Presenter: Joe Chang Presenter's Institution: University of Texas M.D. Anderson Cancer Center
Non-Small Cell Lung Cancer (NSCLC) is a common and deadly disease, and treatment is associated with significant toxicity. Over 200,000 cases are diagnosed per year in the U.S., and over 160,000 deaths occur.
For advanced disease, concurrent chemoradiation with or without surgery is the current standard of care. However, randomized data from RTOG 9410 demonstrated concurrent chemoradiation with conventional photon-based radiation with prescription doses of 60 Gy resulted in less than 60% local control. Additionally, toxicity was significant with 35% of patients developing grade 3 pneumonitis (22%) or esophagitis (13%).
Due to the poor local control with 60 Gy, dose escalation to 69.6 Gy has been attempted with photon-based radiation and demonstrated improved local control; however, the benefits of increased dose resulted in greater than 60% Grade 3 toxicity. Therefore, the improvement in local control must be balanced with increased acute and long-term toxicity.
Recently, at the 2012 ASTRO, preliminary results from RTOG 0617 were presented and demonstrated surprising results that dose escalation with photon-based radiation to 74 Gy had worse outcomes than 60 Gy with concurrent chemotherapy. The median survival was 21 months vs. 20 months in favor of the lower dose. This was thought to be related to increased toxicity of the higher dose.
Over the past several years, MDACC has implemented proton therapy as a means to escalate dose for NSCLC. Proton therapy offers a mechanism of improving conformity while protecting normal structures, including the heart, spinal cord, and contralateral lung. Previous studies have shown that proton therapy reduces normal tissue dose compared with 3DCRT and IMRT in stage III NSCLC patients.
This purpose of this study was to report the results of the Phase II trial evaluating the efficacy and toxicity of dose escalation with proton therapy in patients with Stage III NSCLC treated with concurrent chemotherapy.
Materials and Methods
84 patients with locally advanced Stage III NSCLC were treated with proton therapy with concurrent Carboplatin (AUC 2) and Taxol (50 mg/m2) to 74 GyE in 2 GyE per fraction.
All patients underwent 4D-CT based proton treatment planning with periodic re-simulation for adaptive re-planning.
All patients underwent a PET/CT for disease staging and initial follow up imaging at 2-6 months following completion of therapy. Patients were followed with CT Chest scans every 3 months for 2 years and then every 6 months for 3 years.
All proton plans utilized passively scattered proton beams.
Median follow up was 25.8 months for all patients (Range- 6- 60 months); for patients that remained alive, median follow up was 32 months.
17 patients (20%) had local recurrences within the target volume; 8 patients (9%) had regional nodal recurrence; 39 patients (46%) developed distant metastasis.
Median survival times were 30.9 months, and 40 (47.6%) patients were alive at the time of analysis.
At one year, overall survival was 85.6% and progression-free survival was 50.6%. 2-year rates were 60% and 36%, respectively.
Adaptive re-planning was done in 27% of cases to improve target coverage or avoid organ at risk secondary to tumor regression.
No patients experienced grade 4 or 5 toxicity
32% of patients developed grade 2 esophagitis and 13% developed Grade 3. 10% developed grade 2 pneumonitis and 3.6% developed grade 3.
Although patients who underwent re-planning had larger tumors at diagnosis, there was no observed difference in local control or toxicity in these cases.
With a median follow up of more than 2 years, proton therapy with concurrent chemotherapy for NSCLC appears to produce a local control rate of 80% and a median survival of 30.9 months.
Toxicities seem tolerable and favorable relative to photon-based treatments.
Adaptive planning and motion management are indicated when treating lung cancer.
This study contributes to the growing body of literature supporting the use of proton therapy in locally advanced NSCLC.
The local control rates achieved here are encouraging and certainly appear promising compared to previously published results.
The lack of adverse outcomes and normal tissue toxicity are also promising; additionally, the rate of esophagitis reported in this study was very low. Taken together, the improved local control and decreased toxicity illustrate the potential benefit of dose escalation with proton therapy. In spite of the success of dose escalation to prevent local recurrence, metastasis to distant sites continues to be the more common cause of mortality. As we improve and fine tune local therapy, we also need to consider better treatments to address the problem of distant disease.
More research, specifically prospective randomized phase III controlled trials, are needed to determine the utility of proton therapy in NSCLC.
Jan 12, 2012 - Ganetespib has anticancer activity in KRAS-mutant non-small-cell lung cancer (NSCLC) cells, and works synergistically with other clinical agents to increase cell death; and sorafenib also has clinical activity in patients with KRAS-mutant NSCLC, according to two studies presented at the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy, and Personalized Medicine, held from Jan. 8 to 11 in San Diego.