# Radiation Oncology/NSCLC/Locally Advanced Resectable

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    See also: Post-op RT (in Early Stage Resectable)

## Criteria for resectability

Generally stage IIIA and lower is considered resectable, since all sites of disease can be removed by extended surgery. In contrast, stage IIIB disease (N3 or T4) is generally considered unresectable due to contralateral lymph node involvement or extensive local tumor. However, a subset of T4 patients may actually be able to undergo surgical resection.
* Pulmonary function: FEV1 > 2 L. Predicted post-surgical FEV1 should be > 0.8 L based on qualitative VQ scan.

## Epidemiology

* 16% of NSCLC is IIIA
Heterogenous:
* T3N1 vs. T1-3N2
* N2 nodes: single vs. multiple
* N2 nodes: bulky vs. macroscopic vs. microscopic involvement
* Gustave Roussy, 2000 (France) PMID 10944131 -- "Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications." (Andre F, J Clin Oncol. 2000 Aug;18(16):2981-9.)
** Retrospective. 702 patients with resected N2 disease, stratified into clinically positive and clinically negative but microscopically positive at surgery. Multi-institutional, 6 centers. Median F/U 4.3 years
** 5-year OS treated with surgery only:
*** single level microscopic N2: 34% (site of LN+ had no prognostic significance)
*** multiple levels microscopic N2: 11%
*** single level clinical N2: 8%
*** multiple levels clinical N2: 3%
** 5-year OS in clinical N2: surgery only 5% vs. preop chemo 18%

## Use of PET to assess response after induction chemo/RT

* Maryland: DeYoung CM et al (ASTRO 2004, Abstract 122)
** 39 pts. Stage IIIA-IIIB. Induction chemo (carboplatin + Navelbine) + concurrent hyperfractionated RT (69.6 Gy). After induction, restaging with PET 4-6 weeks after and mediastinoscopy (MED) @ 6-8 weeks. If negative MED, underwent resection + consolidative therapy; otherwise, consolidation only.
** 32 completed MED. For the mediastinum: SUV after induction could not differentiate between those with and without pCR; PET false negative 30%, false positive 45%. For the primary tumor, false negative 73%, false positive 57%.
** PET not useful for restaging within 4-6 weeks after induction chemo/RT.

## Pre-op RT vs. Surgery Only

* VA Trial
** Randomized. 331 patients, with centrally located tumors amenable to endoscopic biopsy (peripheral lesions excluded). Arm 1) Pre-op RT vs. Arm 2) Surgery alone. RT given 40-50 Gy to primary tumor + mediastinum. Surgery 4-6 week later (maximum 12 weeks). Lobectomy 12%, majority pneumonectomy.
** 4-years; 1972 PMID 5083076 -- "Preoperative radiation therapy in the treatment of bronchial carcinoma." (Shields TW, Cancer. 1972 Nov;30(5):1388-94.)
*** Outcome: pCR 25%. 1-year OS pre-op RT 44% vs. surgery only 60% (SS); 4-year OS 12% vs. 21%. Survival decrement during first 6 months, then curves comparable. Survival also worse with higher pre-op RT dose
*** Toxicity: post-op mortality 12% both groups
*** Conclusion: Pre-op RT worse survival, manifested during first 6 months

## Induction Chemo/RT + Surgery

* RTOG 02-29 - Phase II
** 2010 RedJournal Abstract: Stage IIIA(T1-3N2) or IIIB(N3) resectable at diagnosis. Treated with induction chemo/RT, carboplatin and taxol weekly x 6 weeks and RT to 61.2 Gy. Surgery evaluation 4-6 wks after chemo/RT. Consolidative carbo/taxol x 2 cycles. Recommended prophylactic cranial irradiation (on RTOG 02-14). RT dose: 50.4 Gy (offcord by 45 Gy) + 10.8 Gy boost
** Result: 43 pts (75%) were evaluable; 36 pts underwent resection. 7 pts had residual mediastinal dz. 27/43 (63%) achieved mediastinal clearance: improved mediastinal sterilization (50-->70%, power of 80%, p=0.05)
** Med f/u 20 months,** med OS: 26.6 mos; med PFS: 13.1 mos; 1-y OS: 77%; 1-y PFS: 52%
** Toxicity: 14% (5/37) G3 post-op pulmonary complications; 1 post-op G5 toxicity (3%).
** Conclusion: confirms the ability of neoadj CCRT to sterilize known mediastinal nodal disease.
* SWOG 8805 - Phase II
** 1999 PMID 7636530 — "Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805." Albain KS et al. J Clin Oncol. 1995 Aug;13(8):1880-92.
** 126 pts. Biopsy proven N2, N3, or T4. IIIA 60%, IIIB 40%. 85% of IIIA and 80% of IIIB were resected. Concurrent chemo/RT (2 cycles cisplatin + etoposide + 45 Gy RT), followed by surgery.
** Median f/u 2.4 yrs. 2-yr OS 37%, 3-yr 24-27%. Strongest predictor of survival was pCR in mediastinal LN (30 months vs 10 month MS; 5-yr OS 33% vs 11)%.
** Conclusion: induction chemo/RT before surgery is feasible
* Duke, 1994
** PMID 8055445 — "Phase II study of neoadjuvant chemotherapy and radiation therapy with thoracotomy in the treatment of clinically staged IIIA non-small cell lung cancer." Deutsch M et al. Cancer. 1994 Aug 15;74(4):1243-52.
** 28 pts. Carbo/etoposide followed by carbo + 60 Gy followed by surgery.
** Conclusion: well tolerated

## Induction Chemo/RT + Surgery vs Definitive Chemo/XRT

* Intergroup INT-0139 (RTOG 93-09, SWOG 93-36) (1994-2001) -- induction CRT + surgery vs definitive CRT
** Randomized. 396 patients with stage IIIA (pN2) lymph node positive NSCLC. Arm 1) Induction chemo-RT (cisplatin 50 mg/m2 x2 cycles, etoposide 50 mg/m2 x2 cycles, concurrent RT 45/25), followed by CT restaging 2-4 weeks later, and complete surgical resection with LN evaluation vs. Arm 2) Same cisplatin/etoposide + concurrent RT 61 Gy. Consolidation cisplatin/etoposide in both groups x2 cycles. Primary endpoint OS.
** 2003 ASTRO Abstract 2497 Video Presentation — Turrisi et al.
*** Initial results suggest a disease-free survival benefit for the surgical arm (median, 13.4 vs. 11.8 months) without any difference in overall survival at a follow up of 22 months.
** 2005 ASCO Abstract -- "Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). (Albain KS, Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 7014). Median F/U 2.5 years
*** Outcome: median PFS: CRT+S 12.8 months vs. CRT 10.5 months (SS); 5-year PFS 22% vs. 11% (SS); median OS: 23.6 month vs. 22.2 months (NS); 5-year OS: 27% vs. 20% (p=0.1)
*** Subgroup analysis revealed better survival for patients who underwent a lobectomy (p = .002).
*** Trimodality therapy was not optimal when a pneumonectomy was required owing to the high mortality risk.
*** N0 status at surgery significantly predicted a higher 5-year survival rate.
*** Conclusion: significantly improved PFS but not OS with trimodality
** 2009 Lancet, PMID 19632716 -- "Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial" (Albain KS, The Lancet, Early Online Publication, 27 July 2009). Median F/U 1.8 years, for survivors 5.8 years
*** Outcome: Median OS Induction 24 months vs. definitive 22 months (NS). 5-year OS 27% vs. 20% (NS). Median PFS 13 months vs. 11 months (SS). 5-year DFS 22% vs 11%. First relapse: primary tumor site 2% vs. 14%, regional LNs 7% vs. 3%, brain 11% vs. 15%, other DM 37% vs. 42%
*** Subset analysis: Lobectomy vs matched CRT 2.8 years vs. 1.8 years (SS); pneumonectomy vs matched CRT 1.6 years vs. 2.4 years (NS)
*** Toxicity: Treatment-related death 8% vs. 2%. Grade 3-4 esophagitis 10% vs. 23% (SS), no difference in pneumonitis or nausea/vomiting
*** Conclusion: Chemo-RT with or without resection (preferably lobectomy) all options for IIIA NSCLC

## Induction before Surgery vs Surgery alone

Meta-Analysis
* MRC; 2007 (UK) PMID 17636828 -- "Chemotherapy and surgery versus surgery alone in non-small cell lung cancer." (Burdett SS, Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006157.)
** Meta-analysis. 12 randomized trials, data available for 988 patients (75%)
** Outcome: Pre-op chemo increased OS with HR 0.82 (SS), equivalent to 5-year OS benefit 6% (14% to 20%)
** Conclusion: Significant increase in survival attributable to pre-op chemotherapy
Randomized Trials
* Roth (MDACC) (1987-93)
** 60 patients with resectable IIIA NSCLC randomized to induction chemo (cyclophosphamide, etoposide, cisplatin) x 3 cycles followed by surgery, followed by 3 more cycles chemo if response, vs. immediate surgical resection alone. Both groups received RT if incompletely resected at the discretion of treating physician (66 Gy for gross residual, 60 Gy for microscopic). Trial stopped early as stoppage criteria met.
** >50% of patients received RT in each arm
** 1994: PMID 8158698 -- "A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer." (Roth JA, J Natl Cancer Inst. 1994 May 4;86(9):673-80.)
*** estimated 3-year OS 56% vs. 15% for perioperative chemo vs. immediate surgery, respectively. MS 64 months vs 11 months. Clinical response rate of 35% with preoperative chemotherapy.
** 1998: PMID 9792048 -- "Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer." (Roth JA, Lung Cancer. 1998 Jul;21(1):1-6.) -- Median f/u 82 months.
*** updated 3- and 5-year OS, respectively, 43% and 36% for periop chemo, 19% and 15% for immediate surgery.
* Rosell (Spain) (1989-?)
** 60 patients with resectable IIIA NSCLC randomized to induction chemo (mitomycin, ifosphamide, cisplatin) x 3 courses followed by surgery, followed by 50 Gy thoracic RT, vs. immediate surgical resection followed by 50 Gy thoracic RT
** 1994: PMID 8043059 -- "A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer." (Rosell R, N Engl J Med. 1994 Jan 20;330(3):153-8.)
*** median OS 26 months vs. 8 months, median DFS 20 months vs. 5 months (p < 0.001 for both)
** 7-year, 1999: PMID 10574676 -- "Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial." (Rosell R, Lung Cancer. 1999 Oct;26(1):7-14.)
*** updated median OS 22 months vs. 10 months, updated 3- and 5-year OS, respectively, 20% and 17% for pre-op chemo, 5% and 0% for immediate surgery.
* Depierre (French) (1991-97) - Induction chemo + surgery vs surgery
** 355 pts. Stage IB - IIIA. Preoperative chemotherapy (PCT) consisted of 2 cycles mitomycin, ifosfamide, and cisplatin. 2 additional cycles were given postoperatively for pts who responded. Pts in both arms received post-op RT for pathologic T3 or N2 disease.
** PMID 11773176, 2002 — "Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer." Depierre A et al. J Clin Oncol. 2002 Jan 1;20(1):247-53.
** Median survival 37 m (PCT) vs 26 m (S), N.S. Survival difference 8.6% at 4 yrs (S.S.). Survival difference was S.S. only for pts with N0-N1 disease.

## Induction Chemo vs Induction Chemo-RT

* RTOG 04-12 / SWOG S0332
** Stage IIIA (N2). Randomized to induction chemotherapy (cisplatin/docetaxel) vs induction chemo/RT (RT to 50.4 Gy). Followed by surgical resection then consolidative chemotherapy with docetaxel. N2 status must be confirmed pathologically. RT technique: uses 3D-CRT, no field reductions, no elective nodal irradiation.
** Terminated due to poor accrual
* German GLCCG (1995-2003) -- Induction cisplatin/etoposide then concurrent chemo-RT followed by surgery vs. induction cisplatin/etoposide then surgery then postop RT
** Randomized. 524 patients with NSCLC Stage IIIA (33%) or resectable IIIB (67%). Arm 1) Induction cisplatin 55 mg/m2 + etoposide 100 mg/m2 x3 cycles, then concurrent RT 45/30 in 1.5 Gy BID with carboplatin 100 mg/m2 + vindesine 3mg, followed by surgery vs. Arm 2) Same induction, followed by surgery, followed by RT (54/30 if R0, 68.4/38. Surgery after 4-6 weeks. Primary endpoint PFS.
** 2004 Abstract ASTRO Plenary Session — "Neoadjuvant chemotherapy followed by preoperative radiochemotherapy (hfRCT) plus surgery or surgery plus postoperative radiotherapy in stage III non-small cell lung cancer: results of a randomized phase III trial of the German Lung Cancer Cooperative Group." Ruebe et al.
*** 3-year OS 26.2% (Arm A) vs 24.6% (Arm B) (NS). 3-year PFS 17.8% vs 19.9% (NS). Difference was in toxicity, with worse Grade 3/4 esophagitis in Arm A (19% vs 3%), and worse Grade 3/4 pneumonitis in Arm B (6% vs 1%). No difference in treatment related toxicity. Concluded that both regimens are effective.
** 2008 PMID 18583190 -- "Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer." (Thomas M, Lancet Oncol. 2008 Jul;9(7):636-648. Epub 2008 Jun 24.)
*** Outcome: Surgery chemo 59% vs. chemo-RT 59%; mediastinal downstaging 29% vs. 46% (SS). Median PFS (primary endpoint) 10.0 months vs. 9.5 months (NS).
*** Toxicity: If pneumonectomy (35% in both groups), worse mortality 14% vs. 6%
*** Conclusion: Preop chemo-RT increases mediastinal downstaging, but doesn't improve survival. After induction, pneumonectomy should be avoided

## Induction Chemo + Surgery vs Induction Chemo + RT

* EORTC 08941 -- Induction platinum x3 cycles, then surgery vs. RT
** Randomized. 579 patients with unresectable IIIA-N2 NSCLC. Unresectable considered N2 non-squamous; or N2 squamous exceeding Station 4R for right or Station 5/6 for left side. Platinum-based induction x3 cycles, then randomized to surgical resection or RT. Had to show at least "minor" response. Induction response rate 61%.
** RT: Start within 70 days of last chemo cycle. 3D planning + tissue correction. Dose 60-62.5 Gy involved mediastinum and 40-46 uninvolved mediastinum. Post-op RT given to 40% patients in the surgery-only arm (if R1/R2, to 56 Gy). RT arm compliance 55%
** 5-years, 2007 PMID 17374834 -- "Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer." (van Meerbeeck JP, J Natl Cancer Inst. 2007 Mar 21;99(6):442-50.)
*** 5-year outcome: OS resection 16% vs. RT 14% (NS); median OS 16 months vs. 17 months (NS)
*** Toxicity: After surgery 4% deaths. After RT Grade 3-4 pulmonary toxicity 7%, one death of RT pneumonitis (0.6%)
*** Conclusion: Surgery did not improve OS or PFS. Given low morbidity and mortality, RT should be preferred modality
*** Editorial PMID 17374824: high number of pneumonectomies, which have negative outcome after induction chemo; better local control with surgery. Surgery may be an option if patients experience "downstaging" and clear their mediastinal LNs. On the other hand, RT techniques also improving for better toxicity. Conclusion that chemotherapy-radiation is appropriate for IIIA patients with initial N2 disease
** RT Arm, 2006 PMID 16785054 -- "Quality assurance of thoracic radiotherapy in EORTC 08941: a randomised trial of surgery versus thoracic radiotherapy in patients with stage IIIA non-small-cell lung cancer (NSCLC) after response to induction chemotherapy. (Kramer GW, Eur J Cancer. 2006 Jul;42(10):1391-8.)
*** QA Review
** Surgery Arm, 2005 PMID 16055865 -- "Morbidity and mortality in the surgery arm of EORTC 08941 trial." (Van Schil P, Eur Respir J. 2005 Aug;26(2):192-7.)
*** 167 patients in surgery arm: 50% R0; 47% pneumonectomies worse survival on subgroup analysis
*** Outcome: 50% R0, 40% pathologic downstaging to N0/N1
*** Toxicity: 30-day perioperative mortality 4%; reoperation 8%
*** Conclusion: morbidity and mortality acceptable
* RTOG 89-01 (1990-1994) -- Induction chemo, then surgery vs. RT
** 2002 PMID 12243809 -- "Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group." (Johnstone DW, Int J Radiat Oncol Biol Phys. 2002 Oct 1;54(2):365-9.)
** Randomized. Trial stopped early after initiation of INT 0139. 73 (goal 224) patients, mediastinoscopy-verified N2 NSCLC (T1-T3N2). Induction with cisplatin/vinblastine x2 cycles, then Arm 1) surgery vs. Arm 2) RT 64/32. Adjuvant cisplatin/vinblastine. 45 patients actually randomized post induction.
*** Outcome: Median OS chemo + surgery 1.6 years vs chemo + RT 1.4 years (NS); 1-year OS 70% vs. 66% (NS). If induction chemo only, median OS 9 months. No difference in PFS or LC
*** Conclusion: Trial inconclusive due to limited accrual, nevertheless, surgery and RT arms comparable and similar to historical controls

## Neoadjuvant Chemotherapy +/- Neoadjuvant Immunotherapy

* CheckMate 816 -- Induction platinum-doublet x3 cycles, with or without nivolumab, then surgery.
** Randomized 358 patients with stage IB-IIIA resectable NSCLC (64% Stage IIIA)
** 2022 PMID 35403841 -- "Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer," (PM Forde, NEJM 2022, 386(21):1973)
*** Median event free survival: ChemoImmunotherapy 32 months; Chemo alone 21 months (SS)
*** Pathological CR: ChemoImmunotherapy 24%, Chemo alone 2%
*** Toxicity similar.

## Surgery +/- Adjuvant Chemo

* Adjuvant chemo has become standard of care in patients who are treated with surgery and found to have stage IIIA disease. This is based on the IALT trial, as well as by extrapolating from NCIC (Stage I-II) and CALGB 9633 (Stage IB) trials
* Please see early stage operable NSCLC section

## Surgery + Adjuvant RT +/- Chemo

* Please see Early stage operable NSCLC section

## Induction Chemo biology

* Netherlands; 2003 PMID 14676792 -- "Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy." (El Sharouni SY, Br J Cancer. 2003 Dec 15;89(12):2184-9.)
** Retrospective. 23 patients with NSCLC. Interval times between end of induction of start of RT evaluated. Mean time to RT 80 days
** Outcome: 41% potentially curable patients became incurable; tumor median doubling 29 days (8.3-171 days)
** Conclusion: Accelerated tumor cell proliferation, much shorter doubling time than for untreated tumors. Gain from chemo (tumor decrease) was lost with waiting for RT

## Special cases
### Superior sulcus (Pancoast) tumors

Complete resection in 50%, 5-year OS 30%.
* SWOG 9416 / Intergroup 0160, 2001 (1995-99) - Phase II
** PMID 11241082 — "Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160)." Rusch VW et al. J Thorac Cardiovasc Surg. 2001 Mar;121(3):472-83.
** 111 pts. T3-4 N0-1, mediastinoscopy negative. Treated with 2 cycles of cisplatin and etoposide concurrent with 45 Gy RT. Pts who responded or had stable disease underwent resection 3-5 weeks later. Two additional cycles of adjuvant chemotherapy were given.
** Of 95 pts eligible for surgery, 83 had thoracotomy and 76 (92%) had complete resection. 54 (65%) showed pCR or microscopic residual disease. 2-year OS 55% for all pts and 70% for those with complete resection.

## Practice Guideline

* ACCP; 2007 PMID 17873172 -- "Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition)." (Robinson LA, Chest. 2007 Sep;132(3 Suppl):243S-265S.)
** Stage IIIA NSCLC evidence review
** Conclusion: Combination chemo-RT is preferred treatment for prospectively recognized IIIA. Neoadjuvant therapy followed by surgery is not supported by current evidence