Randall S. Hughes

Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With Limited but Progressive Metastatic Non–Small-Cell Lung Cancer

PURPOSE Patients with stage IV non-small-cell lung cancer (NSCLC) who progress through first-line therapy have poor progression-free survival (PFS) and overall survival (OS), most commonly failing in original sites of gross disease. Cytoreduction with stereotactic body radiation therapy (SBRT) may help systemic agents delay relapse. PATIENTS AND METHODS Patients in our single arm phase II study had stage IV NSCLC with no more than six sites of extracranial disease who failed early systemic chemotherapy and were able to receive SBRT and concurrent erlotinib until disease progression. After erlotinib commencement, SBRT with equipotent fractionation was delivered to all sites of disease. PFS, OS, and other end points were evaluated. RESULTS Twenty-four patients (13 men and 11 women) with a median age of 67 years (range, 56-86 years) were enrolled with median follow-up of 11.6 months. All patients had progressed through platinum-based chemotherapy. A total of 52 sites were treated with 16 of 24 patients receiving SBRT to more than one site. Lung parenchyma was most often irradiated. Median PFS was 14.7 months, and median OS was 20.4 months. Most patients progressed in new distant sites with only three of 47 measurable lesions recurring within the SBRT field. Two grade 3 toxicities were radiation related. Zero of 13 patients tested were positive for an EGFR mutation. CONCLUSION Use of SBRT with erlotinib for unselected patients with stage IV NSCLC as a second- or subsequent line therapy resulted in dramatic changes in patterns of failure, was well tolerated, and resulted in high PFS and OS, substantially greater than historical values for patients who only received systemic agents.

Primary colonic lymphoma

The colon is a rare location for gastrointestinal non‐Hodgkins lymphoma (NHL). This study was undertaken to identify risk factors, presentation, treatment, and prognosis for primary colonic lymphoma (PCL) through review of a large tertiary care hospital system experience.

Malignant Pleural Mesothelioma

Malignant pleural mesothelioma is an uncommon tumor; only about 3000 cases are diagnosed annually in the United States. Cases were described early in the 20th century, but their relationship to asbestos exposure was not documented until 1960. Since then, the incidence has appeared to increase, and numerous epidemiologic studies have confirmed that exposure to asbestos in a variety of settings and occupations is the most significant risk factor for the development of malignant pleural mesothelioma. More recently, the oncogenic virus SV40 has also been implicated as a potential etiologic agent. Surgery, radiotherapy, and chemotherapy have each been used in the treatment of mesothelioma, but generally with little impact on survival. New directions in therapy include aggressive multimodality programs for potentially resectable patients and targeted therapies, including antifolates, antiangiogenesis agents, and drugs directed at epidermal growth factor receptor for the majority of patients presenting with unresectable disease.

The role of chemotherapy in head and neck cancer

We studied the effect of cytoreductive chemotherapy in head and neck cancer and analyzed it in terms of efficacy, remission rates, and duration, as well effect on survival. Single-agent chemotherapy, which formerly was used as a palliative therapy in recurrent and metastatic disease, had little affect on survival. More recently, multi-agent chemotherapy trials have shown significantly higher response rates, but this success has not translated into an added survival benefit. These findings led to the introduction of multi-agent chemotherapy into the induction (neoadjuvant) clinical setting. In these clinical circumstances, better objective response rates were found, particularly in the previously untreated patient. Although this therapy has resulted in better control of local disease, the impact on survival is not yet clear. Adjuvant chemotherapy is most useful in patients who have a high risk of relapse. Therapy appears to decrease its incidence, particularly at distant sites. Finally, chemoradiation trials have shown that this treatment provides a survival advantage, but at the cost of a significant increase in toxicity.

Consolidative Radiotherapy for Limited Metastatic Non–Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial

Importance Patterns-of-failure studies suggest that in metastatic non–small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited. Objective To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non–progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS). Design, Setting, and Participants This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy. Interventions Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy. Main Outcomes and Measures The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival. Results A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy–alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy–alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly. Conclusions and Relevance Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings. Trial Registration clinicaltrials.gov Identifier: NCT02045446

A phase II study of concurrent chemoradiation with weekly docetaxel, carboplatin, and radiation therapy followed by consolidation chemotherapy with docetaxel and carboplatin for locally advanced inoperable non-small cell lung cancer (NSCLC).

Introduction: The current standard of care for good performance status patients with locally advanced non-small cell lung carcinoma is concurrent chemoradiation, although a clearly superior regimen has not been identified. Docetaxel has been shown to possess good single-agent activity against non-small cell lung cancer (NSCLC) and radiosensitizing properties, both alone and synergistically with carboplatin. We undertook this phase II study to determine the safety and efficacy of weekly docetaxel-carboplatin and concurrent radiation therapy followed by docetaxel-carboplatin consolidation for the treatment of locally advanced NSCLC. Methods: Sixty-seven patients having previously untreated stage IIIA or IIIB unresectable NSCLC were enrolled, with 61 patients evaluated for endpoints. Docetaxel 20 mg/m2 IV infusion over 30 minutes followed by carboplatin area under the curve = 2 over 30 minutes was administered weekly during concurrent thoracic radiotherapy. After 3 week rest, consolidation docetaxel 75 mg/m2 IV infusion over 60 minutes and carboplatin area under the curve = 6 over 30 minutes was administered every 3 weeks for two cycles. Concurrent thoracic radiation consisted of 45 Gy (1.8 Gy fractions 5 d/wk for first 5 weeks) followed by 18 Gy boost (2.0 Gy fractions 5 d/wk for 2 weeks) for a total dose of 63 Gy. Results: One and 2 years overall survival rates were 45 and 20%, respectively. Progression free survival at 1 year was 27%. Median survival time was 12 months. Median time to progression was 8 months. The primary hematologic toxicity was leukopenia. The primary nonhematologic toxicity was esophagitis. Conclusion: The administered regimen of weekly docetaxel-carboplatin and concurrent radiation therapy followed by docetaxel-carboplatin consolidation has acceptable toxicity profile. However, the overall survivals at 1 and 2 years are somewhat disappointing.

Malignant infiltration of the liver presenting as acute liver failure.

There have been few reports of acute liver failure (ALF), with encephalopathy and coagulopathy, caused by infiltration of the liver by malignant cells. We describe a case series of 27 patients with ALF caused by malignancy. We examined a large, multicenter ALF registry (1910 patients; mean age, 47.1 ± 13.9 y) and found only 27 cases (1.4%) of ALF attributed to malignancy. Twenty cases (74%) presented with abdominal pain and 11 presented with ascites. The most common malignancies included lymphoma or leukemia (33%), breast cancer, (30%), and colon cancer (7%); 90% of the patients with lymphoma or leukemia had no history of cancer, compared with 25% of patients with breast cancer. Overall, 44% of the patients had evidence of liver masses on imaging. Diagnosis was confirmed by biopsy in 15 cases (55%) and by autopsy for 6 cases. Twenty-four patients (89%) died within 3 weeks of ALF.

Premorbid body mass index and mortality in patients with lung cancer: A systematic review and meta-analysis

OBJECTIVES We aimed to assess the association between premorbid obesity, measured using body mass index (BMI) and lung cancer-related mortality, through a systematic review and meta-analysis. MATERIALS AND METHODS Observational studies reporting statistical measures of association between premorbid BMI categories and lung cancer-related mortality were included in our study. We estimated hazard ratios (aHR) with 95% confidence intervals (CI), comparing lung cancer-related mortality across BMI categories. The main outcome measure was lung cancer-related mortality in obese (BMI≥30kg/m2) and overweight participants (BMI 25.0-29.9kg/m2), compared with normal BMI participants. RESULTS We included 14 studies (including 2 pooled cohort studies) comprising 3,008,137 cancer-free participants at inception, reporting 28,592 lung cancer-related deaths. On meta-analysis, we observed a significantly lower lung cancer-related mortality in overweight (aHR, 0.76; 95% CI, 0.68-0.85) and obese (aHR, 0.68, 95% CI; 0.57-0.81) participants as compared to participants with normal BMI, with considerable heterogeneity; after excluding one study with large effect size, a more conservative and consistent association was observed between BMI and lung cancer-related mortality (overweight vs. normal BMI: aHR, 0.84; 95% CI, 0.79-0.90; obese vs. normal BMI: aHR, 0.81; 95% CI, 0.75-0.87), with moderate heterogeneity. Were similar in men vs. women, non-smokers vs. smokers, and Western vs Asia-Pacific populations. CONCLUSIONS Based on meta-analysis, we observed an independent protective association between premorbid obesity and lung cancer-related mortality. This association was observed across sex, smoking status and geographic region. Further studies are needed to prospectively study this association.

Toxicity and Response of Pemetrexed Plus Carboplatin or Cisplatin with Concurrent Chest Radiation Therapy for Patients with Locally Advanced Non-small Cell Lung Cancer: A Phase I Trial

Introduction: Pemetrexed is an effective and a tolerable drug in advanced non-small cell lung cancer (NSCLC). This study sought to ascertain maximum tolerated dose (MTD) and phase II dose of carboplatin or cisplatin given with pemetrexed and concurrent chest radiation therapy (CRT) in locally advanced NSCLC. Methods: Eligible, previously untreated patients were enrolled with the initial intent of establishing the MTD of both weekly cisplatin or carboplatin combined with pemetrexed 500 mg/m2 every 3 weeks and concurrent CRT in an alternating, two arm, phase I trial. Secondary objectives included response rate and toxicity. The protocol was subsequently amended to establish the safety of planned phase II doses of cisplatin or carboplatin combined with pemetrexed 500 mg/m2 given every 3 weeks × 3 cycles with CRT. Results: Patients received pemetrexed combined with carboplatin area under curve = 2 (n = 9), cisplatin 30 mg/m2 (n = 9), or cisplatin 75 mg/m2 (n = 4). One dose-limiting toxicity occurred in both the carboplatin and in the cisplatin 30 mg/m2 cohorts. No dose-limiting toxicities occurred in the cisplatin 75 mg/m2 cohort. Because these are standard doses without radiation therapy in lung cancer, there was no further dose escalation. Partial response rates were 11% (carboplatin) and 46% (combined cisplatin). Stable disease rates were 33% (carboplatin) and 46% (combined cisplatin). Two patients receiving carboplatin experienced disease progression. Conclusions: The MTD of cisplatin combined with pemetrexed was not reached. Based on these and Cancer and Leukemia Group B 30407 results, pemetrexed with either carboplatin or cisplatin at full systemic doses with CRT seems to be well tolerated. A multicenter, randomized phase II trial of both regimens is underway.

Comparative effectiveness of induction chemotherapy for oropharyngeal squamous cell carcinoma: A population-based analysis

OBJECTIVES Despite several randomized trials, the optimal chemotherapy paradigm for locally advanced oropharyngeal carcinoma (OPSCC) is controversial. This population-based analysis assessed the overall survival (OS) benefit of induction chemotherapy (IC) for patients with stage III-IVB OPSCC. MATERIALS AND METHODS Patients in the National Cancer Database with stage III-IVA-B OPSCC treated with curative-dose radiotherapy and IC or concurrent chemotherapy (CRT) between 2003 and 2011 were eligible. The primary outcome was OS, and secondary endpoints included OS for high-risk (T4 and/or N3 disease) and human papillomavirus (HPV) subsets. RESULTS Of the 14,856 analyzed patients, 78% and 22% received CRT and IC, respectively. With a median follow-up for surviving patients of 44 months, the 5-year OS probability for the entire cohort was 66% (66% CRT vs. 64% IC, p=0.022). Multivariable survival analysis showed no significant difference between CRT and IC (hazard ratio, HR, 0.95 for IC, p=0.255), and sensitivity analyses to adjust for immortal time bias brought the HR to 1.0 (p=0.859). There was also no OS difference for high-risk patients. There was a trend in favor of CRT for HPV-positive OPSCC (HR 1.63 with IC, p=0.064), with a significant OS benefit for HPV-negative, high-risk OPSCC (HR 0.63, p=0.048). CONCLUSION For the vast majority of patients, including HPV-positive individuals, there was no difference in OS with IC, arguing for CRT to remain as the standard therapy. Subset analysis revealed a small cohort of aggressive cancer (T4/N3 HPV-negative) which may benefit from from IC, although selection bias could not be ruled out.