Mike Hernandez

Treatment with Tyrosine Kinase Inhibitors for Patients with Differentiated Thyroid Cancer: the M. D. Anderson Experience

OBJECTIVES Until recently, treatment options for patients with progressive, radioactive iodine-resistant differentiated thyroid cancer (DTC) have been limited. In our clinical practice, we have begun to use sorafenib and sunitinib for patients with progressive DTC who are not able or willing to participate in clinical trials. In this paper, we describe the University of Texas M. D. Anderson Cancer Centers experience with the off-label use of these tyrosine kinase inhibitors for DTC. METHODS Adult patients were included if they had a diagnosis of radioactive iodine-refractory DTC, were treated with single agent sorafenib or sunitinib, and had both baseline and at least one follow-up scan for restaging purposes. All imaging data were collected, as well as the TSH-suppressed thyroglobulin (Tg) levels corresponding to each scan date. The primary endpoints were radiographic response and progression-free survival (PFS). Secondary objectives were tissue-specific radiographic responses and correlation of Tg with overall response. RESULTS We identified 33 patients from our clinical database. Fifteen patients (nine women, six men) met inclusion criteria, with a median age of 61 yr (range, 38-83 yr). Eight patients had papillary and seven had follicular thyroid carcinoma. Sorafenib was used in 13 and sunitinib in two, including one patient who failed prior sorafenib therapy. All patients had evidence of progressive disease (PD) before start of therapy, with a median PFS of only 4 months. Best response in target lesions was: partial response (PR) in three (20%), stable disease (SD) in nine (60%), and PD in three (20%). Clinical benefit (PR+SD) was 80%. The sunitinib patient previously refractory to sorafenib had a 38% reduction in tumor size. The most noticeable organ-specific response was observed in lung (median change, -22%) compared to lymph nodes (median change, 0%). Pleural disease and nonirradiated bone metastases demonstrated PD. All histological subtypes had similar responses. The median PFS was 19 months. The median overall survival has not yet been reached, but at 2 yr of follow-up, overall survival is 67%. Log Tg correlated with radiographic response (P = 0.0005). CONCLUSIONS Sorafenib and sunitinib appear to be effective in patients with widely metastatic, progressive DTC, with most patients achieving SD or PR, despite having PD at baseline. The most noticeable responses occurred in the lungs in contrast with minimal changes in nodal metastases and PD in pleural and nonirradiated bone metastases, suggesting a tissue-specific response to therapy. Log Tg significantly correlated with response to treatment and therefore may have value as a surrogate marker of response.

Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.

Summary Background Retrospective evidence indicates that disease progression after first-line chemotherapy for metastatic non-small cell lung cancer (NSCLC) occurs most often at sites of disease known to exist at baseline. However, the potential benefit of aggressive local consolidative therapy (LCT) on progression-free survival (PFS) for patients with oligometastatic NSCLC is unknown. Methods We conducted a multicenter randomized study (NCT01725165; currently ongoing but not recruiting participants) to assess the effect of LCT on progression-free survival ((PFS). Eligible patients hadwere (1) histologic confirmation of (2) stage IV NSCLC, (3) ≤3 disease sites after systemic therapy, and (4) no disease progression before randomization. Front line therapy was ≥4 cycles of platinum doublet therapy or ≥3 months of inhibitors of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) for patients with EGFR mutations or ALK rearrangements. Patients were randomized to either LCT ([chemo]radiation or resection of all lesions) +/− maintenance therapy versus maintenance therapy/observation only. Maintenance therapy was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic therapy. Randomization was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, central nervous system metastases, intrathoracic nodal status, and EGFR/ALK status. The primary endpoint was PFS, powered to detect an increase from 4 months to 7 months (hazard ratio [HR}=0.57) using intent-to-treat analysis. The plan was to study 94 randomized patients, with an interim analysis at 44 events. PFS, overall survival (OS), and time to develop a new lesion were compared between arms with log-rank tests. Results The study was terminated early after treatment of 49 patients (25 LCT, 24 control), when at a median follow-up time for PFS of 18.7 months, the median PFS time in the LCT group was 11.9 months (90% confidence interval [CI] 5.72 ,20.90) versus 3.9 months (90% CI 2.30, 6.64) in the maintenance group (HR=0.35, 90% CI 0.18,0.66, log rank p=0.005). Toxicity was similar between groups, with no grade 4–5 events. Grade 3 or higher adverse events in the maintenance therapy arm were fatigue (n=1) and anemia (n=1). In the LCT arm, Grade 3 events were: esophagitis (n=2), anemia (n=1), pneumothorax (n=1), and abdominal pain (n=1). Overall survival data are immature, with only 14 deaths recorded. Interpretation LCT +/− maintenance therapy for patients with ≤3 metastases from NSCLC that did not progress after initial systemic therapy improved PFS relative to maintenance therapy alone. These findings imply that aggressive local therapy should be further explored in phase III trials as a standard treatment option in this clinical scenario.

Inhibition of the Ras/Raf/MEK/ERK and RET Kinase Pathways with the Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Medullary and Differentiated Thyroid Malignancies

PURPOSE Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins. PATIENTS AND METHODS We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle. RESULTS We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1-2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3-4 toxicities were rash, rise in amylase/lipase, and fatigue. CONCLUSIONS Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.

Early lymphocyte recovery as a prognostic indicator for high-risk Ewing sarcoma

Background Increasing evidence suggests that lymphocyte recovery plays a major part in tumor control. Facilitating immune reconstitution might be a novel direction of cancer therapy. The purpose of this study was to determine if early lymphocyte recovery is an independent prognostic indicator for high-risk Ewing sarcoma outcome. Results Data of 24 Ewing sarcoma patients were analyzed (age, 3 to 50 y; median, 16.5; male to female, 16:8). The 5-year overall survival (OS) of the total population was 47.9% [10.6 standard error (SE)]. Patients were separated into 2 groups: prolonged lymphopenia versus early lymphocyte recovery, using a threshold absolute lymphocyte count (ALC) of ≥500 cells/μL on day 15. The majority (67%; n=16) of the patients had an ALC ≥500 cells/μL, and of these 10/16 are alive with a 5-year OS of 58.7% (13.2 SE). In contrast, 33% (n=8) of patients had an ALC <500 cells/μL on day 15 and only 2/8 are alive with a 5-year OS of 25% (15.3 SE). This difference was significant (P=0.007 using the log rank test). When comparing patients with metastatic disease, patients with an ALC-15 <500 cells/μL had a median survival of 13 months, whereas patients with an ALC-15 ≥500 cells/μL had a median survival of 29.5 months. All patients had an ALC before chemotherapy of >1000 cells/μL. The difference was significant (P value=0.001 using the log rank test). Univariate analysis of platelet counts, age, sex, and absolute neutrophil count showed no statistically significant association with OS. Conclusions The data demonstrate that an ALC ≥500 cells/μL on day 15 of the first course of chemotherapy is an independent prognostic factor associated with superior OS in high-risk Ewing sarcoma.

Role of Salvage Targeted Therapy in Differentiated Thyroid Cancer Patients Who Failed First-Line Sorafenib

CONTEXT Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. OBJECTIVE The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. DESIGN This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. PATIENTS The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). PATIENTS who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). OUTCOME MEASURES Progression-free survival, best response, and median OS were measured. RESULTS Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3). CONCLUSIONS Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.

Epidural space identification: A meta-analysis of complications after air versus liquid as the medium for loss of resistance

BACKGROUND: The best method for identifying the epidural space for neuraxial blocks is controversial. We conducted this meta-analysis to test the hypothesis that loss of resistance with liquid reduces complications with epidural placement. METHODS: The MEDLINE, EMBASE, and Cochrane databases were searched for prospective, randomized studies comparing air versus liquid as the medium for loss of resistance during epidural space identification in adults. Data were abstracted from 5 studies (4 obstetric and 1 nonobstetric) (n = 4422 patients) that met inclusion criteria and analyzed for the following 6 outcomes: difficult catheter insertion, paresthesia, intravascular catheter insertion, accidental dural puncture, postdural puncture headache, and partial block. RESULTS: The overall risk differences for adverse outcome between the different mediums were not statistically different for the obstetric population. A small, but statistically significant, risk difference for postdural puncture headache was observed when fluid was used during epidural placement for chronic pain management. CONCLUSION: Larger studies that overcome limitations of heterogeneity across studies and a relatively infrequent occurrence of complications are required to determine the optimal medium for loss of resistance during epidural block.

Intensity-modulated proton beam therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for patients with oropharynx cancer - A case matched analysis.

BACKGROUND Owing to its physical properties, intensity-modulated proton therapy (IMPT) used for patients with oropharyngeal carcinoma has the ability to reduce the dose to organs at risk compared to intensity-modulated radiotherapy (IMRT) while maintaining adequate tumor coverage. Our aim was to compare the clinical outcomes of these two treatment modalities. METHODS We performed a 1:2 matching of IMPT to IMRT patients. Our study cohort consisted of IMPT patients from a prospective quality of life study and consecutive IMRT patients treated at a single institution during the period 2010-2014. Patients were matched on unilateral/bilateral treatment, disease site, human papillomavirus status, T and N status, smoking status, and receipt of concomitant chemotherapy. Survival analyzes were performed using a Cox model and binary toxicity endpoints using a logistic regression analysis. RESULTS Fifty IMPT and 100 IMRT patients were included. The median follow-up time was 32months. There were no imbalances in patient/tumor characteristics except for age (mean age 56.8years for IMRT patients and 61.1years for IMPT patients, p-value=0.010). Statistically significant differences were not observed in overall survival (hazard ratio (HR)=0.55; 95% confidence interval (CI): 0.12-2.50, p-value=0.44) or in progression-free survival (HR=1.02; 95% CI: 0.41-2.54; p-value=0.96). The age-adjusted odds ratio (OR) for the presence of a gastrostomy (G)-tube during treatment for IMPT vs IMRT were OR=0.53; 95% CI: 0.24-1.15; p-value=0.11 and OR=0.43; 95% CI: 0.16-1.17; p-value=0.10 at 3months after treatment. When considering the pre-planned composite endpoint of grade 3 weight loss or G-tube presence, the ORs were OR=0.44; 95% CI: 0.19-1.0; p-value=0.05 at 3months after treatment and OR=0.23; 95% CI: 0.07-0.73; p-value=0.01 at 1year after treatment. CONCLUSION Our results suggest that IMPT is associated with reduced rates of feeding tube dependency and severe weight loss without jeopardizing outcome. Prospective multicenter randomized trials are needed to validate such findings.

Can regional anesthesia and analgesia prolong cancer survival after orthopaedic oncologic surgery

BackgroundThe perioperative period of major oncologic surgery is characterized by immunosuppression, angiogenesis, and an increased load of circulating malignant cells. It is a window period in which cancer cells may seed, invade, and proliferate. Thus, it has been hypothesized that the use of regional anesthesia with the goal of reducing surgical stress and opioid and volatile anesthetic consumption would avoid perioperative immune suppression and angiogenesis and ultimately cancer recurrence.Questions/purposesWe performed a systematic review of the literature on the use of regional anesthesia and postoperative analgesia to improve cancer-related survival after oncologic surgery. Our primary topic of interest is survival after orthopaedic oncologic surgery, but because that literature is limited, we also have systematically reviewed the question of survival after breast, gastrointestinal, and genitourologic cancers.MethodsWe searched the PubMed and Embase databases with the search terms: “anesthesia and analgesia”, “local neoplasm recurrence”, “cancer recurrence”, “loco-regional neoplasm recurrence”, “disease-free survival”, and “cumulative survival rates”. Our initial search of the two databases provided 836 studies of which 693 were rejected. Of the remaining 143 studies, only 13 articles qualified for inclusion in this systematic review, based on defined inclusion criteria. All these studies had retrospective design. Due to the high heterogeneity among the identified studies and the complete absence of randomized controlled trials from the literature on this topic, the results of a meta-analysis would be heavily confounded; hence, we instead performed a systematic review of the literature.ResultsNo eligible studies addressed the question of whether regional anesthesia and analgesia have an impact on survival after musculoskeletal cancer surgery. Only one relevant clinical study was identified on regional breast cancer survival; it suggested a benefit. The literature on gastrointestinal and genitourinary surgery was larger but mixed, although some preliminary studies do suggest a benefit of regional anesthesia on survival after oncologic surgery in those patient populations.ConclusionsAlthough basic science studies suggest a potential benefit of regional anesthesia and stress response reduction in cancer formation, we found little clinical evidence to support the theory that regional anesthesia and analgesia improve overall patient survival after oncologic surgery.

Was race a factor in the outcomes of the Women's Health Eating and Living Study?

The objective of this study was to determine whether women who were participating in the Womens Healthy Eating and Living (WHEL) Study exhibited similar dietary changes, second breast cancer events, and overall survival regardless of race/ethnicity.

High Prevalence of Preinvasive Lesions Adjacent to BRCA1/2-Associated Breast Cancers

Mutations in BRCA1 and BRCA2 increase a womans lifetime risk of developing breast cancer by 43% to 84%. It was originally postulated that BRCA1/2-associated breast cancers develop more rapidly than sporadic cancers and may lack preinvasive lesions. More recent studies have found preinvasive lesions in prophylactic mastectomy specimens from mutation carriers; however, there is little information on the presence of preinvasive lesions in tissue adjacent to breast cancers. Our aim is to investigate the role of preinvasive lesions in BRCA-associated breast carcinogenesis. We retrospectively compared BRCA1/2-associated breast cancers and sporadic breast cancers for the prevalence of preinvasive lesions [ductal carcinoma in situ (DCIS), lobular carcinoma in situ, and atypical lobular hyperplasia] in tissue adjacent to invasive breast cancers. Pathology was reviewed for 73 BRCA1/2-associated tumors from patients with breast cancer. We selected 146 patients with mutation-negative breast cancer as age-matched controls. Among the BRCA1/2-associated breast cancers, 59% had at least one associated preinvasive lesion compared with 75% of controls. Preinvasive lesions were more prevalent in BRCA2 mutation carriers than in BRCA1 mutation carriers (70% versus 52%, respectively). The most common preinvasive lesion in both groups was DCIS; 56% of BRCA1/2-associated breast cancers and 71% of the sporadic breast cancers had adjacent intraductal disease, respectively. Preinvasive lesions, most notably DCIS, are common in BRCA1/2-associated breast cancers. These findings suggest that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRCA1/2 tumor spectrum.