Ravinder K. Grewal

Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer

BACKGROUND Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known. METHODS We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib. RESULTS Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia. CONCLUSIONS Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).

Recombinant Human TSH–Assisted Radioactive Iodine Remnant Ablation Achieves Short-Term Clinical Recurrence Rates Similar to Those of Traditional Thyroid Hormone Withdrawal

Recent studies have confirmed that radioactive iodine therapy after recombinant human TSH (rhTSH) stimulation effectively ablates the normal thyroid remnant. However, no published study has determined the effectiveness of rhTSH preparations on the important endpoint of disease recurrence. Methods: Disease recurrence was retrospectively assessed a median of 2.5 y after radioiodine remnant ablation (RRA) in 394 consecutive thyroid cancer patients (93% papillary, 71% female, 47 ± 15 y old [mean ± SD], median 131I dose of 3,996 MBq [108 mCi]). Results: Similar rates of clinically evident disease recurrence (4% rhTSH vs. 7% thyroid hormone withdrawal [THW], P = not statistically significant) and residual thyroid bed uptake without other evidence of persistent disease (4% rhTSH vs. 7% THW, P = not statistically significant) were seen in the 320 patients undergoing rhTSH-assisted RRA and the 74 patients prepared for RRA by THW. When the definition of no clinical evidence of disease included a suppressed thyroglobulin level of less than 1 ng/mL and a stimulated thyroglobulin level of less than 2 ng/mL, rhTSH-assisted RRA was associated with significantly higher rates of no clinical evidence of disease (74% rhTSH vs. 55% THW, P = 0.02) and significantly lower rates of persistent disease (19% rhTSH vs. 32% THW, P = 0.02) than was RRA after THW. Patients selected for rhTSH-assisted RRA were older (48 ± 15 vs. 44 ± 15 y, P = 0.03) and received a slightly higher administered activity of 131I (median, 4,033 MBq [109 mCi] vs. 3,811 MBq [103 mCi], P = 0.01) but did not differ with respect to sex, histology, disease stage, or mean time to recurrence (19 ± 9 mo for rhTSH vs. 20 ± 16 mo for THW). Conclusion: rhTSH-assisted RRA is associated with rates of clinically evident disease recurrence and persistent uptake in the thyroid bed that are similar to those for traditional THW.

PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study

BACKGROUND Pre-transplantation (18)F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkins lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). METHODS In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkins lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m(2) in combination with mesna 5000 mg/m(2) continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m(2) every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov, number NCT01508312, and is no longer accruing patients. FINDINGS Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkins lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13-40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60-86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53-85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62-89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3-4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4). INTERPRETATION PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkins lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. FUNDING Seattle Genetics.

Salivary Gland Side Effects Commonly Develop Several Weeks After Initial Radioactive Iodine Ablation

Salivary gland side effects (SSEs) can be a source of significant morbidity in thyroid cancer patients receiving radioactive iodine (RAI) for remnant ablation or therapy. However, the incidence, time course, and ultimate resolution of SSEs that develop in the first few months after a single administered activity of RAI for remnant ablation has not be adequately defined. Methods: We retrospectively reviewed the clinical records of patients after RAI remnant ablation (RRA) to determine the incidence of salivary gland–related side effects reported within the first year of RRA, the dose-response relationship between administered activity and specific SSEs, and the incidence of specific SSEs based on the method of preparation for remnant ablation (recombinant human thyroid-stimulating hormone [rhTSH] vs. traditional thyroid hormone withdrawal [THW]). Results: SSEs were reported within the first year of RAI ablation in 39% of a cohort of 262 patients (66% women, 93% papillary thyroid cancer; median dose, 5,217 MBq [141 mCi]). Persistent side effects were noted after a median of 7 y in 5% or less of the entire cohort. However, when side effects developed in patients during the first year, the incidence of persistence of the symptom at last follow-up ranged from 5% to 13%. A statistically significant dose response was seen between administered activity of RAI and development of salivary gland swelling (P = 0.001, logistic dose-response curve) but not with dry mouth (P = 0.63), altered taste (P = 0.27), or salivary gland pain (P = 0.152). SSEs developed in 14% of patients receiving administered activities of 1,110 MBq (30 mCi); administered activities of 2,775 MBq (75 mCi) or more were associated with symptoms in 40% of patients (P = 0.046). Despite receiving a statistically higher administered activity (5,661 ± 2,997 MBq [153 ± 81 mCi] for THW vs. 4,958 ± 2,294 MBq [134 ± 62 mCi] for rhTSH), THW was associated with a lower rate of salivary gland swelling than the rhTSH preparation (20% vs. 10%; P = 0.017), without differences in the development of dry mouth, altered taste, or salivary gland pain. Conclusion: Although SSEs occurred in 39% of patients after routine RRA, they were usually transient, so that the overall incidence of persistent side effects at a median follow-up of 7 y was only 5%. Even though the risk for persistent side effects is rather small, these data do emphasize the need to select patients carefully for RRA who are thought to be at moderate to high risk for recurrence and to use the minimally effective dose of RAI activity, in an attempt to maximize the potential benefit while minimizing the risk for adverse events for an individual patient.

The Effect of Posttherapy 131I SPECT/CT on Risk Classification and Management of Patients with Differentiated Thyroid Cancer

The objective of this study was to determine whether posttherapy 131I SPECT/CT changed the need for additional cross-sectional imaging or modified the American Thyroid Association risk of recurrence classification. We performed planar imaging and SPECT/CT in a consecutive series of patients after 131I therapy. Methods: Planar imaging and SPECT/CT were performed on 148 consecutive patients with thyroid carcinoma (125 papillary, 2 follicular, 8 Hürthle cell, and 13 poorly differentiated) approximately 5 d after the therapeutic administration of 1,739–8,066 MBq (47–218 mCi) of 131I. The indication for treatment was postsurgical ablation (n = 109) or recurrent or metastatic disease with rising thyroglobulin levels (n = 39). SPECT/CT scans were obtained for all subjects for 1 bed position (38 cm), which included the neck and upper chest. Additional SPECT/CT scans of the abdomen or pelvis were acquired if suggestive findings were noted on planar images. All patients were treated in real time, according to the standard of care in our practice. At that time, clinical decisions regarding thyroid tumor classification were made by our multidisciplinary group based on all data, including operative findings, pathology, imaging, and thyroglobulin levels. In a retrospective analysis, planar and SPECT/CT images were interpreted independently, and sites of uptake were categorized as likely benign, malignant, or equivocal. An experienced thyroid endocrinologist used a combination of surgical histopathology and scan findings to determine whether additional cross-sectional imaging was required and determined if the imaging findings changed the patients risk category. Results: In 29 patients, 61 additional cross-sectional imaging studies were avoided using SPECT/CT, compared with medical decision making based on the planar images alone. In 7 of 109 postsurgical patients, SPECT/CT findings changed the initial American Thyroid Association risk of recurrence classification. The sensitivity of planar imaging and SPECT/CT for identification of focal 131I uptake in the thyroid bed was similar in the postsurgical and recurrence cohorts. For metastatic disease in the neck, characterization of 131I uptake by SPECT/CT in the postsurgical group was significantly better than that by planar scanning (P < 0.01). Among the 109 postsurgical patients, the characterization of iodine uptake in the lung, liver, and bone was also more accurate using SPECT/CT than planar scanning (P < 0.01). The CT portion of SPECT/CT demonstrated non–iodine-avid lesions in 32 of 148 patients. Conclusion: SPECT/CT data provided information that reduced the need for additional cross-sectional imaging in 29 patients (20%) and significantly altered the initial risk of recurrence estimates in 7 of 109 patients (6.4%), thereby altering patient management recommendations with regard to frequency and intensity of follow-up studies.

In Differentiated Thyroid Cancer, an Incomplete Structural Response to Therapy Is Associated with Significantly Worse Clinical Outcomes Than Only an Incomplete Thyroglobulin Response

BACKGROUND We previously demonstrated the clinical utility of using response to therapy variables obtained during the first 2 years of follow-up to actively modify initial risk estimates which were obtained using standard clinic-pathologic staging systems. While our proposed dynamic risk stratification system accurately reclassified patients who demonstrated an excellent response to therapy as low-risk patients, it grouped patients with either biochemical or structural evidence of disease into a single incomplete response to therapy cohort. This cohort included a wide variety of patients ranging from very minor thyroglobulin (Tg) elevations in the absence of structurally identifiable disease to widespread, progressive structural disease. Here we determined whether subdivision of the incomplete response to therapy category more precisely predicted clinical outcomes. We hypothesized that patients with an incomplete response to therapy based on persistently abnormal Tg values alone would have better clinical outcomes than patients having structurally identifiable disease. METHODS Following total thyroidectomy and radioactive iodine (RAI) ablation, 192 adult thyroid cancer patients were retrospectively identified as having either a biochemical incomplete response (abnormal Tg without structural evidence of disease) or structural incomplete response (structurally identifiable disease with or without abnormal Tg) as the best response to initial therapy within the first 24 months after RAI ablation. Clinical outcomes evaluated included structural disease progression, biochemical disease progression, and overall survival. RESULTS Sixty-three patients (33%) had a biochemical incomplete response while 129 (67%) had a structural incomplete response. Eleven to 156 months after evaluation of their responses (mean=70 months), patients with structural incomplete response were significantly more likely to have structural evidence of disease at final follow-up (37% vs. 17%, p=0.0004), structural progression (52% vs. 5%, p<0.001), biochemical progression (45% vs. 11%, p<0.001), and death from disease (38% vs. 0%, p<0.0001) than patients demonstrating a biochemical incomplete response. Overall survival was significantly better in patients with either a biochemical incomplete response or a loco-regional structural incomplete response than patients demonstrating a structural incomplete response with distant metastasis (Kaplan-Meier analysis, p<0.0001). CONCLUSIONS A structural incomplete response to initial therapy is associated with significantly worse clinical outcome than a biochemical incomplete response to therapy.

Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases.

BACKGROUND Radioiodine (RAI) remains the mainstay of therapy for RAI-avid (RAIA) distant metastatic thyroid carcinoma. We previously demonstrated that RAI-refractory distant metastatic thyroid cancers commonly harbor BRAF mutations. However, the molecular profile of RAIA metastatic thyroid cancer is unknown. Here we describe the mutational profile of thyroid tumors from follicular cell-derived cancer (FCDTC) patients presenting with RAIA distant metastases. In addition, we aimed to correlate clinical outcomes of RAI therapy with clinicopathological factors and tumor mutational status. METHODS We retrospectively identified 43 patients with FCDTC who had RAI uptake in the lungs and/or bones on their initial ¹³¹I postablation scan. Primary tumors were genotyped for known mutations in thyroid cancer genes. Structural response to RAI was assessed 6-18 months after each administered RAI activity and at the end of follow-up. RESULTS RAS, BRAF, RET/PTC, and PIK3CA mutations were found in 42, 23, 10, and 2% of tumors, respectively, and the remaining 23% were wild type. None of these patients achieved cure after repeat RAI therapies, and most patients (54%) experienced disease progression despite repeated RAI administration. There was an increased prevalence of RAS mutations in these RAIA tumors. RAS-mutant cancers were more likely to concentrate iodine on diagnostic whole body scans. Despite this, structural response to RAI was not influenced by tumor genotype. CONCLUSIONS RAIA metastatic FCDTC are overrepresented with RAS mutations, whereas RAI refractory metastatic thyroid cancers are enriched with BRAF mutations. Despite a seemingly preserved ability to concentrate iodine, RAI therapy is ineffective in achieving cure in most patients with RAIA metastatic FCDTC, even in RAS-mutant disease. These poor outcomes may be improved based on recent evidence that pretreatment with MAPK kinase 1/2 inhibitors enhances responses to RAI, particularly in patients with RAS-mutant tumors.

Radioactive Iodine Administered for Thyroid Remnant Ablation Following Recombinant Human Thyroid Stimulating Hormone Preparation Also Has an Important Adjuvant Therapy Function

BACKGROUND In December 2007, the USFDA approved recombinant human thyroid stimulating hormone (rhTSH) for radioiodine remnant ablation after total thyroidectomy in patients with well-differentiated thyroid cancer without evidence of metastatic disease. Because previously undetected radioactive iodine (RAI)-avid metastatic lesions can be identified during remnant ablation, we sought to determine if rhTSH-stimulated uptake of RAI into these incidentally discovered metastases is associated with a significant therapeutic (tumoricidal) effect. METHODS This retrospective review describes the clinical outcome of 84 well-differentiated thyroid cancer patients in whom RAI-avid lesions outside the thyroid bed were first identified at the time of RAI remnant ablation (64 rhTSH stimulated, 20 thyroid hormone withdrawal [THW]) on either the diagnostic (63/84, 75%) or posttherapy (21/84, 25%) whole body scan (76 with locoregional metastasis only and 8 with pulmonary uptake). Following ablation, patients were classified as having either no evidence of disease or persistent disease on the basis of subsequent diagnostic whole body RAI scans, stimulated thyroglobulin, and cross-sectional imaging studies. RESULTS Despite having RAI-avid metastatic disease identified outside the thyroid bed at the time of initial ablation, 70% (45/64) of rhTSH-assisted patients and 55% (11/20) of the THW group had no evidence of disease at a median of 2.7 years following the initial RAI ablation (p = 0.159). THW and rhTSH-stimulated RAI ablation had similar efficacy in eliminating RAI-avid locoregional metastases (42/60, 70% of rhTSH and 10/16, 63% of THW, p = 0.65) and pulmonary metastases (3/4, 75% of rhTSH and 1/4, 25% of THW, p = 0.41). CONCLUSIONS Preparation with either rhTSH or THW in this retrospective study appears to have similar therapeutic (tumoricidal) effects on small volume RAI-avid metastatic disease incidentally discovered at the time of ablation in both locoregional lymph nodes and pulmonary parenchyma.

Recombinant Human Thyroid Stimulating Hormone–Assisted Radioactive Iodine Remnant Ablation in Thyroid Cancer Patients at Intermediate to High Risk of Recurrence

BACKGROUND Multiple studies have demonstrated successful radioactive iodine remnant ablation (RRA) following preparation with recombinant human thyroid stimulating hormone (rhTSH). Short-term studies in relatively low-risk patients have also suggested that rhTSH-stimulated RRA can have an effective adjuvant therapy function in destroying residual microscopic thyroid cancer cells. However, very few of these studies have included a significant number of intermediate or high-risk patients. The goal of this study was to examine clinical outcomes after rhTSH stimulated RRA in a larger cohort of thyroid cancer patients at higher risk of recurrence and disease-specific mortality. METHODS A retrospective chart review identified 586 thyroid cancer patients prepared for RRA with either a thyroid hormone withdrawal (THW) (n=321) or rhTSH preparation (n=265). The primary end points included both the best response to initial therapy and the clinical status at final follow-up. Clinical outcomes were compared within each of the American Thyroid Association (ATA) risk groups (low, intermediate, and high) and American Joint Committee on Cancer (AJCC) stages (I-IV) based on the method of preparation for RRA (THW vs. rhTSH). RESULTS Preparation with rhTSH was more likely to be associated with an excellent response to therapy (39.4% for rhTSH vs. 30% for TWH, p=0.03) and fewer additional therapies (29% for rhTSH vs. 37% for TWH, p=0.05) than THW. However, after a median follow-up period of 9 years, the final clinical outcomes were not significantly different with respect to recurrence rates (1.5% for rhTSH vs. 1.2% for TWH), likelihood of having persistent disease (46% for rhTSH vs. 48% for THW) or likelihood of having no evidence of disease (53% for rhTSH vs. 52% for TWH). Furthermore, clinical outcomes were similar between rhTSH and THW preparation across all ATA risk groups and AJCC stages. CONCLUSIONS rhTSH preparation for RRA is associated with a small, but statistically significant improvement in an initial response to therapy and similar final clinical outcomes across a wide range of risk of recurrence and risk of disease-specific mortality. These data suggest that rhTSH preparation for RRA can be effectively used in intermediate and high-risk patients without known distant metastases.

The Results of Selective Use of Radioactive Iodine on Survival and on Recurrence in the Management of Papillary Thyroid Cancer, Based on Memorial Sloan-Kettering Cancer Center Risk Group Stratification

BACKGROUND The American Thyroid Association guidelines recommend the routine use of radioactive iodine for remnant ablation (RRA) in all T3 or greater primary tumors, and selective use in patients with intrathyroidal disease >1 cm, or evidence of nodal metastases. The guidelines recognize that there is conflicting and inadequate data to make firm recommendations for most patients. The aim of this study was to analyze our institutional experience of the use of RRA in the management of papillary thyroid cancer, with a particular focus on outcomes for those patients selected not to receive RRA. METHODS We retrospectively reviewed 1129 consecutive patients who underwent total thyroidectomy at the Memorial Sloan-Kettering Cancer Center between 1986 and 2005. Of these, 490 were pT1-2 N0, 193 pT1-2 N1, and 444 pT3-4. Details on recurrence and disease-specific survival were recorded by the Kaplan-Meier method and compared using the log-rank test. RESULTS The five-year disease-specific survival and recurrence-free survival in the pT1/T2 N0, pT1-2 N1, and pT3-4 were 100% and 92%, 100% and 92%, and 98% and 87% respectively. Low-risk patients who were managed without RRA (who tended to have limited primary disease, pT1-2, and low-volume metastatic disease in the neck, pT1-2 N1-fewer than five nodes, all <1 cm greatest dimension) had five-year recurrence-free survival of >97%. In the group with advanced local tumors (pT3-4), those patients who did not receive RRA (who tended to have pT3 N0 disease) had five-year recurrence-free survival of >90%. CONCLUSION Following appropriate surgical management, the majority of patients with low-risk local disease and even some patients with more advanced-stage (pT3) tumors or regional metastases have low rates of recurrence and high rates of survival when managed without RRA.