NEW YORK (Reuters Health) - Occult micrometastases, present in 14% of patients, do not fully explain the poor survival rates in stage I non-small-cell lung cancer (NSCLC), according to results from the Cancer and Leukemia Group B (CALGB 9761) study.
"Occult involvement of regional nodes may be one facet of this problem, but we have yet to fully understand why there is so much heterogeneity in outcomes of stage I lung cancer," Dr. Linda W. Martin, from the University of Maryland Medical School, Baltimore, told Reuters Health by email. "Our goal should be to develop tools to better define the early stage NSCLC patients who will be adequately treated with surgery alone, and those who are at increased risk for recurrence, so that we can adjust our treatment strategy accordingly."
Dr. Martin and colleagues in CALGB 9761 chose carcinoembryonic antigen (CEA) as a marker for quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) to see if it was useful in identifying and quantifying metastases in patients with NSCLC.
Out of 298 patients studied with immunohistochemistry (IHC) for cytokeratin, 14% were positive for occult micrometastases. Overall and disease-free survival did not differ between IHC-positive and IHC-negative patients. In subgroup analysis, patients with N2 IHC-positive disease had lower five-year survival (50%) than those with N2 IHC-negative disease, but there was no difference in survival in patients with N1 IHC-positive and -negative disease.
RT-PCR for CEA, on the other hand, was positive for occult micrometastases in 68.8% of patients, but there was no significant relationship between PCR status and overall or disease-free survival in patients with N1 or N2 disease, according to the February 29 Journal of Clinical Oncology online report.
"We had hoped that quantitative RT-PCR would be a reliable way to find occult metastases in an objective manner; unfortunately our results were not reliable and we had to revert to qualitative (yes/no) for RT-PCR and even with that, there was a rather high rate of positivity (nearly 70%) for RT-PCR for CEA mRNA in nodes that were declared negative by standard H & E (hematoxylin and eosin) pathological evaluation," Dr. Martin said. "But this had no correlation with disease-free or overall survival. It suggests that this is either much too sensitive or simply not clinically useful for NSCLC; perhaps CEA is not the marker we should be evaluating for non-small-cell lung cancer."
"It is difficult to take these results to the next step and say these occult positive patients should get adjuvant chemotherapy," Dr. Martin said. "We do not know if microscopic, occult involvement of N2 behaves the same clinically as N2-positive nodes identified by standard pathology techniques, and that therefore the same treatment algorithms apply."
"Ideally, we would study outcomes of adjuvant therapy (chemo or radiation) in this occult-positive node population to see if these interventions impact their disease compared to treating them as stage I patients," she said. "Given the impracticalities of designing and executing yet another trial for this small subset of patients (13.8% of stage I lung cancer patients in this study), I think we have to exercise clinical judgment, discuss these patients in a multidisciplinary tumor board, and perhaps err on the side of being a bit more aggressive with adjuvant chemotherapy in this higher-risk subset of patients."
"The truly node-negative stage I patients experienced 67% five-year survival, compared to the IHC-positive N2 patients with a 50% five-year survival," Dr. Martin concluded. "This leaves room for more aggressive clinical interventions. The best strategy, however, remains to be determined."
The authors reported no funding. Two coauthors reported disclosures.
J Clin Oncol 2016.