Radiation Oncology: A Question-Based Review

Advanced-Stage (III-IV) Non-Small Cell Lung Cancer

Steven H. Lin and James Welsh

image 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.

image Workup/Staging

What is the TNM staging that defines advanced NSCLC?

1.     Stage IIIA: T3N1, T1-3N2

2.     Stage IIIB: T4NX, TXN3

3.     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?

1.     PET/CT may improve the staging to spare pts from futile thoracotomies b/c of unresectable Dz that is not detectable by conventional imaging.

2.     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.

image Treatment/Prognosis

What are the Tx options for pts with cN2, stage IIIA Dz?

Tx options with cN2, stage IIIA Dz:

1.     Definitive CRT

2.     Neoadj CRT → lobectomy (INT-0139)

3.     Induction chemo → surgery

(Roth J et al., JNCI 1994Rosell 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?

1.     MDACC data (Roth JA et al., JNCI 1994Roth 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.

2.     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.

3.     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?

1.     Yes. Several phase II–III trials have demonstrated this benefit.

2.     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%.

3.     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.

4.     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?

1.     Only postoperatively in stage II–IIIA pts.

2.     LACE meta-analysis for 5 of the adj trials demonstrated 5-yr OS advantage of 5.4%. (Pignon JP et al., JCO 2008)

3.     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.

PORT Meta-Analysis Trialist Group, Cochrane database, 2005 (Burdett S et al., Lung Cancer 2005): meta-analysis of 10 trials of pts treated after 1965. Suggested OS was a detriment to PORT overall. Subset analysis showed a detriment in resected stage I–II Dz but no adverse effect in N2 Dz.

Criticism: (a) 25% of pts were T1N0; (b) the staging technique is no longer used; (c) the RT technique is no longer used (large fields and fx, high total doses, Co-60 machines); (d) >30% of the meta-analysis relied on a poorly done study using poor techniques/technology (Dautzenberg B et al., Cancer 1999) that showed PORT to be detrimental due to a high 5-yr mortality from PORT (31% vs. 8%), mostly due to Tx-related cardiac or respiratory deaths.

SEER analysis (Lally BE et al., JCO 2006): 7,465 pts, stage II–III NSCLC from 1988–2002, PORT vs. observation, median follow-up 3.5 yrs. Overall, PORT did not affect OS. However, for the N2 subset, PORT was associated with better OS (HR 0.85) but detrimental for N0-N1.

Reanalysis of the ANITA trial (Douillard JY et al., IJROBP 2008): RCT of adj cisplatin/vinorelbine vs. observation for IB–IIIA pts after resection. 232 pts rcv PORT. Overall as a group, PORT was detrimental on survival (HR 1.34). In subset analysis based on pN stage, PORT was detrimental for pN0 pts. However, there was improved survival in pN1 Dz in the observation arm but detrimental in the chemo arm. PORT improved survival for both observation and chemo arms in pN2 pts.

Is there an advantage of postop CRT vs. postop RT alone for stage III N2 NSCLC?

No. INT-0115/RTOG 9105/ECOG (Keller MB et al., NEJM 2000) tested postop RT vs. CRT in resected stage II or III NSCLC. There was no difference in OS (3.2 yrs) or LC.

What are the anatomic areas targeted with PORT when given for unexpected N2 NSCLC? What is the recommended dose?

Bronchial stump, ipsi hilum, and ipsi mediastinum. The total dose is 50.4 Gy; 54–60 Gy for extracapsular extension or microscopic +margin and 60–70 Gy for gross residual Dz (NCCN 2010).

What should be the rate of Tx-related deaths (death from intercurrent disease [DID]) following PORT for NSCLC?

1.     Based on old data with old techniques, DID was 20%–30%, mainly due to pulmonary or cardiovascular excess deaths from PORT. New data suggests much lower rates (2%–3%).

2.     Penn retrospective (Machtay M et al., JCO 2001): 202 pts, Tx with surgery + PORT; 4-yr DID PORT (13.4%), vs. matched controls (10%). If <54 Gy, DID was 2%; but <54 Gy, DID was 17%.

3.     ECOG 3590 reanalysis (Wakelee H et al., Lung Cancer 2005): 488 pts randomized to PORT vs. PORT + chemo; 50.4 Gy RT. Overall 4-yr DID was 12.9% vs. matched controls at 10.1%.

What were the 2 seminal studies that demonstrated the importance of adding chemo to radiotherapy compared to radiotherapy alone in treating stage IIIA–B NSCLC?

CALGB 8433 “Dillman regimen” (Dillman RO et al., NEJM 1990): 155 pts with stage IIIA Dz (T3 or N2) treated with (a) RT alone (60 Gy) or (b) sequential chemo (CDDP/vinblastine) → RT (60 Gy). Sequential CRT improved MS from 10 mos to 14 mos, 2-yr OS from 13% to 26%, and 5-yr OS from 7% to 19%.

RTOG 88-08 (Sause W et al., Chest 2000): 458 pts with unresectable NSCLC (stage II–IIIB) randomized to 3 arms: 2 Gy qd/60 Gy alone (arm 1); 1.2 bid/69.6 Gy alone (arm 2); or sequential chemo (CDDP/vinblastine) + 60 Gy RT (arm 3). There was improved MS in arm 3 with sequential chemo → RT (13.2 mos) compared with conventional RT (11.4 mos) or bid RT (12 mos).

Which important randomized studies demonstrated the superiority of concurrent CRT over sequential CRT for unresectable or medically inoperable stage II–III NSCLC?

West Japan Lung Cancer Study Group (Furuse K et al., JCO 1999): 320 stage II–III pts randomized to sequential vs. concurrent CRT. Concurrent arm: CDDP/vindesine/MMC split-course RT (28 Gy × 2). Sequential arm: same chemo → RT (56 Gy conventional, nonsplit course). There was better OS and PFS in pts with concurrent CRT. MS was 16.5 mos vs. 13.3 mos (SS); 5-yr OS was 15.8% vs. 8.9% (SS).

RTOG 9410 (Curran W et al., ASCO 2003): 610 pts randomized to 3 arms: sequential (Dillman regimen with RT to 63 Gy) (arm 1); concurrent CRT (to 63 Gy) (arm 2); and concurrent hyperfractionated RT (1.2 bid/69.6 Gy) + chemo (arm 3). Chemo was CDDP/vinblastine (except etoposide/cisplatin [EP] for arm 3). Definitive concurrent CRT (arm 2) had a better outcome in MS (17 mos) vs. 14.6 mos (arm 1) or 15.2 mos (arm 3) or 4-yr OS (21% vs. 12% vs. 12%). However, there was ↑ toxicity in the concurrent CRT arm.

Which chemo regimen allows a full dose, and which would need to be dose reduced during the course of concurrent CRT?

EP or cisplatin/vinblastine allows a full dose to be administered with RT. Carboplatin/Taxol, gemcitabine, or vinorelbine requires a significant dose reduction during RT administration.

Is there a benefit of adding induction chemo → CRT for pts with unresectable stage IIIA–B NSCLC?

No. There was initial enthusiasm in 2 small randomized studies that suggested benefit, but 2 prospective studies (LAMP and CALGB 39801 trials) demonstrated no benefit to neoadj chemo. Definitive CRT is still the standard.

LAMP trial (Belani CP et al., JCO 2005): randomized phase II, 276 pts with stage IIIA–B NSCLC randomized to arm 1: chemo × 2 cycles → 63 Gy RT (Dillman regimen); arm 2: induction chemo × 2 cycles → concurrent CRT (63 Gy); and arm 3: concurrent CRT → consolidation chemo × 2 cycles. Chemo was carboplatin/Taxol. Arm 3 (concurrent CRT) had a better outcome, where MS was 16.3 mos vs. 13 mos (arm 1) or 12.7 mos (arm 2).

CALGB 39801 (Vokes E et al., JCO 2007): randomized phase III trial, enrolled 366 pts with unresectable stage IIIA–B randomized to arm 1: CRT vs. arm 2: induction chemo × 2 cycles → CRT. Chemo was carboplatin/Taxol. There was no difference in MS or OS. MS 12 mos (CRT) vs. 14 mos (induction) (p = NS), 2-yr OS 29% vs. 31% (p = NS). Upfront chemo ↑ grade 3–4 heme toxicity.

Should pts with locally advanced NSCLC who have a cCR after Tx with CRT undergo surgical resection?

This is extremely controversial and should be investigated in a clinical trial. So far, the strongest proof that benefit may be seen in a subset of pts is in the INT-0139 trial showing a benefit for pts who rcv CRT and a lobectomy. However, this still does not answer the question whether adding surgery after cCR is beneficial.

Is there a benefit of adding surgical resection after neoadj CRT in pts with stage IIIA Dz?

Possibly. There may be an improvement in LC, but there is no survival benefit. Pts with lobectomy may have an improved survival outcome.

INT-0139 (Albain KS et al., Lancet 2009): 396 technically resectable stage IIIA pts randomized to induction CRT to 45 Gy (50.4 Gy with heterogeneity correction) + surgery vs. definitive CRT (61 Gy) alone. Both therapies were proceeded with 2 additional cycles of chemo. Chemo was cisplatin (50 mg/m2 days 1, 8) with etoposide (50 mg/m2 days 1–5), q28day cycle. In the group overall, local relapse was much better for the surgery arm (10% vs. 22%, p = 0.002) but there was no difference in DM and no OS benefit. There was OS benefit in subset analysis in matched pts with lobectomy (5-yr OS 36% vs. 18%; MS 34 mos vs. 22 mos, p = 0.002) but not in pts who had pneumonectomy. 26% of pts with pneumonectomy died, but only 1% died from lobectomy.

Is preop chemo alone adequate as an induction regimen in stage IIIA–B lung cancer pts or is CRT necessary?

Induction CRT may not be absolutely necessary, although there may never be a clear answer since the U.S. trial is closed due to poor accrual and the German study used a nonstandard CRT regimen. It is still uncertain whether adding surgery to induction therapy is superior to definitive CRT alone, and it may add unwarranted toxicities.

RTOG 0412/SWOG 0332: pts randomized to induction chemo +/− RT → surgery. Unfortunately, this trial has been closed due to poor accrual.

German Lung Cancer Cooperative Group Trial (Thomas M et al., Lancet Oncol 2008): 558 pts, stage IIIA–B NSCLC, randomized to induction chemo EP × 3 cycles → surgery → RT (arm 1) vs. chemo → CRT (bid RT with carboplatin/vindesine) → surgery (arm 2). If +margin/unresectable Dz, the pt rcv more bid RT. There was greater pCR (60% vs. 20%) and mediastinal downstaging (46% vs. 29%) in the CRT group but no difference in PFS or survival. If pts required a pneumonectomy, postop mortality ↑ in the CRT group.

After an objective response to induction chemo for a pt with stage IIIA Dz, is adding postinduction surgical resection more beneficial than adding sequential radiotherapy?

No. In this case, resection is not more beneficial than radiotherapy.

EORTC 08941 (Van Meerbeeck J et al., JNCI 2007): randomized trial for stage IIIA Dz. All were treated with induction chemo (response rate 61%) and randomized to RT 60 Gy in 2 Gy/fx (arm 1) vs. surgery (arm 2). Only 50% had radical resection, with only 5% pCR (42% pathology downstage). Operative 30-day mortality was 4%. There was only 55% compliance in the RT arm. There was no difference in OS or PFS.

Does adding surgical resection in pts with stage IIIA–B lung cancers improve outcomes?

It is controversial whether adding surgery to induction CRT would improve outcomes in stage IIIA pts.

The EORTC 08941 study demonstrated no advantage of chemo → surgery vs. chemo → RT. Since concurrent CRT was better than sequential CRT and there was nonsuperiority of the surgical arm in INT-0139, definitive CRT is probably preferred over surgery in most pts with stage IIIA–B lung cancers.

However, in select pts (min nonbulky N2 pts who can get lobectomy) and since the LC rate for primary Dz with CRT is still rather poor (~50% LC), upfront CRT → lobectomy may be beneficial (INT-0139 subgroup analysis).

In the off-protocol setting, when can induction chemo be considered prior to surgical resection?

Induction chemo can be considered for those with min N2 Dz or for those with poor performance status due to Dz.

Under what circumstances should preop CRT be considered for stage IIIA lung cancer pts?

In stage IIIA lung cancer pts, preop CRT would be considered for those with nonbulky but intermediate-sized N2 nodes (1.5–2 cm).

What is the Tx paradigm for resectable T3-4N0-1 superior sulcus tumors?

Resectable T3-4N0-1 superior sulcus tumor Tx paradigm: preop CRT → surgery → chemo × 2 (SWOG 9417/INT-0160) or surgery → postop RT to at least 55 Gy (MDACC: Komaki R et al., IJROBP 2000). If + for Surgical Margin + postop CRT should be done using hyperfractionation b/c of potential toxicity to the brachial plexus (60 Gy at 1.2 Gy bid).

What trial established the role of induction CRT for superior sulcus NSCLC? What was the induction regimen and the primary outcome of this study?

A single-arm phase II trial by SWOG 9416/INT-0160 (Rusch VW et al., JCO 2007) evaluated induction CRT + surgery for resectable T3-4N0-1 superior sulcus tumors. The induction regimen was with concurrent cisplatin, etoposide, and RT to 45 Gy → restage; if no progression, then surgery → chemo × 2 cycles. Chemo was cisplatin (50 mg/m2 days 1 and 8) with etoposide (50 mg/m2 days 1–5), repeated q28days for a total of 4 cycles. 95% completed induction therapy. Of the pts that had thoracotomy (88 of 110 pts [80%]) based on preop judgment of resectability, 94% had complete resection (83 pts). The study showed a 56% pCR or near CR rate and a 5-yr OS of 44% (compared to 30% for historical controls). Survival was better with complete resection (54%). There was no difference between T3-T4 tumors.

What are the appropriate Tx volumes, dose, and field arrangement for a superior sulcus tumor?

GTV defined by PET + 2 cm and ipsi supraclavicular (SCV) region. AP/PA to 41.4 Gy, then off-cord to 45 Gy. Cord should not exceed 110% of the Rx dose.

Are all pts with stage IIIB NSCLC unresectable?

No. Pts with T4 Dz with invasion of vertebral bodies and multiple nodules in different ipsi lung lobes are still resectable.

Is there a role for consolidation chemo after definitive CRT for locally advanced NSCLC?

This is uncertain, at least for docetaxel. Despite initial enthusiasm with the SWOG 9504 phase II study showing ↑ MS with consolidation docetaxel in stage IIIB pts after definitive CRT (26 mos), the randomized phase III trial (Hanna N et al., JCO 2008) demonstrated no benefit of consolidation chemo with docetaxel but only ↑ toxicities and Tx-related deaths.

Thus, there may not be a role of consolidation with docetaxel, but there may be a role for other agents, such as pemetrexed, as maintenance therapy.

Is there a role for elective nodal irradiation for the Tx of inoperable, locally advanced NSCLC?

No. The current recommendation is to treat with CRT only the involved areas (assessed either by imaging or pathology) to improve dose escalation and improve toxicity.

MSKCC data (Rosenzweig K et al., JCO 2007): retrospective analysis of pts treated with IFRT alone. 524 pts treated with definitive 3D-CRT to areas of gross Dz; mean dose 66 Gy. Total elective nodal failures (ENF) (initial uninvolved nodal areas that fail) were 6.1%. The 2-yr primary tumor control rate was 51%. Overall, 2-yr ENF was 7.6%. Pts with local Dz control had a 2-yr ENF of 9%. Ipsi mediastinum had ↑ nodal failures (3%).

Prospective phase III trial (Yuan et al., ASCO 2007): inoperable stage III NSCLC randomized to involved-field irradiation vs. elective nodal irradiation. Involved-field irradiation achieved better overall response and improved 5-yr LC of 51% vs. 36% (p = 0.032).

What are the volumes and Tx techniques used for RT of locally advanced NSCLC?

Using the MSKCC technique, GTV is defined by +FDG uptake areas, Bx-proven LN areas, or any LN <15 mm on CT. PTV = GTV + 1−1.5 cm. 3D-CRT or IMRT technique to 63–66 Gy or higher in 1.8–2 Gy/fx should be given.

What are the Tx options for pts with malignant pleural effusion?

Treat as a stage 4 pt: thoracentesis, chest tube + drainage, sclerotherapy with talc or bleomycin, or placement of a chronic indwelling catheter. Depending on performance status, chemo can be considered.

What should be done for pts with 2 synchronous nodules of NSCLC (i.e., occurring in different lobes)?

If there is identical histology, consider M1. If a different histology or genetic signature, it can be considered synchronous stage I NSCLC and definitive surgery can be considered after full workup for nodal/distant involvement is excluded.

Are the outcomes of stage IIIB pts with +SCV nodes worse than those without SCV node involvement?

How should pts with newly diagnosed NSCLC with a solitary brain lesion be managed?

Surgical resection should be considered, especially if the pt is symptomatic or to exclude a possible primary brain tumor, then either SRS or WBRT. Otherwise, SRS +/− WBRT should be used, as per the NCCN. The primary lung tumor should be managed according to the appropriate TN stage.

Overall, what is the 5-yr OS in this group of pts?

5-yr OS is 20%–40% as a group.

Is there a role for PCI after Tx for locally advanced NSCLC?

No. 4 randomized trials showed only improvement in brain relapse rates (9% vs. 19%) but no survival benefit in adding PCI (Cox JD et al., JAMA 1981; Umsawasdi T et al., J Neurooncol 1984; Miller TP et al., Cancer Ther 1998; Russell AH et al., IJROBP 1991). A meta-analysis summarizes this data (Lester JF et al., IJROBP 2005).

Is there a benefit of dose escalation in locally advanced NSCLC?

Yes. Dose escalation improves LC and probably translates to better survival.

RTOG 73-01: RCT testing 40 Gy split vs. 40 Gy continuous vs. 50 Gy continuous vs. 60 Gy continuous. The 60 Gy continuous had the best survival. 60 Gy became standard b/c of this trial, and since then 55–66 Gy is standard.

RTOG 93-11: dose escalation without chemo to 70.9 Gy, 77.4 Gy, 83.8 Gy, and 90.3 Gy. The 90.3 Gy is too toxic, but 77.4 Gy and 83.8 Gy is safe if V20 is 25%–36% and <25%, respectively. LC 50% to 78%, with LF in elective nodal areas <8%.

Michigan dose escalation (Kong FM et al., IJROBP 2005): 106 pts, stage I–III NSCLC, treated with 63–103 Gy in 2.1 Gy/fx with 3D-CRT; primary tumor + LN + <1 cm; no chemo in 81%. MS was 19 mos. MVA showed that the RT dose was the only predictor of better survival.

The safety of 74 Gy + chemo has been demonstrated in a number of phase I–II trials: RTOG 0117 (74 Gy + chemo), NCCTG 0028 (74 Gy + chemo), and UNC phase I–II (74 Gy + chemo is safe).

Intergroup Trial (RTOG 0617/NCCTG N0628/CALGB 30609/ECOG R0617): RCT phase III comparison of 60 Gy vs. 74 Gy CRT with concurrent and consolidation carboplatin/Taxol +/− cetuximab in stage IIIA–B NSCLC. This trial is accruing.

What is the role of endobronchial/intraluminal brachy-therapy for palliation for lung cancer?

1.     Various fractionation schemes (15 Gy × 2 or 8–10 Gy × 1, prescribed to 0.5 cm) have been used in prior irradiated pts with endobronchial Dz causing Sx. Sx relief can be seen in 80% of pts. Complications included fatal hemoptysis (5%–10%), bronchoesophogeal fistula (2%), and bronchial edema (1%).

2.     MDACC published a series of 81 previously irradiated lung cancer pts who were treated with palliative HDR endobronchial brachytherapy, 15 Gy × 2, 6 mm depth, over 2 wks. Response was seen in 84%. Pts with excellent response had better survival (MS 13.3 mos) vs. those with poor response (MS 5.4 mos) (p = 0.01). 2 fatal complications were due to fistula and tracheomalacia. (Delclos ME et al., Radiology 1996).

What fractionation scheme is optimal for pts with lung cancers treated with palliative RT for Sx such as hemoptysis, cough, pain, and shortness of breath?

Conventional fractionation is probably no better than hypofractionation. In a Norwegian RCT, Sundstrom S et al. tested 30 Gy in 10 fx vs. 17 Gy in 2 fx (1 wk apart) vs. 10 Gy in 1 fx. All achieved equivalent palliation. (JCO 2007)

image Toxicity

What is the typical follow-up schedule of pts treated for lung cancer?

Typical lung cancer follow-up: H&P, CT chest with contrast q4–6mos for yrs 1–2, then noncontrast CT chest annually yrs 3–5, and continued smoking cessation counseling (NCCN 2010)

What are the expected acute and late toxicities of RT for lung cancer?

1.     Acute: Skin reaction, fatigue, dysphagia, odynophagia, cough

2.     Subacute and late: RT pneumonitis, lung fibrosis, brachial plexopathy, L–hermitte syndrome, RT myelitis, esophageal fibrosis/stricture, pericarditis, 2nd cancers

What are the signs and Sx of RT pneumonitis, and how is it managed?

RT pneumonitis is a subacute reaction that begins as early as 3–6 mos after RT. Typically, Sx include chest pain, shortness of breath, fever, and hypoxia. CT scan shows ground glass changes within the RT port. Check oxygenation and supplement if necessary. If symptomatic, treat with prednisone 1 mg/kg/day for at least 3 wks with a very slow taper. Bactrim can be used for PCP prophylaxis.

What is total lung V20 dose-volume constraint for RT alone and concurrent CRT in definitive lung cancer Tx?

1.     NCCN 2010: V20 <37%

2.     MDACCRT alone → V20: <40%; CRT → V20: <35% (based on Lee HK et al., IJROBP 2003)

What is mean lung dose (MLD) constraint for definitive RT to lung cancer?

MLD is <15 Gy; max is ≤20 Gy.

What is the heart RT dose-volume constraint for RT alone and concurrent CRT?

1.     NCCN 2010: V40 <100%, V45 <67%, V60 <33%

2.     MDACCRT alone→ V40: <50%; CRT → V40: <40%

What is the dose constraint for the brachial plexus?

The dose constraint is 1 cc below 60 Gy; the max dose point should be <66 Gy.

What is the max esophageal dose?

Ideally, MLD <34 Gy. Try to minimize the V60 as much as possible (V60 <33%, V50 <50%, ≤45 Gy to the entire esophagus, max dose point <70 Gy).

What is the expected grade 3–4 esophagitis rate in pts treated with sequential CRT vs. concurrent CRT in locally advanced NSCLC?

1.     Sequential: ~4%

2.     Concurrent: ~22%

(Choy H, ASTRO 2003 [summary of multiple studies])