Updates in the Management of Early-stage Non-Small Cell Lung Cancer: Highlights from the 12th World Conference on Lung Cancer
Non–small cell lung cancer (NSCLC) accounts for about 87% of all cases of lung cancer diagnosed in the United States. Approximately 40% of NSCLC patients have Stage IIIB or IV disease at diagnosis. At the 12th World Conference on Lung Cancer, there were a large number of presentations on prognostic factors, staging, neoadjuvant therapy, treatment of patients with poor performance status, targeted therapies, and vaccine therapy strategies. We have attempted to put these in perspective with the present “standard of care.”
Researchers from Irvine, California, presented the analysis of the California Cancer Registry data on prognostic factors for survival of patients with Stage I NSCLC. These authors reported that advanced age, male sex, low socioeconomic status, non–surgical treatment, and poorly differentiated histology were associated with increased mortality on multivariate analyses. Among all Stage I patients, poorly differentiated histology was associated with worse outcome. For patients with Stage IB disease, the location outside the upper lobe and increased tumor size (≥ 4cm) were also associated with worse outcome. Bronchioloalveolar histology and patients of Asian ethnicity had the best overall outcome. Observations like these require further validation in prospective trials.
Researchers from France reported survival data and predictive factors associated with survival post-tri-modality treatment for patients with Stage IIB/III NSCLC.This study included 107 patients who received neoadjuvant radiotherapy and concurrent chemotherapy followed by reassessment for suitability for surgery. Seventy-two patients had a thoracotomy performed and all but five had a surgical procedure including pneumonectomy or (bi)lobectomy. The perioperative mortality rate was 7%, with four of the five deaths occurring post pneumonectomy. The pathologic complete response (CR), including those with microscopic residual disease, was observed in 40% of patients with a mediastinal sterilization rate of 61%. The two- and three-year survival rates were 55% and 40%, respectively. For the 71 resected patients, the two- and three-year survival rates were 62% and 51%. In this small study, surgical resection or tumor necrosis greater than 50% in the resected specimen was associated with improved survival. These authors concluded that surgery was feasible after neoadjuvant chemo-radiotherapy but that pneumonectomy should be avoided after chemoradiotherapy because it carries a high treatment-related mortality.
In inoperable Stage IIIA or IIIB NSCLC, researchers from an international Phase II trial reported outcomes of 54 patients utilizing the non-surgical approach of concomitant chemo-radiotherapy post-neoadjuvant or induction chemotherapy. The induction chemotherapy consisted of oral vinorelbine and cisplatin followed by the same agents administered with thoracic radiotherapy. The overall response rate was 54%; median progression free survival (PFS) was 12.5 months; median overall survival (OS) was 23.4 months. Treatment was well-tolerated and allowed completion of definitive planned radiotherapy in 94% of patients. Thus, this appears to be a reasonable alternative for the treatment of patients with inoperable Stage III NSCLC.
The Swedish group evaluated three methods for increasing loco-regional control in patients with Stage IIIA or IIIB NSCLC. All patients in this study received two cycles of induction chemotherapy with paclitaxel and carboplatin.
- Arm A received a third cycle of paclitaxel and carboplatin concomitant with accelerated radiotherapy to 64.6 Gy over 4.5 weeks.
- Arm B received daily paclitaxel 12mg/m2 with conventional daily radiotherapy to 60 Gy over 6 weeks.
- Arm C received weekly concomitant paclitaxel 60mg/m2 and conventional daily radiotherapy to 60 Gy.
These authors reported that median time to progression was 8.9, 10.3, and 9.1 months for arms A, B, and C, respectively. Median survival was 17.7, 17.8, and 20.6 months, and two-year survivals were 41%, 43%, and 45% for arms A, B, and C, respectively. Though the treatment results of all three arms were similar, intensification with accelerated radiotherapy does not offer improvement in loco-regional control.
Targeted Therapies for NSCLC
Lung cancer, a disease with wide molecular heterogeneity, lends itself to treatment with a variety of molecularly targeted agents. Inhibitors of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are already in routine clinical use. Several new molecular targets have been identified and are the subject of ongoing clinical trials. The agents currently being studied include bevacizumab, gefitinib, erlotinib, sorafenib, and sunitinib. One of the major research issues concerning targeted therapy is predicting responses or identifying patients who are unlikely to respond. In an educational session, Dr. Ramalingam from Emory University presented an overview of targeted therapy for NSCLC. He spoke about the role of targets and targeted agents beyond EGFR and VEGF such as proteosome inhibition, inhibitors of mammalian target for rapamycin, and histone deacetylase (HDAC) inhibitors.
The HDAC inhibitors act by modulating both histone and non–histone targets. A number of non–histone proteins such as heat shock protein 90, HIF-1 alpha, and tubulin are acetylated by HDAC inhibitors. Our group has recently demonstrated promising anticancer activity when vorinostat, a HDAC inhibitor, was given in combination with carboplatin and paclitaxel to patients with advanced NSCLC. Based on this observation, randomized clinical trials are underway to evaluate whether vorinostat enhances the efficacy of standard chemotherapy in patients with advanced-stage NSCLC. The results from these ongoing studies are eagerly awaited and have the potential to usher in a new treatment paradigm for NSCLC.
Inhibition of the proteosomal degradation pathway has a therapeutic effect in a variety of malignancies. Bortezomib, a proteosome inhibitor, is active as a single agent in NSCLC and also appears to enhance the efficacy of chemotherapy. A recent study has demonstrated promising efficacy for bortezomib in patients with advanced bronchioloalveolar carcinoma, a histological sub-entity that is generally not responsive to chemotherapy.
Another molecular pathway that has a strong therapeutic potential is the Akt-mTOR pathway, which serves as a downstream event for a number of growth factor receptor-mediated cell-signaling. Phase II studies in NSCLC have demonstrated single-agent activity for temsirolimus and everolimus (mTOR inhibitors). These agents are now being evaluated in combination with other molecularly-targeted agents.
Because several of these targeted agents have activity in selected patients with advanced NSCLC, there is interest in applying these therapies to patients with early-stage disease.
Researchers from the Netherlands reported the outcome of a patient with early-stage NSCLC who had received three weeks of treatment with erlotinib in the neoadjuvant setting for Stage I NSCLC. There was no clinical response to erlotinib, but the surgical specimen showed fibrotic degeneration of the original tumor with less than 10% viable tumor cells. Though anecdotal, the observation is hypothesis-generating and requires validation in a prospective study. It would also be useful to select patients based on either clinical features, EGFR mutation, or gene amplification (copy number) when utilizing targeted agents such as erlotinib in this setting.
Researchers from Memorial Sloan-Kettering Cancer Center reported 14-day regression data on 13 patients with non–squamous Stage IB, IIB, and III NSCLC receiving bevacizumab in a neoadjuvant regimen. Patients received a single dose of bevacizumab and had a second CT on day 14. The average tumor regression at 14 days was 13%. These patients then received three cycles of bevacizumab with docetaxel and cisplatin. The partial response (PR) rate was observed in six of ten patients who underwent surgery post neoadjuvant therapy. Resections were R0 in six patients. Single-dose bevacizumab results in a measurable response in patients with non–squamous NSCLC. Thus, early evidence of measurable shrinkage may prove as a predictive marker of benefit.
Elderly and Poor Performance Status Patients
Researchers from Memorial Sloan-Kettering Cancer Center reported that fewer advanced-age patients end up receiving adjuvant therapy for NSCLC post surgical resection for Stages IB-III NSCLC. These authors reviewed the details of treating 389 patients with resected Stage IB-III NSCLC. The median age of this group of patients was 69 years. Only 33% of patients in this analysis received adjuvant chemotherapy. The main predictors for not receiving adjuvant chemotherapy were advancing age and presence of Stage IB disease. There was no association of chemotherapy administration in this setting with presence of significant co-morbidities. It is unclear whether these patients were not offered chemotherapy by their physicians or were reluctant to accept the same therapeutic options as younger patients.
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Dr. Vansteenkiste from Belgium reported the results of an international study evaluating the activity of melanoma-associated antigen-A3 (MAGE-A3) vaccination in patients with Stage IB/II NSCLC. The MAGE-A3 vaccine is directed at the MAGE-A3 gene, which is expressed specifically in tumor cells and not in normal cells. The vaccine consisted of MAGE-A3 recombinant protein administered with a proprietary GSK adjuvant. The MAGE-A3 antigen is expressed in approximately one third of patients with NSCLC; all patients in this study had tumors that expressed the MAGE-A3 antigen. This study included 182 patients from 59 centers in 14 European countries who had Stage IB or II NSCLC. Sixty-five percent of these patients had undergone radical mediastinal lymphadenectomy. Patients received MAGE-A3 adjuvant vaccine or placebo after completion of all other therapy. The median follow-up was 28 months. They reported a 37% improvement in disease-free survival in completely resected Stage IB-II patients. Overall the treatment was well tolerated. A Phase III study has been instituted to further validate these provocative data.
The Canadian and British investigators have previously reported an improved survival of patients with Stage IIIB NSCLC with vaccination to MUC1 protein with L-BLP25 vaccine. This study showed a possible survival advantage for patients with Stage IIIB but not Stage IV disease. It was also reported that patients in the vaccine group had a better quality of life.
The current analysis on a longer term follow-up shows a greater magnitude of benefit with the vaccine in the Stage IIIB subset. Sixty-five of the 171 patients in the trial had Stage IIIB disease. Of these 65 patients, 35 were allocated to vaccine treatment and 30 to best supportive care. Median survival was 30.6 months for the vaccine group and 13.3 months for the best supportive care group. The only way that maintenance L-BLP25 vaccine can become “standard of care” is if these results are confirmed in the ongoing randomized Phase III study.
Table 1: One-, two-, and three-year survival in Stage IIIB NSCLC patients treated with L-BLP25 vaccine versus best supportive care
Chemotherapy is of benefit for all stages of lung cancer except for those who present with Stage IA disease. Parallel to the development of targeted agents, which have started to show a great deal of promise, studies are also being conducted to evaluate appropriate patient selection methods to individualize therapy. Thus, the increasing number of targeted agents and evolving patient selection methods will provide great hope for improving the outcome of patients with NSCLC in the near future.
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