Clive Harmer

Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer

BACKGROUND It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Differentiated thyroid carcinoma with distant metastases at presentation: prognostic factors and outcome

Background Differentiated thyroid cancer (DTC) presenting with distant metastases is uncommon. Prognostic factors that affect survival remain unclear.

Testicular dose and fertility in men following I131 therapy for thyroid cancer

objective Young adults with differentiated thyroid cancer are treated with high doses of radioiodine and have an excellent long‐term prognosis. However, there is limited information on the effects of this treatment on the gonads and fertility in male patients. We have reviewed the outcome of treatment in our centre with respect to male fertility. We have also assessed directly the radiation dose received by the testes.

Improvements in target coverage and reduced spinal cord irradiation using intensity-modulated radiotherapy (IMRT) in patients with carcinoma of the thyroid gland.

BACKGROUND AND PURPOSE External beam radiotherapy for thyroid carcinoma poses a significant technical challenge as the target volume lies close to or surrounds the spinal cord. The potential of intensity-modulated radiotherapy (IMRT) to improve the dose distributions was investigated. MATERIALS AND METHODS A planning study was performed on patients with thyroid carcinoma. Plans were generated to irradiate the thyroid bed alone or to treat the thyroid bed and the loco-regional lymph nodes in two phases. Conventional plans with minimal beam shaping were compared to three-dimensional conformal radiotherapy (3DCRT) and inverse-planned IMRT plans to assess target coverage and normal tissue sparing. IMRT techniques were optimized to find the minimum number of equispaced beams required to achieve the clinical benefit and a concomitant boost technique was explored. RESULTS For the thyroid bed alone and the thyroid bed plus loco-regional lymph nodes, conventional and conformal techniques produced low minimum doses to the planning target volume (PTV) if spinal cord tolerance was respected. 3DCRT reduced the irradiated volume of normal tissue (P=0.01). IMRT plans achieved the goal dose to the PTV (P<0.01) and also reduced the spinal cord maximum dose (P<0.01). IMRT, using a concomitant boost technique, produced better target coverage than a two-phase technique. For both the two-phase and concomitant boost techniques, IMRT plans with seven and five equispaced fields produced similar dose distributions to nine fields, but three fields were significantly worse. CONCLUSIONS 3DCRT reduced normal tissue irradiation compared to conventional techniques, but did not improve PTV or spinal cord doses. IMRT improved the PTV coverage and reduced the spinal cord dose. A simultaneous integrated boost technique with five equispaced fields produced the best dose distribution. IMRT should reduce the risk of myelopathy or may allow dose escalation in patients with thyroid cancer.

Breast conservation in the treatment of early breast cancer a 20-year follow-up

Two hundred sixty‐three patients with unilateral primary breast cancer, treated by local excision of the primary tumor and radical radiation therapy between 1954 and 1969, were followed up for a minimum of 10 years and a maximum of 20 years. The treatment plan delivered 4500 rad in fractions of orthovoltage irradiation to five fields: tangential breast fields, axilla with posterior axillary field, parasternal and supraclavicular, with a subsequent boost of 1000 rad to the primary tumor site, axilla, and supraclavicular fossa. Patients were clinically staged using the TNM (UICC) system; 115 patients had tumors less than 2 cm in diameter and a clinically negative axilla (T1N0N1a), 96 had tumors 2 to 5 cm in diameter with a clinically negative axilla (T2N0N1a), and 52 had tumors less than 5 cm in diameter and clinical axillary lymph node metastases (T1T2N1b). The actuarial relapse‐free survival of patients with T1N0N1a tumors was 72% at 5 years, 59% at 10 years, and 47% at both 15 and 20 years. The relapse‐free survival of patients with T2N0N1a tumors was not statistically different (P > 0.05). A significantly worse survival was observed in patients with clinical axillary lymph node metastases (T1T2N1b), with a survival of 37% at 5 years, 29% at 10 years, 23% at 15 years, and 22% at 20 years, when compared with patients with clinically negative lymph nodes (P < 0.01). Locoregional relapse occurred in 22%, at 10 years, of those patients with T1 or T2N0N1a tumors and 52% of the patients with T1T2N1b tumors. The pattern of locoregional relapses indicated that approximately 50% occur at least 5 years after treatment; this contrasts with the pattern of early locoregional relapse after mastectomy. The commonest sites of relapse were in the breast in 19% and axilla in 6% of patients with T1 or T2N0N1a tumors. There was no attenuation of the radiation dose administered at the site of a subsequent relapse. Surgery for radiation failure produced a 42% crude relapse‐free survival at 5 years after salvage mastectomy in those patients originally treated for T1 or T1N0N1a tumors. The results of this study suggest that a significant proportion of patients relapse locally over a prolonged period after breast conservation. The evolution of new radiation techniques may provide better locoregional control and early salvage surgery may result in improved long‐term survival.

Thyroid cancer in children: the Royal Marsden Hospital experience

The first child with well-differentiated thyroid cancer treated at the Royal Marsden Hospital presented in 1917. Since that time 30 children under the age of 16 years have been treated over a period during which many new treatments have been introduced. We have reviewed their management and outcome. The median follow-up is 22.5 years (range: 1-66). The median time to recurrence was 7 years (range: 2-44). There were events up to 44 years after presentation. The risk of recurrence was higher in children aged 10 years or younger [HR 3.45, 95% CI (1.04-11.11) P = 0.03]. Thyroid stimulating hormone (TSH) suppression was the only intervention to be shown to reduce the recurrence rate [HR 11, 95% CI (2.27-50) P = 0.0003]. The median overall survival is 53 years. The only presenting feature predictive of poorer survival was the presence of metastases (HR 28.96, 95% CI 2.51-334, P < 0.001). Patients who developed recurrence had a higher risk of death (HR 9.90, 95% CI 0.98-100, P = 0.02) and a shorter median survival of 30 years. No therapeutic intervention could be shown statistically to impact on survival. Our recommendation for treatment is total or near-total thyroidectomy for all patients and radioiodine ablation for all except those with early T stage node-negative disease aged over 10 years. Modified neck dissection is recommended for children with clinically positive neck nodes and TSH suppression for all. Follow-up with serial thyroglobulin measurement should be lifelong.

Results of external beam radiotherapy in differentiated thyroid carcinoma: a retrospective study from the Royal Marsden Hospital

Between 1969 and 1991, 113 patients with differentiated thyroid carcinoma (follicular and papillary) received radical dose megavoltage external beam radiotherapy. There were 70 females and 43 males, mean age 53 years (range 11-84). Radiotherapy was delivered to both sides of the neck and superior mediastinum, using either megavoltage photons via anterior and posterior portals, delivering a 60 Gy mid-plane dose in 30 fractions and treating daily over 6 weeks (with spinal cord shielding from the posterior field after 40 Gy), or matched 20 MeV and 35 MeV electron beams (to the neck and superior mediastinum, respectively) delivering a 75 Gy applied dose in 30 daily fractions. All patients received suppressive thyroid hormone and 74 radioiodine. Local recurrence, mostly within field, occurred in 19% of 53 patients with probable and definite residual microscopic disease (both follicular and papillary histologies). For gross residual disease (both follicular and papillary) in 49 patients, complete regression was obtained in 37.5%, partial regression in 25% and no regression in 37.5%. Median follow-up from diagnosis was 49 months (range 3-335). Overall 5-year survival rates were 85% for residual microscopic disease but only 27% for gross disease. 61 patients have died. Nineteen deaths were due to unrelated causes, 15 to distant metastases, 15 to uncontrolled local disease and 12 died with both local and distant tumours.

Chemodectoma of the head and neck: Results of treatment in 84 patients

Eighty-four patients with chemodectoma of the head and neck presented to the Royal Marsden Hospital between 1949 and 1985. For tumors arising at the skull base (glomus jugulare and glomus tympanicum) 46 were treated with radiotherapy alone resulting in an actuarial local control rate of 73% at 25 years; 13 were treated with surgery plus radiotherapy with no recurrences during a median follow-up of 9 years; 4 had surgery alone but all recurred by 7 years. For tumors of the soft tissues of the neck (carotid body and glomus vagale) 13 were treated with surgery alone with an actuarial control rate of 54% at 15 years; 4 were treated with radiotherapy which resulted in local control at 1, 2, 8 and 11 years; and one patient who received both surgery and radiotherapy remained controlled at 1 year. Although comparison between radiotherapy and surgery in terms of tumor control is not simple, the case is argued for more frequent use of radiotherapy at all sites. This case is strengthened by minimal morbidity from radiotherapy in doses which appear effective: in the range of 45-50 Gy in 25 daily fractions over 5 weeks.

Management of thyroid cancer

Thyroid cancers are a diverse group of malignant disorders ranging from indolent micropapillary carcinoma, which has no effect on life expectancy, to anaplastic tumours, which are invariably fatal even with aggressive treatment. Although the estimated incidence has increased by 14.6% over the past 40 years, the estimated death rate has fallen by 21%, probably as a result of earlier diagnosis. The natural history of thyroid tumours is no longer a mystery, and the prognostic factors identified can predict outcome fairly accurately. Improvements in management have mostly depended on information from large retrospective series, though there are still many areas open to debate. There has been, however, a general acceptance that thyroid cancer should be managed by multidisciplinary teams in specialised units following evidence-based guidelines.

Factors Affecting Acute Skin Toxicity in Patients Having Breast Irradiation After Conservative Surgery: A Prospective Study of Treatment Practice at the Royal Marsden Hospital

The results are presented of a prospective study of acute skin toxicity in 197 patients with early stage breast cancer, who were treated by conservative surgery and postoperative radiotherapy. We have examined the factors determining the severity of the acute skin reaction with particular reference to the degree of dry or moist desquamation at the completion of treatment. One hundred and ten patients had treatment with radiotherapy alone. The remaining 87 received synchronous chemotherapy with breast irradiation, using either the 3M or the 2M regimen, consisting of mitoxantrone and methotrexate, with (3M) or without Mitomycin-C (2M). Patients were analysed according to both the severity and the site of the skin reaction, age, dose, dose variation across the central outline, treatment technique, beam energy, field separation and breast size. A univariate analysis of these results, which has been presented as an odds ratio of the likelihood of developing a moderate or severe reaction in comparison with those scored as mild, has shown that several factors are associated with an increase in the acute skin reaction. These include the use of the semi-supine technique (odds ratio (OR) = 7.3 (95% CI 3.7-14.6)), beam energy (60Co: 6-10 MV photons OR = 5.9 (95% CI 2.6-13.4)), field separation (> or = 20 cm: < 20 cm OR = 4.1 (95% CI 2.2-7.8)), dose variation across the central outline (> or = 10%: < 10% OR = 9.7 (95% CI 2.6-36.4)), inclusion of the axilla (OR = 4.6 (95% CI 2.4-8.9)), and bust size (bra cup size C and D: A and B OR = 4.6 (95% CI 2.7-11.9)). Using multivariate logistic regression, the technique of radiation delivery and bust size were shown to be independently significant variables affecting acute skin reaction. In view of the high correlation between variables (e.g. radiotherapy technique and beam energy) it is still not possible to specify with definite certainty which is the primary variable causing the skin reaction. However 20/57 (35%) of patients treated by the semisupine technique sustained a severe skin reaction, with > 10% dry or moist desquamation in the treatment field. This compares with only 6/140 (4%) patients treated by the supine method. A possible mechanism by which treatment using the semisupine technique may enhance acute toxicity is discussed. We conclude that there are both treatment and patient related factors that will increase the acute skin reaction after breast irradiation.