Comparing Risk for Second Primary Cancers After Intensity-Modulated vs 3-Dimensional Conformal Radiation Therapy for Prostate Cancer, 2002-2015.

Importance: Compared with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) can spare nearby tissue but may result in increased scatter radiation to distant normal tissue, including red bone marrow. It is unclear whether second primary cancer risk varies by radiotherapy type. Objective: To evaluate whether radiotherapy type (IMRT vs 3DCRT) is associated with second primary cancer risk among older men treated for prostate cancer. Design, Setting, and Participants: In this retrospective cohort study of a linked database of Medicare claims and Surveillance, Epidemiology, and End Results (SEER) Program population-based cancer registries (2002-2015), male patients aged 66 to 84 diagnosed with a first primary nonmetastatic prostate cancer from 2002 to 2013, as reported to SEER, and who received radiotherapy (IMRT and/or 3DCRT without proton therapy) within the first year following prostate cancer were identified. The data were analyzed from January 2022 through June 2022. Exposure: Receipt of IMRT and 3DCRT, based on Medicare claims. Main Outcomes and Measures: The association between radiotherapy type and development of a subsequent hematologic cancer at least 2 years after prostate cancer diagnosis or a subsequent solid cancer at least 5 years after prostate cancer diagnosis. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional regression. Results: The study included 65 235 2-year first primary prostate cancer survivors (median [range] age, 72 [66-82] years; 82.2% White patients) and 45 811 5-year survivors with similar demographic characteristics (median [range] age, 72 [66-79] years; 82.4% White patients). Among 2-year prostate cancer survivors (median [range] follow-up, 4.6 [0.003-12.0] years), 1107 second hematologic cancers were diagnosed (IMRT, 603; 3DCRT, 504). Radiotherapy type was not associated with second hematologic cancers overall or any specific types evaluated. Among 5-year survivors (median [range] follow-up, 3.1 [0.003-9.0] years), 2688 men were diagnosed with a second primary solid cancer (IMRT, 1306; 3DCRT, 1382). The overall HR for IMRT vs 3DCRT was 0.91 (95% CI, 0.83-0.99). This inverse association was restricted to the earlier calendar year period of prostate cancer diagnosis (HR2002-2005 = 0.85; 95% CI, 0.76-0.94; HR2006-2010 = 1.14; 95% CI, 0.96-1.36), with a similar pattern observed for colon cancer (HR2002-2005 = 0.66; 95% CI, 0.46-0.94; HR2006-2010 = 1.06; 95% CI, 0.59-1.88). Conclusions and Relevance: The results of this large, population-based cohort study suggest that IMRT for prostate cancer is not associated with an increased risk of second primary cancers, either solid or hematologic, and any inverse associations may be associated with calendar year of treatment.

A Rare Case of Ruptured Appendicitis Secondary to Metastatic Ovarian Cancer.

BACKGROUND Patients with advanced stage ovarian cancer typically have vague non-specific abdominal symptoms related to pelvic tumor, metastasis, and ascites. When these patients present with more acute abdominal pain, appendicitis is rarely considered. Acute appendicitis due to metastatic ovarian cancer has been sparsely documented in the medical literature; only twice, to our knowledge. CASE REPORT A 61-year-old woman with a 3-week history of abdominal pain, shortness of breath, and bloating was diagnosed with ovarian cancer after computed tomography (CT) demonstrated a large pelvic cystic and solid mass. Five weeks later she underwent an omental biopsy to determine cell type and potential upstaging of the ovarian cancer to stage IV, as other aggressive cancers such as breast cancer can also involve the pelvis/omentum. Seven hours after her biopsy, she presented with increasing abdominal pain. Post-biopsy complications such as hemorrhage or bowel perforation were initially suspected to be the cause of her abdominal pain. However, CT demonstrated ruptured appendicitis. The patient underwent an appendectomy and histopathologic examination of the specimen revealed infiltration by low-grade ovarian serous carcinoma. CONCLUSIONS Given the low incidence of spontaneous acute appendicitis in this patient's age group, and the lack of any other clinical, surgical, or histopathological evidence to suggest another cause, metastatic disease was ruled to be the likely source of her acute appendicitis. Providers should be aware of appendicitis in a broad differential diagnosis and have a low threshold for ordering abdominal pelvis CT when advanced stage ovarian cancer patients present with acute abdominal pain.

Successful Bypass Surgery in a Healthy 24-Year-Old Male with Peripheral Artery Disease.

Approximately 40% of peripheral artery disease cases occur in individuals less than 50 years old. Diagnosis is often delayed due to fewer risk factors, atypical presentation, and symptoms attributed to a benign cause. We present an unusual case of an otherwise healthy 24-year-old male presenting with unilateral, intermittent claudication (IC) due to diffuse atherosclerotic disease in his left femoral arteries. Lifestyle-limiting symptoms caused by a four-year delay in diagnosis were improved with successful left femoropopliteal bypass. We use this case to review the differential diagnosis for IC and recommend early revascularization in young patients with severe disease and few comorbidities.

Dysphagia, Hyperglycemia, and Presyncope.

There have been over 80 documented cases of swallow syncope-a rare form of reflex or neurally mediated syncope-with most cases associated with an underlying esophageal disorder. Here, we describe the first reported case of swallow syncope or presyncope caused by an infectious esophagitis. Our 65-year-old patient initially developed dysphagia, odynophagia, and presyncope with swallowing. This lead to nutrition and medication avoidance behavior, which was followed by the development of diabetic ketoacidosis. The diagnosis of swallow presyncope was confirmed with a provocative swallow study demonstrating 8 s sinus arrest, and an underlying cause of Candida esophagitis was found by upper endoscopy. Symptoms completely resolved after treatment with micafungin.

Risk Factors for Repeat Debridement, Spacer Retention, Amputation, Arthrodesis, and Mortality After Removal of an Infected Total Knee Arthroplasty With Spacer Placement.

BACKGROUND: Chronic periprosthetic joint infection (PJI) after total knee arthroplasty (TKA) is most commonly addressed with a 2-stage exchange procedure. The purpose of this study is to examine the natural history of patients who have undergone prosthesis removal and spacer placement and evaluate risk factors for outcomes other than reimplantation. METHODS: Patients who underwent removal of an infected TKA and placement of an antibiotic spacer for PJI were identified in a Medicare database. Patients with a study outcome within 1 year were then identified: (1) in hospital mortality, (2) knee arthrodesis, (3) amputation, (4) repeat debridement procedure without reimplantation, and (5) reimplantation. Independent risk factors for these outcomes were evaluated with a multivariate logistic regression analysis. RESULTS: A total of 18,533 patients were included. Within 1 year postoperatively, 691 patients (3.7%) died in a hospital setting, 852 patients (4.5%) underwent a knee arthrodesis, 574 patients (3.1%) underwent an amputation, 2683 patients (14.5%) underwent a repeat debridement procedure without being reimplanted, 2323 patients (12.5%) retained their spacer, and 11,420 patients (61.6%) underwent spacer removal and reimplantation within 1 year. Numerous independent patient-related risk factors for these outcomes were identified. CONCLUSION: A large number of patients (38.4%) do not undergo reimplantation within 1 year of prosthesis removal and spacer placement. Outcomes after prosthesis removal and antibiotic spacer placement are variable, and there are several independent risk factors for such outcomes that may be used to develop and improve existing treatment strategies for patients presenting with chronic PJI after TKA.

Narcotic Use and Total Knee Arthroplasty.

BACKGROUND: Although the United States is in the midst of a narcotic epidemic, risk factors for use and the impact of perioperative narcotic use on total knee arthroplasty (TKA) outcomes is ill-defined. METHODS: A national database was queried for patients who underwent primary TKA from 2007 to 2015. Patients taking narcotics in the preoperative, and for a prolonged period of time postoperatively, were identified. The risk factors for prolonged narcotic use were analyzed with a regression analysis, in addition to evaluating preoperative and prolonged postoperative use as independent risk factors for short-term and long-term complications. RESULTS: In total, 113,337 patients met inclusion criteria, of which 31,733 patients were prescribed narcotics preoperatively and 35,770 patients were prescribed narcotics more than 3 months postoperatively. There are several independent risk factors for prolonged narcotic use postoperatively, the most significant being the number of narcotic prescriptions prescribed preoperatively. Preoperative narcotic use was independently associated with an increased risk of emergency room visits, readmission, infection, stiffness, and aseptic revision. Prolonged postoperative use was also associated with significantly increased rates of infection, stiffness, and aseptic revision. CONCLUSION: Preoperative and prolonged narcotic use following TKA was associated with an increased risk of short-term and long-term complications following TKA. The liberal use of narcotics in the perioperative period should be considered a modifiable risk factor when considering elective TKA.

Risk of thromboembolism in cisplatin versus carboplatin-treated patients with lung cancer.

INTRODUCTION: Carboplatin is widely used to treat lung cancer in the United States as an alternative to cisplatin. Several studies have demonstrated that cisplatin-based regimen is associated with a high frequency of thromboembolic complications. However, there has been limited investigation directly comparing the risk of thromboembolic events (TEEs) between cisplatin- and carboplatin-treated patients with lung cancer. METHODS: All lung cancer patients treated with cisplatin or carboplatin at Wilmot Cancer Center, University of Rochester between 2011 and 2014 were included. Patient characteristics including exposure (cisplatin vs. carboplatin) and outcome (TEEs between the time of the first dose of cisplatin or carboplatin and 4 weeks after the last dose) were collected by reviewing electronic medical records. A Fisher's exact test was used to compare the proportion of incident TEEs between cisplatin and carboplatin groups. The risk of TEE associated with carboplatin compared to cisplatin was assessed using multiple logistic regression. RESULTS: Among 415 subjects, 317 patients (76.4%) received carboplatin and 98 (23.6%) patients received cisplatin. In the carboplatin group, 10.9% (33/302) of evaluable patients developed treatment-related TEEs vs. 14.7% (14/95) in the cisplatin group. There was no significant difference in the risk of developing TEEs between the two groups (P = 0.32). However, 15.2% of carboplatin-related TEEs were arterial thromboses compared to none in the cisplatin group. CONCLUSIONS: The incidence of carboplatin-related TEEs was high in lung cancer patients without significant difference in the risk of developing TEEs between cisplatin and carboplatin groups. Potential use of prophylactic anticoagulation in all platinum-treated patients should be further investigated.

Double-blind, randomized phase 3 trial of low-dose 13-cis retinoic acid in the prevention of second primaries in head and neck cancer: Long-term follow-up of a trial of the Eastern Cooperative Oncology Group-ACRIN Cancer Research Group (C0590).

BACKGROUND: 13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS). METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups. RESULTS: 13-CRA neither significantly reduced the cumulative incidence of SPT (P = .61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P = .61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P = .14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P = .057) and among women (N = 39; HR, 0.44; P = .065) and never/former smokers (N = 129; HR, 0.61; P = .055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis. CONCLUSIONS: Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662. © 2017 American Cancer Society.

Phase 3 Randomized Low-Dose Paclitaxel Chemoradiotherapy Study for Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC) but is associated with poor chest tumor control. Here, we report results of a randomized phase 3 study comparing two CCRT regimens in improving chest tumor control by low-dose paclitaxel chemoradiation for LA-NSCLC. METHODS: Due to the logistics of local referral pattern, the study was designed to enroll patients with stage III LA-NSCLC who had completed 2-4 cycles of full-dose chemotherapy. One hundred thirty four were randomized to either Arm 1 [paclitaxel at 15 mg/m2, three times per week (Monday, Wednesday, and Friday) for 6 weeks, n = 74] or Arm 2 (weekly paclitaxel at 45 mg/m2 for 6 weeks, n = 60). Chest radiotherapy was 60-70 Gy in standard fractionation. Response rate was the primary endpoint, with recurrence-free survival (RFS) as the secondary endpoint. RESULTS: From March 2006 to February 2013, 71 patients completed Arm 1 treatment and 59 completed Arm 2 treatment. The response rate for Arm 1 was significantly higher (83.1%) than Arm 2 (54.2%) (p=0.001). RFS was superior in Arm 1: median 14.6 vs. 9.4 months, p = 0.005, Hazard ratio (HR) 1.87 [95% confidence interval (CI) 1.20, 2.90]. Overall survival was not significantly different: median 32.6 months in Arm 1 vs. 31.3 months in Arm 2, p = 0.91, HR 0.97 (95% CI 0.55, 1.70). Toxicity was significantly lower in Arm 1 for Grade 3 and 4 leukopenia/neutropenia (p < 0.001). CONCLUSION: Pulsed low-dose paclitaxel CCRT resulted in significantly better RFS and tumor response rate, and less hematologic toxicities than weekly CCRT for LA-NSCLC.

A Pilot Trial of Cisplatin/Etoposide/Radiotherapy Followed by Consolidation Docetaxel and the Combination of Bevacizumab (NSC-704865) in Patients With Inoperable Locally Advanced Stage III Non-Small-Cell Lung Cancer: SWOG S0533.

BACKGROUND: The aim of this trial was to determine feasibility of incorporating bevacizumab (B) into concurrent chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with unresectable stage III NSCLC, performance status of 0 to 1, and adequate organ function were accrued in 2 strata, low- and high-risk (squamous histology, hemoptysis, tumor with cavitation and/or adjacent to a major vessel). Cohort 1 patients received cisplatin 50 mg/m(2) days (d) 1 and 8, etoposide 50 mg/m(2) (d 1-5) for 2 cycles concurrent with radiotherapy (64.8 Gy) followed by docetaxel (D) 75 mg/m(2) and B 15 mg/kg for 3 cycles. If safety was established, then accrual would continue to cohort 2 (B, d 15, 36, 57) and then subsequently to cohort 3 (B, d 1, 22, 43). RESULTS: Twenty-nine patients (17 low- and 12 high-risk) registered to cohort 1. Twenty-six patients (including 4 squamous, 1 adenosquamous) were assessable. Twenty-five completed CRT. Grade 3/4 toxicities during CRT included acceptable rates of hematologic toxicity, esophagitis, and pneumonitis. Of 21 assessable for safety with D/B consolidation, major adverse events were pneumonitis (2 Grade 3) and 2 episodes of fatal hemoptysis in the high-risk group, resulting in closure of this stratum. The low-risk stratum subsequently closed because of slow accrual. Median overall survival was 46 months for low-risk and 17 months for high-risk strata. CONCLUSION: Bevacizumab was not safely integrated into CRT for stage III NSCLC in patients considered at high risk for hemoptysis. In lower risk patients, data are insufficient to determine safety or efficacy.

A Pilot Study (SWOG S0429) of Weekly Cetuximab and Chest Radiotherapy for Poor-Risk Stage III Non-Small Cell Lung Cancer.

PURPOSE: Stage III non-small cell lung cancer (NSCLC) patients with poor performance status (PS) or co-morbidities are often not candidates for standard chemoradiotherapy (chemoRT) due to poor tolerance to treatments. A pilot study for poor-risk stage III NSCLC patients was conducted combining cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR), with chest radiation (RT). METHODS: Stage III NSCLC patients with Zubrod PS 2, or Zubrod PS 0-1 with poor pulmonary function and co-morbidities prohibiting chemoRT were eligible. A loading dose of cetuximab (400 mg/m(2)) was delivered week 1, followed by weekly cetuximab (250 mg/m(2))/RT to 64.8 Gy in 1.8 Gy daily fractions, and maintenance weekly cetuximab (250 mg/m(2)) for 2 years or until disease progression. H-score for EGFR protein expression was conducted in available tumors. RESULTS: Twenty-four patients were enrolled. Twenty-two were assessed for outcome and toxicity. Median survival was 14 months and median progression-free survival was 8 months. The response rate was 47% and disease control rate was 74%. Toxicity assessment revealed 22.7% overall ≥Grade 3 non-hematologic toxicities. Grade 3 esophagitis was observed in one patient (5%). The skin reactions were mostly Grade 1 or 2 except two of 22 (9%) had Grade 3 acne and one of 22 (5%) had Grade 3 radiation skin burn. Grade 3-4 hypomagnesemia was seen in four (18%) patients. One patient (5%) had elevated cardiac troponin and pulmonary emboli. H-score did not reveal prognostic significance. An initially planned second cohort of the study did not commence due to slow accrual, which would have added weekly docetaxel to cetuximab/RT after completion of the first cohort of patients. CONCLUSION: Concurrent weekly cetuximab/chest RT followed by maintenance cetuximab for poor-risk stage III NSCLC was well tolerated. Further studies with larger sample sizes will be useful to establish the optimal therapeutic ratio of this regimen.

Advances in personalized therapy for lung cancer.

INTRODUCTION: Personalized medicine based on tumor characteristics is transforming the management of lung cancer. This review provides an overview of clinically approved strategies to personalize treatment for lung cancer as well as evolving strategies in various stages of clinical development. AREAS COVERED: Selecting therapy based on various tumor characteristics such as histology and presence of specific molecular alterations will be covered. This review will not only discuss the role of targeted agents in personalizing care for lung cancer but also the strategies to personalize traditional chemotherapeutic agents. EXPERT OPINION: Advances in genomic medicine to identify key genetic alterations with subsequent development of matching targeted agents are rapidly changing the management of lung cancer. Being able to target key driver molecular aberrations is certainly exciting and clinically meaningful, but only for a limited period of time. Intra- and intertumoral heterogeneity is a major contributor to therapy resistance, a substantial roadblock to durable response. Better understanding of resistance mechanism is at least as important as identifying new targetable genetic changes to effectively advance personalized therapy for lung cancer. Finally, optimization of biopsy specimens and rigorous validation steps to ensure reliability of diagnostic methods would be critical in moving forward.

Preclinical and pilot clinical studies of docetaxel chemoradiation for Stage III non-small-cell lung cancer.

PURPOSE: Local and distant failure rates remain high despite aggressive chemoradiation (CRT) treatment for Stage III non-small-cell lung cancer. We conducted preclinical studies of docetaxel's cytotoxic and radiosensitizing effects on lung cancer cell lines and designed a pilot study to target distant micrometastasis upfront with one-cycle induction chemotherapy, followed by low-dose radiosensitizing docetaxel CRT. METHODS AND MATERIALS: A preclinical study was conducted in human lung cancer cell lines NCI 520 and A549. Cells were treated with two concentrations of docetaxel for 3 h and then irradiated immediately or after a 24-h delay. A clonogenic survival assay was conducted and analyzed for cytotoxic effects vs. radiosensitizing effects of docetaxel. A pilot clinical study was designed based on preclinical study findings. Twenty-two patients were enrolled with a median follow-up of 4 years. Induction chemotherapy consisted of 75 mg/m(2) of docetaxel and 75 mg/m(2) of cisplatin on Day 1 and 150 mg/m(2) of recombinant human granulocyte colony-stimulating factor on Days 2 through 10. Concurrent CRT was started 3 to 6 weeks later with twice-weekly docetaxel at 10 to 12 mg/m(2) and daily delayed radiation in 1.8-Gy fractions to 64.5 Gy for gross disease. RESULTS: The preclinical study showed potent cytotoxic effects of docetaxel and subadditive radiosensitizing effects. Delaying radiation resulted in more cancer cell death. The pilot clinical study resulted in a median survival of 32.6 months for the entire cohort, with 3- and 5-year survival rates of 50% and 19%, respectively, and a distant metastasis-free survival rate of 61% for both 3 and 5 years. A pattern-of-failure analysis showed 75% chest failures and 36% all-distant failures. Therapy was well tolerated with Grade 3 esophagitis observed in 23% of patients. CONCLUSIONS: One-cycle full-dose docetaxel/cisplatin induction chemotherapy with recombinant human granulocyte colony-stimulating factor followed by pulsed low-dose docetaxel CRT is promising with regard to its antitumor activity, low rates of distant failure, and low toxicity, suggesting that this regimen deserves further investigation.

Multicenter, randomized, phase 2 study of zoledronic acid in combination with docetaxel and carboplatin in patients with unresectable stage IIIB or stage IV non-small cell lung cancer.

This study was designed to evaluate the efficacy and safety of combined zoledronic acid and docetaxel/carboplatin in patients with non-small cell lung cancer (NSCLC) as preclinical studies showed synergistic antitumoral activity with bisphosphonates and docetaxel. Patients with inoperable stage IIIB or stage IV NSCLC were randomized 2:1 to receive docetaxel 75mg/m(2) and carboplatin area under the concentration time curve 6 with (Arm A) or without (Arm B) zoledronic acid 4mg every 3 weeks for 6 cycles. Patients responding in Arm A were rerandomized to receive monthly zoledronic acid (maximum: 12 months [Arm A1] or no zoledronic acid [Arm A2]). Patients responding in Arm B entered Arm B1 for follow-up evaluation only. The primary endpoint was the proportion of patients without disease progression; secondary endpoints were time to disease progression (TTP), TTP in bone, best overall response rate, 1-year overall survival (OS) time, and safety; study not powered to detect endpoint differences. Of 150 patients, 98 were randomized to Arm A and 52 to Arm B. In the treatment phase, results were similar between groups in the proportion of patients without disease progression (40.9% vs 38.8%; P=.8096) and median TTP (132d vs 132d; P=.9622). One-year OS times and best overall response rates were 266d vs 206d (P=.4855) and 64.1% vs 72% (P=.3423), respectively; the study was not powered to detect differences. In the follow-up phase, TTP and OS time were similar. Adding zoledronic acid to docetaxel/carboplatin in advanced stage NSCLC patients was well tolerated, but provided little to no effect on disease progression endpoints.

Assessing persistent cancer pain: a comparison of current pain ratings and pain recalled from the past week.

Recent guidelines developed by the U.S. Food and Drug Administration for the use of patient-reported outcomes discuss the rating of pain and other symptoms at their current level of severity versus rating these symptoms using a recall period, such as the past 24 hours or past week. To explore whether the overall experience of cancer patients is better represented by ratings of current pain or pain recalled from the past week, we conducted a secondary analysis of Eastern Cooperative Oncology Group data from 1147 patients with cancer who had reported having persistent pain during the past week. Patients used the Brief Pain Inventory (BPI) to rate their current pain along with their pain at its worst, least, and average during the past week. T-tests were used to compare ratings of current pain and pain recalled from the past week. Linear regressions described the extent to which the various pain ratings contributed to overall pain interference, also derived from the BPI. Overall, patients rated their current pain as less severe than their worst or average pain recalled from the past week. Worst pain recalled from the past week contributed most to ratings of pain interference. These findings indicate that ratings of recalled worst pain, rather than ratings of current pain, might better reflect the overall experience of pain and its impact on function in cancer patients with persistent pain. Our results provide information that might guide the choice of recall period for cancer clinical trials with pain as a self-reported outcome.

Tumor response kinetics after schedule-dependent paclitaxel chemoradiation treatment for inoperable non-small cell lung cancer: a model for low-dose chemotherapy radiosensitization.

PURPOSE: Poor local disease control remains a major obstacle for inoperable non-small cell lung cancer (NSCLC) after radiotherapy. We previously reported results of a phase I/II clinical study based on preclinical investigations of paclitaxel radiation interactions for inoperable locally advanced NSCLC, which yielded remarkable local tumor responses and durable in-field tumor control using schedule-dependent low-dose paclitaxel for radiosensitization. Given our unique results, we analyzed the tumor response kinetics and conducted a statistical modeling of tumor response to characterize this regimen. METHODS AND MATERIALS: A total of 104 chest CT scans from 27 patients treated in the clinical trial were evaluated. Tumor volumes were calculated by three-dimensional measurements of pretreatment and serial post-therapy CT scans. A nonlinear mixed effects model was used to model response kinetics. RESULTS: The average tumor volume reduction at 1 month post-therapy was 69.9 +/- 22.6% (standard deviation), and was 80.6 +/- 17.9% at the last follow-up. The nonlinear mixed effects model predicts that tumor volume will ultimately shrink by at least 75% for more than 75% of patients treated by this regimen. The model also suggests that maximum shrinkage is reached within 2 months after treatment. CONCLUSION: Tumor volume response kinetics revealed a rapid shrinkage of gross tumors using schedule-dependent pulsed low-dose paclitaxel radiosensitization. This is contrary to the protracted tumor regression process observed in radiation alone or other chemoradiation combinations. Statistical modeling may prove useful in characterizing and comparing different therapeutic regimens.

Phase II study of palifermin and concurrent chemoradiation in head and neck squamous cell carcinoma.

PURPOSE: Acute mucositis is a dose-limiting toxicity of concurrent chemoradiotherapy regimens for locally advanced head and neck cancer. Palifermin (a recombinant human keratinocyte growth factor; DeltaN23-KGF) stimulates the proliferation and differentiation of mucosal epithelium to reduce mucositis in patients receiving intensive therapy for hematologic cancers. This study assessed the efficacy and safety of palifermin in patients receiving concurrent chemoradiotherapy for advanced head and neck squamous cell carcinoma. PATIENTS AND METHODS: In a phase II trial, standard radiotherapy was delivered in daily 2-Gy fractions to 70 Gy, or hyperfractionated radiotherapy was delivered in 1.25-Gy fractions twice daily to 72 Gy, over 7 weeks. Chemotherapy included cisplatin 20 mg/m(2) for 4 days and continuous-infusion fluorouracil 1,000 mg/m(2)/d for 4 days on weeks 1 and 5 of irradiation. Patients were randomly assigned 2:1 to palifermin 60 microg/kg or placebo once weekly for 10 doses. A follow-up trial evaluated long-term survival. RESULTS: Sixty-seven patients received palifermin and 32 received placebo. The median duration of grade >or= 2 mucositis was 6.5 and 8.1 weeks in the palifermin and placebo groups, respectively (P = .157). Palifermin appeared to reduce mucositis, dysphagia, and xerostomia during hyperfractionated radiotherapy (n = 40) but not standard radiation therapy (n = 59). Adverse events were similar between treatment groups. Palifermin did not alter tumor response or survival. CONCLUSION: Ten once-weekly doses of palifermin at 60 microg/kg were well tolerated. Most patients completed treatment, but palifermin did not reduce the morbidity of concurrent chemotherapy and radiotherapy. Future studies should evaluate higher palifermin doses with longer and more standardized assessment of acute mucositis.

Phase 1/2 dose escalating study of twice-monthly pemetrexed and gemcitabine in patients with advanced cancer and non-small cell lung cancer.

INTRODUCTION: Pemetrexed is synergistic with gemcitabine in preclinical models of non-small cell lung cancer (NSCLC). The optimal dose and utility of gemcitabine and pemetrexed was evaluated in a dose-escalating study. METHODS: The phase 1 study included patients with advanced tumors, whereas the phase 2 study included patients with locally advanced or metastatic NSCLC. Gemcitabine was infused over 30 minutes, followed by pemetrexed administered over 10 minutes on day 1 of a 14-day cycle. Treatment continued for 12 cycles or until disease progression. All patients received folic acid, Vitamin B12, and steroid prophylaxis. RESULTS: Maximum tolerated dose was gemcitabine 1500 mg/m, followed by pemetrexed 500 mg/m. Fifty-three patients (29 male, 24 female) were enrolled in the phase 2 study. Response rate was 20.8% (95% CI: 0.108-0.341), and the clinical benefit rate (CR + PR + SD) was 64.2%. Median time to disease progression was 4.6 months (95% CI: 2.79-6.18), median survival was 10.1 month (95% CI: 5.95-14.09, censorship = 20.75%), and 1-year survival was 41.0%. Common grade 3 or 4 adverse events (% of patients) were neutropenia (28.3%), fatigue (22.6%), and febrile neutropenia (9.4%). CONCLUSIONS: Twice-monthly gemcitabine and pemetrexed was well tolerated, with overall survival and clinical benefit indicating disease activity in NSCLC patients.

Combined effect of GSTM1, GSTT1 and GSTP1 polymorphisms on histological subtypes of lung cancer.

Genetic polymorphisms are natural genetic variations in the gene sequence that occur at a frequency of >1% in the population. This genetic variability (polymorphisms) can be a factor in cancer risk. The functional polymorphisms in GST genes play an important role in susceptibility to lung cancer. In our previous study, we reported that the combination of certain genotypes of GSTM1, GSTT1 and CYP1A1 is associated with lung cancer. The study has been extended to investigate the potential role of polymorphism in GSTP1 alone or in combination with the status of GSTM1 and GSTT1 genes in the likelihood of development of lung cancer. A total of 302 subjects (151 cases and 151 controls) were evaluated. Using a case-control design, individuals were genotyped for GSTs using multiplex polymerase chain reaction and restriction fragment length polymorphism techniques. The data obtained were analyzed using multiple logistic regression. The combined 'at risk' genotypes of GSTM1 null and GSTT1 null in comparison with 'wild-type' genotypes seems to be associated with a greater risk of lung cancer, but the results are not significant (odds ratio (OR) 2.0, 95% confidence interval (CI) 0.68-5.96) and for squamous cell carcinoma (SqCC) it was 1.6-fold (OR 1.6, 95% CI 0.49-5.68). In summary, our case-control study of lung cancer revealed that the effect of these polymorphisms is not very marked for different genotypic combinations of GSTP1, GSTM1 and GSTT1 in the context of developing lung cancer in a north Indian population. However, the increased risk was limited to SqCC, and was not found for other histological subtypes. Further analyses on this topic are needed.

Toxicity profile and pharmacokinetic study of a phase I low-dose schedule-dependent radiosensitizing paclitaxel chemoradiation regimen for inoperable non-small-cell lung cancer.

PURPOSE: We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non-small-cell lung cancer. METHODS AND MATERIALS: Paclitaxel at escalating doses of 15 mg/m(2), 20 mg/m(2), and 25 mg/m(2) were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography. RESULTS: Dose-limiting toxicities included 3 of 18 patients with Grade 3 pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m(2)), II (20 mg/m(2)), and III (25 mg/m(2)), the mean peak plasma level was 0.23 +/- 0.06 micromol/l, 0.32 +/- 0.05 micromol/l, and 0.52 +/- 0.14 micromol/l, respectively; AUC was 0.44 +/- 0.09 micromol/l, 0.61 +/- 0.1 micromol/l, and 0.96 +/- 0.23 micromol/l, respectively; and duration of drug concentration >0.05 micromol/l (t > 0.05 micromol/l) was 1.6 +/- 0.3 h, 1.9 +/- 0.2 h, and 3.0 +/- 0.9 h, respectively. CONCLUSION: Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 micromol/l for a minimum of 1.6 h was sufficient for effective radiosensitization.