Brachytherapy-related complications for medically inoperable Stage I endometrial carcinoma

Int. J. Radiation

Pergamon

Oncology

Biol.

Phys., Vol. 31, No. 1, pp. 37-42, 1995 Copyright 0 1994 Elsevier Science Ltd Printed in the USA. All rights reserved 0360-30 16195 $9.50 + .OO

0360-3016(94)00399-8

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Clinical Original Contribution BRACHYTHERAPY-RELATED COMPLICATIONS STAGE I ENDOMETRIAL CLIFFORD K. S. CHAO, M.D.,*?, PERRY H. MARVIN CAMEL, M.D.,$ MING-SHIAN AND WALTER

FOR MEDICALLY CARCINOMA*

INOPERABLE

W. GRIGSBY, M.D.,? CARLOS A. PEREZ, M.D.,+ KAO, M.D.,* ANDREW E. GALAKATOS, M.D.* A. BOYLE III, M.D.§

+RadiationOncology Center, Mallinckrodt Institute of Radiology;*Departmentof Obstetricsand Gynecology, Division of GynecologicOncology; and “Departmentof Anesthesiology,WashingtonUniversity Schoolof Medicine, St. Louis, MO 63 110 Purpose: The current study was conducted to investigate the incidence and risk factors for medical complications aed with low dose rate brachytherapy in patients with medically inoperable Stage I endometrial cancer treated with irradiation alone. Methods and Materials: From 1965 through 1991 at Mallinckrodt Institute of Radiology, 150 implants were performed on 96 patients who were deemed medically unfit for hysterectomy because of advanced age, obesity, and various medical problems. The records of these patients were examined retrospectively to determine the incidence of medical complications that occurred in the first 30 days following the initiation of brachytherapy. The association of risk factors that precluded major surgery and the occurrence of brachytherapy-related complications was examined by logistic regression. Results: Of these 96 patients, 40 patients were older than 75 years, and 31 patients were deemed morbidly obese. Medical problems included hypertension in 45 patients, and diabetes in 37; there was a history of congestive heart failure in 23, stroke in 11,myocardial infarction in 10, and thromboembolism in 8. There were concurrent malignancies in five patients. Implants were performed using intrauterine Simon-Heyman capsules, tandems, and vaginal ovoids in all patients. General anesthesia was used for 98 implants, spinal anesthesia for 26, local anesthesia for 25, and epidural anesthesia for 1. The duration of anesthesia ranged from 30 to 120 min (median, 60 min). The duration of radioisotope application ranged from 11 to 96 h (median, 46 h). Preventive measures included low dose subcutaneous heparin in 55 patients (since 1978), and intermittent pneumatic compression boots in 29 (since 1985). Four patients developed life-threatening complications including myocardial infarction (two patients), congestive heart failure (one patient), and pulmonary embolism (one patient). Two of these four patients died; one with a myocardial infarction and the other with pulmonary embolism. The morbidity rate was thus 4.2% (4 out of 96), and the mortality was 2.1% (2 out of 96). Although the four serious complications occurred within 30 days of the procedure, only one complication and one death occurred during treatment. There was no correlation between occurrence of complications and medical risk factors, type and duration of anesthesia, or type and duration of implant. Conclusions: There is a low incidence of complications associated with conventional low dose rate brachytherapy. The procedure is well tolerated in patients with medically inoperable Stage I endometrial cancer. In comparison to the predicted serious complication rate of surgery in these patients, the number of life-threatening complications from brachytherapy appears to be quite acceptable. Endometrial

carcinoma,

Brachytherapy,

Complications,

Radiation

INTRODUCTION

therapy.

diation therapy, either external treatment plus intracavitary brachytherapy or brachytherapy alone, has been shown to be effective (12). However, the risk factors for hysterectomy-related morbidity and mortality (including obesity, advanced age, diabetes mellitus, cardiovascular disease, thromboembolism, and cerebrovascular disease), which precluded surgery in these patients, may also increase the risk for the occurance of brachytherapy-related

Surgery is considered the main therapeutic

approach for Stage I endometrial carcinoma. However, a number of women with endometrial cancer cannot undergo surgical treatment because of their medical condition. In those patients who are unable to tolerate surgery, radiation therapy is generally used as the primary treatment. Ra-

* Recipient of ResidentEssayAward,and presentedat the SixteenthAnnual American EndocurietherapySocietyMeeting, December8-1 I, 1993,Scottsdale,AZ. Reprint requeststo: Clifford K. S. Chao, M.D., Radiation

Oncology Center,Box 8224,4939Children’sPlace,Suite 5500, St. Louis, MO 63 110. Accepted for publication 14July 1994. 37

I. J. Radiation Oncology 0 Biology 0 Physics

38

40 35 2 30 B 5 25 a 8 20 a g 15 z

10 5 0 35 40 45 50 55 60 65 70 75 80 85 90 95 AGE (years)

Fig. I. Distribution of patient age. complications. The reported incidence of low dose brachytherapy-related complications among these highrisk patients in the literature has been contradicted (14, 26). The current study was therefore conducted to assess the safety and elicit the predictor of complications for low dose rate intracavitary brachytherapy in these high-risk patients. METHODS

AND MATERIALS

Ninety-six patients with endometrial carcinoma, Stage I according to the International Federation of Gynecology and Obstetrics (FIGO), who were deemed inoperable on the basis of their unrelated medical condition, were treated at Mallinckrodt Institute of Radiology from I965 through 199 1. The decision that the patient was not a candidate for hysterectomy due to her overall medical condition was made by the gynecologic oncologist following anesthesiology and medicine consultations as indicated. The records of these patients were examined retrospectively to determine the incidence of any medical complications that occurred in the first 30 days following the initiation

Volume 31, Number 1, 1995

of brachytherapy. The association of risk factors for major surgery and the risk of a brachytherapy-related complication was examined by logistic regression analysis. The analysis was based on the patient’s characteristics at the time when the brachytherapy was performed. Those complications that occurred within 30 days after the brachytherapy were considered procedure- or treatmentrelated. Logistic regression analysis was undertaken to examine the possible association, with age, race, weight, performance status, past medical history, American Society of Anesthesiologists (ASA) score, type and length of anesthesia, type and duration of implant, preventive methods, and whether or not the patient had received external radiation therapy (9). RESULTS

Patient characteristics There were 85 white and 11 black or Hispanic women. The distribution of patient ages at the time of implant is shown in Fig. 1. Patient ages ranged from 39 to 94 years (median, 70 years); 40 patients were older than 75 years. The distribution of body weights at the time of implant is shown in Fig. 2. Thirty-one patients were morbidly obese, as defined by weight 100 pounds greater than ideal body weight. Hypertension was present in 45 patients who underwent the procedure, and diabetes was present in 37 patients. There was a history of congestive heart failure in 23 patients, stroke in 11, myocardial infarction in 10, deep vein thrombosis in 5, and pulmonary embolism in 3. There was a coexistent malignancy in five patients. The physical status of each patient was recorded by an anesthesiologist before the procedure using the ASA classification (Table 1). The distribution of ASA scores and the type of anesthesia is shown in Table 2. The duration of the anesthesia ranged from 30 to 120 min (median, 60 min). Sixty-eight patients received external irradiation and intracavitary brachytherapy, and 28 patients were treated with brachytherapy alone. Forty-two patients underwent

Endometrial carcinoma 0 C. K. S. CHAO et al.

Table 1. Physical status classification adopted by the American Society of Anesthesiologists (32) ASA ASA ASA ASA

I II III IV

ASA V

Normally healthy patient Patient with mild systemic disease Patient with severe systemic disease Patient with severe systemic disease that is a constant threat to life Moribund patient who is not expected to survive for 24 h with or without

an

operation

one implant, and 54 patients had two brachytherapy procedures. A total of 150 implants were performed. The procedures were directed jointly by gynecologic oncologists and radiation oncologists. Dilatation and curettage (D and C) of the endocervix and endometrium was routinely performed before insertion of the brachytherapy applicators, which included intrauterine Simon-Heyman capsules, tandems, and vaginal ovoids. Capsule packing was used in 54 patients for 80 implants. The duration of radioisotope application ranged from 11 to 96 h (median, 46 h). Before 1978, there were no specific preventive measures for venous thrombosis during the implant period. Subsequently, SC heparin injections (3000 to 5000 units every 8 to 12 h) were administered to patients for prevention of thromboembolism. In addition, after 1985,29 patients were given intermittent pneumatic compression boots as well. Eight patients were taking warfarin (Coumadin) for previous histories of deep vein thrombosis or pulmonary embolism. Anticoagulation medication was discontinued 2 days before the brachytherapy procedure and resumed postoperatively in these patients. Complications. Eleven complications occurred. Seven episodes of fever > 38°C resolved with observation or antibiotic treatment. Four life-threatening cardiovascular or thromboembolic events occurred during the first 30 days after the implant procedure. Among the four lifethreatening complications, one patient died of pulmonary embolism 4 weeks after treatment and one patient with a history of aortic insufficiency died of cardiac arrest on the second day of treatment, apparently due to an acute myocardial infarction. One patient with a history of aortic stenosis, myocardial infarction, and congestive heart failure developed congestive heart failure 2 weeks after the Table 2. Distribution of ASA score vs. the type of anesthesia ASA Scores Anesthesia

I

II

III

IV

Total

General Spinal Local

2

49

47

0 0

5

18

8

14

0 3 3

98 26 25

EpiduraI

0

0

1

0

1

Total

2

62

80

6

150

39

implant, which resolved with medical management. The fourth event occurred in a patient who went through the implant uneventfully. A laparotomy for resection of gastric leiomyosarcoma 1 week after the implant provoked myocardial infarction, which resolved with conservative management. All four serious complications occurred after the first implant; there were no life-threatening complications among the 54 patients who underwent a second implant. The morbidity and mortality rates per patient were 4.2% and 2.1%, and 2.6% and 1.3% per procedure, respectively. The variables of patient characteristics and implant procedures failed to identify the risk factors for complications. Analysis of the risk factors for life-threatening complications are summarized in Tables 3 and 4. There was no association between the occurrences of life-threatening complications and patient age, race, obesity, hypertension, diabetes, history of cardiovascular disease, thromboembolism, cerebrovascular disease, concurrent neoplasm, ASA score, type and duration of anesthesia, type and duration of implant, and whether or not prophylactic measures against thromboembolism had been used. DISCUSSION

Definitive radiation therapy has proven to be an effective modality for treating Stage I endometrial carcinoma in patients unable to undergo hysterectomy due to severe underlying medical problems (4, 12, 15). Grigsby et al. ( 12) reported 5- and 1O-year actuarially adjusted diseasefree survivals of 88.1% and 82.4%, respectively. A similar result (87% 5-year disease-free survival) was also achieved at M.D. Anderson Cancer Center ( 14). Intracavitary brachytherapy is considered a crucial part of radiation treatment because it delivers higher doses to the endometrium and myometrium. When advanced age, obesity, or poor medical condition precludes surgery, those risk factors associated with hysterectomy-related morbidity and mortality will presumably increase the medical complications of brachytherapy. However, in the current study, only four life-threatening complications occurred within the first 30 postoperative days in 150 implant events. None of them had shown to be a predictor for the occurrence of life-threatening complications. Morbidly obese patients are presupposed to have a marked increase in perioperative morbidity and mortality, including an increased incidence of wound infection, thromboembolism, and cardiovascular complications (19, 2 1, 27). Obesity also greatly exacerbates underlying cardiopulmonary dysfunction and diabetes mellitus (2, 13). Obese patients may also be at increased risk of respiratory insufficiency due to their upper airway anatomy and heavy chest wall (24). Thirty-two percent of our patients had morbid obesity and associated medical problems; however, morbid obesity was not predictive for the occurrence of life-threatening brachytherapy-related complications. Among women who underwent an abdominal hyster-

40

I. J. Radiation Oncology 0 Biology 0 Physics

Table 3. Descriptivecharacteristicsof patientsin logistic regressionanalysis Variable Race White Nonwhite Kamofsky Score 100 90 80 70 Obesity Yes No Hypertension Yes No DiabetesMellitus Yes No CongestiveHeart Failure Yes No Myocardial Infarction Yes No Angina Yes No Arrythmia Yes No Pulmonary Embolism Yes No DeepVenousThrombosis Yes No Stroke Yes No Concurrent Malignancy Yes No External Radiation Therapy Yes No

Number

Percent

131 19

87 13

3 38 99

2 25 99 I

p-value 0.623 0.683

10

0.575 95

31 63

69 81

46 54

58 92

38 62

34 116

23 77

15

10

55

0.535 0.153 0.879 0.41I 135

90

15 125

10 90

18 132

12 88

6 144

4 96

0.456 0.583

Volume 31, Number 1, 1995

status has been a predictor for perioperative noncardiac complications (16, 32, 33). The reported postoperative death rate is less than 0.5% for class II and 10% to 23% for class IV among those patients undergoing major surgery (18). The intracavitary brachytherapy procedure is less aggressive and traumatic than hysterectomy and other major surgeries, and the current study shows that a higher ASA score in our medically inoperable patients is not necessarily translated into a higher incidence of complication. Cardiac-related morbidity and mortality in surgical patients are significant problems. Perioperative cardiac mortality was first recognized in 19 12, when a women died of a myocardial infarction reported on the first postoperative day after undergoing major abdominal surgery (34). Today, with a greater number of aged patients undergoing operative procedures, the gynecologic oncologist frequently faces the dithcult task of estimating the patient’s cardiac risk for hysterectomy. Assessing the risk is essential because anesthesia and surgery inflict additional insults on an already compromised cardiac system. For example, postoperative reinfarction rates after general anesthesia range from 3% to 18% (11, 22, 3 I), and 6% of patients with a history of congestive heart failure experienced postoperative heart failure (22). Moreover, a study conducted at the Mayo Clinic revealed that patients with a Table 4. Descriptivecharacteristicsof brachytherapy proceduresin logisticregressionanalysis

0.674

Variable

0.616 8 142

5 95 0.583

18 132

12 88 0.355

10 140

7 93

108 42

72 28

0.099

ectomy, standardized for age and race, the mortality rates are 3.8% and .06% for cancer-related and other benign conditions, respectively. The mortality rate increases with age (35). However, in the current study, in which more than 40% of the patients were older than 75, the age failed to show a direct correlation with the occurrence of complications. We believe that the pathophysiologic changes associated with the aging process, but not age itself, contribute to the higher mortality rate. The brachytherapy procedures and low dose rate implant treatment at Mallinckrodt Institute of Radiology are well tolerated, and thus did not greatly challenge the compromised physiological status of advanced aged patients. Although not a risk index per se, the ASA physical

ASA Score I II

Number

Percent

2 62 5

1 42 54 3

51 84 15

34 56 10

6 136 8

4 91 5

84 57 9

56 38

55 95

37 63

11 139

7

0.843

III IV

81

AnesthesiaTime I 45 min 46-89 min 2 90 min Type of Implant Preloading Afterloading RemoteAfterloading Implant Duration 5 48 h 49-71 h r 72 h Preventive Measures Heparin Yes No Warfarin Yes No IPC

Yes No ASA = American

p-value

0.448

0.784

0.545

0.445 0.545 93 0.560 29 121

19 81

Society of Anesthesiologists;

mittent pneumaticcompressionboots.

IPC = Inter-

Endometrialcarcinoma 0 C. K. S. CHAO

history of a myocardial infarction who suffered perioperative myocardial reinfarction exhibited a 54% mortality rate, with 80% of the deaths occurring within 48 h of the operation (3 1). In the current study, three of four life-threatening complications were cardiac-related. However, a medical history of cardiovascular disease was not predictive for the occurrence of life-threatening complications. In comparison, Dusenbery et al. (10) reported complications of gynecologic brachytherapy from the University of Minnesota. Their patients were treated for different sites of cancers (cervix, endometrium, vagina) and different stages of disease. Most had ASA scores of II and a median age of 62 years. Cardiovascular complications accounted for 16 of the 21 patients with life-threatening brachytherapy complications. A history of cardiac disease was present in 9 of the 2 1 patients with complications and was a significant risk factor. This discrepancy between their findings and ours may be due to different patient populations studied. In particular, many of their patients were young, without obesity, or other significant medical problems, and the occurrence of cardiac complications may thus be more closely related to a history of heart disease. On the contrary, most of our patients had multiple medical problems at presentation, which contributed to the complication rate and diminished the importance of a history of cardiovascular disease, per se, on the occurrence of complications. Conventional low dose rate gynecologic brachytherapy requires bedrest for 2 to 3 days for each implant, which could increase the risk for thromboembolism because prolonged immobilization might result in venous stasis in the lower legs (1, 6). Rotte et al. (26) reported the experience in Wtirzburg. Among 106 patients with various stages of cancer of the corpus uteri undergoing intracavitary low dose rate implant, 7.5% had thromboembolic complications, while none of those treated with high dose rate (HDR) had thromboembolism. Although these data suggest that HDR may be associated with fewer thromboembolic complications, the data needs to be interpreted with caution because the information with regard to the medical history of their patients was lacking (26). The detail in preventive measures was not explicit. The incidence of thromboembolic complication was much higher than that reported here and elsewhere ( 14), not to mention that our patients were expected to be at higher risk than the general population of endometrial patients in the Rotte et al. series (26). HDR treatment usually requires more

et al.

41

applications than LDR therapy, and thus could be associated with more complications unrelated to bed rest in patients with cardiac problems. With the prevalence of HDR brachytherapy treatment, this concern needs to be addressed (7). Patients constituting a high-risk group for thromboembolic complications are those with trauma to the lower extremities or pelvis, those with a malignant disease, those with a history of prior thromboembolisms, and those with obesity, advanced age, and prolonged bedrest (1, 6, 23, 29). All of our patients possessed at least two or more of these risk factors. However, only one event of pulmonary embolism occurred and there was no deep vein thrombosis of legs. This incidence of 0.6% is comparable with the experience of the University of Minnesota ( IO), although the general condition of our patients was poorer. An extremely low incidence of thromboembolism in the current series (one pulmonary embolism occurred 4 weeks after implant) prevents us from a meaningful analysis of the contribution of preventive measures. However, our data implies that with an adequate preoperative assessment and the implementation of preventive measures, as is now routinely used at the Institute, the incidence of thromboembolism for low dose rate gynecological brachytherapy can be lower than 1% among high-risk patients. For those patients with a previous history of thromboembolism and taking warfarin, the medication is discontinued 48 h before the procedure and resumed postoperatively ( 17). For those not taking warfarin, routine 5000 units of heparin is given subcutaneously every 8 to 12 h (5,20,23,25,36). The external pneumatic compression device serves as a supplement when indicated (3, 8, 28, 30). CONCLUSIONS

The medical risk factors of brachytherapy-related complications reported in other series were not shown to be significant in the current study. With judicious preoperative assessment and adequate preventive measures, the morbidity and mortality rate of life-threatening complications has been shown to be 4.2% and 2.1%, respectively. We conclude that the brachytherapy-related medical complication is uncommon in this compromised patient population, and that conventional low dose rate brachytherapy is a safe component of definitive radiation therapy for patients with Stage I medically inoperable endometrial cancer.

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