Advanced-Stage (III–IV) Non–Small Cell Lung Cancer
Background
What % of pts present with stage IIIA non–small cell lung cancer (NSCLC)?
~30% of all NSCLC pts have stage IIIA Dz at presentation.
What % of pts will have occult N2 Dz found at the time of surgery?
25% of pts will have occult N2 Dz found at surgery.
After definitive Tx of a primary lung tumor, what is the time period after which it is considered a 2nd primary tumor?
A tumor that develops ≥2 yrs after definitive Tx of primary lung cancer is likely a 2nd primary. Whenever a recurrence with identical histology occurs at <2 yrs, it is considered a met.
What % of pts with locally advanced NSCLC develop brain mets as a 1st site of relapse?
~15%–30% of NSCLC pts develop brain mets as a site of 1st relapse.
What is Pancoast syndrome?
Pancoast syndrome is a result of apical tumors (aka, superior sulcus tumors) invading the thoracic inlet, and compression on structures such as the sympathetic ganglion, brachial plexus, recurrent larygeal nerve and vasculature causing shoulder/arm pain, Horner syndrome, paresthesias of the hand in ulnar nerve distribution, hoarseness, and SVC syndrome. Tumors that cause these Sx are referred to as Pancoast tumors.
What is Horner syndrome?
Horner syndrome is a result of tumor compression on the sympathetic ganglion, resulting in a triad of symptoms: ipsi miosis, ptosis, and anhidrosis.
How prevalent are superior sulcus tumors?
Superior sulcus tumors account for ~3% of NSCLC.
Workup/Staging
What is the TNM staging that defines advanced NSCLC?
Stage IIIA: T3N1, T1-3N2
Stage IIIB: T4NX, TXN3
Stage IV: TXNXM1
What is the MS of pts who present with malignant pleural effusion with NSCLC?
MS is 3–9 mos. These pts are staged as M1a Dz in the new staging system.
What is the 5-yr survival rate of pts who present with metachronous (2nd) primary lung cancer a few yrs after definitive Tx of a 1st tumor?
Can be as high as 40% depending on TN staging.
What are the survival outcomes of stage IIIA Dz with T3N1 vs. TXN2 Dz?
Stage IIIA is a heterogeneous group, with 5-yr survival ranging from 20%–25% for T3N1 and 3%–8% for T1-3N2 Dz. There is a lot of heterogeneity in the prognosis of the T1-3N2 group due to the # and bulk of LNs involved.
What is the utility of PET/CT to determine the resectability of the lung cancer pts?
PET/CT may improve the staging to spare pts from futile thoracotomies b/c of unresectable Dz that is not detectable by conventional imaging.
A Danish RCT (Fischer B et al., NEJM 2009) randomized 189 pts using either conventional preop staging (CT + meds) or PET/CT staging (PET + meds). PET reduced the # of futile thoracotomies (21 vs. 38) and the total # of thoracotomies (60 vs. 73) (both SS). But the overall mortality did not differ between groups.
Treatment/Prognosis
What are the Tx options for pts with cN2, stage IIIA Dz?
Tx options with cN2, stage IIIA Dz:
Definitive CRT
Neoadj CRT → lobectomy (INT-0139)
Induction chemo → surgery
(Roth J et al., JNCI 1994; Rosell R et al., NEJM 1994)
What should be done in pts with incidental N2 Dz found at the time of surgery?
If technically resectable, with only an occult, single-station mediastinal nodal met at surgery, surgical resection should proceed with lung resection + mediastinal LND → adj chemo, with consideration of postop RT.
What are the clinical trials that demonstrated a survival benefit with adding induction chemo → surgery for stage IIIA–B NSCLC pts?
MDACC data (Roth JA et al., JNCI 1994; Roth JA et al., Lung Cancer 1998): 60 pts randomized to surgery alone vs. cisplatin/etoposide/cyclophosphamide × 1 cycle → surgery. MS was 21 mos (induction chemo) vs. 14 mos for surgery alone.
Madrid data (Rosell R et al., NEJM 1994; Rosell R et al., Lung Cancer 1999): 60 pts randomized to surgery alone vs. cisplatin/ifosfamide/mitomycin-C × 3 cycles → surgery. MS was 22 mos (chemo) vs. 10 mos for surgery alone.
Spanish Lung Cancer Group Trial 9901 (Garrido P et al., J Clin Oncol 2007): phase II study, 136 pts, all with stage IIIA (N2) or stage IIIB (T4N0-1) Dz. Pts underwent cisplatin/gemcitabine/docetaxel × 3 cycles → surgery. There was pCR in 13%. MS was 48.5 mos for R0 resection vs. 12.9 mos for R1-R2 resection. The overall complete resection rate was 69%. MS was 16 mos, 3-yr OS was 37%, and 5-yr OS was 21%.
What trial demonstrated no benefit of induction chemo with surgery for stage IIIA N2 NSCLC pts?
JCOG 9209 (Japan: Nagai K et al., J Thorac Cardiovasc Surg 2003): trial closed early due to poor accrual. 62 pts with stage IIIA N2 NSCLC randomized to surgery alone vs. cisplatin/vindesine × 3 cycles → surgery. There was no difference in MS (16–17 mos) or 5-yr OS (10% with chemo vs. 22% with surgery).
What randomized study established a min dose of 60 Gy for definitive RT for stage III NSCLC?
RTOG 7301 (Perez C et al., Cancer 1980): stage IIIA–B pts, dose escalation trial with RT alone of 40 Gy, 50 Gy, and 60 Gy vs. 40 Gy (split course), all in 2 Gy/fx. LC improved with 60 Gy. 60 Gy was established as the standard. MS was ~10 mos and 3-yr OS was <10% for all arms.
Is there a benefit of altered fractionation of definitive RT for stage III NSCLC?
Yes. Several phase II–III trials have demonstrated this benefit.
RTOG 8311 (Cox JD et al., J Clin Oncol 1990): randomized phase I–II, 848 pts with unresectable N2, 1.2 Gy bid to 60, 64.8, 69.6, 74.4, and 79.2 Gy. Favorable pts did better overall, and favorable pts with good performance status that rcv ≥69.6 Gy had significantly better 3-yr OS at 20%.
CHART (Saunders MI et al., Lancet 1997): phase III, 563 pts randomized to 54 Gy at 150 tid (450/day) × 12 consecutive days vs. 60 Gy for 6 wks. There was 10% improvement in 3-year absolute survival for CHART compared to standard RT. Severe esophagitis was most common (19% vs. 3%). The trial included many stage I pts. Results were very similar if chemo was added to the standard RT regimen.
ECOG 2597 (Belani CP et al., JCO 2005): 141 pts, stage IIIA–B unresectable NSCLC treated with induction carboplatin/Taxol × 2 cycles → definitive RT with either (a) qd RT 64 Gy or (b) HART 1.5 Gy tid × 2.5 wks to 57.6 Gy. The study closed early due to poor accrual. There was a trend to better MS with HART (20.3 mos vs. 14.9 mos, p = 0.28). There was ↑ esophagitis with HART.
RT should be limited to what dose if the pt is undergoing preop CRT for Tx of locally advanced NSCLC?
45 Gy. >50 Gy has been shown to have complications of bronchopleural fistula, prolonged air leak with empyema, and prolonged postop ventilation.
Is there data to suggest that a pCR (pN2 → pN0) after induction CRT improves survival in NSCLC pts?
SWOG 8805: phase II study in stage IIIA–B pts receiving induction CRT → surgery. pCR was 22%, with 3-yr OS of 27%. Those with pN0 Dz after induction therapy had MS of 30 mos vs. only 10 mos in those with residual N2 Dz. (Albain KS et al., J Clin Oncol 1995)
What is considered bulky, unresectable Dz in NSCLC pts?
Pts with a histologically involved LN > 2 cm on CT, +extranodal involvement, or multistation nodal Dz (regardless of size)
What is the preferred Tx strategy for pts with stage IIIB T4N0 Dz?
Neoadj chemo or CRT, or definitive CRT. 5-yr OS may approach 25%–30%. R0 resection should be attempted if this is technically feasible.
What is the 5-yr OS of pts with satellite nodules in the same lobe?
5-yr OS is 33% if pts undergo lobectomy. Careful nodal assessment to exclude N2 Dz must be done.
What is the role of adj platinum-based chemo in NSCLC?
Only postoperatively in stage II–IIIA pts.
LACE meta-analysis for 5 of the adj trials demonstrated 5-yr OS advantage of 5.4%. (Pignon JP et al., JCO 2008)
The CALGB 9633 study demonstrated a trend to survival benefit for stage IB pts with tumors <4 cm in subset analysis. (Strauss GM et al., JCO 2008)
Is there data to demonstrate the need for adding RT to adj chemo in pts with completed resected stage IIIA N2 NSCLC?
This cannot be adequately answered at this point. CALGB 9734 attempted to address this question (adj chemo alone vs. chemo → RT), but the trial was closed due to poor accrual (Perry C et al., Lung Cancer 2007). There was no difference in DFS or OS.
However, based on retrospective analysis, pts with N2 Dz should be evaluated for chemo → PORT
Does postoperative radiotherapy (PORT) for pts with resectable lung cancers improve outcomes? What subset of pts may benefit from PORT?
Possibly. Based on several randomized trials and meta-analysis, pts with N2 Dz may benefit from PORT. There are ongoing prospective phase III trials testing the role of PORT in pN2 pts.
LCSG 773 (Weisenburger TH et al., NEJM 1986): RCT, 210 pts, stage II–IIIA (T3 or N2), margin– resection, randomized to PORT or observation. RT: ≥Co-60 to the mediastinum to 50 Gy on postop day 28 (turned out to be nearly all squamous cell carcinoma). Overall LR was better in PORT (3% vs. 41%), and DFS was better in N2 pts. There was no difference in OS between the arms.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
