Sofia Haque

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.).

A phase 2 study of bevacizumab with cisplatin plus intensity‐modulated radiation therapy for stage III/IVB head and neck squamous cell cancer

For patients with stage III through IVB head and neck squamous cell carcinoma (HNSCC), concurrent high‐dose cisplatin plus radiation therapy is a widely accepted standard of care. HNSCC tumors that express high levels of vascular endothelial growth factor have been associated with a worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation.

Evaluation of romidepsin for clinical activity and radioactive iodine reuptake in radioactive iodine-refractory thyroid carcinoma.

BACKGROUND Historically, systemic therapy for radioactive iodine (RAI)-refractory thyroid cancer has been understudied. Available drugs have modest efficacy. Romidepsin is a histone deacetylase inhibitor with potent antitumor effects both in vitro and in vivo. In thyroid cancer cell lines, romidepsin increases expression of both thyroglobulin and the sodium iodide symporter messenger RNAs, suggesting the possibility of improved iodine concentrating ability of RAI-resistant tumors. METHODS This was a single-institution Simon 2-stage phase II clinical study. Eligible patients had progressive, RAI-refractory, recurrent/metastatic, nonmedullary, nonanaplastic thyroid cancer. Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 measurable disease and adequate organ/marrow function were required. Romidepsin 13 mg/m² was administered intravenously on days 1, 8, and 15, in cycles of 28 days. The primary endpoint was the response rate by RECIST; change in RAI avidity was a secondary endpoint. The study closed after the first stage due to the lack of response. RESULTS Twenty patients were enrolled: female, 50%; median age, 64 years; histology, 8 papillary/1 follicular/11 Hürthle. Grade 4-5 adverse events (AEs) possibly related to the drug: grade 5, 1 sudden death; grade 4, 1 pulmonary embolus. Twelve of 20 subjects had a reported adverse event. No RECIST major responses have been seen. Response per protocol: stable disease, 13; disease progression, 7. Restoration of RAI avidity was documented in two patients. Median overall survival and time on study was 33.2 (1-71+) and 1.7 (0.46-12) months, respectively. CONCLUSIONS We observed preliminary signs of in vivo reversal of RAI resistance after treatment with romidepsin. However, no major responses were observed and accrual was poor after the grade 5 AE.

Spectrum of central nervous system abnormalities in neurocutaneous melanocytosis.

Aim  Neurocutaneous melanocytosis is a rare neurocutaneous syndrome defined by the presence of large and/or multiple congenital cutaneous nevi and melanocytic deposits in the central nervous system. We sought to define the spectrum of central nervous system abnormalities in children with neurocutaneous melanocytosis.

A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer.

PURPOSE Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation. METHODS AND MATERIALS This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m(2) weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design. RESULTS Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day. CONCLUSIONS Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins.

A phase 1 study of everolimus plus docetaxel plus cisplatin as induction chemotherapy for patients with locally and/or regionally advanced head and neck cancer

Activation of the phosphatidylinositol‐3‐kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in head and neck cancers, and it has been demonstrated that inhibition of mTOR complex 1 sensitizes cell lines to platinum and taxane chemotherapy. The authors conducted a phase 1 study to evaluate the addition of oral everolimus to cisplatin and docetaxel as induction chemotherapy for head and neck cancer.

Phase II trial of bevacizumab + cetuximab + cisplatin with concurrent intensity-modulated radiation therapy for patients with stage III/IVB head and neck squamous cell carcinoma

The purpose of this study was to evaluate the efficacy and tolerability of the addition of 2 monoclonal antibodies, bevacizumab and cetuximab, to 2 cycles of high‐dose cisplatin administered concurrently with intensity‐modulated radiation therapy (IMRT) for head and neck squamous cell carcinoma (HNSCC).

Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III–IVB head and neck squamous cell carcinoma (HNSCC)

BACKGROUND There is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes. PATIENTS AND METHODS This was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m2), given with standard weekly cetuximab (450 mg/m2 loading dose followed by 250 mg/m2 weekly) and concurrent IMRT (total dose, 70 Gy). RESULTS Twenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46-84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m2) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m2), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69-97). CONCLUSION The recommended phase II dose for nab-paclitaxel is 60 mg/m2 weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone. CLINICALTRIALS. GOV ID NCT00736619.BACKGROUND There is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes. PATIENTS AND METHODS This was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m(2)), given with standard weekly cetuximab (450 mg/m(2) loading dose followed by 250 mg/m(2) weekly) and concurrent IMRT (total dose, 70 Gy). RESULTS Twenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46-84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m(2)) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m(2)), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69-97). CONCLUSION The recommended phase II dose for nab-paclitaxel is 60 mg/m(2) weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone. CLINICALTRIALSGOV ID NCT00736619.

Second-opinion interpretations of neuroimaging studies by oncologic neuroradiologists can help reduce errors in cancer care.

The purpose of this study was to investigate the utility and clinical impact of second‐opinion interpretations of outside neuroimaging studies by oncologic neuroradiologists at a National Cancer Institute–designated cancer center.

A phase 2 study of pemetrexed plus gemcitabine every 2 weeks for patients with recurrent or metastatic head and neck squamous cell cancer.

Preclinical studies suggest that additive or synergistic effects are achieved with the combination of pemetrexed plus gemcitabine. A phase 1 study of pemetrexed plus gemcitabine given every 2 weeks demonstrated encouraging preliminary efficacy against head and neck squamous cell cancer (HNSCC).