BY HEATHER WAKELEE, MD
The critical factors I take into account when talking to a patient with resected early stage non-small cell lung cancer are the pathology, the performance status of the patient, and how aggressive the patient wants to be with treatment.
To focus first on the pathology, I look at tumor factors, surgery factors, and lymph nodes. I also verify that adequate preoperative staging was done including a brain MRI in all patients except those with small stage I tumors.
Imaging with either a CT of chest, abdomen, and pelvis or a PET scan is what I prefer to make sure there are no occult metastases. Presumably this has been done preoperatively, though, and doesn’t need to be repeated if that is the case.
Tumor specific factors I think about are the size of the tumor, for determining which patients are more likely to benefit from therapy, and the histology for helping with chemotherapy selection.
In a patient with any lymph node involvement, the size of the tumor becomes secondary, but in patients without lymph node involvement the size of the tumor is a critical factor in my mind for determining the strength of the recommendation for adjuvant chemotherapy. In subset analysis of the JBR.10 and CALGB9633 trials, stage IB patients who had a tumor at least 4 cm in size seemed to benefit from the addition of adjuvant chemotherapy.
Those with smaller tumors did not. Those are subset analyses but consistent and, and it certainly is logical that larger tumors indicate a worse prognosis (and this is reflected in the updated AJCC staging).
I therefore use size to help decide on treatment. I do not use a strict cut-off at 4 cm, but as I talk with patients about the decision on treatment I do keep this number in mind. With the new staging, tumors over 5 cm are now classified as stage IIA.
Adequate Lymph Node Sampling
I look to be sure there has been adequate lymph node sampling. Unfortunately in the United States there are a high number of lobectomies done for lung cancer without adequate lymph node sampling. Though standards have not been defined, most board-certified thoracic surgeons try to sample from representative regions to get a total of at least 10 mediastinal lymph nodes.
I know from screening patients for eligibility for clinical trials of adjuvant therapy that a minimum sampling is often not done, limiting patients’ eligibility for trials and more importantly, inadequately staging them.
The requirement for the ongoing E1505 clinical trial only requires that two nodal stations be sampled (level 7, subcarinal, for all patients) and level 4 for right-sided tumors or level 5 or 6 for left sided tumors. Yet, 15% of enrolled patients and countless others who never get enrolled do not have this minimum level of sampling. Similar trends have been seen in other large adjuvant trials as well, highlighting this significant deficit in proper care of early stage NSCLC patients in the United States.
In patients with N1 nodal involvement, I believe the evidence in favor of adjuvant chemotherapy is fairly convincing. Unless a patient has significant co-morbidities or is not recovering well from surgery by two months postoperatively, I tend to strongly recommend that they proceed with chemotherapy.
Of course some patients when they hear that the absolute survival benefit is on the order of 5-10% decide not to get the three months of chemotherapy, but that becomes a personal decision after a detailed discussion. There is no role for radiation therapy postoperatively in patients with N1 disease unless they have a positive margin.
Patients with N2 disease will hopefully have had that known prior to undergoing surgical resection and will already be on a multidisciplinary plan. However, for those patients discovered at the time of surgery to have N2 nodal disease, I strongly recommend adjuvant chemotherapy because we know that the likelihood of recurrence is far higher than 50%.
The role of radiation therapy here is far more controversial. In general I do not recommend postoperative radiation therapy for patients with minimal N2 involvement as there is no definitive evidence of its benefit, but for patients with more extensive disease there is certainly database analyses and subset analyses from some of the adjuvant trials like ANITA to support this approach.
The ongoing LungART trial in Europe is enrolling patients currently to try to prospectively answer the question of the role of postoperative radiation in patients with resected N2 disease. A full discussion at a multidisciplinary thoracic tumor board is definitely warranted for these patients.
Taking all these factors into account I talk to the patient about how aggressive they want to be. We know that age is one factor that can play a role in these decisions, but I don’t have a strict age cut-off for offering adjuvant therapy.
Once the decision is made to proceed with chemotherapy, the next decision is on which chemotherapy drugs to offer. The positive trials have all used a cisplatin-based regimen, and that is my choice as well. I will only use carboplatin as a substitute in patients who absolutely cannot tolerate cisplatin and tell patients that with the substitution we are losing some efficacy, although the magnitude of that is hard to measure.
Most of the positive adjuvant trials used vinorelbine as the doublet combination. However, unlike with the cisplatin/carboplatin substitution, I am more comfortable with using other agents instead of vinorelbine based on data from metastatic NSCLC.
In the metastatic setting there have been randomized trials showing superiority of cisplatin/docetaxel to cisplatin/vinorelbine and other trials showing equivalency of other platinum doublets.
There is an adjuvant trial showing intolerability of cisplatin/docetaxel, but it was a small single-institution study and we know the regimen is being used on the E1505 trial. A small, randomized phase II study of cisplatin/vinorelbine versus cisplatin/pemetrexed was presented at ASCO 2011 showing better drug delivery and tolerability with the cisplatin/pemetrexed regimen, but no efficacy data was presented.
I personally use cisplatin/pemetrexed in my patients with non-squamous histology and cisplatin/gemcitabine in patients with squamous histology for four cycles (three-week cycles) as adjuvant therapy.
Of course, whenever possible, I do advise patients to go on clinical trials for adjuvant therapy. The current treatment options of four cycles of a cisplatin doublet offer only a 5-10% absolute survival benefit. We need to do better than this for our patients.
The Southwest Oncology Group and several groups in Europe have open trials looking at some of the predictors of chemotherapy benefit to help guide the choice of chemotherapy. These include ERCC1 for platinum, RRM1 for gemcitabine, TS for pemetrexed and EGFR mutation status for erlotinib/gefitinib.
I personally do not use any of those now to guide my choice of treatment, but I eagerly await the results of the ongoing prospective trials.
The use of EGFR TKI drugs in those with EGFR mutations is another consideration that comes up. There are ongoing trials focused on this patient population and the RADIANT trial of adjuvant erlotinib has completed accrual and did look for EGFR mutations in enrolled patients for a subset analysis.
The results of JBR.19, looking at adjuvant gefitinib, suggest caution for this approach outside of a clinical trial, though. That study was closed early, with short-term therapy for enrolled patients, but in that trial the gefitinib did not appear to be beneficial as adjuvant therapy, even in those with EGFR mutations. I do not give adjuvant erlotinib outside of a clinical trial.
There are two ongoing large phase III adjuvant trials in the United States currently. The MAGRIT study is open for patients with the MAGE-A3 tumor antigen (predominantly squamous cell histology) and randomizes them to the vaccine over a two-year period versus placebo. The other trial is ECOG E1505, which in a randomized fashion, adds bevacizumab to the standard four cycles of adjuvant cisplatin-based chemotherapy.
So, in summary, I offer adjuvant chemotherapy to all patients with stage IB-IIIA NSCLC who have had a resection. I tend not to offer it to those with smaller IB tumors < 4 cm in size, but have been swayed but more aggressive looking histology and by patients who will be very nervous that they have been undertreated.
I usually use cisplatin/pemetrexed for non-squamous and cisplatin/gemcitabine for squamous histology tumors. I strongly encourage enrollment on clinical trials whenever possible and hope we as a nation can improve the degree of lymph node sampling done during lung cancer resections.
HEATHER WAKELEE, MD, is Assistant Professor of Medicine, Oncology, at Stanford University, Stanford Clinical Cancer Center.