Tolerance of half-body irradiation as systemic therapy for patients with locally advanced breast cancerкод для вставкиСкачать
Medical and Pediatric Oncology 33:558–562 (1999) Tolerance of Half-Body Irradiation as Systemic Therapy for Patients With Locally Advanced Breast Cancer Lilia Gocheva, MD,1* Jordan Todorov, MD,1 and Samuel Danon, MD 2 Background. Locally advanced breast cancer (LABC) is one of the main causes of cancer death among women in Bulgaria. In 1988, when this study started, there was still controversy about the role of chemotherapy in controlling systemic disease. There were encouraging results from the Radiation Therapy Oncology Group (RTOG) 82-06 study suggesting that half-body irradiation (HBI) should be used earlier in the disease course to prevent the development of metastases. There were many patients with LABC requiring treatment, but there was a problem with obtaining the drugs needed; they were expensive and not consistently available. Procedure. Taking into account the medical contraindications to chemo- therapy treatment, its toxicity, and the possibility of chemoresistance, we initiated this study to look at the effects of HBI given as two fractions of 4 Gy to the upper and then lower parts of the body, after surgery and before local radiotherapy. Results. The acute tolerance of this regimen in 36 patients with LABC was as good as it was in 4 additional LABC patients with M1 disease, and hematologic recovery was satisfactory. Conclusions. We conclude that systemic treatment with HBI is tolerable. It therefore may be a convenient and cost-effective treatment for LABC, although better treatments are still needed. Med. Pediatr. Oncol. 33:558– 562, 1999. © 1999 Wiley-Liss, Inc. Key words: half-body irradiation; locally advanced breast cancer; systemic treatment of breast cancer INTRODUCTION Breast cancer is one of the most common forms of malignancy in women in Bulgaria, with 1 in 19 being affected at some time during life, and locally advanced breast cancer (LABC) is a major cause of death among Bulgarian women. LABC is defined in this study as breast cancers that were mainly T3, T4 and N2, N3 tumors, technically resectable lesions in patients who had not received previous treatment with neoadjuvant chemotherapy, locoregional radiotherapy, or hormonal treatment. The Radiotherapy Department of the Medical University in Sofia is one of the two main centers in the capital and one of 13 radiotherapy centers in Bulgaria. The treatment of women with breast cancer forms the bulk of the routine daily workload. Bearing in mind the medical problems associated with chemotherapy and economic problems (availability of drugs, irregular supply, and high price), we investigated the role of half-body irradiation (HBI) as first-line systemic therapy as an alternative to chemotherapy in 36 patients with LABC. This represented all the patients with LABC as defined above who presented to our clinic from the geographic region affiliated with it (population of 650,000) during the period of the study. Experimental studies have indicated that single doses of 6–8 Gy are capable of achieving 1–3 logs of cell kill . Responses to HBI in patients with advanced disease have been short-lived, and for these reasons HBI seemed © 1999 Wiley-Liss, Inc. more likely to be effective in the treatment of microscopic and occult metastases [2–5]. It is relatively easy to add local radiotherapy to HBI to boost the dose to the tumor locally, and there is a possible beneficial hormonal action if ovarian ablation is produced. The study was designed to determine the clinical and hematologic tolerance of HBI as first-line systemic therapy in patients with LABC. MATERIALS AND METHODS From January, 1988, to December, 1996, 36 consecutive patients with technically resectable LABC (34 females and 2 males) received HBI as first-line systemic therapy instead of chemotherapy in the Radiotherapy Department of the Medical University in Sofia. Four additional patients with LABC and monostatic metastatic disease identified only by bone scan were treated in the same way as those with LABC except that three of the four were also given three cycles of adjuvant CMF (cyclophosphamide, methotrexate, and fluorouracil) chemotherapy after completing HBI and local radiotherapy. 1 Radiotherapy Department, Medical University, Sofia, Bulgaria 2 National Oncological Center, Sofia, Bulgaria *Correspondence to: Assist. Prof. Dr. Lilia Gocheva, M.D., Dimitar Nestorov St., Bl. 120A, Sofia 1612, Bulgaria. E-mail: firstname.lastname@example.org Received 13 October 1998; Accepted 15 June 1999 HBI for Breast Cancer This treatment did not appear to distort the assessments of toxicity, so their data are also included in those analyses that follow. Patient Characteristics Staging investigations included clinical examination, chest X-ray films, complete blood count and serum chemistry, serum carcinoembryonic antigen (CEA) and CA 15-3 levels, abdominal ultrasound, bone scans, CT scan, and, if considered relevant, bone marrow biopsy. Patients with pathologically documented breast cancer were eligible for entry to the study if: Karnofsky performance status was at least 90, there was no history of prior malignant tumor, no previous tumor treatment, hemoglobin >11 g/100 ml, WBC count >4,000/l, platelet count >150,000/l, urea (8.0 mmol, serum creatinine <1.5 mg/ dl, and serum bilirubin <1.5 mg/dl, and they were less than 65 years of age, with no history of myocardial infarction or congestive cardiac failure or arrhythmia, no uncontrolled hypertension, and no uncontrolled infectious disease. All patients were clinically evaluated by a surgeon and an oncologist. Histologic information was obtained from the original pathologist’s detailed report of local disease and nodal and other invasion. Biopsy samples were classified and graded according to the WHO classification. Disease was staged clinically according to the UICC TNM classification. Hormone receptor studies were carried out whenever possible. Treatment Surgery. The local tumor in the breast was removed by radical mastectomy or quandrantectomy. Axillary dissection was limited to lymph nodes at levels I and II. Large-field radiotherapy. HBI was given with parallel-opposed fields at 182 cm or 280 cm. At the shorter treatment distance, irradiation of the upper half body was effected through two pairs of parallel opposed fields. At the longer treatment distance, one pair of parallel opposed fields was used. Eight Gy was given in two fractions of 4 Gy with a 6 hr interval. Four weeks later irradiation of the lower half body was given again in two fractions of the same dose. Local radiotherapy was given 4 weeks later. Upper HBI included the entire upper torso, head, and upper extremities down to the level of L1/L2. The lower half of the body included the remaining part of the trunk and the thighs. Lithium fluoride dosimetry and semiconductor detectors were used to obtain in vivo measurements at a number of specified body sites. Lens shielding was not used, and lung shielding was used in 30% of the patients. Patients were hospitalized for a mean of 4 days to ensure adequate premedication with antiemetics and oral steroids. Patients were discharged when all vital signs were normal. 559 Local radiotherapy. After HBI, local irradiation was given to a clinical target volume (CTV), which included the chest wall with the deep internal border (defined by a CT scan) in the middle of the ribs. The planning target volume (PTV) gave a margin of 5–7 mm around the clinical target volume. Patients were treated with parallel opposed medial and lateral tangential cobalt 60 beams to a dose of 30 or 40 Gy. Dose was specified so that the PTV was encompassed within the 95% isodose. Wedge filters were added as necessary to improve dose distribution. Lymph node irradiation was given to some patients to a dose of 30 or 40 Gy using a telecobalt unit at 110 cm SSD. Assessment of Response Acute toxicity was recorded by the patient on a questionnaire, which was completed on the first day of radiotherapy, weekly during radiotherapy, in the first month after completion of treatment, and then monthly up to 6 months. The questionnaire was designed to record the onset, peak, and duration of acute side-effects resulting from HBI. As well as specific effects, general effects such as tiredness, nausea, and activity levels were included. Side effects were graded according to the WHO/ RTOG guidelines, and the worst grade for each patient was used. Follow-Up Patients were followed until death or until the end of the study in December, 1996, and no one was lost to follow-up. Follow-up was by clinical examination, with chest radiography, abdominal ultrasound, bone scan, and blood tests. Patients were seen every month for the first year, quarterly, until the third year, and every 6 months thereafter. Disease control and complication of treatments were evaluated at each follow-up. RESULTS Thirty-eight patients underwent a radical mastectomy, and two had a quadrantectomy. Axillary dissection limited to levels I and II nodes was performed in 38 patients. The median number of nodes removed was 10 (range 3–23). Lymph nodes were positive in 38 cases (95%). In 30% of the cases, at least 10 positive nodes were removed. The median interval between the date of surgery and start of HBI was 56 days. This long interval was caused by delayed wound healing or late referral. The patients were hospitalized for a mean of 4 days (range 2–14). Lung shielding was used in 12 patients (30%). Following HBI, 38 patients received chest-wall irradiation; two of four patients with bone involvement also received local irradiation. Twelve patients (30%) received 30 Gy in 2 Gy fractions given as five fractions/week, and 25 560 Fig. 1. Gocheva et al. Nausea, vomiting at the day of HBI and after the treatment. patients (62.5%) received 40 Gy. In one patient, a dose of 50 Gy was given because the risk of local recurrence in the chest wall was considered very high. Twelve patients had irradiation to nodal areas (including the supraclavicular, axillary, and internal mammary node chains) of 30 Gy, and 26 patients received 40 Gy (2 Gy per fraction per day/5 fractions per week using a telecobalt unit at 110 cm SSD). Three patients received chemotherapy after completing HBI and local radiotherapy, and 39 of the 40 were given tamoxifen on a 5 year regimen starting immediately after surgery. Side Effects of Treatment No symptoms of fever, muscular pains, or diarrhea were seen. The major acute problems were nausea and vomiting, mouth dryness, parotitis, erythema, pneumonitis, and alopecia. Nausea and vomiting were the most common side effect, especially after upper HBI. This occurred after each 4 Gy fraction, which were given between 7:00 and 8:00 AM and between 1:00 and 2:00 PM. Symptoms were most pronounced during the time of irradiation and 5–9 hr after the start of treatment. Patients were therefore still suffering symptoms from the first fraction while the second was being given. Grade I toxicity was shown in 29 patients (73%) 7 hr after the first treatment, with eight patients (20%) showing grade II toxicity and three (8%) grade III toxicity between 7 and 9 hr after the first treatment. Thereafter nausea and vomiting resolved rapidly and patients had recovered their appetite by 8 PM (13 hr after the first treatment). After lower HBI, 26 patients (65%) had vomiting 7–9 hr after the first treatment, which resolved by 13 hr after the first treatment. Figure 1 shows the pattern of nausea and vomiting after upper HBI and lower HBI. Thirty-five patients (88%) had grade I toxicity up to 7 days after upper HBI, and three (8%) had grade II toxicity. Seven (18%) patients suffered from transient nausea on day 14. After lower HBI 22 (55%) of patients had persisting nausea (grade I) on day 7; only six (15%) had persisting symp- Fig. 2. Effects of study treatment on leukocytes, neutrophils, and lymphocytes over time. toms at day 14 (grade I). During local radiotherapy, only two (5%) patients experienced nausea. The most pronounced symptoms were a feeling of tiredness and loss of appetite, which continued in some patients for 2–3 months after the completion of local radiotherapy. Symptoms such as dry mouth, parotitis, and erythema required no treatment and subsided spontaneously. Pneumonitis is known to be the dose-limiting complication for HBI. During the period of observation, 15 patients developed pneumonitis (8/28 without and 5/12 with lung shielding), 13 grades I and II, and two (with lung shielding) grade IV. Lung changes were predominantly (in 10 patients) seen on the side of the primary tumor. Variation in AP separation (average 21 cm, range 15.5–27 cm) or known emphysema (six patients) did not correlate with incidence of pneumonitis. The diagnosis was made when the clinical characteristics of cough and shortness of breath were seen in combination with characteristic X-ray changes and lung scintigraphy with 99m TC LyoMAA. Onset was commonly in the fourth month (range 2–6 months). Two patients were shown to have cytomegalovirus-associated pneumonitis with bone marrow depression, and they both died. The in vivo measurements in these two patients did not show a dose in excess of lung tolerance (8 Gy). Hematologic Tolerance The patterns of fall and recovery of white cells and platelets are shown in Figures 2 and 3. None of the patients experienced life-threatening hematologic toxicity, and recovery was comparatively fast and complete. Peripheral counts returned to normal levels by 1 year after systemic radiotherapy but did not reach preradiation levels. The fall in leukocyte count persisted to the fourteenth day and was more pronounced after lower HBI. Spontaneous recovery occurred after 3 or 4 weeks. Similar responses were seen both in neutrophils and in lympho- HBI for Breast Cancer 561 DISCUSSION Fig. 3. Effects of study treatment on thrombocytes over time. cytes, although the ratios were different, with a relative increase in neutrophil numbers after the upper HBI and a fall in lymphocytes. Platelet recovery was slower. The nadir of the count was reached at the end of local radiotherapy, but no episodes of bleeding occurred and transfusions were not needed. The fall in red blood cell count, in hemoglobin, and in hematocrit was less marked and statistically significant only during the first 2 or 3 months after completing local radiotherapy. No significant changes in liver enzymes, urea, or creatinine were observed. Hematologic toxicity caused no major delays or interruptions in treatment. Follow-Up All patients were followed (average 36 months, range 5–89 months). By the time the study was concluded (December, 1996), 16 of 40 had died. Twenty-two patients with median follow-up of 46 months are alive with no evidence of disease, and two with disease recurrence have been successfully treated with chemotherapy. Overall survival (OS) of the 36 patients with only LABC was 80% at 1 year, 65% at 2 years, and 54% at 3 and 5 years. Disease-free survival (DFS) was 78% at 1 year, 61% at 2 years, and 30% at 3 and 5 years. Two (6%) patients had local recurrences on the thoracic wall (within the radiation field). The intervals from the beginning of treatment to local recurrence are 19 and 21 months, and both occurred at the site of the operation scar after doses of 30 Gy. After this experience the dose was increased to 40 Gy for all patients, and no further recurrences were seen. Both of these two patients developed distant metastases (lung metastases at 1 month and soft tissue metastases at 4 months, respectively). Distant metastases developed in 12 of the 36 patients (33%). Two were regional (contralateral supraclavicular lymph nodes and contralateral breast, both with 30 Gy local radiotherapy). Other sites of metastases were lung (three; all without lung shielding), soft tissue (two; outside the irradiated area), bones (two), and liver, abdomen, and spinal cord (one each). A low number of potential HBI-related complications was observed in this study: thyroid abnormalities in two patients, and acute myeloid leukemia in one. All irradiated women developed primary ovarian ablation. The present study of HBI as systemic therapy for patients with LABC shows that it is a well-tolerated procedure. With lung doses of 7.3–7.5 Gy only two patients died of pneumonitis after upper HBI, a rate of 5%. The hematologic changes seen in the first month after HBI correspond well with those described by other authors [6–9]. Patients who subsequently required systemic chemotherapy tolerated this without any problem. The use of HBI systemic therapy is attractive insofar as it addresses both local control and systemic relapse. Bergsagel  suggested that a dose of 725 cGy upper HBI and 1,000 cGy lower HBI might theoretically achieve a 3 log cell kill. Tumor debulking of this magnitude might be expected to extend survival significantly. In addition, radiation may circumvent some of the problems of drug resistance at the cell membrane level. If systemic radiotherapy fails, chemotherapy can subsequently be given with good response rates, whereas it is well known that remission after use of second-line systemic chemotherapy occurs less frequently [11,12]. The effect of chemotherapy in prolonging long-term survival in premenopausal patients is demonstrated most clearly in those who have become amenorrheic after treatment. The effect of HBI might therefore be prolonged because ovarian function is ablated as was seen in the patients in this study. When we decided to use HBI as a systemic therapy, we took into account the large number of high-risk breast cancer patients in this country. We considered a number of medical (contraindications, toxicity, chemoresistance) and economic (limited number of cytostatics, high prices, supply problems) factors that restricted the use of chemotherapy. We were encouraged by the results and recommendations of the RTOG 82-06 study , in which earlier application of HBI as adjuvant treatment for occult metastases in high-risk cancer patients was proposed. Forty Gy after 8 Gy of upper hemibody irradiation is a dose that corresponds to that used in many centers for radical local treatment. 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