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Second primary oesophageal cancer following radiation for breast cancer
Radiotherapy and Oncology 65 (2002) 159–163 www.elsevier.com/locate/radonline
Second primary oesophageal cancer following radiation for breast cancer J. Bronwyn Matheson, Bryan H. Burmeister*, B. Mark Smithers, David Gotley, Jennifer A. Harvey, Lisa Doyle Upper Gastrointestinal Oncology Clinic, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Qld. 4102, Australia Received 4 April 2001; received in revised form 3 March 2002; accepted 22 May 2002
Abstract The management of 12 women who presented with a second primary oesophageal cancer following radiotherapy for breast cancer was reviewed. It was concluded that nine cases fitted the classical description of a radiation-induced malignancy. Most cases were successfully managed with combined modality therapy in spite of their previous radiotherapy. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Breast cancer; Oesophageal cancer; Radiation-induced neoplasm; Radiotherapy; Second primary malignancy
1. Introduction Although any cancer can occur on the basis of previous radiotherapy, there is little published on possible radiation induction of oesophageal cancer. There have been several case reports [5,8] and small series [4,11] published of second primary oesophageal cancer occurring after breast cancer. Almost all reported cases have been squamous cell carcinomas. The best evidence to date for an association between radiotherapy for breast cancer and subsequent development of oesophageal cancer is epidemiological. A retrospective cohort study was conducted by the NCI SEER database of over 220 000 women with primary breast cancer diagnosed between 1973 and 1993 [1]. There was a statistically significant increased relative risk of second primary oesophageal squamous cell carcinoma only in the women treated with radiation therapy and who had a follow-up period of greater than 10 years. The relative risk was 5.42 (95% confidence interval: 2.33–10.68) for squamous cell carcinoma with eight cases observed and an expected rate of 1.47 cases in 30 938 person-years of follow-up. A less definite trend was seen for oesophageal adenocarcinoma. The Upper Gastrointestinal Oncology Clinic at the Princess Alexandra Hospital registers more than 70 patients with oesophageal cancer each year. A series of patients presented over a relatively short time with oesophageal cancer and a history of radiation for previous breast cancer. The aim of this report was firstly to review the initial presentation and treatment for breast cancer and then to evaluate the role of
* Corresponding author.
the previous malignancy on the management of the oesophageal cancer. 2. Materials and methods The database of the Upper Gastrointestinal Clinic at Princess Alexandra Hospital was searched since its inception in 1993 until October 2000 for patients who had developed oesophageal cancer and who also had a previous history of breast cancer. In addition we were able to search The Queensland Radium Institute (QRI) database from 1982 to 2000 as a further source of patients with the two malignancies. Information on risk factors, histology, clinical stage, management, complications and outcome was obtained from the databases. Further information on the management of the breast cancer including radiation doses and fields and other adjuvant treatment was obtained if possible from the original treating institution. Overall survival from the registration of the second oesophageal cancer was calculated using the Kaplan–Meier method [7]. 3. Results Twelve patients were identified who had both a previous history of breast cancer and who had recently been managed for a second primary oesophageal cancer. All patients had had primary breast adenocarcinomas and subsequent primary squamous cell carcinomas of the oesophagus. No patients had been lost to follow-up. At the time of this analysis the median follow-up time for breast cancer was 19.9 years (range 3.3–35.8). No patient had developed
0167-8140/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0167-814 0(02)00135-4
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J.B. Matheson et al. / Radiotherapy and Oncology 65 (2002) 159–163
recurrence of their breast cancer. The median follow-up time for the oesophageal cancer was 20 months (range 2– 70). Initial surgery for breast cancer was mastectomy in all cases and one had a further local excision for scar recurrence. All patients received postoperative radiation therapy as part of the management, 11 following the initial presentation and one following a scar recurrence. Adjuvant chemotherapy was given to one patient and no patients received tamoxifen. The mean age at radiation treatment for breast carcinoma was 54 years (range 36–73). Details of radiation field sizes, doses and hand planned isodose plots were available. The chest wall was treated in all cases, the supraclavicular nodes in 11 and the internal mammary nodes in ten. The mean age at diagnosis of the oesophageal cancer was 72 years (range 62–82). Clinical and radiological staging showed no obvious metastases to lymph nodes or viscera in 10 patients. One patient had a regional node involved and another had a solitary small hepatic metastasis which was cytologically proven to be carcinoma of uncertain origin. All tumours were at or below cricopharyngeus. The site of the oesophageal cancer was in the cervical or upper thoracic segment in eight, upper/middle thoracic in one, middle thoracic in two and lower thoracic in one. All were biopsy proven squamous cell carcinomas. This information is summarized in Table 1. Nine cases fitted the typical criteria for a radiationinduced malignancy. This included the eight cases which occurred in the cervical or upper thoracic oesophagus and one case at the junction of the upper and middle thoracic oesophagus. These portions of the oesophagus would have been included in a supraclavicular field with the upper margin at the cricoid cartilage and lower margin at the second costal cartilage. Techniques used were combinations of anterior and posterior fields with varying boost fields. From isodose plots estimated oesophageal dose was 25–30 Gy of orthovoltage or 35–40 Gy of megavoltage in 20 fractions. In two cases (cases 3 and 8), it is questionable whether the tumours were radiation induced, as the tumour site had only received an estimated 2–3 Gy from internal mammary node boost fields. Case 12 clearly did not fit the criteria for a radiation-induced malignancy, having occurred only 4 years after the breast cancer. The mean latent period to diagnosis of oesophageal cancer in the nine cases which were radiation-induced was 18 years (range 11–34). The intent of treatment was cure in eight cases and palliation in four cases. Six patients had surgery for their disease: three as the sole modality, two following preoperative chemoradiation therapy and one when radiotherapy was abandoned due to development of a tracheo-oesophageal fistula. Radiotherapy was given to ten patients (including one as salvage after surgery), with nine having concurrent chemotherapy. Doses varied from 35 Gy in 15 fractions (preoperative) to 60 Gy in 30 fractions (definitive). One patient received a combination of 40 Gy in 20 fractions external beam followed by a brachytherapy boost of 20
Gy. The chemotherapy contained 5-fluorouracil in all cases with cisplatin added in six cases. Radiation treatment planning was assisted by computerized tomography scans in the treatment position, and computer planning to avoid incident beams through previous breast fields and to restrict spinal cord dose to within tolerance. Composite plans were prepared in some cases but limited by the uncertainty of the exact placement of original radiotherapy fields. In some normal tissues such as the brachial plexus, higher tolerance doses were accepted in areas of overlap. The median overall survival time for the oesophageal cancer was 21 months (range 2–70). At the time of this analysis, there have been seven deaths attributed to oesophageal cancer, mostly due to local recurrence in the neck or upper chest, and one death due to a pre-existing medical condition. Four patients are alive and disease-free, including one patient who developed a local recurrence following surgery and who was salvaged with radical chemoradiation therapy. The longest survivor was still alive and free of disease 70 months after radical chemoradiation therapy. Acute complications occurred with all modalities of treatment, with one fatality. In this patient extensive fibrosis resulted in poor healing after surgery alone. This resulted in a tracheo-gastric fistula and subsequent overwhelming sepsis. In the other two cases treated with oesophagectomy alone no technical difficulties were encountered. In the two cases treated with preoperative chemoradiotherapy to 35 Gy reference dose, oesophagectomy was successfully completed with preservation of the larynx. Major surgical complications included a non-fatal myocardial infarct, a perforated gastric ulcer and two anastomotic leaks. In the radical chemoradiation group one patient with a cervical oesophageal cancer developed an acute oesophageal perforation into the subcutaneous tissues of the neck after 7 fractions of radiotherapy and the first course of concurrent chemotherapy. Following conservative management, treatment was completed with concurrent infusional 5-fluorouracil. The patient survived for 19 months and died of a preexisting respiratory complaint with no evidence of recurrence on endoscopy or computed tomography scan of the chest. Oesophageal strictures requiring repeated dilatations occurred in five patients and brachial plexopathy was noted in one long-term survivor. No cases of myelopathy or severe radiation pneumonitis have occurred.
4. Discussion 4.1. Possible radiation-induced malignancy Review of our series has shown that the supraclavicular field was associated with the subsequent site of the second malignancy. In all cases the medial border of the field was at the midline and the oesophagus was in the edge of the beam. This finding is at variance with the findings of others. In the epidemiological study [1], a higher relative risk (7.59) for
Latent interval c Oesophageal cancer
Case Breast cancer
1 2 3 4 5 6 7 8 9 10 11 12 a b c d e f
Year Age (years) TNM Stage
RT beam energy a RT fields b
1979 1982 1973 1965 1979 1964 1981 1970 1979 1972 1979 1996
MV MV OV/MV OV OV/MV OV MV OV/MV MV MV/OV MV MV
60 55 47 36 57 45 68 46 59 47 49 73
T1aN0p T1aN1p T2N1 T1N0c T2N0c T2N1 T1N0p T4N1p Scar recurrence T1N1p T1N0p T2N1p
cw, ax, sc, imc cw, ax, sc, imc cw, ax, sc, imc cw, ax, sc cw, imc/ax, sc cw, ax, sc, imc cw, ax, sc, imc cw, ax, sc/imc cw, ax, sc, imc sc/imc cw, ax, sc, imc cw, ax, sc, imc
14 years 11 years 24 years 30 years 17 years 34 years 13 years 27 years 15 years 15 years 19 years 3 years
Age (years) TNM Stage Site d (cm) Treatment e
Survival (months) Status f
74 66 71 66 75 79 82 74 75 62 68 76
2 35 30 55 26 21 8 9 70 13 19 4
T3N0M0 T1N0M0 T2N0M0 T3N0M0 T3N0M0 T2N1M0 T2N0M0 T2N0Ml T1N0M0 T4N0M0 T1N0M0 T2N0M0
17–20 18–20 24–30 17–23 15–20 18–21 18–23 At 33 17–21 21–27 15–17 24–29
SU SU SU, salvage CT-RT PO CT-RT, SU PO CT-RT, SU Pall CT-RT Pall CT-RT, BT, CT Pall CT-RT Radical CT-RT Radical RT, SU Radical split CT-RT Radical CT-RT
Radiotherapy beam energy: MV, megavoltage; OV, orthovoltage, 250–300 kV. Radiotherapy fields: cw, chest wall; ax, axilla; sc, supraclavicular; imc, internal mammary chain. Latent interval in years from radiotherapy for breast cancer to diagnosis of oesophageal cancer. Site of oesophageal cancer in centimetres from the incisors on endoscopic examination. Treatment: SU, surgery; CT-RT, concurrent chemoradiation; PO, preoperative; Pall, palliative; BT, brachytherapy. Status at time of last follow-up for oesophageal cancer: DOD, dead of oesophageal cancer; A, NED; alive, no evidence of disease; D, NED, dead, no evidence of disease.
DOD DOD A, NED A, NED DOD DOD DOD DOD A, NED DOD D, NED A, NED
J.B. Matheson et al. / Radiotherapy and Oncology 65 (2002) 159–163
Table 1 Patient, tumour and treatment characteristics
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oesophageal cancers was found for women whose tumours were in the inner half of the breast. Radiation fields were not noted. They suggested that the internal mammary field was more likely to include the oesophagus and thus be implicated. Discussion by Perrier et al. [11] of possible preventative measures also focused on the internal mammary nodal radiotherapy technique to avoid the oesophagus. In our series a wide tangential field technique was used to treat the internal mammary node chain with boosts using 1 or 2 fractions of a direct anterior field being used in a few cases. Estimated total doses to the mid oesophagus were in the order of 2–3 Gy, whereas the estimated dose to the upper oesophagus from the supraclavicular field was 25–35 Gy. The relationship between dose and risk of radiation carcinogenesis for solid tumours is thought to be a bell-shaped curve. Risk increases supralinearly above a minimum dose level presumably as sublethal mutations accumulate and then decreases at higher therapeutic radiation doses where damage to the cell is more likely to be lethal [13]. The minimum dose for induction of oesophageal cancer is not known. In the 15-year period from 1970 to 1984, approximately 2750 patients received radiation as part of curative treatment for breast cancer at the Queensland Radium Institute which was the sole facility for radiation therapy in Queensland. Six of the nine cases in our series that fitted the criteria for radiation-induced cancer were treated over this period. Two others were treated prior to 1970 (when data collection was poor) and one was treated at another facility. There may have been other cases not detected by our exhaustive review. We are therefore unable to define a true risk of second primary oesophageal malignancy from this study, but our findings do support the notion of a small but increased risk of squamous cell carcinoma of the oesophagus for 10-year survivors. The management of the breast cancers reflects the standard treatment of the 1960s and 1970s. All had mastectomy and all had post-operative radiation therapy as this was best practice at the time. Although our findings were historical, there is some relevance for current and future practice. A recent meta-analysis [14] and three large randomized trials [9,10,12] have renewed the controversy [3] of the role of post-mastectomy radiation therapy in conjunction with systemic therapy, These studies have shown a significant reduction in mortality in patients having post-mastectomy radiation therapy. The relative contributions of specific nodal irradiation to possible survival benefits will be known when the results of the EORTC study 22922/10925 become available. In the setting of positive axillary nodes, the risk of the supraclavicular fossa being the first site of failure occurs in 5–10% of patients and the ultimate site of failure in 15–20%. Radiation reduces this rate of failure to less than 1%. However, the oesophagus is likely to be irradiated if direct anterior fields are used, suggesting that precautions should be taken to avoid including the oesophagus in the supraclavicular fields.
4.2. Management of second oesophageal primary malignancy The median overall survival time for our series of nine patients with probable radiation-induced cancer was 21 months and is comparable with the median survival time of 18 months for non-radiation-induced oesophageal cancer. The two long-term survivors (cases 4 and 9) had tumours high in the cervical oesophagus, which itself is a good prognostic factor. Treatment decisions are more complex in these patients and the input from a multidisciplinary clinic invaluable, particularly as experience has been accumulated from these patients with previous breast radiotherapy as well as some with mediastinal radiotherapy for Hodgkin’s disease. The experience of the surgically related death occurred early in the experience of the multi-disciplinary clinic. Since then, the problem of cervical oesophageal sited tumours has been managed with either moderate-dose preoperative chemoradiation therapy (to limit the extent of surgery and allow laryngeal preservation) or with radical chemoradiation therapy. The latter approach has been particularly successful in our hands [2]. In most cases, comorbidity precluded surgery, so that radiation therapy was the only local option. As a result of previous therapies, stricture formation was common and required repeated dilatations. This has been a feature of other chemoradiation studies [6] 4.3. Conclusion In our series nine out of 12 cases fitted the criteria for a radiation-induced second primary malignancy. The majority of the second primary cancers arose in the cervical and upper thoracic portion of the oesophagus. The main associated factor identified was previous supraclavicular nodal irradiation. This series gives support to the epidemiological evidence for a small but increased risk of radiation-induced oesophageal cancer in breast cancer survivors. This and other series reported may represent an increasing historical cluster. Risk associated with current practices will only become clear with the passage of time and further analysis of more contemporary cohorts. We conclude that second primary oesophageal cancer arising on a background of breast cancer can be successfully managed using multimodality therapy with similar complication and survival rates to non-radiation-associated cohorts. References [1] Ahsan H, Neuget AI. Radiation therapy for breast cancer and increased risk for esophageal carcinoma. Ann Intern Med 1998;128:114–117. [2] Burmeister BH, Dickie G, Smithers M, Hodge R, Morton K. Thirtyfour patients with carcinoma of the cervical esophagus treated with chemoradiation therapy. Arch Otolaryngol Head Neck Surg 2000;126:205–208. [3] Cutuli B, Delozier T, Mauriac L. Current controversies in cancer. The
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[4] [5]
[6]
[7] [8]
[9]
impact of loco-regional radiotherapy on the survival of breast cancer patients. Eur J Cancer 2000;36:1895–1908. Fekete F, Mosnier H, Belghiti J, Uribe M, Sauvanet A. Esophageal cancer after mediastinal irradiation. Dysphagia 1993;8:289–291. Goffman TE, McKeen EA, Curtis RE, Schein PS. Esophageal carcinoma following irradiation for breast cancer. Cancer 1983;52:1808– 1809. Herskovic A, Martz K, Al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593–1598. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;3:457–481. MacLeod C, Moylan E, Falk GL. Carcinoma of the oesophagus treated with radical chemoradiation 19 years after irradiation for recurrent breast cancer. Dis Esophagus 1997;10:145–148. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949–955.
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[10] Overgaard M, Jensen M-B, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641–1648. [11] Perrier G, Teniere P, Graoc Y, Scotte M, Leblanc-Louvry I, Michot F. Squamous cell carcinoma of the thoracic esophagus following radiation therapy for breast cancer. Hepato-Gastroenterology 1998;45: 2197–2201. [12] Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956–962. [13] United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and effects of ionizing radiation. New York: United Nations, 1994. [14] Whelan TJ, Julian J, Wright J, et al. Does locoregional radiation improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220–1229.
Second primary oesophageal cancer following radiation for breast cancer J. Bronwyn Matheson, Bryan H. Burmeister*, B. Mark Smithers, David Gotley, Jennifer A. Harvey, Lisa Doyle Upper Gastrointestinal Oncology Clinic, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Qld. 4102, Australia Received 4 April 2001; received in revised form 3 March 2002; accepted 22 May 2002
Abstract The management of 12 women who presented with a second primary oesophageal cancer following radiotherapy for breast cancer was reviewed. It was concluded that nine cases fitted the classical description of a radiation-induced malignancy. Most cases were successfully managed with combined modality therapy in spite of their previous radiotherapy. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Breast cancer; Oesophageal cancer; Radiation-induced neoplasm; Radiotherapy; Second primary malignancy
1. Introduction Although any cancer can occur on the basis of previous radiotherapy, there is little published on possible radiation induction of oesophageal cancer. There have been several case reports [5,8] and small series [4,11] published of second primary oesophageal cancer occurring after breast cancer. Almost all reported cases have been squamous cell carcinomas. The best evidence to date for an association between radiotherapy for breast cancer and subsequent development of oesophageal cancer is epidemiological. A retrospective cohort study was conducted by the NCI SEER database of over 220 000 women with primary breast cancer diagnosed between 1973 and 1993 [1]. There was a statistically significant increased relative risk of second primary oesophageal squamous cell carcinoma only in the women treated with radiation therapy and who had a follow-up period of greater than 10 years. The relative risk was 5.42 (95% confidence interval: 2.33–10.68) for squamous cell carcinoma with eight cases observed and an expected rate of 1.47 cases in 30 938 person-years of follow-up. A less definite trend was seen for oesophageal adenocarcinoma. The Upper Gastrointestinal Oncology Clinic at the Princess Alexandra Hospital registers more than 70 patients with oesophageal cancer each year. A series of patients presented over a relatively short time with oesophageal cancer and a history of radiation for previous breast cancer. The aim of this report was firstly to review the initial presentation and treatment for breast cancer and then to evaluate the role of
* Corresponding author.
the previous malignancy on the management of the oesophageal cancer. 2. Materials and methods The database of the Upper Gastrointestinal Clinic at Princess Alexandra Hospital was searched since its inception in 1993 until October 2000 for patients who had developed oesophageal cancer and who also had a previous history of breast cancer. In addition we were able to search The Queensland Radium Institute (QRI) database from 1982 to 2000 as a further source of patients with the two malignancies. Information on risk factors, histology, clinical stage, management, complications and outcome was obtained from the databases. Further information on the management of the breast cancer including radiation doses and fields and other adjuvant treatment was obtained if possible from the original treating institution. Overall survival from the registration of the second oesophageal cancer was calculated using the Kaplan–Meier method [7]. 3. Results Twelve patients were identified who had both a previous history of breast cancer and who had recently been managed for a second primary oesophageal cancer. All patients had had primary breast adenocarcinomas and subsequent primary squamous cell carcinomas of the oesophagus. No patients had been lost to follow-up. At the time of this analysis the median follow-up time for breast cancer was 19.9 years (range 3.3–35.8). No patient had developed
0167-8140/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0167-814 0(02)00135-4
160
J.B. Matheson et al. / Radiotherapy and Oncology 65 (2002) 159–163
recurrence of their breast cancer. The median follow-up time for the oesophageal cancer was 20 months (range 2– 70). Initial surgery for breast cancer was mastectomy in all cases and one had a further local excision for scar recurrence. All patients received postoperative radiation therapy as part of the management, 11 following the initial presentation and one following a scar recurrence. Adjuvant chemotherapy was given to one patient and no patients received tamoxifen. The mean age at radiation treatment for breast carcinoma was 54 years (range 36–73). Details of radiation field sizes, doses and hand planned isodose plots were available. The chest wall was treated in all cases, the supraclavicular nodes in 11 and the internal mammary nodes in ten. The mean age at diagnosis of the oesophageal cancer was 72 years (range 62–82). Clinical and radiological staging showed no obvious metastases to lymph nodes or viscera in 10 patients. One patient had a regional node involved and another had a solitary small hepatic metastasis which was cytologically proven to be carcinoma of uncertain origin. All tumours were at or below cricopharyngeus. The site of the oesophageal cancer was in the cervical or upper thoracic segment in eight, upper/middle thoracic in one, middle thoracic in two and lower thoracic in one. All were biopsy proven squamous cell carcinomas. This information is summarized in Table 1. Nine cases fitted the typical criteria for a radiationinduced malignancy. This included the eight cases which occurred in the cervical or upper thoracic oesophagus and one case at the junction of the upper and middle thoracic oesophagus. These portions of the oesophagus would have been included in a supraclavicular field with the upper margin at the cricoid cartilage and lower margin at the second costal cartilage. Techniques used were combinations of anterior and posterior fields with varying boost fields. From isodose plots estimated oesophageal dose was 25–30 Gy of orthovoltage or 35–40 Gy of megavoltage in 20 fractions. In two cases (cases 3 and 8), it is questionable whether the tumours were radiation induced, as the tumour site had only received an estimated 2–3 Gy from internal mammary node boost fields. Case 12 clearly did not fit the criteria for a radiation-induced malignancy, having occurred only 4 years after the breast cancer. The mean latent period to diagnosis of oesophageal cancer in the nine cases which were radiation-induced was 18 years (range 11–34). The intent of treatment was cure in eight cases and palliation in four cases. Six patients had surgery for their disease: three as the sole modality, two following preoperative chemoradiation therapy and one when radiotherapy was abandoned due to development of a tracheo-oesophageal fistula. Radiotherapy was given to ten patients (including one as salvage after surgery), with nine having concurrent chemotherapy. Doses varied from 35 Gy in 15 fractions (preoperative) to 60 Gy in 30 fractions (definitive). One patient received a combination of 40 Gy in 20 fractions external beam followed by a brachytherapy boost of 20
Gy. The chemotherapy contained 5-fluorouracil in all cases with cisplatin added in six cases. Radiation treatment planning was assisted by computerized tomography scans in the treatment position, and computer planning to avoid incident beams through previous breast fields and to restrict spinal cord dose to within tolerance. Composite plans were prepared in some cases but limited by the uncertainty of the exact placement of original radiotherapy fields. In some normal tissues such as the brachial plexus, higher tolerance doses were accepted in areas of overlap. The median overall survival time for the oesophageal cancer was 21 months (range 2–70). At the time of this analysis, there have been seven deaths attributed to oesophageal cancer, mostly due to local recurrence in the neck or upper chest, and one death due to a pre-existing medical condition. Four patients are alive and disease-free, including one patient who developed a local recurrence following surgery and who was salvaged with radical chemoradiation therapy. The longest survivor was still alive and free of disease 70 months after radical chemoradiation therapy. Acute complications occurred with all modalities of treatment, with one fatality. In this patient extensive fibrosis resulted in poor healing after surgery alone. This resulted in a tracheo-gastric fistula and subsequent overwhelming sepsis. In the other two cases treated with oesophagectomy alone no technical difficulties were encountered. In the two cases treated with preoperative chemoradiotherapy to 35 Gy reference dose, oesophagectomy was successfully completed with preservation of the larynx. Major surgical complications included a non-fatal myocardial infarct, a perforated gastric ulcer and two anastomotic leaks. In the radical chemoradiation group one patient with a cervical oesophageal cancer developed an acute oesophageal perforation into the subcutaneous tissues of the neck after 7 fractions of radiotherapy and the first course of concurrent chemotherapy. Following conservative management, treatment was completed with concurrent infusional 5-fluorouracil. The patient survived for 19 months and died of a preexisting respiratory complaint with no evidence of recurrence on endoscopy or computed tomography scan of the chest. Oesophageal strictures requiring repeated dilatations occurred in five patients and brachial plexopathy was noted in one long-term survivor. No cases of myelopathy or severe radiation pneumonitis have occurred.
4. Discussion 4.1. Possible radiation-induced malignancy Review of our series has shown that the supraclavicular field was associated with the subsequent site of the second malignancy. In all cases the medial border of the field was at the midline and the oesophagus was in the edge of the beam. This finding is at variance with the findings of others. In the epidemiological study [1], a higher relative risk (7.59) for
Latent interval c Oesophageal cancer
Case Breast cancer
1 2 3 4 5 6 7 8 9 10 11 12 a b c d e f
Year Age (years) TNM Stage
RT beam energy a RT fields b
1979 1982 1973 1965 1979 1964 1981 1970 1979 1972 1979 1996
MV MV OV/MV OV OV/MV OV MV OV/MV MV MV/OV MV MV
60 55 47 36 57 45 68 46 59 47 49 73
T1aN0p T1aN1p T2N1 T1N0c T2N0c T2N1 T1N0p T4N1p Scar recurrence T1N1p T1N0p T2N1p
cw, ax, sc, imc cw, ax, sc, imc cw, ax, sc, imc cw, ax, sc cw, imc/ax, sc cw, ax, sc, imc cw, ax, sc, imc cw, ax, sc/imc cw, ax, sc, imc sc/imc cw, ax, sc, imc cw, ax, sc, imc
14 years 11 years 24 years 30 years 17 years 34 years 13 years 27 years 15 years 15 years 19 years 3 years
Age (years) TNM Stage Site d (cm) Treatment e
Survival (months) Status f
74 66 71 66 75 79 82 74 75 62 68 76
2 35 30 55 26 21 8 9 70 13 19 4
T3N0M0 T1N0M0 T2N0M0 T3N0M0 T3N0M0 T2N1M0 T2N0M0 T2N0Ml T1N0M0 T4N0M0 T1N0M0 T2N0M0
17–20 18–20 24–30 17–23 15–20 18–21 18–23 At 33 17–21 21–27 15–17 24–29
SU SU SU, salvage CT-RT PO CT-RT, SU PO CT-RT, SU Pall CT-RT Pall CT-RT, BT, CT Pall CT-RT Radical CT-RT Radical RT, SU Radical split CT-RT Radical CT-RT
Radiotherapy beam energy: MV, megavoltage; OV, orthovoltage, 250–300 kV. Radiotherapy fields: cw, chest wall; ax, axilla; sc, supraclavicular; imc, internal mammary chain. Latent interval in years from radiotherapy for breast cancer to diagnosis of oesophageal cancer. Site of oesophageal cancer in centimetres from the incisors on endoscopic examination. Treatment: SU, surgery; CT-RT, concurrent chemoradiation; PO, preoperative; Pall, palliative; BT, brachytherapy. Status at time of last follow-up for oesophageal cancer: DOD, dead of oesophageal cancer; A, NED; alive, no evidence of disease; D, NED, dead, no evidence of disease.
DOD DOD A, NED A, NED DOD DOD DOD DOD A, NED DOD D, NED A, NED
J.B. Matheson et al. / Radiotherapy and Oncology 65 (2002) 159–163
Table 1 Patient, tumour and treatment characteristics
161
162
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oesophageal cancers was found for women whose tumours were in the inner half of the breast. Radiation fields were not noted. They suggested that the internal mammary field was more likely to include the oesophagus and thus be implicated. Discussion by Perrier et al. [11] of possible preventative measures also focused on the internal mammary nodal radiotherapy technique to avoid the oesophagus. In our series a wide tangential field technique was used to treat the internal mammary node chain with boosts using 1 or 2 fractions of a direct anterior field being used in a few cases. Estimated total doses to the mid oesophagus were in the order of 2–3 Gy, whereas the estimated dose to the upper oesophagus from the supraclavicular field was 25–35 Gy. The relationship between dose and risk of radiation carcinogenesis for solid tumours is thought to be a bell-shaped curve. Risk increases supralinearly above a minimum dose level presumably as sublethal mutations accumulate and then decreases at higher therapeutic radiation doses where damage to the cell is more likely to be lethal [13]. The minimum dose for induction of oesophageal cancer is not known. In the 15-year period from 1970 to 1984, approximately 2750 patients received radiation as part of curative treatment for breast cancer at the Queensland Radium Institute which was the sole facility for radiation therapy in Queensland. Six of the nine cases in our series that fitted the criteria for radiation-induced cancer were treated over this period. Two others were treated prior to 1970 (when data collection was poor) and one was treated at another facility. There may have been other cases not detected by our exhaustive review. We are therefore unable to define a true risk of second primary oesophageal malignancy from this study, but our findings do support the notion of a small but increased risk of squamous cell carcinoma of the oesophagus for 10-year survivors. The management of the breast cancers reflects the standard treatment of the 1960s and 1970s. All had mastectomy and all had post-operative radiation therapy as this was best practice at the time. Although our findings were historical, there is some relevance for current and future practice. A recent meta-analysis [14] and three large randomized trials [9,10,12] have renewed the controversy [3] of the role of post-mastectomy radiation therapy in conjunction with systemic therapy, These studies have shown a significant reduction in mortality in patients having post-mastectomy radiation therapy. The relative contributions of specific nodal irradiation to possible survival benefits will be known when the results of the EORTC study 22922/10925 become available. In the setting of positive axillary nodes, the risk of the supraclavicular fossa being the first site of failure occurs in 5–10% of patients and the ultimate site of failure in 15–20%. Radiation reduces this rate of failure to less than 1%. However, the oesophagus is likely to be irradiated if direct anterior fields are used, suggesting that precautions should be taken to avoid including the oesophagus in the supraclavicular fields.
4.2. Management of second oesophageal primary malignancy The median overall survival time for our series of nine patients with probable radiation-induced cancer was 21 months and is comparable with the median survival time of 18 months for non-radiation-induced oesophageal cancer. The two long-term survivors (cases 4 and 9) had tumours high in the cervical oesophagus, which itself is a good prognostic factor. Treatment decisions are more complex in these patients and the input from a multidisciplinary clinic invaluable, particularly as experience has been accumulated from these patients with previous breast radiotherapy as well as some with mediastinal radiotherapy for Hodgkin’s disease. The experience of the surgically related death occurred early in the experience of the multi-disciplinary clinic. Since then, the problem of cervical oesophageal sited tumours has been managed with either moderate-dose preoperative chemoradiation therapy (to limit the extent of surgery and allow laryngeal preservation) or with radical chemoradiation therapy. The latter approach has been particularly successful in our hands [2]. In most cases, comorbidity precluded surgery, so that radiation therapy was the only local option. As a result of previous therapies, stricture formation was common and required repeated dilatations. This has been a feature of other chemoradiation studies [6] 4.3. Conclusion In our series nine out of 12 cases fitted the criteria for a radiation-induced second primary malignancy. The majority of the second primary cancers arose in the cervical and upper thoracic portion of the oesophagus. The main associated factor identified was previous supraclavicular nodal irradiation. This series gives support to the epidemiological evidence for a small but increased risk of radiation-induced oesophageal cancer in breast cancer survivors. This and other series reported may represent an increasing historical cluster. Risk associated with current practices will only become clear with the passage of time and further analysis of more contemporary cohorts. We conclude that second primary oesophageal cancer arising on a background of breast cancer can be successfully managed using multimodality therapy with similar complication and survival rates to non-radiation-associated cohorts. References [1] Ahsan H, Neuget AI. Radiation therapy for breast cancer and increased risk for esophageal carcinoma. Ann Intern Med 1998;128:114–117. [2] Burmeister BH, Dickie G, Smithers M, Hodge R, Morton K. Thirtyfour patients with carcinoma of the cervical esophagus treated with chemoradiation therapy. Arch Otolaryngol Head Neck Surg 2000;126:205–208. [3] Cutuli B, Delozier T, Mauriac L. Current controversies in cancer. The
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[4] [5]
[6]
[7] [8]
[9]
impact of loco-regional radiotherapy on the survival of breast cancer patients. Eur J Cancer 2000;36:1895–1908. Fekete F, Mosnier H, Belghiti J, Uribe M, Sauvanet A. Esophageal cancer after mediastinal irradiation. Dysphagia 1993;8:289–291. Goffman TE, McKeen EA, Curtis RE, Schein PS. Esophageal carcinoma following irradiation for breast cancer. Cancer 1983;52:1808– 1809. Herskovic A, Martz K, Al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593–1598. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;3:457–481. MacLeod C, Moylan E, Falk GL. Carcinoma of the oesophagus treated with radical chemoradiation 19 years after irradiation for recurrent breast cancer. Dis Esophagus 1997;10:145–148. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949–955.
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[10] Overgaard M, Jensen M-B, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 1999;353:1641–1648. [11] Perrier G, Teniere P, Graoc Y, Scotte M, Leblanc-Louvry I, Michot F. Squamous cell carcinoma of the thoracic esophagus following radiation therapy for breast cancer. Hepato-Gastroenterology 1998;45: 2197–2201. [12] Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956–962. [13] United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and effects of ionizing radiation. New York: United Nations, 1994. [14] Whelan TJ, Julian J, Wright J, et al. Does locoregional radiation improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220–1229.