Pemetrexed and cisplatin with concurrent radiotherapy for locally advanced non-small cell and limited disease small cell lung cancer: Results from 2 phase I studies
Introduction
Lung cancer is the leading cause of cancer-related death in the United States and Europe for both men and women. Non-small cell lung cancer (NSCLC) accounts for 87% of all lung cancer cases. One third of them presents with locally advanced disease, of which the majority is unresectable. Concomitant chemo-radiotherapy improves survival of patients with locally advanced NSCLC by 5.7% at 3 years compared to sequential chemo-radiotherapy, but at the cost of increased acute esophageal toxicity [1]. The 70% relapse, occurring approximately one third locally, one third distantly and one third both locally and distantly [2], [3], [4], [5], [6], [7], is a major drawback. A major challenge today is to reduce this high relapse rate by identifying the optimal radiation dose in combination with the most effective systemic therapy. So far, neither the best drug combination nor the optimum radiation dose has been defined. Therefore, new chemo-radiotherapy combinations are needed.
In LD-SCLC, sequential chemo-radiotherapy has improved 5-year survival rates by 5% compared to radiotherapy alone [8], [9] and has been further improved by the combination of early thoracic radiotherapy (TRT) and concurrent chemotherapy [10], [11], [12], [13]. Like in NSCLC, major challenge is to reduce the high relapse rate and to improve survival. Therefore, also for LS-SCLC new chemo-radiotherapy combinations are needed.
Pemetrexed is a multitargeted antifolate which has activity in a wide range of cancers. It has been approved by the U.S. Food and Drug Administration for single-agent second-line therapy in metastatic NSCLC [14], [15], [16] and for first-line treatment in malignant pleural mesothelioma in combination with cisplatin [17] and recently in first-line metastatic NSCLC in combination with cisplatin for non-squamous histology [18].
In preclinical studies, the combination of pemetrexed with radiotherapy appeared to be synergistic [19]. Vokes et al. was the first to demonstrate in a phase I study in patients with locally advanced NSCLC or esophagus cancer that the combination of pemetrexed (500 mg/m2) and carboplatin (area under the curve 5 or 6) with concurrent radiation was well tolerated and active [20]. However, in patients with NSCLC, cisplatin-based regimens are superior to carboplatin-based regimens in terms of response rate and, in certain subgroups (patients treated with third-generation platinum-based regimens and patients with non-squamous histology) in prolonging survival [21]. Cisplatin is also a potent radiosensitizer, while the radiosensitizing properties of carboplatin are not as well established. Therefore, we decided to investigate the combination of pemetrexed and cisplatin with concurrent TRT in patients with LS-SCLC and stage III NSCLC in two separate studies. Primary objective of these studies was to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent TRT. Secondary objectives were acute and late toxicity, objective tumor response and overall survival.
Section snippets
Patients and methods
Study I was approved by the Ethical Committee of the Erasmus University Hospital Rotterdam, study II by the Ethical Committee Vrije Universiteit Amsterdam.
Results
Study I was prematurely terminated because of poor accrual and study II because of the inferior activity of pemetrexed in SCLC [24].
In study I, between April 2006 and January 2008, 3 males and 1 female were enrolled. Median age was 59 years (range 54–64); 3 had ECOG performance status (PS) 1, 1 PS 0; 3 had stage IIIA, 1 stage IIIB; 1 squamous cell carcinoma, 1 adenocarcinoma and 2 undifferentiated carcinomas were diagnosed.
In study II, between March 2007 and December 2007, 6 males and 3 females
Discussion
Because these two phase I trials were terminated prematurely and prior to the occurrence of DLT's, we are unable to establish the MTD of cisplatin and pemetrexed with concurrent radiotherapy in locally advanced NSCLC and LS-SCLC. However, these two studies provide additional data on the toxicity of this new combination and are important for future trials.
From our data we may conclude that systemic doses of pemetrexed and cisplatin up to 500 and 75 mg/m2, respectively, can safely be combined with
References (29)
- et al.
Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients
Ann Oncol
(2006) - et al.
Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non-small-cell lung carcinoma: analysis of the radiation therapy oncology group (RTOG) experience
Int J Radiat Oncol Biol Phys
(2005) - et al.
The long-term results of a pilot study of three times a day radiotherapy and escalating doses of daily cisplatin for locally advanced non-small cell lung cancer
Int J Radiat Oncol Biol Phys
(2005) - et al.
Current standards and ongoing controversies in the management of locally advanced non-small cell lung cancer
Semin Oncol
(2005) - et al.
Phase II study of radiotherapy with three-dimensional conformal boost concurrent with paclitaxel and cisplatin for stage IIIB non-small-cell lung cancer
Int J Radiat Oncol Biol Phys
(2005) - et al.
Induction chemotherapy and radiotherapy in locally advanced non-small cell lung cancer
Hematol Oncol Clin North Am
(2004) Limited-disease small-cell lung cancer research: sense and nonsense
Int J Radiat Oncol Biol Phys
(2004)- et al.
Interaction of pemetrexed (Alimta, multi-targeted antifolate) and irradiation in vitro
Int J Radiat Oncol Biol Phys
(2002) - et al.
Pemetrexed in second line and beyond small cell lung cancer: a Hoosier Oncology Group phase II study
Thorac Oncol
(2009) - et al.
Randomized trials of radiotherapy alone versus combined chemotherapy and radiotherapy in stages IIIa and IIIb non-small cell lung cancer. A meta-analysis
Cancer
(1995)
Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis
J Clin Oncol
A meta-analysis of thoracic radiotherapy for small-cell lung cancer
N Engl J Med
Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104
J Clin Oncol
Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide
N Engl J Med
Cited by (17)
Concurrent pemetrexed and radiation therapy in the treatment of patients with inoperable stage III non-small cell lung cancer: A systematic review of completed and ongoing studies
2015, Lung CancerCitation Excerpt :Two trials evaluated single-agent pemetrexed plus RT without consolidation [39,40]. Eight studies evaluated chemoradiation with pemetrexed–cisplatin [14–16,41–44], and three studies evaluated chemoradiation with pemetrexed–carboplatin [39,45]. One study evaluated both pemetrexed–carboplatin and pemetrexed–cisplatin, each in a separate arm of the study [38].
Phase 2 study of pemetrexed plus carboplatin, or pemetrexed plus cisplatin with concurrent radiation therapy followed by pemetrexed consolidation in patients with favorable-prognosis inoperable stage IIIA/B non-small-cell lung cancer
2013, Journal of Thoracic OncologyCitation Excerpt :Here, we report the results of a randomized phase II trial studying pemetrexed in combination with carboplatin or cisplatin and RT followed by pemetrexed consolidation. Pemetrexed has radiosensitizing activity in vitro and in xenografts, and it has been well tolerated when combined with platinum in patients with NSCLC.6–17 In this trial, the 2-year OS rates were 45.4% and 58.4% with PCb and PC, respectively.
Phase I study of concurrent chemoradiation with pemetrexed and cisplatin followed by consolidation pemetrexed for patients with unresectable stage III non-small cell lung cancer
2011, Lung CancerCitation Excerpt :Cisplatin at full dose is currently used concurrently with radiotherapy in small cell lung cancer, head and neck cancer and esophageal cancer. As suggested by recently published phase I trials [13–15], pemetrexed may represent the only third-generation agent to be safely administered at full dose in conjunction with cisplatin and radiotherapy, thus avoiding compromise on activity against distant disease while optimizing local control. We designed a phase I study to investigate the feasibility of 3 cycles of the combination of pemetrexed plus cisplatin at systemic doses concomitant with 66 Gy of thoracic radiotherapy in 33 fractions without the dose limiting toxicity (DLT) exceeding 33% of the patients.