Melenda Jeter

Stereotactic Body Radiation Therapy in Centrally and Superiorly Located Stage I or Isolated Recurrent Non–Small-Cell Lung Cancer

PURPOSE To evaluate the efficacy and adverse effects of image-guided stereotactic body radiation therapy (SBRT) in centrally/superiorly located non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS We delivered SBRT to 27 patients, 13 with Stage I and 14 with isolated recurrent NSCLC. A central/superior location was defined as being within 2 cm of the bronchial tree, major vessels, esophagus, heart, trachea, pericardium, brachial plexus, or vertebral body, but 1 cm away from the spinal canal. All patients underwent four-dimensional computed tomography-based planning, and daily computed tomography-on-rail guided SBRT. The prescribed dose of 40 Gy (n = 7) to the planning target volume was escalated to 50 Gy (n = 20) in 4 consecutive days. RESULTS With a median follow-up of 17 months (range, 6-40 months), the crude local control at the treated site was 100% using 50 Gy. However, 3 of 7 patients had local recurrences when treated using 40 Gy. Of the patients with Stage I disease, 1 (7.7%) and 2 (15.4%) developed mediastinal lymph node metastasis and distant metastases, respectively. Of the patients with recurrent disease, 3 (21.4%) and 5 (35.7%) developed mediastinal lymph node metastasis and distant metastasis, respectively. Four patients (28.6%) with recurrent disease but none with Stage I disease developed Grade 2 pneumonitis. Three patients (11.1%) developed Grade 2-3 dermatitis and chest wall pain. One patient developed brachial plexus neuropathy. No esophagitis was noted in any patient. CONCLUSIONS Image-guided SBRT using 50 Gy delivered in four fractions is feasible and resulted in excellent local control.

Gemcitabine-induced radiation recall

PURPOSE To study and report 6 patients with radiation recall in unique sites, secondary to gemcitabine chemotherapy. METHODS AND MATERIALS The clinical presentations and outcomes of 6 patients with radiation recall secondary to gemcitabine chemotherapy were retrospectively analyzed over the course of a 1-year period. RESULTS Radiation recall reactions were seen in the central nervous system, skin, gastrointestinal tract, and in the lymphatic and musculoskeletal systems. The time between initiation of radiation and recall of the radiation phenomenon ranged from 3 weeks to 8 months from the time gemcitabine was initiated. The usual dosage of gemcitabine in these cases was 1000 mg/m(2) given on a weekly basis. No radiation therapy was given concomitantly with gemcitabine. Treatment of the recall reaction consisted of discontinuing gemcitabine and initiating steroid therapy, supportive therapy, and/or nonsteroidal anti-inflammatory agents. Minimal improvement was seen in 3 out of 6 patients, and resolution of the radiation recall was seen in 3 out of 6 patients. A comprehensive review of the literature revealed that radiation recall with gemcitabine has been related to skin reactions only; no previous cases of radiation recall occurring in the central nervous system have been reported with any chemotherapy agent. CONCLUSION Radiation recall from gemcitabine chemotherapy is rare, but can potentially arise in any site that has been previously irradiated. Treating physicians must be aware of this potential toxicity from gemcitabine and radiation and discontinue the gemcitabine if radiation recall is observed.

A Phase I Clinical Trial of Thoracic Radiotherapy and Concurrent Celecoxib for Patients with Unfavorable Performance Status Inoperable/Unresectable Non–Small Cell Lung Cancer

Objectives: Preclinical observations that selective cyclooxygenase-2 inhibitors enhance in vitro cell radiosensitivity and in vivo tumor radioresponse led to clinical trials testing therapeutic efficacy of these agents. Our study was designed to determine whether the COX-2 inhibitor celecoxib could be safely administered in doses within those approved by the Food and Drug Administration when used concurrently with thoracic radiotherapy in patients with poor prognosis non–small cell lung cancer (NSCLC). Patients and Methods: The trial consisted of three cohorts of patients: (a) locally advanced NSCLC with obstructive pneumonia, hemoptysis, and/or minimal metastatic disease treated with 45 Gy in 15 fractions; (b) medically inoperable early-stage NSCLC treated with definitive radiation of 66 Gy in 33 fractions; and (c) patients who received induction chemotherapy but who were not eligible for concurrent chemoradiotherapy trials. These patients received 63 Gy in 35 fractions. Celecoxib was administered p.o. on a daily basis 5 days before and throughout the course of radiotherapy. Celecoxib doses were escalated from 200, 400, 600, to 800 mg/d given in two equally divided doses. Two to eight patients of each cohort were assigned to each dose level of celecoxib. Results: Forty-seven patients were enrolled in this protocol (19 in cohort I, 22 in cohort II, and 6 in cohort III). The main toxicities were grades 1 and 2 nausea and esophagitis, and they were independent of the dose of celecoxib or radiotherapy schedule. Only two patients in group II developed grade 3 pneumonitis 1 month after treatment, one on 200 mg, and the other on 400 mg celecoxib. Celecoxib-related toxicity developed in 3 of 47 patients: an uncontrolled hypertension in one patient on 800 mg celecoxib and hemorrhagic episodes in 2 patients (shoulder hematoma in one and hemoptysis in the other) on 200 mg celecoxib who were on warfarin for other medical reasons. Of 37 patients evaluable for tumor response, 14 had complete response, 13 partial responses, and 10 stable or progressive disease. The actuarial local progression-free survival was 66.0% at 1 year and 42.2% at 2 years following initiation of radiotherapy. Conclusions: These results show that celecoxib can be safely administered concurrently with thoracic radiotherapy when given up to the highest Food and Drug Administration–approved dose of 800 mg/d, which we used. A maximal tolerated dose was not reached in this study. The treatment resulted in actuarial local progression-free survival of 66.0% at 1 year and 42.2% at 2 years, an encouraging outcome that warrants further assessment in a phase II/III trial.

Equivalent outcome of patients with clinical Stage IIIA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection

PURPOSE To compare the outcome of induction chemotherapy followed by surgery (C/S) and concurrent chemoradiotherapy (CRT) for clinical Stage IIIA non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Between 1990 and 2000, 107 patients underwent either induction C/S (n = 55) or concurrent CRT (n = 52) for clinical Stage IIIA NSCLC at The University of Texas M. D. Anderson Cancer Center. Patient and tumor characteristics were balanced in the two treatment groups with respect to T and N stage, race, median age, performance status, weight loss, and histologic findings. In the C/S group, induction chemotherapy included two to four cycles of cisplatin-based chemotherapy followed by lobectomy and mediastinal lymph node dissection. Postoperative RT was delivered in 35 patients, with referral for RT made at the discretion of the treating physician. CRT consisted of three cycles of cisplatin-based chemotherapy given every 3 weeks concurrent with RT to 60-63 Gy in 30-35 fractions in 27 patients and 69.6 Gy in 58 fractions (b.i.d.) in 25 patients. Local control, overall disease-free survival, and distant metastasis-free survival rates were calculated using the Kaplan-Meier method. The median follow-up duration was 20 months in all patients and 32 months in surviving patients. RESULTS No statistically significant differences were found in the end points measured in the two treatment groups. Specifically, the median survival time was 31 and 27 months and the 5-year overall survival rate was 33% and 30% in the C/S and CRT groups, respectively. Likewise, the 5-year local control (58% vs. 61%), disease-free (24% vs. 23%), and distant metastasis-free (44% vs. 36%) survival rates in the two groups were not significantly different. In the C/S group, postoperative RT significantly improved the 5-year local control rate from 33.8% to 81.5% (p = 0.007) but did not significantly improve overall survival. Additionally, patients in the C/S group whose disease responded to induction chemotherapy had a significantly improved 5-year overall survival rate (50%) compared with those who had stable or progressive disease (16%, p = 0001). CONCLUSION Treatment of Stage IIIA NSCLC using either induction C/S or CRT resulted in similar outcomes in terms of local control and median overall, 5-year overall, distant metastasis-free, and disease-free survival. However, patients undergoing induction C/S often needed postoperative RT to achieve local control equivalent to that achieved with concurrent CRT. Advances in radiation-based treatment as reflected in this study have resulted in similar outcomes compared with modern induction C/S. To improve survival, however, newer systemic agents that reduce and control distant metastasis are required.

Potential Dosimetric Benefits of Four-Dimensional Radiation Treatment Planning

PURPOSE To determine the extent of dosimetric differences between conventional three-dimensional (3D) dose calculations and four-dimensional (4D) dose calculations based on deformation of organ models. METHODS AND MATERIALS Four-dimensional dose calculations were retrospectively performed on computed tomography data sets for 15 patients with Stage III non-small-cell lung cancer, using a model-based deformable registration algorithm on a research version of a commercial radiation treatment planning system. Target volume coverage and doses to critical structures calculated using the 4D methodology were compared with those calculated using conventional 3D methodology. RESULTS For 11 of 15 patients, clinical target volume coverage was comparable in the 3D and 4D calculations, whereas for 7 of 15 patients, planning target volume coverage was comparable. For the other patients, the 4D calculation indicated a difference in target volume dose sufficiently great to warrant replanning. No correlations could be established between differences in 3D and 4D calculations and gross tumor volume size or extent of motion. Negligible differences were observed between 3D and 4D dose-volume relationships for normal anatomic structures. CONCLUSIONS Use of 4D dose calculations, when possible, helps ensure that target volumes will not be underirradiated when respiratory motion may affect the dose distribution.

Patterns of care and locoregional treatment outcomes in older esophageal cancer patients: The SEER-Medicare Cohort.

PURPOSE Optimal management of elderly patients with nonmetastatic esophageal cancer is unclear. Outcomes data after locoregional treatment are lacking for this group. METHODS We assessed outcomes associated with standard locoregional treatments in 2,626 patients (age > 65 years) from the Surveillance Epidemiology and End Results (SEER)-Medicare cohort diagnosed with nonmetastatic esophageal cancer from 1992 to 2002. In patients treated with radiotherapy alone (RT), surgery alone (S), chemoradiotherapy (CRT), or preoperative chemotherapy followed by surgery (CRT + S), overall and disease-free survival were compared using proportional hazards regression. Postoperative complications were compared using logistic regression. RESULTS Mean age was 76 +/- 6 years. Seven percent underwent CRT + S, 39% CRT, 30% S, and 24% RT. One-year survival was 68% (CRT + S), 52% (CRT), 53% (S), and 16% (RT), respectively (p < 0.001). Patients who underwent CRT + S demonstrated improved overall survival compared with S alone (hazard ratio [HR] = 0.81; 95% confidence interval [CI], 0.66-0.98; p = 0.03) and RT (HR = 0.44; 95% CI, 0.35-0.55; p < 0.0001); and comparable survival to CRT (HR = 0.82; 95% CI, 0.67-1.01; p = 0.06). Patients who underwent CRT + S also had comparable postoperative mortality (HR = 0.96; 95% CI, 0.87-1.07; p = 0.45) and complications (OR = 0.89; 95% CI, 0.70-1.14; p = 0.36) compared with S alone. CONCLUSIONS Preoperative chemoradiotherapy may be an acceptable treatment option in appropriately selected older esophageal cancer patients. This treatment modality did not appear to increase surgical complications and offered potential therapeutic benefit, particularly compared with surgery alone.

Proton Beam Radiotherapy and Concurrent Chemotherapy for Unresectable Stage III Non–Small Cell Lung Cancer: Final Results of a Phase 2 Study

Importance Proton beam radiotherapy (PBT) has the potential to reduce toxic effects in the definitive management of locally advanced non–small cell lung cancer (NSCLC), but long-term prospective data are lacking. Objective To report the final (5-year) results of a prospective study evaluating concurrent chemotherapy and high-dose PBT to treat unresectable stage III NSCLC. Design, Setting, and Participants In this open-label, single-group assignment study, with median follow-up of 27.3 months for all patients and 79.6 months for survivors, 64 patients were enrolled and analyzed; inclusion criteria were unresectable IIIA/IIIB histologically confirmed NSCLC, Karnofsky performance status 70 to 100, and 6-month prediagnosis weight loss of no more than 10%. Staging used positron emission tomography and/or computed tomography. Induction chemotherapy was allowed. Interventions Concurrent chemotherapy (carboplatin-paclitaxel) and passively scattered PBT (74-Gy relative biological effectiveness) in all patients. Main Outcomes and Measures Kaplan-Meier analysis of overall survival (OS), progression-free survival (PFS), actuarial distant metastasis, and locoregional recurrence. Patterns of treatment failure were categorized as local/regional or distant. Acute and late toxic effects were prospectively assigned using Common Terminology Criteria for Adverse Events, v3.0. Results Of 64 patients (22 [34%] female; median [range] age, 70 [37-78] years; stage IIIA, 30 [47%]; IIIB, 34 [53%]), 17 (27%) were alive at last follow-up. Median OS was 26.5 months (5-year OS, 29%; 95% CI, 18%-41%). Five-year PFS was 22% (95% CI, 12%-32%); 5-year actuarial distant metastasis and locoregional recurrence were 54% (n = 36) and 28% (n = 22), respectively. Treatment failures were largely (31 [48%] patients) distant, with low rates of crude local (10 [16%]) and regional (9 [14%]) recurrences. Rates of grade 2 and 3 acute esophagitis were 18 (28%) and 5 (8%), respectively. Acute grade 2 pneumonitis occurred in 1 (2%) patient. Late toxic effects were uncommon: 1 (2%) patient developed an esophageal stricture (grade 2) and 1 (2%) grade 4 esophagitis. Late grades 2 and 3 pneumonitis occurred in 10 (16%) and 8 (12%), respectively. Two (3%) patients developed a bronchial stricture (grade 2), and 1 (2%) a grade 4 bronchial fistula. There were no acute or late grade 5 toxic effects. Conclusions and Relevance Concurrent chemotherapy and PBT to treat unresectable NSCLC afford promising clinical outcomes and rates of toxic effects compared with historical photon therapy data. Further optimization of proton therapy, particularly intensity-modulated proton therapy, is still needed.

7-year follow-up after stereotactic ablative radiotherapy for patients with stage I non–small cell lung cancer: Results of a phase 2 clinical trial

The authors evaluated the efficacy, patterns of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for patients with medically inoperable, clinical stage I non–small cell lung cancer (NSCLC) in a prospective clinical trial with 7 years of follow‐up. Clinical staging was performed according to the seventh edition of the American Joint Committee on Cancer TNM staging system.

Long-Term Outcomes of Salvage Stereotactic Ablative Radiotherapy for Isolated Lung Recurrence of Non–Small Cell Lung Cancer: A Phase II Clinical Trial

Objectives: Our goal was to evaluate stereotactic ablative radiotherapy (SABR) as a salvage option for isolated recurrence of NSCLC in the lung parenchyma after definitive treatment of stage I to III disease. Methods: Patients who had histologically confirmed, positron emission tomography–staged, isolated NSCLC recurring locally or metastasis in the lung parenchyma (≤3 cm, suitable for SABR) after previous definitive treatment were prospectively enrolled in this trial and treated with volumetric, image‐guided SABR to 50 Gy in four fractions. Patients were then followed with computed tomography or positron emission tomography/computed tomography. Primary end points included the pattern of failure after salvage SABR, overall survival (OS), and progression‐free survival (PFS). Results: Fifty‐nine patients with recurrent disease were treated with salvage SABR. The median age was 70 years (range 45–86 years), and the median follow‐up time after salvage SABR was 58.3 months. Re‐recurrence after salvage SABR developed in 19 patients (32%). Measuring from the date of salvage SABR, the estimated 5‐year rates of local, regional, and distant failure were 5.2%, 10.3%, and 22.4%, respectively; the estimated PFS was 46.2% at 3 years and 41.1% at 5 years; and the OS rates were 63.5% at 3 years and 56.5% at 5 years. A high post‐SABR neutrophil‐to‐lymphocyte ratio was found to predict poor survival. Grade 3 treatment‐related adverse events developed in three patients (5%). No patient had a grade 4 or 5 event. Conclusion: Our study showed that salvage SABR provides excellent 5‐year OS, local control, and PFS rates with minimal toxicity for patients with isolated NSCLC recurrence in the lung parenchyma. These results are striking and comparable to historically reported outcomes of patients with primary early‐stage NSCLC treated with definitive SABR. SABR appears to be a very effective and safe salvage option for patients with isolated lung parenchyma recurrent disease after definitive treatment and should be considered along with surgery as a potential first‐line option for patients with local lung parenchymal recurrent disease.

Phase I study of celecoxib with concurrent irinotecan, cisplatin, and radiation therapy for patients with unresectable locally advanced non-small cell lung cancer

Purpose: Preclinical findings suggest that adding targeted therapies to combination radiation-chemotherapy can enhance treatment efficacy; however, this approach may enhance normal tissue toxicity. We investigated the maximum tolerated dose, dose-limiting toxicities, and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan, cisplatin, and radiation therapy for patients with inoperable stage II–III non-small cell lung cancer (NSCLC). Methods and Materials: Eighteen patients were analyzed in a phase I clinical dose-escalation trial. Celecoxib was given daily beginning 5 days before radiation followed by maintenance doses for 12 weeks. Toxicity was graded with the Common Terminology Criteria for Adverse Events V3.0 and response with the World Health Organization system. Primary endpoints were maximum tolerated dose of celecoxib and treatment toxicity; secondary endpoints were response and survival rates. Results: The maximum tolerated dose of celecoxib was not reached, in part owing to discontinuation of the drug supply. At doses of 200 or 400 mg/day, no patients experienced any dose-limiting toxicity (acute grade ≥4 esophagitis or pneumonitis, neutropenic fever or thrombocytopenia requiring transfusion, or acute grade ≥3 diarrhea). Grade 3 toxicities were leukopenia (five patients), fatigue (3), pneumonitis (2), dyspnea (1), pain (1), and esophageal stricture (1). Interestingly, pulmonary fibrosis (a late toxicity) was no more severe in the higher-dose (400-mg) group and may have been less common than in the lower-dose group. The clinical response rate was 100% (8 complete, 10 partial). Two-year rates were: overall survival 65%; local-regional control 69%; distant metastasis-free survival 71%; and disease-free survival 64%. Conclusion: Although preliminary, our results suggest that adding celecoxib to concurrent chemoradiation for inoperable NSCLC is safe and can improve outcome without increasing normal tissue toxicity.