The management of patients with locally advanced non-small-cell lung cancer (LA-NSCLC) remains a therapeutic challenge.
In fit patients with minimal weight loss (i.e., under 5% to 10% from baseline) and intact PS (ECOG PS 0-1), I favor concurrent chemoradiation with a platinum-based combination. In the absence of significant comorbidity, hearing loss, or renal compromise, in patients who can readily tolerate an acute fluid load, I will generally use the etoposide-cisplatin combination.
Unlike limited small-cell lung cancer, where we dose cisplatin at 60 mg/m2 every three weeks and etoposide at 80 to 120 mg/m2 daily x 3 both during and after radiation, I favor the Albain or RTOG 9309 schedule: cisplatin 50 mg/m2 days 1 and 8, 29, and 36; and etoposide 50 mg/m2 IV days 1-5 and 29-33.
This schedule, while inconvenient, is tried and tested, and usually safe. We dose simultaneous RT to a minimum of 60 Gy in 2 Gy fractions daily over six weeks, though we will often end up administering doses as high as 66 or 72 Gy over a longer time period.
I have often challenged my radiation oncology colleagues to show me data proving that 66 Gy or more is superior to 60 Gy. None exists, although this question is being formally tested in the ongoing Phase III trial (RTOG 0617) comparing 74 Gy to 60 Gy with the use of 3D conformal technology in combination with concurrent chemotherapy.
Radiation in that trial is being given concurrently with chemotherapy with both modalities begun simultaneously on day 1. This is the strategy I prefer.
Frailer or Older Patients
In frailer patients, or older patients, and in those with significant comorbidity including renal insufficiency (creatinines of 1.5 to 3.0), hearing loss, congestive heart failure, or severe COPD, I will eschew cisplatin in favor of carboplatin and substitute paclitaxel for etoposide.
In such individuals, I use a regimen originally pioneered by Belani and Choy: carboplatin AUC 2 weekly and paclitaxel 50 mg/m2 weekly, both initiated day 1 of thoracic radiation, followed by two cycles of full-dose chemotherapy once radiation is completed.
Conventionally, we administer carboplatin AUC 6 and paclitaxel 200 mg/m2 q 3 weeks for two cycles during the “consolidative” phase, the same regimen employed in the RTOG 0617 study.
Often, however, particularly in older patients or those with underlying neuropathy, I will substitute a regimen piloted by Belani and recently validated by Quoix and colleagues at the 2010 ASCO meeting. In a Phase III elderly-specific trial in patients with advanced, incurable NSCLC, carboplatin AUC 6 every 4 weeks in combination with paclitaxel 90-100 mg/m2 days 1, 8 ,and 15 every 4 weeks was shown unequivocally to be superior to single-agent gemcitabine or vinorelbine with respect to response rates, and progression-free and overall survival, so it seems reasonable to export this regimen to the LA-NSCLC setting post-radiation therapy for two cycles, where it might arguably enhance cure rates.
Many have argued that carboplatin-based therapy is inferior to cisplatin in the treatment of LA-NSCLC. But I disagree.
Recent data from Japan in a combined modality trial (West Japan Oncology Group Trial [WJTOG 0105]) evaluating various concurrent chemoradiation regimens underscores this notion. Investigators led by Nobuyuki Yamamoto compared their erstwhile standard of MVP with weekly carboplatin in combination with either irinotecan or paclitaxel during XRT; in each arm, those without disease progression or untoward toxicity, went on to receive two cycles of full-dose chemotherapy during the “consolidation” period using the same agents administered during XRT.
The paclitaxel-carboplatin regimen resulted in less toxicity, fewer dose reductions or omissions, and equivalent, if not superior, survival at five years: 19.5% vs 17.5% for MVP and 17.8% for irinotecan/carboplatin.
In fairness, this study also compared second-generation with third-generation chemotherapy; but, to the best of my knowledge, this is the only Phase III trial to attempt to address the platinum question, which, to be frank, arises constantly.
An ongoing randomized Phase III trial in the context of chemoradiation is comparing pemetrexed-cisplatin (another third-generation regimen) followed by single-agent pemetrexed during the consolidation period with etoposide-cisplatin followed by investigator’s choice during the consolidation period.
I endorse this industry-sponsored trial, but do not typically use pemetrexed outside of a trial situation.
At the behest of the radiation oncologists, in patients with high baseline V20s (percentage of normal lung that will receive more than 20 Gy) exceeding 35% or in those with borderline pulmonary function, I will often administer chemotherapy first for two or even three cycles, then follow with concurrent chemoradiation if there has been sufficient tumor shrinkage to allow a more reasonable radiation therapy treatment field.
In those with minimal or no tumor shrinkage using this approach, we will frequently omit concurrent chemotherapy during XRT to avoid untoward toxicity and proceed with XRT alone.
These patients are often much more symptomatic than those with smaller-volume tumors, and often have compromised PS.
Toxicity mitigation is another major challenge, which we as investigators have inadequately addressed. Both acute esophagitis and long-term pneumonitis and pulmonary fibrosis are common complications of combined-modality therapy.
A recent meta-analysis by Auperin et al demonstrated a six-fold increase in short-term esophagitis, grade 3 or worse (18% vs 3%) in those receiving concurrent chemoradiation as opposed to asynchronous or sequential chemotherapy and radiation.
A Phase III study evaluating amifostine as an esophageal protectant failed to show a significant reduction in esophagitis rates, as determined by objective measures, compared with a control arm that did not feature this agent; however, a subsequent analysis based on patient reported outcomes suggested a modest benefit with reduction in pain.
There is continued interest in looking at mucosal protectants, including palifermin and other agents; but to date, no prospective randomized Phase III trial has demonstrated a palliative benefit. Our approach, unfortunately, has generally been reactive, rather than pre-emptive.
Newer radiation technologies including proton beam may help to reduce the severity and duration of acute and late effects, both esophageal and pulmonary. This is currently under investigation. Outside of a clinical trial, I do not typically institute amifostine or other putative agents to diminish in-field toxicity.
As for targeted agents, there are no data as yet to support the empiric use of epidermal growth factor (EGF) tyrosine kinase inhibitors, EGF receptor (EGFR) monoclonal antibodies, or angiogenesis inhibitors either during or after chemoradiation.
The RTOG spearheaded a Phase II study evaluating cetuximab in combination with standard thoracic radiation therapy and weekly paclitaxel/carboplatin, and demonstrated both feasibility as well as promising median survival approaching two years.
The same trial comparing higher-dose XRT (74 Gy) with standard dose (60 Gy) has now been amended to address the role of cetuximab in a 2-by-2 design.
If the practitioner has access to this trial and the patient is in reasonably good shape, I enthusiastically endorse the patient’s enrollment on this protocol.
Consolidative Chemotherapy Remains Highly Controversial
Consolidative chemotherapy remains highly controversial. A SWOG trial using the VP/XRT regimen as a platform investigated the role of consolidation docetaxel in stage IIIB patients and yielded a five-year survival rate of nearly 30%--virtually unprecedented in the realm of LA-NSCLC.
However, in a Phase III randomized Hoosier Oncology Group trial, docetaxel consolidation failed to yield a survival advantage compared with standard “observation” in patients who had completed concurrent chemoradiation with etoposide and cisplatin -- in part because the reference arm “out-performed” its historic controls.
This was very disappointing, but it should be noted that there was a borderline significant imbalance in baseline pulmonary function, favoring the control arm: nearly 60% of patients on the arm featuring no consolidation had an FEV1 of 2 liters or greater, compared with just over 40% in the investigational arm.
Similarly empiric use of gefitinib as maintenance therapy in a SWOG trial led to a paradoxical survival decrement compared with placebo after completion of docetaxel consolidation.
In patients who have already received systemically dosed chemotherapy during thoracic XRT, I will usually omit consolidation. But in those who receive a radiosensitizing schedule of chemotherapy during XRT, I will administer at least two cycles of full-dose chemotherapy “out back” after chemoradiation is completed.
Personally, despite the disappointments of docetaxel and empiric gefitinib in this setting, I think the benefits of consolidation remain an open question.
In this context, I have enrolled patients on the START trial evaluating MUCC1 vaccine and would be open to any study evaluating a relatively non-toxic approach geared to this type of patient.
Prophylactic Cranial Irradiation (PCI)
Finally, there is no role (yet) for PCI. This is not a trivial issue since the rate of CNS first-site relapse approaches 20% to 30% in some studies.
Often, it is the only site of relapse, suggesting that the brain is a frequent sanctuary site for metastases. The RTOG addressed this issue in a Phase III randomized, study comparing PCI with observation in patients who had received combined-modality therapy for LA-NSCLC, but this study was terminated early due to insufficiently rapid accrual.
Although the rate of CNS relapse was lowered significantly, this observation did not translate into a survival benefit. Whether newer systemic agents can achieve better CNS penetrance and thus reduce the incidence of brain metastases remains an open question
Finally, in terms of follow-up, I will usually alternate dedicated CT imaging with PET/CT to rule out new second primaries and to facilitate evaluation.
I generally see these patients every three months. After two years, in the absence of obvious clinical recurrence, I will generally see patients every six months for the next three years, and then at yearly intervals, indefinitely.
COREY J. LANGER, MD, is Director of Thoracic Oncology at Abramson Cancer Center and Professor of Medicine at the University of Pennsylvania.