Consolidation Docetaxel Research Articles

Phase I Study of Concurrent and Consolidation Cisplatin and Docetaxel Chemotherapy with Thoracic Radiotherapy in Non-Small Cell Lung Cancer

Background: We designed a phase I study of concurrent chemoradiotherapy (CCRT) with docetaxel (D) and cisplatin (C), followed by consolidation DC, for unresectable stage III non-small cell lung cancer (NSCLC). Methods: Patients with histologically proven and unresectable stage III NSCLC were eligible. During CCRT, C was given every 3 weeks (75 mg/m2) and D given weekly. The starting dose of D was 20 mg/m2, escalated in cohorts of 3 to define the maximum tolerated dose (MTD). Radiotherapy was prescribed to a dose of 60 Gy in 30 fractions. This was followed by 2 cycles of consolidation DC, which were dose escalated if CCRT was tolerated. Results: Twenty-six patients were enrolled, with 1 excluded following evidence of metastatic disease. Nineteen patients completed both phases of treatment. There were 7 grade 3 events during CCRT (5 esophagitis, 2 nausea), and 8 grade 3 events during consolidation (2 neutropenia, 2 leukopenia, 1 esophagitis, 2 nausea, and 1 pneumonitis). Three patients had grade 4 neutropenia. No patients died due to toxicities. The MTD of concurrent weekly D was 20 mg/m2. Consolidation D and C were each dose escalated to 75 mg/m2 in 8 patients. The median overall survival (OS) and progression-free survival (pfs) of all patients were 33.6 months and 17.2 months, respectively, with median follow-up of 26.6 months (range 0.43–110.8). Conclusions: The use of docetaxel 20 mg/m2 weekly and cisplatin 75 mg/m2 every 3 weeks concurrent with thoracic radiotherapy, followed by consolidation docetaxel and cisplatin, both given at 75 mg/m2 every 3 weeks, appears to be safe in this phase I trial.

Phase I study of concurrent and consolidation cisplatin and docetaxel chemotherapy with thoracic radiotherapy in non-small cell lung cancer.

We designed a phase i study of concurrent chemoradiotherapy (ccrt) with docetaxel (D) and cisplatin (C), followed by consolidation dc, for unresectable stage iii non-small cell lung cancer (nsclc). Patients with histologically proven and unresectable stage iii nsclc were eligible. During ccrt, C was given every 3 weeks (75 mg/m2) and D given weekly. The starting dose of D was 20 mg/m2, escalated in cohorts of 3 to define the maximum tolerated dose (mtd). Radiotherapy was prescribed to a dose of 60 Gy in 30 fractions. This was followed by 2 cycles of consolidation dc, which were dose escalated if ccrt was tolerated. Twenty-six patients were enrolled, with 1 excluded following evidence of metastatic disease. Nineteen patients completed both phases of treatment. There were 7 grade 3 events during ccrt (5 esophagitis, 2 nausea), and 8 grade 3 events during consolidation (2 neutropenia, 2 leukopenia, 1 esophagitis, 2 nausea, and 1 pneumonitis). Three patients had grade 4 neutropenia. No patients died due to toxicities. The mtd of concurrent weekly D was 20 mg/m2. Consolidation D and C were each dose escalated to 75 mg/m2 in 8 patients. The median overall survival (os) and progression-free survival (pfs) of all patients were 33.6 months and 17.2 months, respectively, with median follow-up of 26.6 months (range 0.43-110.8). The use of docetaxel 20 mg/m2 weekly and cisplatin 75 mg/m2 every 3 weeks concurrent with thoracic radiotherapy, followed by consolidation docetaxel and cisplatin, both given at 75 mg/m2 every 3 weeks, appears to be safe in this phase i trial.

Safety and feasibility of consolidation pembrolizumab following concurrent chemoradiation for unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN14-179.

8523 Background: The standard of care for unresectable stage III NSCLC is concurrent chemorad. Following treatment, the risk of radiation pneumonitis is greatest at 1-3 mo. Pneumonitis risk increases with consolidation chemotherapy. A previous trial by our group (Hanna et al, JCO 2008) of consolidation docetaxel showed 80.8% completed 3 planned cycles of chemo with a grade 3-5 pneumonitis rate of 9.6% and 1 death. PD-1 inhibitors are also associated with an increased risk of pneumonitis in the metastatic setting. We conducted a phase II trial of consolidation pembro initiated 1-2 mo after concurrent chemorad, a period during which pts are at high risk of developing pneumonitis. Methods: Pts with stage III NSCLC who completed chemorad with either carbo/paclitaxel, cis/etop, or cis/pemetrexed plus 59-66.6 Gy of radiation and had no PD received pembro 200mg IV q3wk for up to 1 yr. Primary endpoint is time to metastatic disease. The objective of the study is to evaluate both safety and efficacy, and here we report preliminary safety and feasibility results. Evaluable pts for this analysis had ≥3 mo of f/u or went off study due to PD, toxicity, or death < 3 mos after initiation of pembro. Results: 93 pts enrolled. Median age 67 (range 46-84), 59 (63.4%) were male. 87 (93.5%) were former or current smokers. 68 (73.1%) received carbo/pac, 24 (25.8%) received cis/etop, and 1 received cis/pemetrexed. SqCC (n = 41), non-SqCC (n = 43), NSCLC NOS (n = 8), mixed (n = 1). IIIA (n = 56), IIIB (n = 37). At the time of analysis, 83 of 93 pts were evaluable. 66 of 83 (79.5%) received ≥ 3 mo of pembro. 17 (20.5%) pts developed any grade pneumonitis with 14 of 17 occurring in the first 12 wks (median 9 wks). Only 3 (3.6%) pts developed grade 3-5 pneumonitis related to pembro. There was 1 pneumonitis-related death and a second death from respiratory failure possibly related to pembro. Conclusions: This early report indicates that most patients can safely receive consolidation pembro within 1-2 mo of completing chemorad. The incidence of serious pneumonitis during the first 3 mo of treatment appears low. Updated safety data on all 93 pts will be presented at the ASCO meeting. Clinical trial information: NCT02343952.

PC02.02 Pro Chemotherapy

PC02.02 Pro Chemotherapy

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

BackgroundThe 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 MethodsPatients 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/m2 days (d) 1 and 8, etoposide 50 mg/m2 (d 1-5) for 2 cycles concurrent with radiotherapy (64.8 Gy) followed by docetaxel (D) 75 mg/m2 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). ResultsTwenty-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. ConclusionBevacizumab 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.

Phase 2 Study of Concurrent Cetuximab Plus Definitive Thoracic Radiation Therapy Followed by Consolidation Docetaxel Plus Cetuximab in Poor Prognosis or Elderly Patients With Locally Advanced Non-Small Cell Lung Cancer

Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab. Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-"dry" IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board-approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications. Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause.

Trimodality Therapy for Superior Sulcus Non-Small Cell Lung Cancer: Southwest Oncology Group-Intergroup Trial S0220

Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy. Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy withcisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45eligible patients. The primary objective was feasibility. Of 46 patients registered, 44 were eligible andassessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%. Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases.

Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology

Concurrent chemoradiation with etoposide and cisplatin (EP/XRT) is standard treatment for inoperable stage III locally advanced non-small-cell lung cancer (LA-NSCLC). Consolidation docetaxel (D; Taxotere) after EP/XRT resulted in increased toxicity but no improvement in survival compared with observation (O). We report updated survival for the entire study population and include an analysis of efficacy and tolerability of EP/XRT with or without D in patients aged ≥ 70 years. Hoosier Oncology Group LUN 01-24 enrolled 243 patients with LA-NSCLC and randomized 166 after EP/XRT to three cycles of D versus O. the trial was terminated after an analysis of the first 203 patients demonstrated futility of D. Median survival time (MST) for the overall study population was 21.5 months, and 3-, 4-, and 5-year survival rates were 30.7%, 18.0%, and 13.9%, respectively. No differences in MST or 3-year survival were noted between D and O arms. Older patients had similar MST (17.1 versus 22.8 months for younger patients, P = 0.15) but higher rates of grade 3/4 toxicity and hospitalization during induction. Consolidation docetaxel after EP/XRT does not improve survival in LA-NSCLC. Fit older adults with LA-NSCLC benefit from concurrent chemoradiation similarly as younger patients but experience higher rates of hospitalization and toxicity.

SWOG S0533: A pilot trial of cisplatin (C)/etoposide (E)/radiotherapy (RT) followed by consolidation docetaxel (D) and bevacizumab (B) (NSC-704865) in three cohorts of patients (pts) with inoperable locally advanced stage III non-small cell lung cancer (NSCLC).

7018 Background: Bevacizumab combined with chemotherapy has improved survival in the treatment of advanced NSCLC. This pilot trial was conducted to determine if bevacizumab could be incorporated into the standard chemotherapy/RT for locally advanced NSCLC. Methods: Pts with unresectable stage III NSCLC, PS 0-1, and adequate organ function were eligible. Pts were accrued in two strata, low and high risk (squamous histology, hemoptysis, tumor with cavitation or near a major vessel). Pts were treated with C 50mg/m2 (d 1 and 8), E 50mg/m2 (d 1-5) for 2 cycles concurrent with RT (64.8 Gy at 1.8 Gy/fx for 36 fxs) followed by consolidation D 75mg/m2 and B 15 mg/kg for 3 cycles (Cohort 1). If safety was established then accrual would continue to Cohort 2 (B, d 15, 36, 57) and then Cohort 3 (B d 1, 22, 43). Results: 29 pts (17 Low, 12 High) were registered, all to Cohort 1. 26 pts (stage IIIB 19 pts, squamous 4 pt, adenosquamous 1 pt) were evaluable. 25 completed chemo/RT. Grade 3/4 toxicities during chemo/RT included: neutropenia 10 pts, thrombocytopenia 2, anemia 2, febrile neutropenia 3, esophagitis 2, pneumonitis 1. 21 were assessed for safety with D/B consolidation. The major adverse events during D/B consolidation were pneumonitis (Gr 3 - 2 pt) 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 poor accrual. Median overall survival was 23 mos for low risk pts and 17 mos for the high risk stratum. Conclusions: In this trial, bevacizumab could not be successfully integrated into chemo-radiation for stage III NSCLC, particularly in pts considered at high risk for hemoptysis. The trial suffered from several temporary closures as mandated by CTEP when new bevacizumab-related toxicities were reported, contributing to slow accrual. In lower risk pts the data are insufficient to determine safety or efficacy. Supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102 and CA38926.

Concurrent Chemoradiation for Elderly Patients with Locally Advanced Non-Small-Cell Lung Cancer: Still a Controversial Issue

Evaluation of: Jalal SI, Riggs HD, Melnyk A et al. Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a Phase III trial from the Hoosier Oncology Group (HOG) and US Oncology. Ann. Oncol. doi:10.1093/annonc/mdr565 (2011) (Epub ahead of print). The paper by Jalal et al. reports updated survival of a Phase III trial of concurrent chemoradiation with or without consolidation docetaxel for locally advanced non-small-cell lung cancer, and efficacy and tolerability data in patients ≥70 years. Of the 243 enrolled patients, 166 were randomized and 64 were aged ≥70 years (26%). There was no benefit of consolidation docetaxel. Median and 3-year survival was 17.1 months and 21.8% in patients ≥70 years, and 22.8 months and 34% in patients <70 years, respectively (p = 0.15). There were significantly more grade 3–4 toxicities (87 vs 73%; p = 0.02) and more hospitalizations in elderly patients (45 vs 32%; p = 0.03), but no increase in toxic deaths. Concurrent chemoradiation can be an option in elderly patients. However, significantly higher toxicity should be taken into account and elderly patients highly selected.

A single‐nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy

This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer. A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting. With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP. This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.

Consolidation docetaxel after paclitaxel-carboplatin chemotherapy in stage Ic-IV ovarian cancer.

e15536 Background: To test the concept of taxane sequencing in combined-modality therapy, this feasibility trial evaluated consolidation docetaxel after paclitaxel/carboplatin combination chemotherapy in patients with pathologically documented stage Ic-IV ovarian cancer. Methods: All the patients received debulking surgery and primary treatment consisted of carboplatin AUC 6 and paclitaxel 180 mg/m2 on day 1. Prior to consolidation chemotherapy, confirmation of no evidence of residual tumor was established by computed tomography scan, magnetic resonance imaging, or ultrasound sonography. Consolidation docetaxel started 4 to 6 weeks after the last chemotherapy at an initial dose of 70 mg/m2and repeated every 4 weeks for no less than 6 cycles. All patients were informed of the investigational nature of this study and signed a written informed consent in accordance with local institutional review board and administrative guidelines. Primary endpoint of this study was the evaluation of toxicities and the secondary endpoint was progression-free survival. Results were compared with those of the previous study with identical eligibility, staging criteria, and treatment, excepting for docetaxel consolidation. Results: Stage subsets in 18 eligible patients were as follows: T1, 1 patient (5.6%), T2, 1 patient (5.6%), T3, 11 patients (61.1%), and T4, 5 patients (27.8%). Paclitaxel-carboplatin combination chemotherapy was generally well tolerated and severe adverse events were not observed in this cohort. Neutropenia during consolidation docetaxel was common (22.2 % with grade 3 or 4) and was most frequent during second cycle. Median progression-free survival was 14.0 months with median follow up period of 15.0 months and 1-year survival rate was 66.7%. In historical control, median survival was 14.1 months and 1-year survival rate was 52.2%. Conclusions: Consolidation docetaxel after paclitaxel/carboplatin combination chemotherapy in ovarian cancer is feasible and generally tolerable. Nevertheless, this study does not provide definitive evidence of the survival benefit of this approach. Phase III trials evaluating the docetaxel consolidation regimen have been initiated to validate these results. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis

Randomized Phase II Trial of Cisplatin, Etoposide, and Radiation Followed by Gemcitabine Alone or by Combined Gemcitabine and Docetaxel in Stage III A/B Unresectable Non-small Cell Lung Cancer

Southwest Oncology Group 9504 demonstrated the feasibility and potential benefit of docetaxel consolidation after etoposide, cisplatin, and radiotherapy in patients with locally advanced non-small cell lung cancer. Our study assessed consolidation with either gemcitabine alone or with docetaxel after identical chemoradiation as used in Southwest Oncology Group 9504. Patients with stage III non-small cell lung cancer and good performance status were included. Treatment consisted of concurrent cisplatin 50 mg/m on days 1 and 8 plus etoposide 50 mg/m on days 1 to 5 for two 28-day cycles plus radiotherapy (62 Gy, 2 Gy daily in 31 fractions over 7 weeks), followed by randomization to either gemcitabine 1000 mg/m on days 1 and 8 (G) or gemcitabine 1000 mg/m on days 1 and 8 plus docetaxel 75 mg/m on day 1 (GD) every 21 days for three cycles. Eighty-three patients were entered, 81 received induction therapy, and 64 were randomized (32 in each arm). Grade 3 or four events, including neutropenia (56.3% vs. 28.1%, p = 0.03), anemia (18.8% vs. 3.1%, p = 0.05), and fatigue (15.6% vs. 6.3%, p = NS), were more frequent with GD compared with G. Among all patients, median survival from registration was 20.8 months (95% confidence interval: 16.4-33.8), and 2-year survival was 46.7% (95% confidence interval: 35.6-57.1). From randomization, median progression-free survival was 5.4 months for G and 13.4 months for GD, and median survival was 16.1 months for G and 29.5 months for GD. Two-year survival rates were 40.6% for G and 55.7% for GD. The doublet, as expected, resulted in more toxicity, particularly myelosuppression and fatigue. Survival associated with the GD treatment arm of this trial exceeds that of previously reported trials.

Efficacy and Toxicity of Chemoradiotherapy with Carboplatin and Irinotecan Followed by Consolidation Docetaxel for Unresectable Stage III Non-small Cell Lung Cancer

In 2003, consolidation docetaxel was a promising concept for unresectable stage IIIA/B nonsmall cell lung cancer (NSCLC). To test the hypothesis that chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel would be feasible and clinically active, we conducted a phase II study. Thirty-two patients with unresectable stage IIIA/B NSCLC received irinotecan (30 mg/m) and carboplatin dosed to a target area under the concentration curve of 2, each administered weekly for 7 weeks. Concurrent radiotherapy was administered more than 7 weeks to a total dose of 63 Gy in 35 fractions. Consolidation docetaxel (75 mg/m) was administered every 3 weeks for 3 doses 4 weeks after chemoradiotherapy. The primary end point was objective response rate by RECIST. Complete responses occurred in 4 patients and partial responses occurred in 14, for an objective response rate of 56.3% (95% confidence interval [CI], 37.7-73.6%). Median progression-free survival was 6.5 months (95% CI, 4.6-13.5); median duration of survival was 14.8 months (95% CI, 6.9-27.3). The most common hematologic toxicity was leukopenia, which were grade 3 or 4 in 16 patients (50%). Radiation pneumonitis (grade >or=2) occurred in 13 of 31 treated patients (42%). These findings suggested that concurrent chemoradiotherapy with carboplatin and irinotecan followed by consolidation docetaxel is clinically active based on median survival in patients with unresectable stage III NSCLC; however, the 42% incidence of clinical radiation pneumonitis was unexpected and warrants further investigation to determine the mechanism and preventive strategies.

Dose–Volume Analysis of Radiation Pneumonitis in Non–Small-Cell Lung Cancer Patients Treated With Concurrent Cisplatinum and Etoposide With or Without Consolidation Docetaxel

To examine the rates and risk factors for radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with chemoradiotherapy. We reviewed dosimetry records from Stage III NSCLC patients treated on a prospective randomized trial. Patients received concurrent cisplatinum/etoposide with radiation therapy to 59.4 Gy. A total of 243 patients were enrolled; 167 did not experience progression and were randomized to observation (OB) or consolidation docetaxel (CD). Toxicity was coded based on the presence of Grade 0 to 1 vs. Grade 2 to 5 RP using the Common Toxicity Criteria and Adverse Events (CTCAE) v3.0. Median age and follow-up were 63 years and 16 months, respectively. Overall, Grade 0 to 1 and Grade 2 to 5 RP were reported in 226 patients and 17 patients (7%) respectively. Median mean lung dose (MLD), V5, V20, and V30 for evaluable patients were 18 Gy, 52%, 35%, and 29%. MLD in Grade 0 to 1 and Grade 2 to 5 patients was 1,748 c Gy and 2,013 cGy in respectively (p = 0.12). Grade 2 to 5 RP developed in 2.2% and 19% of patients with MLD < 18 Gy and MLD > 18 Gy, respectively (p = 0.015). Mean V20 was 33.7% and 37.7% for Grade 0 to 1 and Grade 2 to 5 groups, respectively (p = 0.29). Grade 2 to 5 RP developed in 4.8% and 17% of patients with V20 < 35% and V20 > 35%, respectively. The OB and CD groups had similar MLD and V20, and the RP rates were 3.6% and 14.6%, respectively (p = 0.015). Patients who developed Grade 0 to 1 and Grade 2 to 5 RP had similar mean V5, V10, V15, V20, V25, V30, age, smoking history, and tumor characteristics. The overall rate of Grade 2 to 5 RP was 7% in patients treated with chemoradiotherapy. In this analysis, predictive factors for RP were MLD > 18 Gy and treatment with CD.

Concurrent Chemoradiation Therapy With Docetaxel/Cisplatin Followed by Docetaxel Consolidation Therapy in Inoperable Stage IIIA/B Non–Small-Cell Lung Cancer: Results of a Phase I Study

Introduction Docetaxel consolidation therapy (DCT) after concurrent cisplatin/docetaxel chemoradiation therapy (CRT) produces high tumor control in non–small-cell lung cancer (NSCLC); toxicity is, however, considerable. We aimed to determine the maximally tolerated dose (MTD) for DCT. Patients and Methods Patients with inoperable stage IIIB NSCLC received docetaxel 20 mg/m 2 and cisplatin 25 mg/m 2 on days 1, 8, 15, 22, 29, and 36, with concurrent radiation therapy 5 days per week for a total dose of 66 Gy. Patients achieving stable disease, partial response, or complete response were given DCT on days 71, 92, and 113. DCT was started with 75 mg/m 2 and titrated depending on tolerability. The MTD of docetaxel was defined as the dose preceding that at which 3 or more patients experienced dose-limiting toxicity (DLT). Results Of 23 patients enrolled (median age, 58.8 years ± 7.3 years), 19 received complete CRT (4 withdrew because of toxicity). Of the patients receiving complete CRT, 1 patient died and 1 became operable, leaving 17 patients eligible for DCT starting at 75 mg/m 2. After the third patient with DLT, dose was reduced to 60 mg/m 2. Median survival was 27.6 months ± 23.1 months. Median TTP was 12.4 months ± 10.7 months. Conclusion The MTD of DCT after concurrent cisplatin/docetaxel CRT was determined to be 60 mg/m 2, but toxicity was considerable. The benefit-risk ratio of DCT has, however, been questioned by a placebo-controlled phase III trial. Further phase III trials need to consider further stratification factors (pretreatment forced expiratory volume [FEV] 1, hemoglobin, performance, and stage) to define a role for DCT in patients with NSCLC.

Chemotherapy in stage III non-small cell lung cancer

It has recently become clear that stage III non-small cell lung cancer (NSCLC) can be treated with curative intent either by concurrent chemoradiation or combined modality approaches including surgery in wellselected patient populations [1–3]. Nevertheless, the relapse pattern of stage III NSCLC generally indicates that systemic relapse still accounts for about 40% of the first failures following initial curatively intended therapy [4]. Therefore, systemic drug treatment − similar to that in stage II and stage IV disease – will also have to remain an integrated part of the management for these patient groups [5,6]. Cisplatinbased chemotherapy combinations have proven to be systemically effective on micro-metastatic disease of stage III patients in the adjuvant setting following local treatment with surgery [7,8]. Currently, there is no clear evidence for carboplatin-based protocols or nonplatinum-containing regimens in contrast to cisplatinbased regimens in these stages [6,9–11]. Even in stage IV, cisplatin-based combinations with newer drugs lead to increased response rates and a clear trend for increased overall survival when directly compared to carboplatin-based combinations [12]. However, it should be noted that combination chemotherapy only exerts a systemic risk reduction-effect on relapses outside the brain and cannot adequately protect the central nervous system [4]. When given in combination with local treatment such as definitive chemoradiation or surgery in stage III NSCLC, two different approaches can potentially be pursued. One is to give a small number of chemotherapy cycles as induction prior to definitive local therapy [13,14], while alternatively the other method tries to give adjuvant chemotherapy as post-local treatment [2,15]. With the most effective cisplatin-based protocols, it has to be stated that no large randomised comparison between these two strategies within trials is currently available. However, single agent consolidation therapy with docetaxel following concurrent chemoradiation did not generate a survival benefit within a randomised trial of the Hoosier Oncology Group (HOG), although the multicentre phase-II pilot of the Southwest Oncology Group (SWOG) had generated encouraging longterm survival data [16]. The probable reason for the ultimate failure of the randomised trial was an increased treatment-related toxicity and toxic death rate in the single agent docetaxel consolidation arm during the pneumonitis phase of the post-radiation setting [17]. Currently, a randomised German trial is looking at consolidation cisplatin and oral vinorelbine versus observation following definitive concurrent chemoradiation [18]. However, it is probably unfair to expect definitive conclusions from this rather small randomised trial alone. In the adjuvant setting of early disease, a meta-analysis of more than 4000 patients was needed to prove a survival benefit of about 5% to 6% with adjuvant chemotherapy at 5 years [8]. When looking at the literature of currently published datasets, the largest and best selected patient group has been that from the chemoradiation arm of the Intergroup Trial 0139 [2]. Treatment was based on a concurrent chemoradiation of two cycles of cisplatin and etoposide together with 61 Gray (Gy) conventionally fractionated radiotherapy. Then, two cycles of consolidation chemotherapy with cisplatin and etoposide were added. A 5-year overall survival rate of 20.3% has been reached in stage IIIA(N2) patients with pathologically proven mediastinal N2status, representing probably the best survival data so far in a comparable patient population with chemoradiation within a randomised trial. Therefore, at the moment, the two-drug combinations with the largest evidence from randomised trials available in this concurrent chemoradiation setting are cisplatin and etoposide as well as cisplatin and vinorelbine [19]. There are also randomised trials including carboplatin and paclitaxel, but their results should be interpreted with caution as carboplatin lacks clinical data for being a significant radiation sensitiser in stage III (see Table 1) [9,10,20–22]. Furthermore, its systemic efficacy may be significantly inferior to platinumbased protocols on the micro-metastatic disease [12].

Impact of the ASCO 2007 Presentation of HOG Lun 01-24/USO-023 on the Prescribing Plans of American Medical Oncologists for Patients with Stage IIIB Non-small Cell Lung Cancer

Nonoperative treatment of stage III non-small cell lung cancer has evolved over the past 30 years. The current approach in the Unites States most often includes concurrent chemoradiotherapy. We have used live, case-based research events to document prescribing plans among American medical oncologists for first-line therapy in patients with N3 stage IIIB non-small cell lung cancer. Changes in prescribing plans documented before and after the 2007 American Society of Clinical Oncology (ASCO) presentation of a Hoosier Oncology Group trial testing the role of consolidation docetaxel chemotherapy in this setting are presented. Data from 2007 show a post-ASCO shift away from plans for docetaxel consolidation, increased use of concurrent chemoradiotherapy alone, and stable to increased plans for concurrent chemoradiation followed by additional cycles of the chemotherapy used during concurrent management (20%). Preliminary data from 2008 confirm the durability of these changes. The findings of the Hoosier Oncology Group trial support a transition away from docetaxel consolidation. A trend in this direction among American medical oncologists is clear from our data. However, nearly 20% of oncologists studied in 2008 still plan to use docetaxel consolidation. Furthermore, a majority of those studied after ASCO 2007 continue to report plans to use more than two cycles of chemotherapy as part of their preferred treatment recommendation despite no level I evidence to support this approach.

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)

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. Sixty-seven patients having previously untreated stage IIIA or IIIB unresectable NSCLC were enrolled, with 61 patients evaluated for endpoints. Docetaxel 20 mg/m 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/m(2) 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. 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. 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.

Phase II Trial of Consolidation Docetaxel and Samarium-153 in Patients With Bone Metastases From Castration-Resistant Prostate Cancer

To assess docetaxel combined with samarium-153-ethylene diamine tetramethylene phosphonic acid (EDTMP), a radiopharmaceutical with a high affinity for bone, in patients with castration-resistant prostate cancer (CRPC). Patients with bone metastases from CRPC who achieved a response or stabilization after four cycles of docetaxel and estramustine were given consolidation docetaxel 20 mg/m(2)/wk for 6 weeks and samarium-153-EDTMP (37 MBq/kg) during week 1. Prostate-specific antigen (PSA) response was assessed by using consensus criteria, and pain was assessed by using a visual analog scale (VAS). This study used a Simon two-step design with PSA-progression-free survival (PFS) as the primary end point. Forty-three patients were included in the trial. A PSA response was obtained in 77% (95% CI, 61% to 82%). The pain response rate was 69% (95% CI, 49% to 85%). At least five of the six planned weekly injections of docetaxel were administered to 34 patients (81%). The consolidation docetaxel-samarium-153-EDTMP regimen was well tolerated; there was no febrile neutropenia, and only two episodes (5%) of rapidly reversible grade 3 thrombocytopenia occurred. Although a serum PSA relapse eventually occurred in all patient cases, this regimen resulted in pain control in the long-term. The median PSA-PFS was 6.4 months (95% CI, 6 to 7 months). The median survival was 29 months (95% CI, 22 to 31); the 1-year survival rate was 77% (62% to 87%); and the 2-year survival rate was 56% (41% to 70%). Combining docetaxel and samarium-153-EDTMP in patients with bone metastases from CRPC is well tolerated, and it yields major pain relief that persists long after treatment. Overall survival compares favorably with that expected in this population of patients, most of whom exhibit symptoms.