Cancer Treatment - An Update
Chemotherapy of undifferentiated thyroid cancer (UCT) and sarcoma of the thyroid gland (ST)
F. Kober, A. Heiss, B. Neugebauer, R. Roka
Edited by: P. Banzert, J. F. Holland, D. Khayat, M. Weil
Anaplastic carcinoma and sarcoma of the thyroid gland are among the most lethal cancers in humans. Median life expectancy is usually less than 4 months after the inital diagnosis. Most tumors are unresectable when first seen, because of enormous size and infiltration of adjacent structures such as trachea and oesophagus. Between 1957-1989 a retrospective study on 169 patients with highly malignant thyroid tumors was carried out in the Kaiserin-Elisabeth-Hospital. The retrospective analysis clearly showed that if a radical resection of tumor (R0-R1) can be achieved the median survival time rises to 8 months in comparison with only two months after palliative surgery (R2). Conventional radiotherapy usually failed to induce any significant regression of the tumor. In 1985 on the basis of the results we decided the carry out a prospective study to evalute the effect of highly malignant thyroid tumors by ChtX. We selected the patients according to the following criteria.
Including criteria
Patients with undifferntiated carcinoma and sarcoma of thyroid gland.
Excluding criteria any of the following
Karnovsky index less than 50 %, Tumor stage T2 N0 M0, Chronic renal disease, thrombocytes < 100,000 and leucocytes < 3,000.
Between 1. 1.1985 and 1. 1. 1991 32 patients with undifferentiated thyroid carcinoma or thyroid sarcoma were admitted to our clinic. According to these criteria 10 patients were excluded from ChtX and the others were treated among to the following protocol.
Attempt at a radical tumor resection (R0, R1).
Early postoperative commencement of chemotherapy:
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Day 3 postop.: Mitoxantrone 20 mg/m2 BSA,
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Day 8 postop.: Cisplatin 100 mg/m2 BSA,
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ChtX was repeated 6 times, 3 to 4 weeks apart.
On five patients we achieved an R0 and in another five an R1 resection, and in one further case the patient was operated in another hospital and we do not know the extent of the resection. In 11 patients only palliative resection of tumors was possible. The response of chemotherapy was defined as follows.
Complete remission
Total disappearance of the thryoid tumor and or the distant metastases. No local recurrence and no distant metastases up to 3 months after the end of ChtX, in case of R0 or R1 resection.
Response
More than 25 % reduction of the tumor mass or distant metastases. Local recurrence or distant metastases up to 3 months after start of ChtX, in case of R0 or R1 resection.
Progression
No effect on tumor or metastatic growth. Local recurrence or appearance of metastases up to 3 months after start of ChtX in case of R0 or R1 resection. Of the 22 patients who received ChtX 15 (7 CR, 8 PR) were responders and 7 were nonresponders.
Nonresponders
In the group of nonresponders the median and mean survival times were 3,7 and 4,8 months. All of the nonresponders died from the direct consequences of the tumor growth such as asphyxia or indirect consequences such as cachexia, during the first year.
Responders
Among the responders the mean survival time was 27 months and the median 17 months. 5 patients are still alive and tumor-free, betwwen 20 and 78 months after the beginning of ChtX. Among the respnders 2 of 9 patients died in neutropenic sepsis after ChtX. In the group of responders 7 patients had a comlete remission (according to the above criteria). 3 of them underwent a second look operation at which local tumor control could be confirmed. 6 of 7 responders who died on consequences of the tumor showed local recurrences. It was remarkable that only one of the 15 responders developed metachronous metastases. All other patients remained either free of metastases. By contrast 5 of 7 patients among the group of nonresponders showed metachronous metastases.
Discussion
The results from our prospective unicenter study show a positive effect of ChtX in two third of patients suffering from a highly malignant thyroid tumor. Several factors a probably contributed: ChtX was always the therapy of the first choice and not a last, desperate attempt to influence advanced tumors resistant to other therapies. The dosage of ChtX was significantly higher than that used in most published studies and ChtX was started on the third postop. day. Patients with a low Karnovsky index were excluded from study, because the retrospective study had showed that their general condition cannot be improved by aggressive therapy.
Studies evaluating the effect of ChtX on undifferentiated thyroid carcinoma based on a large number of patients are rare. In most studies tha patients had already been treated by extensive radio therapy and/or high dose radio-Iodine-therapy, so that ChtX was the last resort.
Examples are the studies of Benker et al or Shimaoka [2, 5]. Benker [2] study included 20 patients with undifferentiated thyroid carcinoma treated with Doxorubicin and Bleomycin. In 5 cases a partial remission was achieved, in another 5 no change. Shimaoka was able to show in a randomised comparative study of Doxorubicin versus Cisplatin and Doxorubicin that the combination therapy is superior in monotherapy particularly in the degree of response. He observed a complete remission in three of 18 patients and a partial remission in three patients who received Doxorubicin and Cisplatin (response rate was 33 %). In these clinical cases ChtX was used as second line therapy. It is worth mentioning in this context the therapeutic regimen of Auersperg [1] et al, who varied the ChtX according to the cytoflowmetric DNA analysis. Auersperg and Tallroth [7] et al, both observed a high local response rate to combined ChtX and hyperfractionated radio therapy.
In our prospective study we were able to show that early postoperative chemotherapy (Cisplatin 100 mg/m2 BSA, Mitoxantrone 20 mg/m2 BSA) is effective in patients with undifferentiated thyroid carcinoma and sarcoma of the thyroid gland. However patients of the group of responders had some local recurrences after chemotherapy. Therefore we also recommend combination therapy with chemotherapy and hyperfractionated radiotherapy.
References
Auersperg M, Us-Krasovec M, Petric G, Pogacnik A, Besic N (1990) Results of combined modality treatment in poorly differentiated and anaplastic thyroid carcinoma. Wien Klin. Wochenschr. 102 : 267 Benker G, Reinwein D (1983) Ergebnisse der Chemotherapie des Schilddrüsenkarzinoms. Dtsch Med Wochenschr 108 : 403 Holinsky Ch, Kober F, Hermann M, Loicht U, Keminger K (1990) Prognostische Faktoren bei hoch malignen Schilddrüsentumoren. Wien Klin Wochenschr 102 : 219 Kim JH, Leeper RD (1983) Treatment of anaplastic giant and spindle cell carcinoma of the thyroid gland with combination adriamycin and ratiation therap. Cancer 52 : 954 Shimaoka K, Schoenfeld DA, Dexys WD, Creech RH, De Conti R (1985) A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56 : 2155 Simpson WJ (1980) Anaplastic thyroid carcinoma, a new approach. Can J Surg 23 : 25 Tallroth E, Wallin G, Lundell G, Loewhagen T, Einhorn J (1987) Multimodality treatment in anaplastic giant cell thyroid carcinoma. Cancer 60 : 1428
