Chemotherapy and other anti-tumor therapies
Metastatic papillary or follicular tumors grow slowly and may respond completely (often temporarily) to 131I. Thus, chemotherapy is not indicated until the full value of 131I has been exploited, and then only when the tumor is clearly growing progressively despite hormone suppression. Sporadic experience indicates that bleomycin (544, 545), adriamycin (546), vinblastine (547), methotrexate (548), cisplatinum and other agents (549) may have value in treating disseminated thyroid tumors.Treatment of MTC is generally reserved for definite symptomatic disease. Adriamycin is the most commonly used agent, but usually is used in combinations with other agents. Wu gave patients with metastatic MTC cyclophosphamide (750mg/m2), vinscristine (1.4mg/m2) and dacarbazine (600mg/m2 on 2 days), in cycles every 3 weeks, and found significant improvement and treatment was well tolerated. Lymphomas are often treated initially by chemothrapy. Undifferentiated lesions are given routine postoperative radiotherapy, and chemotherapy for recurrence or known spread. Prophylactic chemotherapy may soon be developed for these lesions. DeBesi et al. (550) found combined bleomycin, adriamycin, and platinum therapy in advanced cancer "probably" increased survival.
Intensive chemotherapy for anaplastic thyroid carcinoma using a combination of cisplatin, doxorubicin, etoposide, and peplomycin, and using granulocyte colony-stimulating factor for support of the bone marrow, was evaluated by the Japanese Society of Thyroid Surgery in a pilot investigation. Cisplatin, 40 mg/m2 intravenous infusion on day 1, plus adriamycin 60 mg/m2 iv on day 1, etoposide 100 mg/m2/day over days 1-3, peplomycin 5 mg/body/day sc on days 1-5, and granulocyte colony-stimulating factor, 2 m g/kg/day sc on days 6-14, was the program, and this was repeated every three weeks (Please review dosages in their publication). Some patients also received local radiation therapy. Several patients survived the anaplastic carcinoma for up to 11 months. This four drug regime did not achieve significant improvement over prior studies using other regimens. Because of the advanced age and the presence of high grade tumors, most patients received less than two cycles of therapy, which may have contributed to the unsatisfactory outcome (551). Paclitaxel has shown significant effects in treating anaplastic cancers but has not altered the lethality of the disease (552). Combined chemotherapy and radiotherapy may also prolong survival significantly (553). Gilliam and associates have reported efficacy of capecitabine (a precursor of 5-fluorouracil) in some cases of MTC and follicular cancer (553a).
A very interesting new approach was recently reported by Santini et al. The slow growth of thyroid tumors has been considered a main reason for their resistance to conventional chemotherapy. These authors stimulated the tumors in 14 patients by either withdrawing a portion of their replacement therapy or giving rhTSH, and then gave chemotherapy with carboplatinum plus epirubicin in six courses at 4-6 week intervals (554). One patient had a complete remission, five had partial remission, and seven had stabilization . While not cures, the results seem significantly better than usually achieved.
Tyrosine
kinase inhibitors have proven amazingly effective in gastrointestinal stromal
tumors. The logical approach has been to use molecules blocking the RTK/MAPK and the PI3K/AKT pathways, those activated by RET/PTC, RAS, and BRAF mutations in thyroid cancers. Some of the experimental drugs have the ability to inhibit several proteins crucial for the survival and expansion of neoplastic cells. Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) are two examples. Inhibiting VEGFR blocks the growth of the tumor’s endothelial cells, and inhibiting EGFR may deprive the tumor of one important growth factor sustaining an aggressive phenotype.MTC, in which
constitutive activity of the RET tyrosine kinase causes the tumor, and in aggressive differentiated thyroid tumors which frequently relate to a ret mutation.
Imatinib therapy yielded no objective responses and induced
considerable toxicity in patients with MTC(554.1).
Gefinib
is a small molecule inhibitor of the EGFR tyrosine kinase, and is beneficial in
non-small cell lung cancer. In a trial involving 27 patients,Gefitinib
therapy did not result in any tumor responses, 32% of patients had reductions in
tumor volume that did not meet criteria for partial response rate. Toxicities
were generally tolerable. Some falling Tg levels and prolonged stable disease in
a subset of patients, suggest it may have some biologic activity(554.2).
Motesanib, an orally active small molecule
inhibitor of VEGF receptors and platelet derived growth factor receptors,
induced modest but definite benefits in a study of 93 patients with progressive
differentiated thyroid cancer ( 61% papillary, others presumably follicular and
Hurthle). Fourteen percent had an objective response, and 67% had stable disease
maintained for up to 24 weeks. Complications included diarrhea, hypertension,
fatigue, weight loss, and evidence of hypothyroidism in 22%(554.3).
Sorafenib- In a Phase II trial, 6 of 41 patients had a partial response by standard RECIST criteria, and 56% had prolonged stable disease (554.4). A dramatic response was observed by another group using sorafenib in a child with papillary cancer(554.5).
Sunitinib-Responses to in some patients with papillary and follicular cancer have been sustained over 4 years(554.6).
Vandetanib, an inhibitor of VEGF, RET, and EGF tyrosine kinase activity is being tried alone and in combination with other agfents such as docetaxel or pemetrexed (554.7-).
Axitinib has also been effective in some cases of aggressive thyroid cancer non-responsive to 131-I.
These agents are currently used only in clinical trials, but it makes sense to offer participation in an on-going trial to patients with aggressive or progressive thyroid cancers that have resisted standard treatments including 131-I therapy.
It appears that all of the kinase inhibitors so far tested have a beneficial effect in some patients and not others,, and further understanding of the individual tumor molecular defect is expected to help elucidate this problem. It is also likely that multiple agents of different types will be combined for treatment, for instance kinase inhibitors and valproic acid, a histone de-acetylase inhibitor. Side effects of these drugs are very significant, which is not surprising because of the centrality of the functions of the inhibited proteins. Rashes, nausea, weakness, mucosal damage, diarrhea, and hypertension often limit or prohibit treatment. Interestingly hypothyroidism is commonly observed as a side effect, and the cause is not yet fully understood.
We are at the very beginning of the “era” of targeted therapy. Many more trials are needed to find the most appropriate drug for an individual patient, and many issues need to be resolved., But there is now a legitimate basis for beneficial treatment of many patients who have until this time had no therapeutic options..
RETINOIC ACID-Experimental data from in vitro studies suggest that retinoic acid can induce re-differentiation of thyroid cancer cells with regain of iodide concentrating ability. Simon et al (555) studied 28 patients with differentiated thyroid cancer using 1.5 mg/kg retinoic acid per day for five weeks. Iodide uptake increased in eight of the patients and thyroglobulin increased in 63%. Thus retinoid appeared to reinduce iodide uptake in half of the treated patients by redifferentiation. They gave 13-cis-retinoic acid. Side effects occurred in half of the patients but were generally well tolerated. A common side effect was dryness of the skin and mucosal surfaces. The reinduction of 131I uptake allowed radioiodine therapy in several of the patients. The effect on tumor size was uncertain. Retinoic acid redifferentiation therapy has been reviewed by Schmutzler and Kohrle. They note that, of twenty documented retinoic acid treated patients, at least eight had exhibited a decrease or stabilization in tumor size, and in serum TG levels, in addition to enhanced radioiodide transport. However, this relatively positive review seems enthusiastic, considering the small evidence of improvement observed in most cases (556). Clearly the benefits of this experimental treatment are as yet uncertain, but it is nevertheless an exciting observation that retinoic acid can have an apparent beneficial redifferentiating effect on some thyroid tumors. Histone deactylase inhibitors also have been found to restore in part the function of NIS, TPO and TG in thyroid tumor cells in vitro (555a), and valproic acid also has an action to restore NIS function, probably via the same mechanism(555b).
Thalidomide-Thirty-six patients with follicular, papillary, insular, or medullary thyroid carcinomas and distant, radioiodine-unresponsive metastases (volumes increasing >/= 30% per year before entry) were given daily thalidomide started at 200 mg, increasing over 6 weeks to 800 mg or maximum tolerated dose. Of these, 5 had partial responses and 9 patients had stable disease Median duration was 4 -6 months. Median survival was 23.5 months for responders (PR + SD) and 11 months for nonresponders. Most frequent toxicity was fatigue (69% grade 1-2, 8% grade 3-4). Four patients had grade 3-4 infections (without neutropenia), one had pericardial effusion, and one had pulmonary embolus. Thalidomide confers therapeutic benefit in subsets of thyroid cancer patients with rapidly progressive, distantly metastatic disease. (Ain KB, Lee C, Williams KD. Phase II Trial of Thalidomide for Therapy of Radioiodine-Unresponsive and Rapidly Progressive Thyroid Carcinomas. Thyroid. 2007 Aug;17(7):663-70.)
PPARgamma agonists-In vitro studies show that PPAR gamma agonists can slow thyroid tumor cell growth and induce apoptosis (557). Results of clinical trials are awaited.
ONYX-015 is an E1B deleted adenovirus that replicates in cells with impaired p53 function. p53 is commonly inactivated in anaplastic thyroid cancers. In vitro studies demonstrate that this virus induced cell death in in vitro trials in anaplastic cancer cell lines, and synergized with treatment with doxorubicin and pacitaxel (558).
Adenoviral vectors producing tk, IL-2, IL-12, and GM-CSF in a cell specific manner are currently under study in animals with encouraging results. Studies in humans are so far very limited, but the methods appear to be safe and effective, especially with the immunomodulator IL-12(558,559,560,561).
A variety of ideas on possible treatments for thyroid cancer have been reviewed by Braga-Basaria and Ringel(564).