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Effect of Delay in Initiating Radiotherapy for Patients with Early Stage Breast Cancer
Clinical Oncology (2004) 16: 6–11 doi:10.1016/j.clon.2003.10.008
Original Article Effect of Delay in Initiating Radiotherapy for Patients with Early Stage Breast Cancer V. Benk*, L. Joseph†, P. Fortin†, G. Zhang*, P. Belisle†, C. Levinton†, V. Ho†, C. R. Freeman* *Department of Radiation Oncology and †Division of Clinical Epidemiology, McGill University Health Centre, McGill University, Montreal, Canada ABSTRACT: Aims: For early stage breast cancer, a standard treatment option is partial mastectomy followed by radiation treatment. The 5-year risk of local recurrence ranges from 6–9%. Variable waiting times for radiation treatment of breast cancer in our institution provided an opportunity to evaluate the impact of waiting time on the risk of local recurrence. Materials and methods: Between January 1988 and December 1989, 482 patients with stage I and II breast cancer were treated with radiotherapy in our institution. Information on prognostic factors, such as age, tumour size, histological grade, number of positive lymph nodes and margins of resection, was abstracted from their charts. The interval between date of surgery and date of initial radiation treatment was noted. Dates of local recurrence, metastasis and deaths were recorded. Results: At 5 years, the local recurrence rate was 8%, the metastatic rate 12% and the ‘cause-specific’ survival rate 90%. In univariate analysis, the risk of local recurrence was associated with younger age, higher histological grade and time to radiation treatment. In the multivariate analysis, the effect of time to radiation treatment on the risk of local recurrence was equivocal. Conclusion: Delay in radiation treatment may be associated with an increased risk of local recurrence of breast cancer, at least in our centre. Future research is needed on a larger data set to more accurately estimate the effect of time to radiation treatment on the risk of local recurrence. Benk V. et al. (2004). Clinical Oncology 16, 6–11 2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Radiotherapy, breast cancer, delay, recurrence, outcome, health services research Received: 12 February 2003
Revised: 6 August 2003
Accepted: 10 October 2003
Introduction
Materials and Methods
For early stage breast cancer, a standard treatment is partial mastectomy followed by breast radiation. The risk of local recurrence at 5 years ranges from 6–9% [1–5]. A Canadian consensus document recommended that all women who undergo breast-conserving surgery should have postoperative irradiation to decrease the risk of local recurrence, which should be started no later than 12 weeks after surgery [6]. In the U.K., the recommended time interval between breast-conserving surgery and postoperative radiation should not exceed 20 working days except for clinical reason [7]. There is concern that increasingly difficult access to radiation oncology departments may be resulting in adverse effects on patient outcome, such as increased local recurrence and lower survival [8–11]. Prolonged waiting time in Quebec provided an ethically acceptable opportunity to evaluate the effect of delay for radiation treatment on the risk of local recurrence in a cohort of patients with stage I or II breast cancer.
Between 1 January 1988 and 31 December 1989, 482 women with clinical stage I or II breast cancer (AJCC) [12] were treated with postoperative adjuvant radiotherapy at the three hospitals affiliated with McGill University. For these patients, the intended treatment was whole-breast radiation with opposed tangential fields to a total dose of 50 Gy, given in fraction sizes of 2 Gy per day, 5 days per week, using a Cobalt 60 unit or a 4/6 MV linear accelerator. A 10 Gy boost was given to patients with a close or positive margin after resection (n=20). If more than four lymph nodes were involved, the intended treatment was to irradiate the axilla and the supra-clavicular regions to a dose of 50 Gy in 25 fractions [13]. The decision to administer adjuvant systemic therapy was based on the patient’s risk for distant recurrence. The standard regimens of chemotherapy were six cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) or four cycles of AC (adriamycin, cyclophosphamide). Radiation treatment was given concurrently with the CMF or after completintg the AC regimen. Adjuvant endocrine treatment with tamoxifen was intended to be given to all women with estrogen-receptor-positive tumours. Patients on clinical
Author for correspondence: Dr. V. Benk, Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. Tel: +1 416 480 4982; Fax: +1 416 217 1338; E-mail: [email protected] 0936-6555/04/010006+6 $30.00/0
2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
IMPACT OF TREATMENT DELAY
trials started the radiation treatment according to protocol guidelines. A data abstractor documented the demographic factors (patient age, median income estimated from the postal code of residence published by Statistics Canada [14]) and the staging and pathological factors (disease stage, tumour grade, tumour size, number of nodes removed and involved, resection margin status). The treatment-related factors (total dose of radiation, number of fractions, radiotherapy technique used, use of a boost, use of chemotherapy, type of chemotherapy regimen, use of tamoxifen, treatment on protocol) were also collected. A random sample of 10% of all the charts was reviewed by the investigator (VB). Errors were found in less than 1% of all entries. Three dates were tracked to indicate the waiting time indicator for radiation treatment. The date of diagnosis was defined as the time of the surgical procedure at which the patient underwent complete gross excision of the tumour with or without axillary lymph-node dissection. The date of first consultation was defined as the time of first visit with the radiation oncologist, and the date of first radiation treatment was defined to be when the patient received the first dose of radiation. Using these dates, the time to radiation treatment was defined by the interval between the date of surgery and the date of first radiation treatment. The time to radiation treatment was divided into time to consultation, defined by the interval between the date of surgery and the date of first consultation, and the time to treatment unit, defined by the interval between the date of the first evaluation and the date of first radiation treatment. Date of local recurrence, defined as a pathologically confirmed recurrence within the radiation field, either in the treated breast or in the lower part of the axilla, was abstracted. Date of metastasis was defined from either clinical or radiological reports. Death was defined as related to the cancer if the patient had proven progression of her disease. With these dates, we defined the total follow-up time from the date of surgery to date of first event or date of last visit if the patient was free of disease at that time.
Statistical Analysis
The primary outcome measure was time to local recurrence, defined as a recurrence within the radiation field. The relationship between local recurrence and waiting time, defined as the time from initial surgical resection to the administration of the first fraction of radiotherapy, was first evaluated by univariate analyses of waiting time. The relationship between local recurrence and all possible confounding factors, such as age, tumour size, histological grade, number of positive lymph nodes, modalities of treatment (tamoxifen, chemotherapy, or both), referring hospital (community or university) and income was also evaluated by univariate analysis. Possible confounders were investigated by a two-step process. First, for continuous variables, a correlation
7
matrix was calculated, and for categorical variables, bivariate tables were constructed to look for relations among the entire set of possible confounders. This allowed us to view which factors were correlated or possibly colinear, which helped in choosing factors to include in multivariate analyses. Since our main variable of interest was time to first treatment, a variety of Cox proportional hazards models were run. Each time, we included waiting time as a variable and viewed how the coefficient for waiting time changed as different potential confounders entered or exited the model. Calculating the exponential of the regression coefficients from the Cox model provided an estimate of the hazard ratio (HR), along with its 95% confidence interval (CI) [15]. If, for example, the point estimate and 95% CI for waiting time remained stable across the variety of possible models run, then there would be no evidence of confounding between the other variables and waiting time.
Results Patient Characteristics
For the entire population, the median time to radiation treatment was 8 weeks, with a median time to consultation of 4.4 weeks and a median time to treatment unit of 3.5 weeks (Table 1). The 90th percentile wait for time to consultation was 10 weeks and the 90th percentile wait for time to treatment unit was 8.5 weeks. Characteristics of women who waited more than 8 weeks and women who did not are included in Table 1. Only three women were reported with a positive margin after resection. One hundred and twenty-nine women had positive axillary lymph nodes, of which 36 had more than four lymph nodes involved (26 were treated with a four-fields radiation technique). The median income and the referring hospital distribution pattern were similar in both groups. As expected, differences were observed between women who received chemotherapy (n=131) and those who did not (n=351). The patients receiving chemotherapy had a longer median time to radiation treatment: 13.7 weeks (standard deviation [SD]: 8.2) compared with 9.3 weeks (SD: 8.7). Patients receiving chemotherapy were also younger (49 years vs 61 years), presented with higher grade tumours (86% grade 2/3 vs 66%), had larger tumour size and positive axillary lymph nodes (52% vs 18%) and were consequently more often stage II (61% vs 34%). Having a stage II disease and being on protocol were associated with shorter delays to receive radiation treatment. Outcome
Median follow-up was 68 months. At 5 years, 11 patients (2%) were lost to follow-up. Thirty-nine local recurrences occurred, 35 in the treated breast and four in the lower axilla. Five local recurrences occurred in three patients with bilateral breast cancers. Fifty-five patients
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CLINICAL ONCOLOGY
Table 1 – Patient characteristics according to time to radiation treatment
Mean age, years (SD) (range) Stage I (%) Stage II (%) (5 missing ‘stage’ data) Mean tumour size, cm (SD) Positive lymph nodes (%) (28 missing ‘lymph nodes’ data) Grade 1 (%) Grade 2 (%) Grade 3 (%) (117 missing ‘grade’ data) On tamoxifen (%) (11 missing ‘tamoxifen’ data) On protocol (%) (17 missing ‘on protocol’ data) On chemotherapy (%) Community hospital (%) (1 missing ‘hospital’ data) University hospital (%) Mean income (SD) ($1000 CDN)
Total n=482
%8 weeks n=246
>8 weeks n=236
57 (11.6) (28–82) 289 (59) 188 (41)
58 (10.8) (29–82) 165 (67) 80 (32)
56 (12) (28–80) 124 (53) 108 (46)
1.5 (1) 129 (28) 107 (29) 155 (41) 111 (30)
1.38 (0.9) 66 (28) 58 (31) 76 (41) 51 (28)
1.6 (1.07) 63 (28) 49 (26) 79 (42) 60 (32)
259 (50) 134 (29) 138 (28) 117 (24) 364 (76) 47 (13.2)
148 (61) 70 (38) 55 (22) 62 (25) 183 (74) 46.7 (13.3)
111 (47) 54 (23) 83 (35) 55 (23) 181 (76) 47.7 (13.2)
cm, centimeters; SD, Standard deviation; $CDN, Canadian dollars.
had distant recurrence, with eight of these developing both local recurrence and metastases. Fifty patients died of their breast cancer. The 5-year local recurrence rate was 8%, the metastatic rate 12% and a survival rate of 90%.
ment (10 weeks). Patients who died from their cancer had a higher histological grade but did not wait longer for their radiation treatment. The percentage of patients receiving chemotherapy was similar between the two groups: 30% in the surviving group and 36% in the non-surviving group.
Prognostic Factors Univariate analysis
Multivariate analysis
Table 2 provides prognostic factors for the development of local recurrence. Patients who developed a local recurrence were younger (49 vs 59 years), had a higher histological grade and waited longer to receive radiation treatment (14 vs 8 weeks). Women who received chemotherapy did not have a significantly different risk of local recurrence compared with women who did not receive chemotherapy. For women who developed a local recurrence, the median time to radiation treatment was 14 weeks. It was split between a median time to first consultation with a radiation oncologist of 5 weeks (90th percentile of wait: 15 weeks) and a median time to first radiation treatment after the consultation of another 5 weeks (90th percentile wait: 18 weeks). For the patient with no local recurrence, the median time to radiation treatment was 8 weeks. It was split between a median time to first consultation of 4.2 weeks (90th percentile wait: 9 weeks) and a median time to first radiation treatment after consultation of 3.5 weeks (90th percentile wait: 7.7 weeks). The HR of the effect of time to radiation treatment on local recurrence rate was 1.08 per additional month of delay (95% CI 1.004–1.16). Characteristics of patients with and without metastatic events were also analysed. Patients with metastatic disease were younger (53 vs 59 years), had a higher histological grade and were more likely stage II, but they did not wait longer before starting their radiation treat-
Multivariate Cox proportional hazard models were conducted, including various combinations of the variables listed in Table 3. No important confounding effects were found in the analysis. In particular, analysis was performed in chemotherapy and non-chemotherapy patients separately, and also together. Near identical effects for delay were found in each of the three analyses. There was no counfounding effect of chemotherapy on waiting time (i.e. the coefficient for waiting time was the same regardless of whether the chemotherapy was or was not in the model). Therefore, the results were reported for all patients together. Depending on the particular model that was selected, the adjusted HR of effect of time to radiation treatment on local recurrence varied slightly. For example, after adjusting for age, the HR of time to radiation treatment was 1.08 per month (95% CI 1.04 to 1.13). After adjusting for both age and tamoxifen, the HR remained identical at 1.08 per month, but the CI varied slightly (95% CI 1.03–1.13). In a model that adjusted for age, grade, tamoxifen and/or chemotherapy use, positive nodes and type of referring hospital, the HR for time to first treatment was 1.13 per additional month of waiting (95% CI 0.96–1.33). Therefore, point estimates for the risk of local recurrence per month of additional waiting time varied between 8% and 13% depending on the particular model used. In the model with all important covariates included (Table 3), the confidence interval included the null value of 1, with
9
IMPACT OF TREATMENT DELAY
Table 2 – Univariate analysis of prognostic factors for local recurrence No recurrence (n=445)
Recurrence (n=37)
Hazard ratio (95% CI*)
59.5 (11.5) (28–82) 269 (60) 1 (1) (0.3–5) 117 (26) 102 (23) 145 (32) 90 (20) 121 (27) 246 (55) 125 (28) 330 (74) 46. 12 (13.21) 8 (8.9)
49 (10.5) (33–68) 20 (53) 1 (0.94) (0.3–4) 12 (33) 5(14) 10 (27) 21 (57) 17 (43) 13 (33) 9 (25) 34 (87) 43. 58 (13.97) 14 (6.8)
0.96 (0.93–0.99)
Mean age, years (SD) (Range) Stage I (%) Mean tumour size, cm (SD) (Range) Positive lymph nodes (%) Grade 1 (%) Grade 2 (%) Grade 3 (%) On chemotherapy (%) On tamoxifen (%) On protocol (%) University hospital (%) Median Income, $1000 CDN (SD) Median time to radiation treatment (weeks) (SD)
1.40 (0.65–3.03) 1.02 (0.71–1.45) 1.06 (0.94–1.18) Reference category 1.38 (0.47–4.03) 3.69 (1.36–10.0) 1.89 (0.96–3.75) 0.51 (0.25–1.03) 0.42 (0.15–1.19) 1.74 (0.67–4.50) 0.985 (0.96–1.01) 1.08 (1.004–1.16) Per month of delay
cm, centimeters; SD, standard deviation; $CDN, Canadian dollars. *CI, confidence interval.
Table 3 – Multivariate analysis of prognostic factors Risk ratio Age Grade 1 vs 2–3 Tamoxifen Chemotherapy Positive nodes University hospital Time to radiation, per month of delay
0.976 0.709 0.721 0.868 1.167 1.31 1.13
95% CI 0.94 0.41 0.47 0.53 0.73 0.78 0.96
to to to to to to to
1.01 1.22 1.09 1.41 1.87 2.19 1.33
Co-efficient (se) 0.02 (0.02) 0.34 (0.28) 0.33 (0.22) 0.14 (0.25) 0.15 (0.24) 0.27 (0.26) 0.12 (0.08)
CI, confidence interval; se, Standard error.
the CI being large. In all smaller models of interest, the lower limit for the CI did not include this null value. Overall, although we cannot exclude the possibility of no effect of waiting time on the risk of local recurrence, we also cannot exclude effects of waiting time to up to 33% per month. The other potentially important prognostic factor of local recurrence was the histological grade, comparing grade 1 and 2 vs 3 in a univariate analysis gives an HR of 0.36 (95% CI 0.17–0.75). However, after adjusting for others factors in the multivariate model, this effect was diminished with a confidence interval that included the null value of 1. There was no evidence that the presence of positive lymph nodes affects the risk of local recurrence. Discussion
Our analysis of stage I and II breast cancer patients, treated with conservative surgery followed by radiation therapy, shows a local recurrence rate of 8%, a metastasis rate of 12% and a survival rate of 90% at 5 years. This is consistent with other published results [1–5]. We found some indication that time to radiation treatment, defined as the interval between the date of surgery and
the date of first radiation treatment, could clinically affect the risk of local recurrence. Given that the HR for the effect of time to radiation treatment on the risk of local recurrence was about 1.08, or about 8% increased risk per month, and that the overall rate of local recurrence at 5 years was 8%, or about 13% per month, then the maximum absolute increase would be about 1% per month of delay (8%13%). This information is consistent with the data for patients whose radiation was delayed indefinitely, or who were treated with lumpectomy alone, where a 35% risk of local recurrence was reported at 12.5 years [2]. However, an ‘acceptable’ delay for radiation treatment is not possible to define from our data. Furthermore, this definition could vary with the individual risk of local recurrence. For instance, histological grade was associated with an increased risk of local recurrence. Patients with grade 3 tumour had a higher risk of local recurrence than those with grade 1 and 2 tumours. Income did not influence the patient’s outcome [16]. Some potential limitations of our study need to be discussed. First, our study was retrospective, but a nearly complete follow-up (2% lost to follow-up at 5 years) was obtained. Moreover, it would clearly be unethical to randomise patients without other adjuvant
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CLINICAL ONCOLOGY
therapy to short or long waiting times. Second, the original pathology was not reviewed to assess the margins of excision or to verify the presence of an extensive intraductal component. However, only three patients were initially described with a positive margin. The pathological assessment was similar for all cases, whether patients waited or not for their radiation treatment, thus resulting in a random misclassification. Third, reported delays included those for patients who did or did not receive chemotherapy. Chemotherapy could be a confounding factor: patients receiving chemotherapy were delayed for their irradiation, and chemotherapy could decrease the risk of local recurrence [17,18]. However, no effect of chemotherapy on the risk of local recurrence was seen in our patients in both univariate and multivariate analysis. Therefore, we believe that we can report the impact of delay for both patient groups combined. Finally, a medical bias could exist in which patients with more severe disease were treated sooner. This information could not be captured in our data collection. Therefore, uncontrolled confounding factors could still have occurred despite our multivariate adjustments. There is biological evidence supporting the view that delaying irradiation has a detrimental effect on treatment outcome [19,20]. Clinical data have been reported for head and neck cancers, and cervical cancers [21]. For breast cancer patients with or without indication of chemotherapy, the link between an increased risk of local recurrence and the delay between surgery and the initiation of radiation remains controversial. Recently, two systematic reviews of the literature on delay to radiation and outcome of breast cancer were reported. Huang et al. [22] concluded that the 5-year local recurrence rate was significantly higher in patients treated with adjuvant radiation for breast cancer more than 8 weeks after surgery than those treated within 8 weeks of surgery. In contrast, Hebert-Croteau et al. [23], in a critical review of the same peer-reviewed articles, concluded that radiotherapy is effective in controlling microscopic disease independently of time to radiation. However, given the methodological weaknesses identified in his critical appraisal of the available evidence, his recommendation was to endorse current Canadian recommendations and to deliver radiation no later than 12 weeks after surgery for women not receiving chemotherapy. In our institution, the median time to reach the treatment unit has increased over the past decade, from 3.5 weeks in the late 1980s to 5 weeks in the early 1990s [16]. The results of a survey showed that Canadians are waiting to receive medical care, including radiation treatment throughout the entire country [8]. In theory, knowing that excessive time to radiation treatment is associated with increased risk of local recurrence and that local recurrence may lead to further dissemination of cancer cells, an increased risk of metastasis could be expected [24]. In this study, we found no evidence that delay to radiation treatment affects the risk of metasta-
sis, but further work is required to more accurately estimate the parameters involved with this question. Furthermore, the time spent waiting to receive treatment could constitute an additional source of anxiety for the women and could affect their quality of life [25]. Additionally, the risk of having a mastectomy for recurrence when the patient requested breast preservation must be considered.
Conclusion
For stage I and II breast cancers, delay of radiation treatment may be associated with local recurrence, at least in our centre. The effect was small, in the order of an absolute increase of 1% per month of delay. This result awaits confirmation from larger data sets in other centres. In the mean time, it is prudent to recommend that adjuvant radiation treatment be delivered as soon as possible after conservative surgery. Acknowledgements. We thank Dr R. Battista, Dr J. M. Esdaile for their helpful comments on our manuscript. Supported by an internal award from The Montreal General Hospital Research Institute. Dr Fortin is a Senior Research Scholar of The Arthritis Society (Canada); Dr Joseph is a Senior Investigator of the Canadian Institute for Health Research.
References 1 Mansfield C, Komarnicky L, Schwartz G, et al. Ten-year results in 1070 patients with stage I and II breast cancer treated by conservative surgery and radiation therapy. Cancer 1995; 75:2328–2336. 2 Fisher B, Anderson S, Redmond C, et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333:1456–1461. 3 Early Breast Cancer Trialist’s Collaborative Group. Effect of radiotherapy and surgery in early breast cancer; an overview of the randomized trials. N Engl J Med 1995;333:1444–1455. 4 Jacobson JA, Danforth D, Cowan K, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995;322:907–911. 5 Gage I, Recht A, Gelman R, et al. Long-term outcome following breast-conserving surgery and radiation therapy. Int J Radiat Oncol Biol Phys 1995;33:245–251. 6 Canadian consensus document. Clinical practice guidelines for the care and treatment of breast cancer. Can Med J Assoc 1998;3:158. 7 Barrett-Lee P. Reducing delays in cancer treatments: some targets. A report of the Joint Council for Clinical Oncology, Royal College of Physicians and Royal College of Radiologists, 1993. 8 Ramsay C, Walker M. Fraser forum: waiting your turn: hospital waiting lists in Canada (7th edn), 1997. Vancouver: The Fraser Institute. 9 Craighead P, Ewing G. Compromise in radiation therapy facilities: local response to a nationwide problem. Can J Oncol 1993; 3:193–199. 10 MacKillop W, Zhou Y, Quizt C. A comparison of delays in the treatment of cancer with radiation in Canada and the United States. Int J Radiat Oncol Biol Phys 1995;32:531–539. 11 Keller DM, Peterson EA, Phil M, et al. Survival rates for four forms of cancer in the United States and Ontario. Am J Public Health 1997;87:1164–1167.
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12 American Joint Committee on Cancer. In: Beahrs OH, Henson DE, Hutter RVP, Myers MH, eds. Manual for staging of cancer, 4th edn. Philadelphia: JB Lipincott Company, 1992. 13 Podgorsak E, Pla M, Gosselin M, et al. The McGill isocentric breast irradiation technique. Med Dosim 1987;12:3–7. 14 Statistics Canada. Demographic and income statistics for postal areas. Quebec: Cat.#17–204. 15 Cox D. Regression models for life tables. J R Stat Soc 1972; 34:187–220. 16 Benk V, Ho V, Fortin P, et al. Predictors of delay in starting radiation treatment for patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 1998;41:109–115. 17 Overgaard M, Hansen P, Overgaard J, et al. Post-operative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949–955. 18 Ragaz J, Jackson S, Le N, et al. Adjuvant radiotherapy and chemotherapy in node positive premenopausal women with breast cancer. N Engl J Med 1997;37:956–962. 19 Thames H. An incomplete repair model for survival after fractionated and continuous irradiation. Int J Radiat Oncol Biol Phys 1985; 47:319–339.
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20 Tubiana M. Repopulation in human tumors, a biological background for fractionation in radiotherapy. Acta Oncol 1988; 27:83–88. 21 Fowler J, Lindstrom M. Loss of local control in radiotherapy. Int J Radiat Oncol Biol Phys 1992;23:457–467. 22 Huang J, Barbera L, Brouwers M, Browman G, MacKillop W. Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 2003;21:555–563. 23 Hebert-Croteau N, Freeman C, Latreille J, Brisson J. Delay in adjuvant radiation treatment and outcomes of breast cancer: a review. Breast Cancer Res Treat 2003;74:77–94. 24 Cowen D, Jacquemier J, Houvenaeghel G, et al. Local and distant recurrence after conservative management of ‘very low-risk’ breast cancer are dependent events: a 10-year follow-up. Int J Radiat Oncol Biol Phys 1998;41:801–807. 25 Miller A, Benk V, Rajan R, et al. The burden of waiting. Curr Oncol 1999;6:188.
Original Article Effect of Delay in Initiating Radiotherapy for Patients with Early Stage Breast Cancer V. Benk*, L. Joseph†, P. Fortin†, G. Zhang*, P. Belisle†, C. Levinton†, V. Ho†, C. R. Freeman* *Department of Radiation Oncology and †Division of Clinical Epidemiology, McGill University Health Centre, McGill University, Montreal, Canada ABSTRACT: Aims: For early stage breast cancer, a standard treatment option is partial mastectomy followed by radiation treatment. The 5-year risk of local recurrence ranges from 6–9%. Variable waiting times for radiation treatment of breast cancer in our institution provided an opportunity to evaluate the impact of waiting time on the risk of local recurrence. Materials and methods: Between January 1988 and December 1989, 482 patients with stage I and II breast cancer were treated with radiotherapy in our institution. Information on prognostic factors, such as age, tumour size, histological grade, number of positive lymph nodes and margins of resection, was abstracted from their charts. The interval between date of surgery and date of initial radiation treatment was noted. Dates of local recurrence, metastasis and deaths were recorded. Results: At 5 years, the local recurrence rate was 8%, the metastatic rate 12% and the ‘cause-specific’ survival rate 90%. In univariate analysis, the risk of local recurrence was associated with younger age, higher histological grade and time to radiation treatment. In the multivariate analysis, the effect of time to radiation treatment on the risk of local recurrence was equivocal. Conclusion: Delay in radiation treatment may be associated with an increased risk of local recurrence of breast cancer, at least in our centre. Future research is needed on a larger data set to more accurately estimate the effect of time to radiation treatment on the risk of local recurrence. Benk V. et al. (2004). Clinical Oncology 16, 6–11 2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Radiotherapy, breast cancer, delay, recurrence, outcome, health services research Received: 12 February 2003
Revised: 6 August 2003
Accepted: 10 October 2003
Introduction
Materials and Methods
For early stage breast cancer, a standard treatment is partial mastectomy followed by breast radiation. The risk of local recurrence at 5 years ranges from 6–9% [1–5]. A Canadian consensus document recommended that all women who undergo breast-conserving surgery should have postoperative irradiation to decrease the risk of local recurrence, which should be started no later than 12 weeks after surgery [6]. In the U.K., the recommended time interval between breast-conserving surgery and postoperative radiation should not exceed 20 working days except for clinical reason [7]. There is concern that increasingly difficult access to radiation oncology departments may be resulting in adverse effects on patient outcome, such as increased local recurrence and lower survival [8–11]. Prolonged waiting time in Quebec provided an ethically acceptable opportunity to evaluate the effect of delay for radiation treatment on the risk of local recurrence in a cohort of patients with stage I or II breast cancer.
Between 1 January 1988 and 31 December 1989, 482 women with clinical stage I or II breast cancer (AJCC) [12] were treated with postoperative adjuvant radiotherapy at the three hospitals affiliated with McGill University. For these patients, the intended treatment was whole-breast radiation with opposed tangential fields to a total dose of 50 Gy, given in fraction sizes of 2 Gy per day, 5 days per week, using a Cobalt 60 unit or a 4/6 MV linear accelerator. A 10 Gy boost was given to patients with a close or positive margin after resection (n=20). If more than four lymph nodes were involved, the intended treatment was to irradiate the axilla and the supra-clavicular regions to a dose of 50 Gy in 25 fractions [13]. The decision to administer adjuvant systemic therapy was based on the patient’s risk for distant recurrence. The standard regimens of chemotherapy were six cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) or four cycles of AC (adriamycin, cyclophosphamide). Radiation treatment was given concurrently with the CMF or after completintg the AC regimen. Adjuvant endocrine treatment with tamoxifen was intended to be given to all women with estrogen-receptor-positive tumours. Patients on clinical
Author for correspondence: Dr. V. Benk, Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. Tel: +1 416 480 4982; Fax: +1 416 217 1338; E-mail: [email protected] 0936-6555/04/010006+6 $30.00/0
2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
IMPACT OF TREATMENT DELAY
trials started the radiation treatment according to protocol guidelines. A data abstractor documented the demographic factors (patient age, median income estimated from the postal code of residence published by Statistics Canada [14]) and the staging and pathological factors (disease stage, tumour grade, tumour size, number of nodes removed and involved, resection margin status). The treatment-related factors (total dose of radiation, number of fractions, radiotherapy technique used, use of a boost, use of chemotherapy, type of chemotherapy regimen, use of tamoxifen, treatment on protocol) were also collected. A random sample of 10% of all the charts was reviewed by the investigator (VB). Errors were found in less than 1% of all entries. Three dates were tracked to indicate the waiting time indicator for radiation treatment. The date of diagnosis was defined as the time of the surgical procedure at which the patient underwent complete gross excision of the tumour with or without axillary lymph-node dissection. The date of first consultation was defined as the time of first visit with the radiation oncologist, and the date of first radiation treatment was defined to be when the patient received the first dose of radiation. Using these dates, the time to radiation treatment was defined by the interval between the date of surgery and the date of first radiation treatment. The time to radiation treatment was divided into time to consultation, defined by the interval between the date of surgery and the date of first consultation, and the time to treatment unit, defined by the interval between the date of the first evaluation and the date of first radiation treatment. Date of local recurrence, defined as a pathologically confirmed recurrence within the radiation field, either in the treated breast or in the lower part of the axilla, was abstracted. Date of metastasis was defined from either clinical or radiological reports. Death was defined as related to the cancer if the patient had proven progression of her disease. With these dates, we defined the total follow-up time from the date of surgery to date of first event or date of last visit if the patient was free of disease at that time.
Statistical Analysis
The primary outcome measure was time to local recurrence, defined as a recurrence within the radiation field. The relationship between local recurrence and waiting time, defined as the time from initial surgical resection to the administration of the first fraction of radiotherapy, was first evaluated by univariate analyses of waiting time. The relationship between local recurrence and all possible confounding factors, such as age, tumour size, histological grade, number of positive lymph nodes, modalities of treatment (tamoxifen, chemotherapy, or both), referring hospital (community or university) and income was also evaluated by univariate analysis. Possible confounders were investigated by a two-step process. First, for continuous variables, a correlation
7
matrix was calculated, and for categorical variables, bivariate tables were constructed to look for relations among the entire set of possible confounders. This allowed us to view which factors were correlated or possibly colinear, which helped in choosing factors to include in multivariate analyses. Since our main variable of interest was time to first treatment, a variety of Cox proportional hazards models were run. Each time, we included waiting time as a variable and viewed how the coefficient for waiting time changed as different potential confounders entered or exited the model. Calculating the exponential of the regression coefficients from the Cox model provided an estimate of the hazard ratio (HR), along with its 95% confidence interval (CI) [15]. If, for example, the point estimate and 95% CI for waiting time remained stable across the variety of possible models run, then there would be no evidence of confounding between the other variables and waiting time.
Results Patient Characteristics
For the entire population, the median time to radiation treatment was 8 weeks, with a median time to consultation of 4.4 weeks and a median time to treatment unit of 3.5 weeks (Table 1). The 90th percentile wait for time to consultation was 10 weeks and the 90th percentile wait for time to treatment unit was 8.5 weeks. Characteristics of women who waited more than 8 weeks and women who did not are included in Table 1. Only three women were reported with a positive margin after resection. One hundred and twenty-nine women had positive axillary lymph nodes, of which 36 had more than four lymph nodes involved (26 were treated with a four-fields radiation technique). The median income and the referring hospital distribution pattern were similar in both groups. As expected, differences were observed between women who received chemotherapy (n=131) and those who did not (n=351). The patients receiving chemotherapy had a longer median time to radiation treatment: 13.7 weeks (standard deviation [SD]: 8.2) compared with 9.3 weeks (SD: 8.7). Patients receiving chemotherapy were also younger (49 years vs 61 years), presented with higher grade tumours (86% grade 2/3 vs 66%), had larger tumour size and positive axillary lymph nodes (52% vs 18%) and were consequently more often stage II (61% vs 34%). Having a stage II disease and being on protocol were associated with shorter delays to receive radiation treatment. Outcome
Median follow-up was 68 months. At 5 years, 11 patients (2%) were lost to follow-up. Thirty-nine local recurrences occurred, 35 in the treated breast and four in the lower axilla. Five local recurrences occurred in three patients with bilateral breast cancers. Fifty-five patients
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CLINICAL ONCOLOGY
Table 1 – Patient characteristics according to time to radiation treatment
Mean age, years (SD) (range) Stage I (%) Stage II (%) (5 missing ‘stage’ data) Mean tumour size, cm (SD) Positive lymph nodes (%) (28 missing ‘lymph nodes’ data) Grade 1 (%) Grade 2 (%) Grade 3 (%) (117 missing ‘grade’ data) On tamoxifen (%) (11 missing ‘tamoxifen’ data) On protocol (%) (17 missing ‘on protocol’ data) On chemotherapy (%) Community hospital (%) (1 missing ‘hospital’ data) University hospital (%) Mean income (SD) ($1000 CDN)
Total n=482
%8 weeks n=246
>8 weeks n=236
57 (11.6) (28–82) 289 (59) 188 (41)
58 (10.8) (29–82) 165 (67) 80 (32)
56 (12) (28–80) 124 (53) 108 (46)
1.5 (1) 129 (28) 107 (29) 155 (41) 111 (30)
1.38 (0.9) 66 (28) 58 (31) 76 (41) 51 (28)
1.6 (1.07) 63 (28) 49 (26) 79 (42) 60 (32)
259 (50) 134 (29) 138 (28) 117 (24) 364 (76) 47 (13.2)
148 (61) 70 (38) 55 (22) 62 (25) 183 (74) 46.7 (13.3)
111 (47) 54 (23) 83 (35) 55 (23) 181 (76) 47.7 (13.2)
cm, centimeters; SD, Standard deviation; $CDN, Canadian dollars.
had distant recurrence, with eight of these developing both local recurrence and metastases. Fifty patients died of their breast cancer. The 5-year local recurrence rate was 8%, the metastatic rate 12% and a survival rate of 90%.
ment (10 weeks). Patients who died from their cancer had a higher histological grade but did not wait longer for their radiation treatment. The percentage of patients receiving chemotherapy was similar between the two groups: 30% in the surviving group and 36% in the non-surviving group.
Prognostic Factors Univariate analysis
Multivariate analysis
Table 2 provides prognostic factors for the development of local recurrence. Patients who developed a local recurrence were younger (49 vs 59 years), had a higher histological grade and waited longer to receive radiation treatment (14 vs 8 weeks). Women who received chemotherapy did not have a significantly different risk of local recurrence compared with women who did not receive chemotherapy. For women who developed a local recurrence, the median time to radiation treatment was 14 weeks. It was split between a median time to first consultation with a radiation oncologist of 5 weeks (90th percentile of wait: 15 weeks) and a median time to first radiation treatment after the consultation of another 5 weeks (90th percentile wait: 18 weeks). For the patient with no local recurrence, the median time to radiation treatment was 8 weeks. It was split between a median time to first consultation of 4.2 weeks (90th percentile wait: 9 weeks) and a median time to first radiation treatment after consultation of 3.5 weeks (90th percentile wait: 7.7 weeks). The HR of the effect of time to radiation treatment on local recurrence rate was 1.08 per additional month of delay (95% CI 1.004–1.16). Characteristics of patients with and without metastatic events were also analysed. Patients with metastatic disease were younger (53 vs 59 years), had a higher histological grade and were more likely stage II, but they did not wait longer before starting their radiation treat-
Multivariate Cox proportional hazard models were conducted, including various combinations of the variables listed in Table 3. No important confounding effects were found in the analysis. In particular, analysis was performed in chemotherapy and non-chemotherapy patients separately, and also together. Near identical effects for delay were found in each of the three analyses. There was no counfounding effect of chemotherapy on waiting time (i.e. the coefficient for waiting time was the same regardless of whether the chemotherapy was or was not in the model). Therefore, the results were reported for all patients together. Depending on the particular model that was selected, the adjusted HR of effect of time to radiation treatment on local recurrence varied slightly. For example, after adjusting for age, the HR of time to radiation treatment was 1.08 per month (95% CI 1.04 to 1.13). After adjusting for both age and tamoxifen, the HR remained identical at 1.08 per month, but the CI varied slightly (95% CI 1.03–1.13). In a model that adjusted for age, grade, tamoxifen and/or chemotherapy use, positive nodes and type of referring hospital, the HR for time to first treatment was 1.13 per additional month of waiting (95% CI 0.96–1.33). Therefore, point estimates for the risk of local recurrence per month of additional waiting time varied between 8% and 13% depending on the particular model used. In the model with all important covariates included (Table 3), the confidence interval included the null value of 1, with
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IMPACT OF TREATMENT DELAY
Table 2 – Univariate analysis of prognostic factors for local recurrence No recurrence (n=445)
Recurrence (n=37)
Hazard ratio (95% CI*)
59.5 (11.5) (28–82) 269 (60) 1 (1) (0.3–5) 117 (26) 102 (23) 145 (32) 90 (20) 121 (27) 246 (55) 125 (28) 330 (74) 46. 12 (13.21) 8 (8.9)
49 (10.5) (33–68) 20 (53) 1 (0.94) (0.3–4) 12 (33) 5(14) 10 (27) 21 (57) 17 (43) 13 (33) 9 (25) 34 (87) 43. 58 (13.97) 14 (6.8)
0.96 (0.93–0.99)
Mean age, years (SD) (Range) Stage I (%) Mean tumour size, cm (SD) (Range) Positive lymph nodes (%) Grade 1 (%) Grade 2 (%) Grade 3 (%) On chemotherapy (%) On tamoxifen (%) On protocol (%) University hospital (%) Median Income, $1000 CDN (SD) Median time to radiation treatment (weeks) (SD)
1.40 (0.65–3.03) 1.02 (0.71–1.45) 1.06 (0.94–1.18) Reference category 1.38 (0.47–4.03) 3.69 (1.36–10.0) 1.89 (0.96–3.75) 0.51 (0.25–1.03) 0.42 (0.15–1.19) 1.74 (0.67–4.50) 0.985 (0.96–1.01) 1.08 (1.004–1.16) Per month of delay
cm, centimeters; SD, standard deviation; $CDN, Canadian dollars. *CI, confidence interval.
Table 3 – Multivariate analysis of prognostic factors Risk ratio Age Grade 1 vs 2–3 Tamoxifen Chemotherapy Positive nodes University hospital Time to radiation, per month of delay
0.976 0.709 0.721 0.868 1.167 1.31 1.13
95% CI 0.94 0.41 0.47 0.53 0.73 0.78 0.96
to to to to to to to
1.01 1.22 1.09 1.41 1.87 2.19 1.33
Co-efficient (se) 0.02 (0.02) 0.34 (0.28) 0.33 (0.22) 0.14 (0.25) 0.15 (0.24) 0.27 (0.26) 0.12 (0.08)
CI, confidence interval; se, Standard error.
the CI being large. In all smaller models of interest, the lower limit for the CI did not include this null value. Overall, although we cannot exclude the possibility of no effect of waiting time on the risk of local recurrence, we also cannot exclude effects of waiting time to up to 33% per month. The other potentially important prognostic factor of local recurrence was the histological grade, comparing grade 1 and 2 vs 3 in a univariate analysis gives an HR of 0.36 (95% CI 0.17–0.75). However, after adjusting for others factors in the multivariate model, this effect was diminished with a confidence interval that included the null value of 1. There was no evidence that the presence of positive lymph nodes affects the risk of local recurrence. Discussion
Our analysis of stage I and II breast cancer patients, treated with conservative surgery followed by radiation therapy, shows a local recurrence rate of 8%, a metastasis rate of 12% and a survival rate of 90% at 5 years. This is consistent with other published results [1–5]. We found some indication that time to radiation treatment, defined as the interval between the date of surgery and
the date of first radiation treatment, could clinically affect the risk of local recurrence. Given that the HR for the effect of time to radiation treatment on the risk of local recurrence was about 1.08, or about 8% increased risk per month, and that the overall rate of local recurrence at 5 years was 8%, or about 13% per month, then the maximum absolute increase would be about 1% per month of delay (8%13%). This information is consistent with the data for patients whose radiation was delayed indefinitely, or who were treated with lumpectomy alone, where a 35% risk of local recurrence was reported at 12.5 years [2]. However, an ‘acceptable’ delay for radiation treatment is not possible to define from our data. Furthermore, this definition could vary with the individual risk of local recurrence. For instance, histological grade was associated with an increased risk of local recurrence. Patients with grade 3 tumour had a higher risk of local recurrence than those with grade 1 and 2 tumours. Income did not influence the patient’s outcome [16]. Some potential limitations of our study need to be discussed. First, our study was retrospective, but a nearly complete follow-up (2% lost to follow-up at 5 years) was obtained. Moreover, it would clearly be unethical to randomise patients without other adjuvant
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CLINICAL ONCOLOGY
therapy to short or long waiting times. Second, the original pathology was not reviewed to assess the margins of excision or to verify the presence of an extensive intraductal component. However, only three patients were initially described with a positive margin. The pathological assessment was similar for all cases, whether patients waited or not for their radiation treatment, thus resulting in a random misclassification. Third, reported delays included those for patients who did or did not receive chemotherapy. Chemotherapy could be a confounding factor: patients receiving chemotherapy were delayed for their irradiation, and chemotherapy could decrease the risk of local recurrence [17,18]. However, no effect of chemotherapy on the risk of local recurrence was seen in our patients in both univariate and multivariate analysis. Therefore, we believe that we can report the impact of delay for both patient groups combined. Finally, a medical bias could exist in which patients with more severe disease were treated sooner. This information could not be captured in our data collection. Therefore, uncontrolled confounding factors could still have occurred despite our multivariate adjustments. There is biological evidence supporting the view that delaying irradiation has a detrimental effect on treatment outcome [19,20]. Clinical data have been reported for head and neck cancers, and cervical cancers [21]. For breast cancer patients with or without indication of chemotherapy, the link between an increased risk of local recurrence and the delay between surgery and the initiation of radiation remains controversial. Recently, two systematic reviews of the literature on delay to radiation and outcome of breast cancer were reported. Huang et al. [22] concluded that the 5-year local recurrence rate was significantly higher in patients treated with adjuvant radiation for breast cancer more than 8 weeks after surgery than those treated within 8 weeks of surgery. In contrast, Hebert-Croteau et al. [23], in a critical review of the same peer-reviewed articles, concluded that radiotherapy is effective in controlling microscopic disease independently of time to radiation. However, given the methodological weaknesses identified in his critical appraisal of the available evidence, his recommendation was to endorse current Canadian recommendations and to deliver radiation no later than 12 weeks after surgery for women not receiving chemotherapy. In our institution, the median time to reach the treatment unit has increased over the past decade, from 3.5 weeks in the late 1980s to 5 weeks in the early 1990s [16]. The results of a survey showed that Canadians are waiting to receive medical care, including radiation treatment throughout the entire country [8]. In theory, knowing that excessive time to radiation treatment is associated with increased risk of local recurrence and that local recurrence may lead to further dissemination of cancer cells, an increased risk of metastasis could be expected [24]. In this study, we found no evidence that delay to radiation treatment affects the risk of metasta-
sis, but further work is required to more accurately estimate the parameters involved with this question. Furthermore, the time spent waiting to receive treatment could constitute an additional source of anxiety for the women and could affect their quality of life [25]. Additionally, the risk of having a mastectomy for recurrence when the patient requested breast preservation must be considered.
Conclusion
For stage I and II breast cancers, delay of radiation treatment may be associated with local recurrence, at least in our centre. The effect was small, in the order of an absolute increase of 1% per month of delay. This result awaits confirmation from larger data sets in other centres. In the mean time, it is prudent to recommend that adjuvant radiation treatment be delivered as soon as possible after conservative surgery. Acknowledgements. We thank Dr R. Battista, Dr J. M. Esdaile for their helpful comments on our manuscript. Supported by an internal award from The Montreal General Hospital Research Institute. Dr Fortin is a Senior Research Scholar of The Arthritis Society (Canada); Dr Joseph is a Senior Investigator of the Canadian Institute for Health Research.
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