Göran Lundell

Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery

Patients with anaplastic thyroid carcinoma can rarely be cured, but every effort should be made to prevent death due to suffocation. Between 1984 and 1999, 55 consecutive patients with anaplastic thyroid carcinoma were prospectively treated according to a combined regimen consisting of hyperfractionated radiotherapy, doxorubicin, and when feasible surgery. Radiotherapy was carried out for 5 days a week. The daily fraction until 1988 was 1.0 Gy × 2 (A) and 1989–92 1.3 Gy × 2 (B) . Thereafter 1.6 Gy × 2 (C) was administered. Radiotherapy was administered to a total target dose of 46 Gy; of which 30 Gy was administered preoperatively in the first two protocols (A and B), while the whole dose was given preoperatively in the third protocol (C). The therapy was otherwise identical. Twenty mg doxorubicin was administered intravenously weekly. Surgery was possible in 40 patients. No patient failed to complete the protocol due to toxicity. In only 13 cases (24%) was death attributed to local failure. Five patients (9%) ‘had a survival’ exceeding 2 years. No signs of local recurrence were seen in 33 patients (60%); 5 out of 16 patients in Protocol A, 11 out of 17 patients in Protocol B, 17 out of 22 patients in Protocol C (P=0.017). In the 40 patients undergoing additional surgery, no signs of local recurrence were seen in 5 out of 9 patients, 11 out of 14 patients and 17 out of 17 patients, respectively (P=0.005).

Aspiration biopsy cytology in diagnosis of thyroid cancer

Aspiration biopsy cytology (ABC) is a diagnostic method that has been used extensively in Sweden for a quarter of a century. The technical steps involved in this biopsy procedure are described, and the differences from large needle biopsy techniques are pointed out. An overview is given of the different pathologic conditions that present as thyroid nodules and are recognizable by ABC. The accuracy of the method as a preoperative diagnostic tool has been shown to be superior to other clinical methods. ABC enables the surgeon not only to better select patients with thyroid nodules for surgery, but also to plan a definite operative strategy in papillary, medullary, and anaplastic neoplasms. In follicular neoplasms, however, the method cannot distinguish with certainty between adenoma and carcinoma. ABC has drastically reduced the number of diagnostic surgical operations for benign lesions. It requires no anesthesia. It has no complications and there is good patient acceptance, even in children.

Anaplastic Giant Cell Carcinoma of the Thyroid Gland: Treatment and Survival Over a 25-Year Period

Abstract. Anaplastic giant cell carcinoma of the thyroid is a rare but highly malignant tumor. At the Karolinska Hospital in Stockholm, surgery, chemotherapy, and radiotherapy have been used separately or in various combinations in 81 patients admitted with this diagnosis during 1971–1997. In this study, we present the various multimodality treatment regimens and their changes over the years and the subsequent differences in survival and local tumor control. Overall, eight patients (10%) survived more than 2 years. All survivors were treated with combinations of chemotherapy, radiotherapy, and surgery. Among the patients who died, local tumor control was achieved by the therapy given in many cases. The results suggest that our current strategy with a combination of preoperative hyperfractionated accelerated radiotherapy, doxorubicin pre- and postoperatively, and debulking surgery whenever possible results in better local tumor control and an increased chance of survival.

Leukaemia incidence after iodine-131 exposure

Leukaemia is one of the most prominent late effects of exposure to ionising radiation. We have studied the incidence of leukaemia among 46,988 Swedish patients exposed to iodine-131 (131I) for diagnostic reasons or to treat hyperthyroidism or thyroid cancer. The observed number of leukaemias was compared with that expected based on incidence data from the general population. The mean absorbed dose to the bone marrow was estimated as 14 mGy (range 0.01-2.226). 195 leukaemias occurred more than 2 years after exposure, and the standardised incidence ratio (SIR) was 1.09 (95% confidence interval 0.94-1.25). Similar, but again not significantly, increased risks were seen for chronic lymphocytic leukaemia (CLL) (SIR = 1.08), a malignant condition not found to be increased after irradiation, and for non-CLL (SIR = 1.09). The risk of leukaemia did not vary by sex, age, time, or radiation dose from 131I. One reason for the absence of a radiation effect, other than chance, includes the possible lowering of risk when exposure is protracted over time as occurs with 131I. Excess leukaemia risks of more than 25% could thus be excluded with high assurance in this population of mainly adults. These results should be reassuring to patients exposed to 131I in medical practice and to most individuals exposed to the fall-out from the Chernobyl accident.

Thyroid cancer risk after thyroid examination with 131I: a population-based cohort study in Sweden.

Ionizing radiation is the only established cause of thyroid cancer, though the effect of diagnostic administration of 131I on thyroid cancer risk appears minimal. The annual number of thyroid examinations using radioiodine is currently 5 per 1,000 individuals worldwide, so this issue is of public health importance. Our objective was to evaluate the excess risk of thyroid cancer following a range of known doses of 131I administered for diagnostic purposes. We conducted a nationwide, population‐based cohort study in Sweden including all 36,792 individuals who received 131I for diagnostic purposes during 1952–1969 and were alive and free of thyroid cancer 2 years after exposure. Accrual of person‐time at risk commenced 2 years after the first 131I administration. Follow‐up for cancer was to the end of 1998. Standardized incidence ratios (SIRs) were calculated as the ratio between the observed and expected numbers of thyroid cancers. Estimates were stratified by previous exposure to external radiation therapy to the neck, reason for thyroid examination, 131I dose, sex, age at exposure and time since exposure. Thyroid cancers (n = 129) were diagnosed during 886,618 person‐years at risk. Excess thyroid cancers were observed only among the 1,767 patients who reported previous external radiation therapy to the neck [SIR = 9.8, 95% confidence interval (CI) 6.3–14.6] and among those originally referred due to suspicion of a thyroid tumor (SIR = 3.5, 95% CI 2.7–4.4 for 11,015 patients without previous external radiation therapy). The 24,010 patients without previous exposure to external radiation therapy to the neck who were referred for a reason other than suspicion of a thyroid tumor received an estimated dose to the thyroid of 0.94 Gy. Among these patients, 36 thyroid cancers were observed compared to 39.5 expected (SIR = 0.91, 95% CI 0.64–1.26). We found no evidence that administration of 131I for diagnostic purposes increases risk of thyroid cancer. However, our study included few patients under age 20, so the results apply primarily to exposure among adults. Our data suggest that protraction of dose may result in a lower risk than brief X‐ray exposure of the same total dose.

Cancer risks in thyroid cancer patients

Cancer risks were studied in 834 thyroid cancer patients given 131I (4,551 MBq, average) and in 1,121 patients treated by other means in Sweden between 1950 and 1975. Record-linkage with the Swedish Cancer Register identified 99 new cancers more than 2 years after 131I therapy [standardised incidence ratio (SIR) = 1.43; 95% confidence interval (CI) 1.17-1.75] vs 122 (SIR = 1.19; 95% CI 0.88-1.42) in patients not receiving 131I. In females treated with 131I overall SIR was 1.45 (95% CI 1.14-1.83) and significantly elevated were noted for tumours of the salivary glands, genital organs, kidney and adrenal gland. No elevated risk of a subsequent breast cancer or leukaemia was noted. SIR did not change over time, arguing against a strong radiation effect of 131I. Organs that were estimated to have received more than 1.0 Gy had together a significantly increased risk of a subsequent cancer following 131I treatment (SIR = 2.59; n = 18). A significant trend was seen for increasing activities of 131I with highest risk for patients exposed to greater than or equal to 3,664 MBq (SIR = 1.80; 95% CI 1.20-2.58). No specific cancer or group of cancers could be convincingly linked to high-dose 131I exposures since SIR did not increase after 10 years of observation. However, upper confidence intervals could not exclude levels of risk that would be predicted based on data from the study of atomic bomb survivors. We conclude that the current practice of extrapolating the effects of high-dose exposures to lower-dose situations is unlikely to seriously underestimate radiation hazards for low LET radiation.

Multimodality treatment in anaplastic giant cell thyroid carcinoma

Anaplastic giant cell thyroid carcinoma is highly malignant. Surgery, chemotherapy, or radiotherapy used separately have not been effective. Combinations of the three modalities have been used at Radiumhemmet since the middle of the 1970s. Nine patients received three‐drug chemotherapy and radiotherapy. One patient was alive after 12 years; eight died. Twenty‐five patients were given a similar regimen (with two fractions of radiotherapy per day), aiming at surgery. Twelve patients could undergo surgery. Two were alive 11 and 3.5 years after diagnosis. One patient died free of tumor after 6.5 years. Of the remaining 22 patients, many died of metastatic disease. A combination of preoperative and postoperative radiotherapy, chemotherapy (bleomycin, cyclophosphamide, and 5‐fluorouracil) and surgery during the remission has given a 12% (four of 34) survival (>3 years). All survivors had undergone surgery. The patients who died had in many cases achieved local tumor control. Adriamycin (Adria Laboratories, Columbus, OH) once a week replaced BCF due to treatment complications in patients receiving BCF. Of five patients, only one was alive more than 10 months after treatment.

Malignant Thyroid Tumors after Iodine-131 Therapy

Abstract We studied the incidence of malignant thyroid tumors after 131I therapy in 2727 patients with hyperthyroidism and in 273 euthyroid patients with cardiac disease. The patients were all adults, with a mean age of 57 years. The 131I therapy was given between 1951 and 1965. The mean follow-up period was 13 years for the hyperthyroid patients (15 years for the 85 per cent surviving for more than five years) and six years for the cardiac patients (12 years for the 41 per cent surviving for more than five years). The incidence of malignant thyroid tumors was based on a search of the Swedish Cancer Registry for the occurrence of such tumors in any of the 3000 patients. At present there is no increased incidence of malignant thyroid tumors after 131I therapy (four cases observed versus 3.2 cases expected). (N Engl J Med. 1980; 303:188–91.)

Hypothyroidism after external radiotherapy for head and neck cancer

PURPOSE To study the development of thyroid hypofunction in patients with head and neck cancers admitted for external radiotherapy. METHODS AND MATERIALS Between November 1990 and July 1996, thyroid function was measured in 264 consecutive patients, where the entire thyroid gland or part of it was included in the target volume. The time to development of hypothyroidism (HT) was calculated from the start of the radiotherapy. RESULTS The median follow-up period was 19 months. Seventeen patients (6%) developed elevated serum thyroid-stimulating hormone levels with depressed (free) thyroxine levels (i.e., clinical HT). Elevated serum thyroid-stimulating hormone level with normal (free) thyroxine levels (i.e., chemical HT) developed in 57 (22%). The median time to clinical HT was 15 months (range: 7 to 32). The median time to chemical HT was also 15 months (range: 2 to 28). The actuarial risk of developing clinical or chemical HT 3 years after treatment was 15 and 40%, respectively. The incidence of chemical HT was significantly higher (p = 0.041) when the whole thyroid was included in the target volume compared to patients where only part of the thyroid was irradiated. The same trend was seen as regards clinical HT (p = 0.063). For those 20 patients who underwent laryngectomy, there was an increased risk of both chemical and clinical HT (p = 0.011 and 0.019, respectively). Increasing age was associated with an increased risk of chemical HT (p = 0.001), but not of clinical HT (p = 0.553). Sex, tumor site, radiation dose, and combination of radiotherapy and chemotherapy were not significant factors for thyroid hypofunction. CONCLUSION Depressed thyroid function is common after external radiotherapy for cancers of the head and neck. Routine testing for possible thyroid hypofunction should be included in the follow-up procedures, even many years after end of radiotherapy.

Allelotyping of follicular thyroid tumors

To elucidate further the genetic mechanisms for follicular thyroid tumor development and progression, we allelotyped follicular thyroid tumors and other thyroid lesions from 92 patients. In general, a low frequency of loss of heterozygosity (LOH) was found, the highest being for chromosomes 3q, 10q, 11p, 11q, 13q, and 22q (10%–15%). However, detailed study of LOH of these chromosome arms with regard to the different histopathological diagnoses indicates that a locus on chromosome 10q may be involved in follicular thyroid tumor progression. In addition, the majority of Hürthle cell adenomas showed LOH on either chromosome 3q or 18q, in contrast to the other tumor types. This discrepancy in genetic alterations may contribute to the divergent clinical features occurring in these tumors.