We demonstrate the feasibility and safety of combining dose-dense (q2-week) pemetrexed and systemic dose carboplatin (AUC = 6) with radiotherapy for NSCLC. All patients were able to receive both doses of carboplatin and at least three (out of four) doses of pemetrexed with concurrent radiation. All but one patient was able to complete radiotherapy. The main toxicity observed in this study was myelosuppression, primarily manifesting as neutropenia.
Toxicity was decreased by amending the study to mandate the use of smaller (involved-field) radiotherapy treatment plans. We found that 2 of the first 6 patients enrolled in our study suffered non-hematologic DLT's when treated with comprehensive mediastinal irradiation. After changing the radiotherapy planning portion of our study, non-hematologic DLT's occurred in 1 of 8 patients. This patient was an 83 year-old man with severe COPD who died from respiratory decompensation following completion of chemoradiotherapy. We conservatively report this as a DLT although intercurrent disease played a significant role.
When the study was originally designed (in 2005), standard RT consisted of comprehensive mediastinal irradiation to 45-50 Gy followed by a boost to gross tumor to 60-64 Gy, as used in the Radiation Therapy Oncology Group (RTOG) clinical trials [2, 23, 24]. More recently, data show that outcomes (local control and survival) are not compromised by using involved-field radiotherapy from the start of treatment, and reduced treatment volume may allow the delivery of higher radiotherapy dose [25, 26].
In contrast to previous chemoradiation regimens containing reduced radiosensitizing doses of carboplatin and paclitaxel, this study investigated the used of systemic doses of carboplatin (AUC = 6), which has independent activity in NSCLC. The dose dense pemetrexed at 300 mg/m2 also approaches systemic dose of pemetrexed. Although our study was not powered for assessment of anti-tumor efficacy, the results of our survival data are very promising with a median survival time of 28.6 months in all patients, and estimated 34.7 months in stage III patients.
We note that almost all evaluable patients had a clinical local response and at least short term in-field local control of their cancer. Although pathologic assessment of local disease was not performed in our study, our data do support the hypothesis that dose-dense carboplatin/pemetrexed is an effective radiosensitization regimen for definitive therapy of locally advanced non-operative NSCLC.
Despite excellent in field control, progression of disease outside the radiation treatment fields remains exceedingly common. Our study included four patients with oligometastatic diease, and each of these patients quickly progressed systemically with a median survival of only 6 months. Three additional patients developed metastatic disease as the first site of recurrence, and two patients recurred locoregionally outside the treatment field. We hypothesize that this reflects chemoresistance in micrometastatic deposits outside of the radiotherapy fields. With improving local control, the ability to control micrometastatic disease has increasing importance in improving overall survival. It is possible that higher dose intensity of platinum, pemetrexed and/or addition of a third cytotoxic drug could be more effective, although at a cost of higher toxicity.
A recent study by Cullen et al. failed to show an advantage to increased dose intensity of pemetrexed in advanced/metastatic (platinum-refractory) NSCLC. This study compared 500 mg/m2 q3week versus 900 mg/m2 q3week. It is unclear whether dose intensification of pemetrexed using a q2week schedule, or in a less heavily pre-treated population such as ours, might yield different results.
Another strategy might be to add a biologic agent such as a vascular targeting drug or an anti-EGFR agent to our regimen. The Cancer and Leukemia Group B (CALGB) study #30407 investigated in a prospective phase II randomized trial combining carboplatin/radiotherapy and pemetrexed (standard 500 mg/m2 q3-week schedule) with or without cetuximab. Presented in abstract form at the 2009 ASCO national meeting, the carboplatin/pemetrexed/RT arm had a promising median survival time of 22.3 months, but the addition of cetuximab did not result in improved survival with a median survival time of 18.7 months .
A complementary strategy may be more careful selection of semi-customized treatments. Randomized studies of single agent pemetrexed in second line chemotherapy treatment of NSCLC and of platinum/pemetrexed in first line treatment of advanced NSCLC demonstrated an improved survival in patients with non-squamous NSCLC, and a worse outcome in patients with squamous histology [16, 17]. This difference may be related to increased expression of thymidylate synthase (TS) in squamous cancers or other proteins relevant to the target of pemetrexed. Our study did not collect tissue to perform this analysis, but evaluation of TS will be important to future studies of pemetrexed and radiation in NSCLC.