results indicate that the risk of RP is increased in patients treated with both a 3-field technique to treat the axillarysupraclavicular region and chemotherapy (particularly when given concurrently with the RT). Radiation pneumonitis and fibrosis of the lung as a result of therapeutic irradiation were described as far back
358
I. J. Radiation Oncology 0 Biology 0 Physics Table 2.
Effect of chemotherapy development No chemotherapy
2-field 3-field
(CT) on the
of RP Chemotherapy
l/457 (0.2%) o/51 (0%) 5/788 (0.6%) c -p = O.OOl- + 1l/328 (3.3%)
as 1922 (7, 10). Physiologic, histologic, and radiographic studies have been performed to evaluate this effect following RT for breast, lung, Hodgkin’s disease, pediatric malignancies, and advanced metastatic disease (2, 5, 8, 11, 13, 21, 25, 27, 28). Certain predisposing factors in individuals have been described as contributing to the evolution of RP, such as age, cigarette smoking, collagen vascular disorders, and steroid therapy (2, 3, 8,9, 12,2 1). More recently, several authors have specifically addressed the issue of RP following RT for breast cancer. both following mastectomy and in women treated with breastconserving therapy (4, 6, 19, 22). In the current study, the timing of the clinical syndrome from 1 to several months after RT was consistent with other published studies (5, 8, 9, 12, 15, 19, 22). The location and nature of the radiographic changes (patchy infiltrates within the region of irradiation) was also in accordance with the rest of the literature (8, 9, 12, 13, 15, 18, 19, 2 1, 24). Of note, we did not perform nuclear medicine scans (9), CT scans (25), or pulmonary function tests (12), as no patient in this series had any long term clinically apparent sequelae of treatment. Our study identified two factors that were correlated with the risk of radiation pneumonitis: the use of chemotherapy and the use of a 3-field RT technique. Each factor had a positive correlation with RP on univariate analysis. However, when both factors were analyzed together, it became evident that neither alone had a significant impact on RP. Rather, it was the combination of chemotherapy and a third field that produced an increased incidence of radiation pneumonitis. This effect was exacerbated by the use of concomitant CT and RT. Pulmonary toxicity from concomitant CT and RT has been well described in patients with Hodgkin’s disease, lymphomas, and pediatric malignancies and is known to have a higher incidence in patients who receive bleomycin, methotrexate, doxorubicin, or prednisone ( 14, 18,2 1,26, 28). It has been less extensively characterized in women receiving definitive RT for breast cancer. In the current study, the incidence of RP was 8.5% with concomitant RT/CT compared with 1.1% for sequential RT/CT (p = 0.001). The association between RP and the use of CT has not been previously documented in breast cancer patients. Glick et al. published results of 96 consecutive women who received concurrent CT and RT using CMF, CMFP, or CF. Only 1 of the 96 developed symptomatic RP in relation to initial therapy. Another patient had RP at the time of relapse after being given additional CT (6). Fowble
July 1991, Volume 21, Number 2
et al. published the results in 63 “high risk” patients who received adjuvant CT and post-mastectomy RT in which 9 of the patients were given CT concurrently with RT, 32 patients had RT after CT, 1 had RT prior to CT, and 21 received “sandwich” CT. Of note, methotrexate was withheld during the course of RT in the concurrent group. In total, 3 of the 63 (5%) of patients developed RP, 1 of whom required steroids. The authors did not specify the incidence of RF in the concurrent group, but the overall incidence is similar to the results presented here (4). Weiss et al. examined 764 patients who received adjuvant CT after conservative surgery and RT or modified radical mastectomy. Patients were given CMF with or without doxorubicin which began 1 week before and continued through RT. The major focus of this paper was the tolerance to CT, however, other toxicities were addressed as well. In 208 patient charts, comment was made as to the presence or absence of radiographic changes. Only 7 of the 208 (3%) were reported to have changes on X ray and none were reported to have developed RP (29). The impact of using a third field to treat the AX/SC region on the development of RP has been debated. Rothwell and colleagues felt that the tangents had a larger effect than the nodal fields, but that apical fibrosis secondary to supraclavicular irradiation could have contributed to RP (19). Polansky et al. commented that fibrosis in the upper lung zones was less likely to cause symptoms because the lung volume in that region is small and pulmonary blood flow is lowest (15). Kaufman et al. calculated the total alveolar lung volume in one lung to be 1346 ml by computerized tomographic reconstruction, and estimated the volume of lung in the supraclavicular field to be 300 ml compared to 220 ml for the internal mammary portion and 48 ml for tangents ( 12). However, a convenient technique for quantifying the amount of lung in the AX/SC field has not yet been developed, and few, if any, patients are now being treated with nodal irradiation only. On a clinical level, physicians are now faced with the decision of whether or not to add a third field to treat nodal areas, often in a patient who will be receiving adjuvant chemotherapy. Although the risk of RP in patients receiving three-field RT and sequential RT and CT was significantly increased (3.3%), it was still uncommon. The survival and local control benefits of nodal irradiation are a matter of debate; the link between such treatment and pulmonary toxicity makes this issue even more complex. Time, dose, fraction size, and volume of lung in the high dose regions are believed to be important in the de-
Table 3. Effect of sequencing on the development Sequential CT 2-field 3-field
of CT and RT of RP Concurrent CT
Of46 (0%) o/3 (0%) 3/236 (I .3%) 4 - p = 0.002 - + 8/92 (8.8%)
Radiation pneumonitis in breast cancer 0 T. 1. LINGOSel d.
velopment of RP (8, 13, 18, 19, 20, 21, 22, 26, 28). The first three parameters are rather constant when dealing with the current treatment for breast cancer patients. Lung volume in the tangential fields is more variable as this is related to patient size and shape and whether or not the internal mammary nodes (IMN) are treated. Some have suggested that the increased risk of RP is due primarily to the placement of the tangential fields (15, 19, 29). In these studies, however, the IMN’s were generally treated with an en-face, 5-6 cm wide, hockey-stick field, thereby increasing the volume of irradiated lung even further than with tangential fields alone ( 17). In our population, even though 14 of the 17 patients with RP had internal mammary nodes treated, this was accomplished with the aid of lymphoscintigraphy to identify the position of the IMN’s and the use of tangential field irradiation which generally did not go farther than 3 cm beyond midline. The median central lung distance (CLD) was 2.6 cm ( lo20% of ipsilateral lung) in patients who developed radia-
359
tion pneumonitis, very similar to that of the control patients. Rothwell et al. found no further cases of RP once the lung area treated was limited to a mean of 17 cm 2. This was calculated using estimated chest wall thickness measurements, internal chest diameter (estimated from chest X ray) and standard chest shape to reconstruct the inner chest wall and measure the area of lung enclosed by 70% isodose line in the mid-plane of the tangential fields ( 19). Schoeppel et al. found no cases of RP in 140 patients who had less than 3.35 cm lung in the tangential fields as measured in centimeters along the central axis of the simulation film (CLD). All of their cases of RP occurred in patients who had had more than 4 cm of lung irradiated. Thus, CLD appears to be a reasonable guide to the risk of radiation pneumonitis, and for patients treated with a CLD less than or equal to 3 cm radiation pneumonitis is rare, except in patients treated with both a third field and chemotherapy, particularly when given concomitantly.
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