William L. Read

Changing Epidemiology of Small-Cell Lung Cancer in the United States Over the Last 30 Years: Analysis of the Surveillance, Epidemiologic, and End Results Database

PURPOSE Small-cell lung cancer (SCLC) is a histologic subtype of lung cancer with a distinct biology and clinical course. It has been observed that the incidence of SCLC has been decreasing over the last several years. METHODS We used the Surveillance, Epidemiologic, and End Results (SEER) database to determine the incidence of SCLC over the last 30 years. In addition, we sought to determine sex- and stage-based differences in the incidence and survival of SCLC among a proportion of reported cases of lung cancer over the last 30 years (1973 to 2002). Joinpoint analyses were applied to test the trends in annual percentage change for statistical significance. RESULTS The proportion of SCLC (among all lung cancer histologic types) decreased from 17.26% in 1986 to 12.95% in 2002. Of all patients with SCLC, the proportion of women with SCLC increased from 28% in 1973% to 50% in 2002. A modest but statistically significant improvement in 2- and 5-year survival was noted among both limited-stage SCLC and extensive-stage SCLC cohorts during the study period. CONCLUSION Our analysis indicates that the incidence of SCLC is decreasing in the United States, and only modest improvements have been seen in survival over the last 30 years. Possible explanations for the decreasing incidence include the decrease in the percentage of smokers and the change to low-tar filter cigarettes. Despite trends toward modest improvement in survival, the outcome remains very poor.

Differential Prognostic Impact of Comorbidity

PURPOSE Cancer patients with concurrent comorbid conditions have worse outcomes than patients with no comorbidities. We hypothesized that the prognostic impact of comorbidities would be greatest for patients with cancers associated with a long natural history and least in patients with aggressive cancers. PATIENTS AND METHODS Using the Barnes-Jewish Hospital Oncology Data Services cancer registry, we grouped 11,558 patients with breast, lung, colon, or prostate cancer by morphologic stage at diagnosis and then determined the 1-year overall survival rate for each group. Overall, severity of comorbidity was assessed from chart review and classified into one of four groups: none, mild, moderate, or severe. The relative prognostic impact of comorbidity was measured by the hazard ratio and adjusted for the prognostic impact of age, race, and sex. RESULTS One-year overall survival rate ranged from 20% for 1,005 patients with distant spread of lung cancer to 98% for 3,325 patients with localized prostate cancer. Adjusted hazard ratio of moderate/severe comorbidity (relative to none/mild) ranged from 1.04 to 4.48. The correlation between overall survival rate and severity of comorbidity was statistically significant (r2 = 0.56; P < .001). The proportion of variance in outcome explained by comorbidity ranged from less than 1% to almost 9%, depending on tumor site and stage. CONCLUSION Concurrent comorbidities had the greatest prognostic impact among groups with the highest survival rate and the least impact in groups with the lowest survival rate. These findings can be used to help determine the role comorbidity information should play in studies of cancer outcomes.

Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma a randomized clinical trial

Importance Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures Progression-free survival (tested at &agr; = .046). The secondary end point was overall survival (tested hierarchically at &agr; = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. Conclusions and Relevance In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration clinicaltrials.gov Identifier: NCT00916409

A Phase II Study of Irinotecan and Carboplatin in Advanced Non-small Cell Lung Cancer with Pharmacogenomic Analysis: Final Report

Purpose: We conducted a phase II study of carboplatin and irinotecan in patients with advanced non-small cell lung cancer (NSCLC). In addition, we studied the correlation between certain genotypes of enzymes involved in irinotecan metabolism with efficacy and toxicity. Patients and Methods: Patients with stage IIIB, IV, or recurrent NSCLC received a combination of irinotecan and carboplatin every 3 weeks at a dose of 200 mg/m2 and area under the curve of 5. Pharmacogenomic analysis was performed on several genes of interest (ABCB1, CYP3A4*1B, ERCC2, GSTP1, UGT1A1*28, and XRCC1). Results: Forty-two patients enrolled between December 2001 and January 2004. Six patients achieved partial responses (14%), and 19 (45%) had stable disease. The median progression-free survival was 6.9 months. The median overall survival was 11.7 months, with 1-year overall survival of 42%. The most common toxicities were hematologic; grade 3 or 4 neutropenia was experienced by 26 patients (62%) during treatment, and 15 patients (36%) experienced grade 3 or 4 thrombocytopenia. The homozygous UGT1A1*28 (7/7) genotype was associated with grade 4 neutropenia in three of four patients (75%), but only eight out of 30 (27%) with 6/6 or 6/7 genotypes experienced grade 4 neutropenia (p = 0.09). None of the 14 patients with the GSTP1 I105V A/A genotype had a partial response, as opposed to five out of 19 (26%) of those with the G/A or G/G genotypes (p = 0.057). Conclusion: The combination of carboplatin and irinotecan is an active combination in NSCLC, with response rates comparable with other platinum-containing doublets. Further studies with irinotecan should incorporate prospective pharmacogenomic analysis to identify markers for response and toxicity.

Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): An international, multicentre, open-label, randomised phase 3 trial

BACKGROUND Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. METHODS We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. FINDINGS Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88-1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6-22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2-22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3-4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3-4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). INTERPRETATION The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. FUNDING Threshold Pharmaceuticals.

A Phase I Study of Bexarotene and Rosiglitazone in Patients with Refractory Cancers

Background: Preclinical studies have shown that binding of PPAR-γ (polysome-proliferator activated receptor gamma) and retinoid-X receptor (RXR) to their ligands can slow growth and promote differentiation of malignant cells. Rosiglitazone, a PPAR-γ ligand, is approved for treatment of insulin-resistant diabetes, and bexarotene, a RXR ligand, is approved for treatment of cutaneous T-cell lymphoma. After binding to its ligand, the PPAR-γ receptor heterodimerizes with the RXR resulting in synergistic effects in preclinical models. We conducted a phase I study of bexarotene and rosiglitazone to define the MTD of rosiglitazone in this combination regimen. Methods: Patients with resistant solid tumors received bexarotene 300 mg/m2/day. The starting dose of rosiglitazone was 4 mg/day and was escalated in five cohorts by 2-mg increments up to 12 mg/day. Both drugs were continued until disease progression or toxicity was observed. Patients received atorvastatin 10 mg/day to control bexarotene-related hypertriglyceridemia. Results: Twenty-three patients were enrolled, with a median of 4 prior regimens (range 0–8). The study was closed after completing the 12 mg/day cohort without encountering dose-limiting toxicity. The most common grade 3 or 4 toxicities were hypertriglyceridemia (17%), dyspnea (9%), nausea (9%), and dehydration (9%). No objective responses were observed. Conclusions: The combination of bexarotene (300 mg/m2/day) and rosiglitazone (12 mg/day) is safe and feasible but did not result in objective responses in heavily pretreated patients with solid tumors. This combination is suitable for evaluation in other conditions such as hematologic malignancies and inflammatory diseases.

A unique case of an indolent CD56-positive T-cell lymphoproliferative disorder of the gastrointestinal tract: a lesion potentially misdiagnosed as natural killer/T-cell lymphoma

Primary intestinal natural killer (NK)/T-cell lymphoma (nasal-type) and enteropathy-associated T-cell lymphoma, type II, are CD56-positive lymphoproliferative disorders with very poor survival rates. We report a long-surviving patient with a CD56-positive T-cell lymphoproliferative disorder of the gastrointestinal tract that presented as vomiting, diarrhea, weight loss, and pain. This patient was referred to the university hospital as a case of peripheral T-cell lymphoma due to this CD56-positive lymphocyte population. There was no evidence of enteropathy; and the infiltrates were negative for CD8, Epstein-Barr virus, and T-cell receptor gene rearrangement. Despite its persistence for 8 years, the clinical course has remained indolent. This report confirms that patients may rarely present with a CD56-positive NK/T-cell-like proliferation of the gastrointestinal tract, yet follow an indolent clinical course. Thus, all pathologic features of enteropathy-associated T-cell lymphoma or NK/T-cell lymphoma should be present before making this diagnosis and exposing the patient to toxic chemotherapy.

A Phase I Study of Docetaxel and Bexarotene

Background: We conducted a single-arm, dose-escalation, phase 1 clinical trial in order to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of bexarotene in combination with docetaxel. Methods: Patients with solid tumors and no other curative treatment options were eligible. Oral bexarotene was taken daily in combination with docetaxel 25 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle. The dose of bexarotene started at 200 mg/m2 and increased by 100 mg/m2/dose level, until either a MTD or the final dose of 400 mg/m2 was reached. Results:Fifteen patients were enrolled in the study. Median age was 58 years. The majority had non-small-cell lung cancer. The study went to completion without reaching an MTD. Hematological toxicities were mild. Three patients developed grade 3 hypertriglyceridemia, all occurring during the first cycle of treatment. No objective responses were noted. Four patients had stable disease as a best response, 3 with non-small-cell lung cancer and 1 with angiosarcoma. Conclusions:Treatment was well tolerated and no DLT was seen at docetaxel 25 mg/m2 and bexarotene 400 mg/m2. Given that stable disease was durable in 4 patients, future studies with this combination may be warranted.

Metastatic Alveolar Soft Part Sarcoma Responsive to Pazopanib after Progression through Sunitinib and Bevacizumab: Two Cases.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma with a propensity for lung metastases and indolent progression. ASPS is not responsive to chemotherapy, but there are case reports and small series describing benefit from drugs targeting the VEGF pathway. These drugs include sunitinib, cediranib and bevacizumab. There is no established second-line treatment for persons with ASPS progressing through first-line targeted therapy. We report two individuals with metastatic ASPS who obtained disease stabilization from sunitinib lasting over a year. After subsequent progression through sunitinib and second-line bevacizumab, both individuals again had disease response and subsequent stabilization from pazopanib.

Metastatic Angiosarcoma with Kasabach-Merritt Syndrome Responsive to Gemcitabine and Vinorelbine after Failure of Liposomal Doxorubicin and Paclitaxel: A Case Report.

Kasabach-Merritt syndrome (KMS) describes a consumptive coagulopathy associated with certain vascular tumors. It is thought that platelets are destroyed as they circulate through the aberrant endothelial surfaces associated with these tumors. Most published literature describes infants with kaposiform hemangioendothelioma, but a similar syndrome can complicate angiosarcoma in adults. This report describes a man with metastatic angiosarcoma arising in the scalp in whom disease progression was complicated by profound thrombocytopenia consistent with KMS. His disease and associated KMS had progressed previously through paclitaxel and then through liposomal doxorubicin. It did not respond to paclitaxel and bevacizumab, but responded almost completely to chemotherapy with gemcitabine and vinorelbine. Six months later, progression through ongoing chemotherapy then responded to chemotherapy with cyclophosphamide and sirolimus.