Cancer Treatment Today » Thyroid Cancer

Axitinib and sorafenib for thyroid cancer – pro

M Levin, MD — Fri, 26 Oct 2012 14:04:33 +0000

Medullary and papillary thyroid carcinoma (MTC and PTC) are two types of thyroid cancer that can originate from activating mutations or rearrangements in the RET gene. Axitinib has been studied for thyroid cancer. Two phase II studies were reported in the Journal of Clinical Oncology evaluating different axitinib and sorafenib therapies in patients with advanced thyroid cancer have special significance. The multicenter trial from Cohen et al used axitinib (AG-013736), an orally administered angiogenesis inhibitor. The study from Gupta-Abramson et al2 at the University of Pennsylvania used the oral agent sorafenib (Nexavar; Bayer Healthcare, West Haven, CT; Onyx Pharmaceuticals, Richmond, CA), which inhibits not only angiogenesis, but also RAF and RET kinases, which are important targets in thyroid cancers. Although these are different agents, the two studies had many similarities.

Eligible patients in both studies included a full spectrum of thyroid cancer histologic subtypes—from differentiated to anaplastic, with both medullary and nonmedullary cancers allowed—but papillary and follicular histologies predominated. All patients were judged by the involved investigators to be resistant or refractory to RAI. Although no complete responses were reported, a significant minority of patients had a major response to therapy by Response Evaluation Criteria in Solid Tumors (RECIST): 30% and 23%, respectively, for axitinib and sorafenib. Stable disease for no less than 3 months was also common, reported in 38% and 53%, respectively. The response waterfall plots indicated that most of these patients with stable disease had some objective disease regression, albeit of insufficient magnitude to fulfill RECIST criterion for a partial response, further suggesting that the reports of stable disease reflected at least in part therapeutic effect rather than simply slow growth of disease. Median progression-free survival rates were similar in both studies at approximately 18 months. The oral route of administration and noncytotoxic, targeted mechanism of action did not mean a lack of side effects. Grade 3 or 4 toxicities with both agents were not rare: 32% of patients treated with axitinib had at least one treatment-related adverse that was grade 3 or worse, and 47% of patients treated with sorafenib required dose reductions to control toxicities. Discontinuation of treatment occurred in 13% and 20% of patients treated with axitinib or sorafenib, respectively, because of toxicity.

Most recently, the DECISION trial, reproted in 2013 ASCO, enrolled 417 patients with locally advanced or metastatic RAI-refractory DTC. Patients had progression within the past 14 months as defined by the Response Evaluation Criteria In Solid Tumors (RECIST). Those who had undergone previous treatment with targeted therapy or chemotherapy were excluded. Patients were randomly assigned 1:1 to 400 mg sorafenib orally twice daily or to placebo. Progression was assessed every 8 weeks, and if disease progressed patients on placebo were allowed to cross over to treatment.

The treatment and study arms were well balanced regarding sex, age, and Eastern Cooperative Oncology Group performance status (PS), with most patients in both arms having a PS of 0 or 1. Baseline disease characteristics including investigator-assessed histology, and lesion sites were well balanced between the study arms, as was median cumulative RAI exposure. The great majority of patients in both groups had distant metastases.

The study met its primary endpoint of PFS, with a statistically significant HR of 0.587. Dr. Brose noted that the curve in the placebo arm was short, at 5.8 months, reflecting the progressive nature of the disease in the patients enrolled in the study. Benefit of treatment was seen in all prespecified subgroups and across all regions (North America, Europe, and Asia) and age groups.

Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol. 2008 Oct 10;26(29):4708-13.

David G. Pfister andJames A. Fagin Refractory Thyroid Cancer: A Paradigm Shift in Treatment Is Not Far Off JCO October 10, 2008:4701-4704

Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma Clin. Cancer Res. Dec 1, 2011:7462-7469

Hans H. G. Verbeek, Maria M. Alves, Jan-Willem B. de Groot, Jan Osinga, John T. M. Plukker, Thera P. Links and Robert M. W. Hofstra
The Effects of Four Different Tyrosine Kinase Inhibitors on Medullary and Papillary Thyroid Cancer Cells J. Clin. Endocrinol. Metab. Jun 1, 2011:E991-E995

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Ethanol ablation of small recurrent thyroid cancer – pro

M Levin, MD — Thu, 04 Oct 2012 21:58:26 +0000

Recurrent thyroid cancer can present as isolated localized nodules, which may persist for a long time, and may conceivably not require systemic treatment. Alcohol ablation involves injecting small recurrent thyroid cancers with alcohol using imaging such as ultrasound for placement. This procedure was pioneered at Mayo clinic and is not universally available. The Thyroid Associations guideline of 2009 says: “Data supporting the safety and efficacy of such techniques come largely from outside the United States. Long-term follow-up exists to 5 years, showing that PEI is effective and safe. In a large series of 125 patients, Tarantino et al. demonstrated an overall cure rate (absent uptake in the nodule) of 93%, and a major complication rate of 3%. These included transient laryngeal nerve damage, abscess, and hematoma. All patients remained euthyroid (low/normal TSH and normal free T₃ and free T₄ estimates) during follow-up. The average reduction in the volume of nodules after PEI was 66%. Given the relative lack of experience with these alternative techniques, ¹³¹I therapy and surgery remain the mainstay of treatment. PEI or alternative treatments should be employed only in the very rare situation when standard therapies have failed, or are contraindicated or refused.”

Hay ID, Charboneau JW 2011, The Coming of Age of Ultrasound-Guided Percutaneous Ethanol Ablation of Selected Neck Nodal Metastases in Well-Differentiated Thyroid Carcinoma. J Clin Endocrinol Metab 96(9): 2717-2723

Hay ID, Hutchinson ME, Gonzalez-Losada T, et. Al. 2008, Papillary Thyroid Microcarcinoma: A Study of 900 Cases Observed in a 60-year Period. Surgery December 2008: 980-988.

Hay ID, McDougall IR, Sisson, J. 2008, Perspective: The Case Against Radioiodine Remnant Ablation in Patients with Well-Differentiated Thyroid Carcinoma. The Journal of Nuclear Medicine: Vol. 49, No. 8: 1395-1397.

David S. Cooper, Gerard M. Doherty, Bryan R. Haugen, Richard T. Kloos, Stephanie L. Lee, Susan J. Mandel, Ernest L. Mazzaferri, Bryan McIver, Furio Pacini, Martin Schlumberger, Steven I. Sherman, David L. Steward, and R. Michael Tuttle. Revised American Thyroid Association management guidelines for patients with thyroid nodules Thyroid. November 2009, 19(11): 1167-1214.

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Nexavar for Thyroid Cancer – pro

M Levin, MD — Mon, 02 Jul 2012 16:28:20 +0000

Sorafenib is an oral multiple kinase inhibitor that targets both tumor-cell proliferation and angiogenesis(1). Approved in December 2005 for advanced renal cell carcinoma, it is being further developed by the manufacturer for metastatic melanoma, advanced primary liver cancer, and NSCLC. Several small studies have been presented or published(2,3). In one recent Phase II clinical trial, 30 patients with advanced iodine-refractory thyroid cancer were treated with Nexavar for a minimum of 16 weeks. The partial response rate was 23%, and the disease stabilization rate was 53%; this made for a disease control rate of 76%. The median progression-free survival was 79 weeks. Seventeen of 19 evaluable patients showed a “marked and rapid response in thyroglobulin levels.” One patient had liver failure, possibly due to Nexavar toxicity. These authors concluded that these results were better than would have been expected from chemotherapy treatment.

On Jan 13, 2013, Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc announced that a Phase 3 trial of Nexavar (sorafenib) tablets in patients with locally advanced or metastatic radioactive iodine-refractory (RAI) differentiated thyroid cancer has met its primary endpoint of a statistically significant improvement of progression-free surviva(4)l. The study, called DECISION, evaluated the efficacy and safety of Nexavar compared to placebo. It has not been reflected in guidelines as of yet.

1.Priya Kundra, MD Kenneth D. Burman, MD Thyroid Cancer Molecular Signaling Pathways and Use of Targeted Therapy Endocrinology and Metabolism Clinics – Volume 36, Issue 3, 2007

2.Mazzaferri EL, Kloos RT. Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001; 86: 1447-63.

3.Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. Journal of Clinical Oncology [early online publication] 2008; on June 9.

4.Marcia S Brose et al,Rationale and design of DECISION: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer BMC Cancer 2011, 11:349

PET scan for Thyroid Cancer – pro

M Levin, MD — Mon, 02 Jul 2012 16:27:27 +0000

Lay Summary: PET scan can detect non-iodine avid thyroid cancers and is standard of care.

PET scan has a defined albeit limited role in thyroid cancer. In the setting of suspected recurrent thyroid cancer, PET scans may be used to perform functional imaging when radioactive iodine scans have proven to be unreliable or difficult to interpret.

Differentiated thyroid cancer cells may undergo a process of transformation whereby they lose some or all of the ability to take up and retain 131-Iodine. Such cells may still retain the ability to absorb a different radioactive tracer called 18-Fluorodeoxyglucose (abbreviated FDG). If a PET scan is performed after a patient receives a tracer dose of FDG, the images could reveal abnormal areas of increased uptake that may indicate the presence of thyroid cancer cells. Images from a survey of the body could reveal abnormal areas of uptake indicating the spread (or metastasis) of thyroid cancer to lymph nodes, lungs, bones, or central nervous system.

However, a common general principle is that it is desirable to identify persistent or recurrent thyroid cancer as soon as possible so that appropriate therapy can be initiated. For differentiated thyroid cancer, 131-I scans are useful, and, for all types of thyroid cancer, radiologic studies such as MRI and CT scans as well as neck sonograms are proving to be increasingly useful. When to utilize PET scans is more controversial.

Golger and colleagues studied 25 patients with elevated serum thyroglobulin levels (average 19 ng/mL). PET scans performed during thyroid hormone withdrawal (average TSH 53 mcU/mL) were found to be more sensitive in detecting metastatic differentiated thyroid cancer than either PET scans performed on the same patients when taking L-thyroxine therapy or when compared with 131-I withdrawal scans.

Robbins and colleagues retrospectively studied 403 patients with differentiated thyroid cancer. Most of these patients had known or suspected metastasis, an elevated serum thyroglobulin level with a negative 131-I scan, or poorly differentiated histology. Of these 403 patients, 61% had positive 131-I withdrawal scans, 55% had positive lesions on FDG-PET scans, and 67% had papillary thyroid cancer. Seventy-one patients had died of their disease. Multivariate analysis showed that age, intensity of PET uptake, and the number of lesions identified on FDG-PET scan correlated with survival. Each increasing decade of age increased the risk of death by 28%; a positive FDG-PET scan was associated with an 8-fold higher risk of death, and each additional lesion identified by FDG-PET scan increased the risk of death by 9%. Of the 179 patients with a negative FDG PET scan, only 3 died.

These abstracts give further information about the importance and utility of performing FDG-PET scans. It appears that PET scans are useful in identifying recurrent or persistent metastatic thyroid cancer that may not be visualized by other radiologic techniques. Furthermore, it now seems that PET scans may contribute significant information relevant to prognosis in thyroid cancer patients. The precise role of PET scan in patients with known thyroid cancer of all types requires further definition, and cost-effectiveness studies would also be important. However, based on the studies reported to date, PET scans are increasingly being recognized as an important diagnostic tool in selected patients with recurrent or persistent thyroid cancer.

There is one (referenced) guideline that recommends PET scanning(1). On the other hand, a recent textbook(5) says: “The use of CT, MRI, and FDG-PET in the routine evaluation of patients with PTC(papillary thyroid cancer), however, is not recommended.” Note that this statement applies to papillary cancer.

1.http://www.thyroid.org/professionals/publications/documents/Guidelinesthy2006.pdf

2.Golger A, Freedman T, Gulenchyn K, et al. Efficacy of 18F-fluorodeoxyglucose positron emission tomography for diagnosis and long-term monitoring of patients with well-differentiated thyroid cancer. Program and abstracts of the 75th Annual Meeting of the American Thyroid Association; September 16-21, 2003; Palm Beach, Florida. Abstract 7.

3.Robbins R, Reibke R, Drucker W. Real-time prognosis in metastatic thyroid cancer based on FDG-PET scanning. Program and abstracts of the 75th Annual Meeting of the American Thyroid Association; September 16-21, 2003; Palm Beach, Florida. Abstract 99.

4. C Marcus et al, PET/CT in the Management of Thyroid Cancers, AJR Volume 202, Issue 6 > PET/CT In The Management Of Thyroid Cancers. June 2014, VOLUME 202

5. Bryan R. Haugen et al, 2015 American Thyroid Association ManagementGuidelines for Adult Patients with Thyroid Nodulesand Differentiated Thyroid CancerThe American Thyroid Association Guidelines Task Forceon Thyroid Nodules and Differentiated Thyroid Cancer THYROID Volume 26, Number 1, 2016

Staging Anaplastic Thyroid Cancer – pro

M Levin, MD — Mon, 02 Jul 2012 12:25:34 +0000

Anaplastic thyroid cancer, is usually too aggressive and invasive to resect. It metastisizes asily and early. Therefore, only a small portion of patients can undergo surgical resection of the cancer for cure. For those patients which are diagnosed at an earlier stage, total thyroidectomy is necessary. It is imperative to perform a full staging to exclude emtastatic disease before consdiering a resection. Thos who have advanced cancer and cannot undergo surgical resection, will benefit from external-beam radiation. Chemotherapy may also be beneficial to patients with anaplastic thyroid cancer.

After the diagnosis of anaplastic thyroid cancer has been established, it is important to see how extensive the disease is. A CT scan of the neck and chest can show how large the tumor is, whether or not it is invading the nearby structures (muscles, trachea or esophagus), and can determine if the disease has spread to the lungs. A flexible laryngoscopy (scope inserted down the throat) can determine if the vocal cords have been affected by the cancer. In addition, NCCN recommends CT of abdomen and pelvsi and even “consider PET and bone scan. (p.30)

http://www.thyroid.org/professionals/publications/documents/Guidelinesthy2006.pdf

Untch BR, Olson JA Jr., Anaplastic thyroid carcinoma, thyroid lymphoma, and metastasis to thyroid.Surg Oncol Clin N Am. 2006 Jul;15(3):661-79

Revlimid for Thyroid Cancer – pro

M Levin, MD — Mon, 02 Jul 2012 12:24:03 +0000

Rapidly-progressive, distantly metastatic thyroid cancers, unresponsive to I-131, are lethal and haven’t known effective systemic therapies. A prior thalidomide trial in this context had 50% response rate (PR + SD), 6 months mean durability and significant toxicity. An open-label phase II trial was recently published that included of 25 adult patients with distantly metastatic, I-131-unresponsive (papillary, follicular, or insular) thyroid cancers with >30% tumor volume progression documented within 12 months of entry, receive 25 mg oral lenalidomide daily. 67% were responders (44% SD, 22% PR). Of 10 patients enrolled by 1/07, 6 were responders (2 PR, 4 SD) with 3 maintaining response to date (>12 months). The authors concldued that Lenalidomide is well tolerated and ferther studies were needed.

Revlimid is in trials for thyroid cancer. REVLIMID® (Lenalidomide) for Therapy of Radioiodine-Unresponsive Papillary and Follicular Thyroid Carcinomas, NCT00287287. The primary objective of this ongoing study is to assess the anti-tumor activity of REVLIMID® (lenalidomide), administered as a single agent, in patients with distantly metastatic thyroid carcinomas which are unresponsive to systemic radioiodine, in terms of tumor response and response duration.

Ain, K. B., Lee, C., Holbrook, K. M., Dziba, J. M., Williams, K. D.
Phase II study of lenalidomide in distantly metastatic, rapidly progressive, and radioiodine-unresponsive thyroid carcinomas: preliminary results
J Clin Oncol (Meeting Abstracts) 2008 26: 6027

Votrient for Thyroid Cancer – pro

M Levin, MD — Mon, 02 Jul 2012 16:21:29 +0000

Votrient is a multi-targeted tyrosine kinase inhibitor and it is currently approved for renal cell carcinoma. A recent study evaluated it in thyroid cancer. This phase II trial included 37 patients who had received up to two prior therapies, had measurable disease, and whose disease had progressed in the six months before they were enrolled in the study. Patients received 800 mg of Votrient daily.

Following a median of 12 four-week cycles of treatment with Votrient, there were 18 partial responses (PRs) to therapy.
Researchers estimated that PRs would last for one year in 66% of patients.
Median progression-free survival was 11.7 months.
Overall survival at one year was 81%.
When PR was measured according to thyroid cancer cell type, eight PRs were observed in11 patients with follicular cell type (72.7%), five PRs in 11 patients with Hürthle cell type (45.4%), and five PRs in 15 patients with papillary cell type (33.3%).
66.7% of patients who were antithyroidglobulin-negative (no antibodies to the protein thyroidglobulin, produced by the thyroid) experienced a decrease in thyroidglobulin of more than 30%.
Side effects were modest, but 15 patients did require a dose reduction due to adverse effects. Frequent side effects included diarrhea and hypertension.

The researchers concluded that Votrient is highly active in advanced differentiated thyroid cancer and well tolerated; the drug may therefore be a promising treatment for patients with this disease. Votrient will be further evaluated in this patient population in an upcoming Phase III clinical trial.

NCCN (p.FOLL-5) mentions Votrient as a level 2B recommendations in a footnote when clinical trials are not available for this specific uncommon situation.

Bible KC, Suman VJ, Molina JR, et at. Evidence of clinical efficacy of the multi-targeted tyrosine kinase inhibitor pazopanib in rapidly progressive radioiodine-refractory metastatic differentiated thyroid cancers: results of the Phase 2 consortium study MC057H. Presented at the 14th International Thyroid Congress, Paris, France, September 11-16, 2010. Abstract OC-022.

PET for Thyroid Cancer and Hurthle Cell – pro

M Levin, MD — Mon, 02 Jul 2012 16:15:00 +0000

F-18 labeled fluorodeoxyglucose (FDG) is coming into increased being used as a scanning agent in positron emission tomography (PET), especially to diagnose and follow patients with different types of cancer, including thyroid.

There is supportive evidence for PET scan’s utility specifically for Hurthle cell type of thyroid cancer. Hurthle cell thyroid cancer is a differentiated thyroid cancer that is more similar to follicular than pappillary papillary thyroid cancer. Hurthle cell thyroid cancer tends to be more aggressive, metastasize more frequently, and trap iodine less avidly than follicular or papillary thyroid cancer. Sarkar and colleagues reviewed 9 patients with Hurthle cell cancer who had 12 PET scans and comparative 131-I scans. The 131-I scans were either performed while the patients were hypothyroid (10 studies) or while euthyroid, with the use of recombinant TSH (2 studies). The results showed that 4 patients had no discernible metastases on either 131-I or PET scans. The remaining 5 patients had a total of 8 FDG studies that showed metastases in the lungs, nodes, bone, and kidney. All the positive FDG scans were associated with elevated serum thyroglobulin concentrations. 131-I scanning was positive in only 1 case. In total, 131-I scanning missed metastases in 11 body regions. The authors concluded that in patients with Hurthle cell cancer, PET scans had greater diagnostic sensitivity than 131-I scanning.

There are several other studies that suggest the same conclusion more generally for thyroid cancer as a group.

Sarkar S, Pugliese P, Palestro C. Metastases from Hurthle cell thyroid cancer are far more avid for fluorodeoxyglucose than for radioiodine. Program and abstracts of the 73rd Annual Meeting of the American Thyroid Association Meeting; November 7-10, 2001; Washington, DC. Abstract 53.
Schluter B, Bohuslavizki KH, Beyer W, Plotkin M, Buchert R, Clausen M. Impact of FDG PET on patients with differentiated thyroid cancer who present with elevated thyroglobulin and negative 131I scan. J Nucl Med. 2001;42:71-76.
Jadvar H, McDougall IR, Segall GM. Evaluation of suspected recurrent papillary thyroid carcinoma with fluorodeoxyglucose positron emission tomography. Nucl Med Commun. 1998;19:547-554.
Wang W, Larson SM, Fazzari M, et al. Prognostic value of fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. J Clin Endocrinol Metab. 2000;85:1107-1113.
Hooft L, Hoekstra OS, Deville W. Diagnostic accuracy of 18-F-fluorodeoxyglucose positron emission tomography in the followup of papillary or follicular thyroid Cancer. J Clin Endocrinol Metab. 2001;86:3779-3786.

Anaplastic Thyroid Cancer and PET – pro

M Levin, MD — Mon, 02 Jul 2012 16:13:41 +0000

FDG-PET has not been studied for surveillance in patients with ATC. A limited number of reports of FDG-PET studies in patients with ATC are available. Jadvar et al described that FDG-PET correctly detected anaplastic thyroid cancer along with other rare tumors evaluation. Conti et al found positive findings in a patient with anaplastic carcinoma in a study of thyroid cancer by FDG-PET. McDougall et al also reported positive FDG-PET findings in the evaluation of patients with recurrent anaplastic thyroid cancer. Thus, FDG-PET may have a positive impact in the follow-up of patients with ATC after initial resection for the detection of residual or metastatic disease and also in patients with advanced disease who underwent chemotherapy (to prolong survival) for assessing therapeutic response. NCCN in ANAP-1 in its Thyroid Cancer guideline says: “Consider PET scan”, although it speaks about general diagnostic use.

REFERENCES:

Jadvar H, Fischman AJ. Evaluation of rare tumors with [F-18]fluorodeoxyglucose positron emission tomography. Clin Positron Imaging. 1999; 2:153-158.

McDougall IR, Jadvar H, Segall G. PET scan in patients with suspected recurrent thyroid cancer. Presented at Thyroid One. Thyroid Cancer Pathogenesis, Diagnosis including PET, and Treatment. International Symposium. October 7-10, 1998, Linz, Austria. Thyroid. 1998;8:1222. Abstract.

Nccn.org, thyroid cancer