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External Beam Radiotherapy in the Management of Differentiated Thyroid Cancer
Clinical Oncology (2003) 15: 337–341 doi:10.1016/S0936-6555(03)00162-6
Original Article External Beam Radiotherapy in the Management of Differentiated Thyroid Cancer D. Ford*, S. Giridharan*, C. McConkey†, A. Hartley*, C. Brammer‡, J. C. Watkinson*, J. Glaholm* *Cancer Centre, Queen Elizabeth Hospital, Edgbaston, Birmingham; †Cancer Research UK Clinical Trials Unit, Edgbaston, Birmingham; ‡Deansley Centre, New Cross Hospital, Wolverhampton, U.K. ABSTRACT: Aims: No randomised trials have addressed the use of external beam radiotherapy (EBRT) in the treatment of differentiated thyroid cancer. The indications for EBRT, the technique and recommended dose all remain controversial. Materials and methods: We included patients treated with EBRT with curative intent from two cancer centres between 1988 and 2001. Data were collected from hospital notes, radiotherapy prescriptions and local cancer registry. Results: The indications for treatment in the 41 identified patients were macroscopic residual disease 23 (56%), microscopic residual disease 10 (25%), Hurthle cell variants 3 (7%), multiple lymph-node involvement 3 (7%) and other 2 (5%). Delivered doses ranged from 37.5–66 Gy over 3–6.5 weeks. Rate of local recurrence and overall survival at 5 years were as follows: papillary 26% and 67%; follicular 43% and 48%; well differentiated 21% and 67%; focus of poor differentiation/Hurthle cell variants 69% and 32%; complete excision 25% and 61%; residual disease 37% and 59%; EBRT total dose <50 Gy 63% and 42%; 50–54 Gy 15% and 72%; >54 Gy 18% and 68%. Conclusions: The results in this study are consistent with previous retrospective studies of EBRT. The wide range of indications and doses used with radical intent highlights the lack of clinical and radiobiological data on the response of differentiated thyroid cancer to EBRT. Despite the small study size, the 5-year local recurrence results indicate a possible dose response within the dose range used. Ford D., et al. (2003). Clinical Oncology 15, 337–341 2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Thyroid cancer, external beam radiotherapy, dose Received: 26 March 2003
Revised: 21 May 2003
Introduction
The role of external beam radiotherapy (EBRT) in thyroid cancer remains controversial [1]. No published randomised controlled trials have examined the addition of EBRT to standard treatment, namely surgery, radioactive iodine and medical suppression of thyroid stimulating hormone. Imbalances in age, sex, completeness of surgical excision, histological type and stage, between patients receiving and not receiving EBRT, confound retrospective studies. Variability also exists between treatment and non-treatment groups in the use of radio-iodine and post-treatment thyroid stimulating hormone suppression. There is also a lack of standardisation in dosimetry and treatment technique between and within retrospective studies. Retrospective comparative studies of EBRT in differentiated thyroid cancer are outlined in Table 1. Tsang Author for correspondence: Dr A. Hartley, Cancer Centre, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH; E-mail: [email protected] 0936-6555/03/060337+5 $30.00/0
Accepted: 22 May 2003
et al. [2] found that EBRT had no advantage on cause-specific survival (P=0.86); however, patients receiving EBRT were significantly older, less likely to have undergone a total thyroidectomy and more likely to have extra-thyroidal invasion, residual disease and larger tumours than patients who did not receive EBRT. Patients not receiving EBRT were more likely to have distant metastases and less likely to have received radioiodine. Similarly, a large U.S. study failed to show any advantage for EBRT, although patients were older, more likely to be men and have distant metastases, and less likely to have had extensive surgical intervention [3]. Tubiana et al. [4] reported an advantage in terms of local recurrence for EBRT (P<0.05). Patients receiving EBRT were more likely to have had incomplete resection of the disease. Conversely, patients in the control group were less likely to have received radioiodine. Farahati et al. [5] and Phlips et al. [6] have also reported local recurrence advantages for EBRT [5,6]. In both studies, all patients received radio-iodine. In the
2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
338
Table 1 – Retrospective studies of external beam radiotherapy for differentiated thyroid cancer
Study Tsang, et al., 1998 [2]
Patient Group All differentiated carcinoma
Number of patients receiving EBRT
Number of Patients not receiving EBRT
185
197
Outcome Cause-specific survival: RR 1.1 (0.6–1.8); P=0.86
Features of EBRT Group 1. Mean Age: 49.1* vs 45.4†; P=0.03. 2. Extrathyroidal invasion: 65%* vs 38%†; P<0.0001. 3. Size: >4 cm; 39%* vs 25%†; P=0.0002. 4. No residual disease: 14%* vs 47%†; P<0.0001. 5. Total thyroidectomy: 23%* vs 35%†; P=0.047
Tubiana, et al., 1985 [4]
All differentiated carcinoma (excluding patients with distant metastasis)
180
336
Samaan, et al., 1992 [3]
All well-differentiated carcinoma
113
1486
Farahati, et al., 1996 [5]
All T4-differentiated carcinoma (excluding patients with distant metastasis)
99
Phlips, et al., 1993 [6]
All differentiated carcinoma
38
Local recurrence: 14%* vs 21%†; P<0.05
1. Incomplete macroscopic excision 54%* vs 17%† 2. Only 53%* treated with megavoltage photons More patients in the EBRT group received radio-iodine 34%* vs 18%†. Mean age: 45.3* vs 40.2†; P<0.01 More men: 9%* vs 6%†; P<0.05 More likely to have distant disease: P<0.02 Less surgical intervention: P<0.001
No advantage in reducing recurrence or death
1. 2. 3. 4.
70
Local recurrence: 7%* vs 30%†; P=0.003
No significant differences between groups. All patients received radio-iodine (EBRT given between two courses)
56
Local recurrence: 3%* vs 25%†; 5-year overall survival: 84%* and 94%†
1. Macroscopic complete resection: 68%* vs 89%† 2. Node positive: 55%* vs 28%† 3. Extracapsular extension: 16%* vs 10%† All patients received radio-iodine.
†
*Patients receiving EBRT; Patients not receiving EBRT. EBRT, external beam radiotherapy.
CLINICAL ONCOLOGY
Fewer patients in the EBRT group had distant metastases (5%* vs 15%†; P=0.002); more patients received radio-iodine (69%* vs 48%†; P<0.0001).
339
EBRT AND THYROID CANCER
study by Farahati et al. [5], the difference in local recurrence reached statistical significance (P=0.003) and confounding factors were reported. In the study by Phlips et al. [6], a difference in local recurrence (no P values quoted) occurred, although patients receiving EBRT were more likely to have node-positive disease, extracapsular extension and incomplete macroscopic excision [6]. The differences in patient groups among these studies, and the difficulties with confounding factors, make evidence-based recommendations for the use of EBRT difficult to formulate. Tsang et al. [2] have suggested a role for EBRT in patients with papillary cancer, with microscopic residual disease based on sub-group analysis showing a statistically significant advantage in terms of cause-specific survival (100% vs 95%; P=0.038) and local recurrence (93% vs 78%; P=0.01). Farahati et al. [5] recommend the use of EBRT in node-positive patients over 40 years of age with papillary histology on the basis of an increase in time to local or distant failure (P=0.0009) [5]. In the U.K., indications for EBRT include high-grade tumours that do not concentrate iodine and tumours with gross local invasion where there is a high suspicion of microscopic or macroscopic disease [7,8]. The aim of this study was to assess the indications for and outcomes from EBRT in differentiated thyroid cancer in two radiotherapy centres in the West Midlands. Method
We identified patients from databases at two radiotherapy centres and included cases of differentiated thyroid cancer treated with EBRT with curative intent between 1988 and 2001. We obtained the following data from hospital notes, radiotherapy prescriptions and local cancer registries: patient age and sex, indication for treatment, histological type, completeness of surgical excision, radiotherapy dose, local and distant recurrence and overall survival. Survival and recurrence estimates were measured from the starting date of EBRT and calculated by the Kaplan–Meier method. Comparisons were made with the Mantel–Cox log-rank statistic. Results
We identified a total of 41 patients (26 women, 15 men). Predominant histological types were papillary 24 (59%) and follicular 17 (41%). A focus of poor differentiation was seen in nine (22%) patients and Hurthle cell variants were seen in three (7%) patients. Complete macroscopic and microscopic clearance was obtained in nine (22%) patients. Indications for EBRT were macroscopic residual disease 23 (56%), microscopic residual disease 10 (24%), Hurthle cell variants 3 (7%), multiple lymph nodes 3 (7%), focus of poor differentiation/anaplastic carcinoma as sole indication 2 (5%) (Table 2).
Table 2 – Indications for external beam radiotherapy Indication Macroscopic residual disease Microscopic residual disease Hurthle cell variants Multiple lymph nodes Other
Number of patients
Percentage
23 10 3 3 2
56 24 7 7 5
The superior border of the target volume was defined at the tip of the mastoid process, the inferior border at the lower border of the sternal notch and the lateral border at the junction of the outer and middle-third of the clavicle. Techniques used to treat this volume varied considerably. Most commonly, anterior and posterior opposed fields were used for a first treatment phase. For the second phase, treatment was continued either with midline lead shielding in the posterior beam or caudally angled lateral fields with posterior border anterior to the spinal cord. A direct electron field, or combinations of anterior and anterior oblique fields, were used in a few patients. Treatment schedules varied, with doses ranging from 37.5–66 Gy over 3–6.5 weeks (Table 3). In addition, 35 patients received at least one ablative dose of radio-iodine (3000 MBq) at initial presentation. Fifteen patients died and thyroid carcinoma recurred in 11 patients (Figs. 1 and 2). The median follow-up for surviving patients is 3.5 years (range 0.3–11.3). The 5-year local recurrence rate and overall survival according to sex, histological type, surgical clearance and radiotherapy dose are given in Table 3. The difference in local recurrence rates between well-differentiated tumours and Hurthle cell variants, or tumours with a focus of poor differentiation and total radiation dose, as shown in Table 3, reached statistical significance. However, the P values are not adjusted for multiple testing and the number of events is small. In addition, it has not been possible to account for the heterogeneity of the techniques used. These results should therefore be treated with caution. Discussion
The indications for treatment in this study largely conform to published guidelines: 88% of patients had either residual disease or non-iodine concentrating tumours. The apparent differences in outcome between welldifferentiated tumours and tumours with a focus of poor differentiation or Hurthle cell variant is as expected. Poor prognostic features in the small group of patients with complete excision probably explain the similarity in outcomes to patients with incomplete surgical excision. The apparent difference in outcomes related to the dose of radiotherapy is subject to the confounding factors in all retrospective studies of EBRT as outlined above. However, there are few published data that define the dose to be used. In one retrospective study,
340
CLINICAL ONCOLOGY
Table 3 – Local recurrence (3–5 years) and overall survival Number
5-year local recurrence % (95% CI*)
5-year survival % (95% CI*)
Sex Females Males
26 15
31 (9,53) 40 (12,68) P=0.20
61 (39,83) 61 (33,89) P=0.47
Histological type Papillary Follicular
24 17
26 (2,50) 43 (19,67) P=0.23 21 (3,39) 69 (35,100) P=0.02
67 (43,90) 48 (20,74) P=0.45 67 (47,87) 32 (0,68) P=0.16
Well differentiated Focus of poor/Hurthle cell
29 12
Surgical clearance Complete Incomplete
9 32
25 (0,55) 37 (17,57) P=0.97
61 (24,97) 59 (39,79) P=0.69
Radiotherapy dose <50 Gy† 50–54 Gy† >54 Gy†
12 13 16
63 (33,93) 15 (0,35) 18 (0,42) P=0.02 trend
42 (14,70) 72 (44,100) 68 (34,100) P=0.09 trend
*CI, confidence interval. † Gy, Gray.
Fig. 1 – Freedom from local recurrence.
114 patients with macroscopically resected, welldifferentiated thyroid cancer were treated with EBRT. An ‘adequate’ total dose was defined as >45 Gy if Co60 or >40 Gy if orthovoltage X-rays were used. Patients receiving an ‘adequate’ dose had a significantly improved local regional relapse-free survival (P<0.001) [9]. However, only three of the 114 patients in this study also received radio-iodine, and therefore the role of EBRT in addition to standard management was not examined. A total dose of 50–60 Gy was used in the two studies, which showed a reduction in local failure where EBRT was used in addition to radio-iodine [5,6].
Fig. 2 – Overall survival.
Although no firm conclusions can be drawn, it is likely that a total dose of at least 50 Gy and possibly higher is required to have any impact on local control. No comment can be made on overall time or fractionation. Intensity-modulated radiotherapy may permit doses higher than this to be delivered. The clinical target volume for thyroid cancer curves around the doselimiting spinal cord, and the possibility of a doseresponse relationship as indicated by our data suggests that locally advanced thyroid cancer may be an ideal application for this technology [10]. Acute reactions, including mucositis, dysphagia, skin reaction, oedema and late reactions, including skin
EBRT AND THYROID CANCER
fibrosis and tracheal compression, have been reported in other retrospective studies [1,3–6]. In common with these studies, we have been unable to report accurately the incidence of such effects after EBRT. Collaboration between centres in implementing new technology, standardising technique and clinical target volume, co-ordinating dose escalation and collecting efficacy and toxicity data is highly desirable because of the small numbers of patients for whom EBRT is indicated. References 1 Vini L, Harmer C. Management of thyroid cancer. Lancet Oncol 2002;3:407–414. 2 Tsang R, Brierley J, Simpson W, et al. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 1998; 82:375–388. 3 Samaan N, Schultz P, Hickey R, et al. The results of various modalities of treatment of well-differentiated thyroid carcinoma: a
4 5
6 7
8 9
10
341
retrospective review of 1599 patients. J Clin Endocrinol Metab 1992;75:714–720. Tubiana M, Hadda E, Schlumberger M, et al. External radiotherapy in thyroid cancers. Cancer 1985;55(suppl):2062–2071. Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid cancer. Impact of adjuvant external beam radiotherapy in patients with perithyroidal tumour infiltration (stage pT4). Cancer 1996; 77:172–180. Phlips P, Hanzen C, Andry G, et al. Postoperative irradiation for thyroid cancer. Eur J Surg Oncol 1993;19:399–404. British Thyroid Association. Guideline for the management of thyroid cancer in adults. London; Royal College of Physicians, 2002. Regional Thyroid Cancer Group. Cancer network guidelines for the management of thyroid cancer. Clin Oncol 2000;12:373–391. Esik O, Nemth G, Eller J. Prophylactic external irradiation in differentiated thyroid cancer: a retrospective study over a 30-year observational period. Oncology 1994;51:372–379. Nutting C, Convery D, Cosgrove V, et al. Improvements in target coverage and reduced spinal cord irradiation using intensitymodulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland. Radiother Oncol 1991;60:173–180.
Original Article External Beam Radiotherapy in the Management of Differentiated Thyroid Cancer D. Ford*, S. Giridharan*, C. McConkey†, A. Hartley*, C. Brammer‡, J. C. Watkinson*, J. Glaholm* *Cancer Centre, Queen Elizabeth Hospital, Edgbaston, Birmingham; †Cancer Research UK Clinical Trials Unit, Edgbaston, Birmingham; ‡Deansley Centre, New Cross Hospital, Wolverhampton, U.K. ABSTRACT: Aims: No randomised trials have addressed the use of external beam radiotherapy (EBRT) in the treatment of differentiated thyroid cancer. The indications for EBRT, the technique and recommended dose all remain controversial. Materials and methods: We included patients treated with EBRT with curative intent from two cancer centres between 1988 and 2001. Data were collected from hospital notes, radiotherapy prescriptions and local cancer registry. Results: The indications for treatment in the 41 identified patients were macroscopic residual disease 23 (56%), microscopic residual disease 10 (25%), Hurthle cell variants 3 (7%), multiple lymph-node involvement 3 (7%) and other 2 (5%). Delivered doses ranged from 37.5–66 Gy over 3–6.5 weeks. Rate of local recurrence and overall survival at 5 years were as follows: papillary 26% and 67%; follicular 43% and 48%; well differentiated 21% and 67%; focus of poor differentiation/Hurthle cell variants 69% and 32%; complete excision 25% and 61%; residual disease 37% and 59%; EBRT total dose <50 Gy 63% and 42%; 50–54 Gy 15% and 72%; >54 Gy 18% and 68%. Conclusions: The results in this study are consistent with previous retrospective studies of EBRT. The wide range of indications and doses used with radical intent highlights the lack of clinical and radiobiological data on the response of differentiated thyroid cancer to EBRT. Despite the small study size, the 5-year local recurrence results indicate a possible dose response within the dose range used. Ford D., et al. (2003). Clinical Oncology 15, 337–341 2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Thyroid cancer, external beam radiotherapy, dose Received: 26 March 2003
Revised: 21 May 2003
Introduction
The role of external beam radiotherapy (EBRT) in thyroid cancer remains controversial [1]. No published randomised controlled trials have examined the addition of EBRT to standard treatment, namely surgery, radioactive iodine and medical suppression of thyroid stimulating hormone. Imbalances in age, sex, completeness of surgical excision, histological type and stage, between patients receiving and not receiving EBRT, confound retrospective studies. Variability also exists between treatment and non-treatment groups in the use of radio-iodine and post-treatment thyroid stimulating hormone suppression. There is also a lack of standardisation in dosimetry and treatment technique between and within retrospective studies. Retrospective comparative studies of EBRT in differentiated thyroid cancer are outlined in Table 1. Tsang Author for correspondence: Dr A. Hartley, Cancer Centre, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH; E-mail: [email protected] 0936-6555/03/060337+5 $30.00/0
Accepted: 22 May 2003
et al. [2] found that EBRT had no advantage on cause-specific survival (P=0.86); however, patients receiving EBRT were significantly older, less likely to have undergone a total thyroidectomy and more likely to have extra-thyroidal invasion, residual disease and larger tumours than patients who did not receive EBRT. Patients not receiving EBRT were more likely to have distant metastases and less likely to have received radioiodine. Similarly, a large U.S. study failed to show any advantage for EBRT, although patients were older, more likely to be men and have distant metastases, and less likely to have had extensive surgical intervention [3]. Tubiana et al. [4] reported an advantage in terms of local recurrence for EBRT (P<0.05). Patients receiving EBRT were more likely to have had incomplete resection of the disease. Conversely, patients in the control group were less likely to have received radioiodine. Farahati et al. [5] and Phlips et al. [6] have also reported local recurrence advantages for EBRT [5,6]. In both studies, all patients received radio-iodine. In the
2003 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
338
Table 1 – Retrospective studies of external beam radiotherapy for differentiated thyroid cancer
Study Tsang, et al., 1998 [2]
Patient Group All differentiated carcinoma
Number of patients receiving EBRT
Number of Patients not receiving EBRT
185
197
Outcome Cause-specific survival: RR 1.1 (0.6–1.8); P=0.86
Features of EBRT Group 1. Mean Age: 49.1* vs 45.4†; P=0.03. 2. Extrathyroidal invasion: 65%* vs 38%†; P<0.0001. 3. Size: >4 cm; 39%* vs 25%†; P=0.0002. 4. No residual disease: 14%* vs 47%†; P<0.0001. 5. Total thyroidectomy: 23%* vs 35%†; P=0.047
Tubiana, et al., 1985 [4]
All differentiated carcinoma (excluding patients with distant metastasis)
180
336
Samaan, et al., 1992 [3]
All well-differentiated carcinoma
113
1486
Farahati, et al., 1996 [5]
All T4-differentiated carcinoma (excluding patients with distant metastasis)
99
Phlips, et al., 1993 [6]
All differentiated carcinoma
38
Local recurrence: 14%* vs 21%†; P<0.05
1. Incomplete macroscopic excision 54%* vs 17%† 2. Only 53%* treated with megavoltage photons More patients in the EBRT group received radio-iodine 34%* vs 18%†. Mean age: 45.3* vs 40.2†; P<0.01 More men: 9%* vs 6%†; P<0.05 More likely to have distant disease: P<0.02 Less surgical intervention: P<0.001
No advantage in reducing recurrence or death
1. 2. 3. 4.
70
Local recurrence: 7%* vs 30%†; P=0.003
No significant differences between groups. All patients received radio-iodine (EBRT given between two courses)
56
Local recurrence: 3%* vs 25%†; 5-year overall survival: 84%* and 94%†
1. Macroscopic complete resection: 68%* vs 89%† 2. Node positive: 55%* vs 28%† 3. Extracapsular extension: 16%* vs 10%† All patients received radio-iodine.
†
*Patients receiving EBRT; Patients not receiving EBRT. EBRT, external beam radiotherapy.
CLINICAL ONCOLOGY
Fewer patients in the EBRT group had distant metastases (5%* vs 15%†; P=0.002); more patients received radio-iodine (69%* vs 48%†; P<0.0001).
339
EBRT AND THYROID CANCER
study by Farahati et al. [5], the difference in local recurrence reached statistical significance (P=0.003) and confounding factors were reported. In the study by Phlips et al. [6], a difference in local recurrence (no P values quoted) occurred, although patients receiving EBRT were more likely to have node-positive disease, extracapsular extension and incomplete macroscopic excision [6]. The differences in patient groups among these studies, and the difficulties with confounding factors, make evidence-based recommendations for the use of EBRT difficult to formulate. Tsang et al. [2] have suggested a role for EBRT in patients with papillary cancer, with microscopic residual disease based on sub-group analysis showing a statistically significant advantage in terms of cause-specific survival (100% vs 95%; P=0.038) and local recurrence (93% vs 78%; P=0.01). Farahati et al. [5] recommend the use of EBRT in node-positive patients over 40 years of age with papillary histology on the basis of an increase in time to local or distant failure (P=0.0009) [5]. In the U.K., indications for EBRT include high-grade tumours that do not concentrate iodine and tumours with gross local invasion where there is a high suspicion of microscopic or macroscopic disease [7,8]. The aim of this study was to assess the indications for and outcomes from EBRT in differentiated thyroid cancer in two radiotherapy centres in the West Midlands. Method
We identified patients from databases at two radiotherapy centres and included cases of differentiated thyroid cancer treated with EBRT with curative intent between 1988 and 2001. We obtained the following data from hospital notes, radiotherapy prescriptions and local cancer registries: patient age and sex, indication for treatment, histological type, completeness of surgical excision, radiotherapy dose, local and distant recurrence and overall survival. Survival and recurrence estimates were measured from the starting date of EBRT and calculated by the Kaplan–Meier method. Comparisons were made with the Mantel–Cox log-rank statistic. Results
We identified a total of 41 patients (26 women, 15 men). Predominant histological types were papillary 24 (59%) and follicular 17 (41%). A focus of poor differentiation was seen in nine (22%) patients and Hurthle cell variants were seen in three (7%) patients. Complete macroscopic and microscopic clearance was obtained in nine (22%) patients. Indications for EBRT were macroscopic residual disease 23 (56%), microscopic residual disease 10 (24%), Hurthle cell variants 3 (7%), multiple lymph nodes 3 (7%), focus of poor differentiation/anaplastic carcinoma as sole indication 2 (5%) (Table 2).
Table 2 – Indications for external beam radiotherapy Indication Macroscopic residual disease Microscopic residual disease Hurthle cell variants Multiple lymph nodes Other
Number of patients
Percentage
23 10 3 3 2
56 24 7 7 5
The superior border of the target volume was defined at the tip of the mastoid process, the inferior border at the lower border of the sternal notch and the lateral border at the junction of the outer and middle-third of the clavicle. Techniques used to treat this volume varied considerably. Most commonly, anterior and posterior opposed fields were used for a first treatment phase. For the second phase, treatment was continued either with midline lead shielding in the posterior beam or caudally angled lateral fields with posterior border anterior to the spinal cord. A direct electron field, or combinations of anterior and anterior oblique fields, were used in a few patients. Treatment schedules varied, with doses ranging from 37.5–66 Gy over 3–6.5 weeks (Table 3). In addition, 35 patients received at least one ablative dose of radio-iodine (3000 MBq) at initial presentation. Fifteen patients died and thyroid carcinoma recurred in 11 patients (Figs. 1 and 2). The median follow-up for surviving patients is 3.5 years (range 0.3–11.3). The 5-year local recurrence rate and overall survival according to sex, histological type, surgical clearance and radiotherapy dose are given in Table 3. The difference in local recurrence rates between well-differentiated tumours and Hurthle cell variants, or tumours with a focus of poor differentiation and total radiation dose, as shown in Table 3, reached statistical significance. However, the P values are not adjusted for multiple testing and the number of events is small. In addition, it has not been possible to account for the heterogeneity of the techniques used. These results should therefore be treated with caution. Discussion
The indications for treatment in this study largely conform to published guidelines: 88% of patients had either residual disease or non-iodine concentrating tumours. The apparent differences in outcome between welldifferentiated tumours and tumours with a focus of poor differentiation or Hurthle cell variant is as expected. Poor prognostic features in the small group of patients with complete excision probably explain the similarity in outcomes to patients with incomplete surgical excision. The apparent difference in outcomes related to the dose of radiotherapy is subject to the confounding factors in all retrospective studies of EBRT as outlined above. However, there are few published data that define the dose to be used. In one retrospective study,
340
CLINICAL ONCOLOGY
Table 3 – Local recurrence (3–5 years) and overall survival Number
5-year local recurrence % (95% CI*)
5-year survival % (95% CI*)
Sex Females Males
26 15
31 (9,53) 40 (12,68) P=0.20
61 (39,83) 61 (33,89) P=0.47
Histological type Papillary Follicular
24 17
26 (2,50) 43 (19,67) P=0.23 21 (3,39) 69 (35,100) P=0.02
67 (43,90) 48 (20,74) P=0.45 67 (47,87) 32 (0,68) P=0.16
Well differentiated Focus of poor/Hurthle cell
29 12
Surgical clearance Complete Incomplete
9 32
25 (0,55) 37 (17,57) P=0.97
61 (24,97) 59 (39,79) P=0.69
Radiotherapy dose <50 Gy† 50–54 Gy† >54 Gy†
12 13 16
63 (33,93) 15 (0,35) 18 (0,42) P=0.02 trend
42 (14,70) 72 (44,100) 68 (34,100) P=0.09 trend
*CI, confidence interval. † Gy, Gray.
Fig. 1 – Freedom from local recurrence.
114 patients with macroscopically resected, welldifferentiated thyroid cancer were treated with EBRT. An ‘adequate’ total dose was defined as >45 Gy if Co60 or >40 Gy if orthovoltage X-rays were used. Patients receiving an ‘adequate’ dose had a significantly improved local regional relapse-free survival (P<0.001) [9]. However, only three of the 114 patients in this study also received radio-iodine, and therefore the role of EBRT in addition to standard management was not examined. A total dose of 50–60 Gy was used in the two studies, which showed a reduction in local failure where EBRT was used in addition to radio-iodine [5,6].
Fig. 2 – Overall survival.
Although no firm conclusions can be drawn, it is likely that a total dose of at least 50 Gy and possibly higher is required to have any impact on local control. No comment can be made on overall time or fractionation. Intensity-modulated radiotherapy may permit doses higher than this to be delivered. The clinical target volume for thyroid cancer curves around the doselimiting spinal cord, and the possibility of a doseresponse relationship as indicated by our data suggests that locally advanced thyroid cancer may be an ideal application for this technology [10]. Acute reactions, including mucositis, dysphagia, skin reaction, oedema and late reactions, including skin
EBRT AND THYROID CANCER
fibrosis and tracheal compression, have been reported in other retrospective studies [1,3–6]. In common with these studies, we have been unable to report accurately the incidence of such effects after EBRT. Collaboration between centres in implementing new technology, standardising technique and clinical target volume, co-ordinating dose escalation and collecting efficacy and toxicity data is highly desirable because of the small numbers of patients for whom EBRT is indicated. References 1 Vini L, Harmer C. Management of thyroid cancer. Lancet Oncol 2002;3:407–414. 2 Tsang R, Brierley J, Simpson W, et al. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 1998; 82:375–388. 3 Samaan N, Schultz P, Hickey R, et al. The results of various modalities of treatment of well-differentiated thyroid carcinoma: a
4 5
6 7
8 9
10
341
retrospective review of 1599 patients. J Clin Endocrinol Metab 1992;75:714–720. Tubiana M, Hadda E, Schlumberger M, et al. External radiotherapy in thyroid cancers. Cancer 1985;55(suppl):2062–2071. Farahati J, Reiners C, Stuschke M, et al. Differentiated thyroid cancer. Impact of adjuvant external beam radiotherapy in patients with perithyroidal tumour infiltration (stage pT4). Cancer 1996; 77:172–180. Phlips P, Hanzen C, Andry G, et al. Postoperative irradiation for thyroid cancer. Eur J Surg Oncol 1993;19:399–404. British Thyroid Association. Guideline for the management of thyroid cancer in adults. London; Royal College of Physicians, 2002. Regional Thyroid Cancer Group. Cancer network guidelines for the management of thyroid cancer. Clin Oncol 2000;12:373–391. Esik O, Nemth G, Eller J. Prophylactic external irradiation in differentiated thyroid cancer: a retrospective study over a 30-year observational period. Oncology 1994;51:372–379. Nutting C, Convery D, Cosgrove V, et al. Improvements in target coverage and reduced spinal cord irradiation using intensitymodulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland. Radiother Oncol 1991;60:173–180.