# Radiation Oncology/NSCLC/Early Stage Operable

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## Pathology

* Moffitt, 2007 PMID 17314339 -- "DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer." (Zheng Z, N Engl J Med. 2007 Feb 22;356(8):800-8.)
** RRM1 expression evaluated in 187 patients with early-stage NSCLC treated with surgery only
** RRM1 expression correlated with ERCC1 (SS) but not PTEN (NS)
** Outcomes: median DFS: high RRM1 >120 months vs. low RRM1 54 months (SS); median OS: >120 months vs. 60 months. Benefit if RRM1+ and ERCC1+
** Conclusion: RRM1 and ERCC1 determinants of survival
* Duke, 2006 PMID 16899777 -- "A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer." (Potti A, N Engl J Med. 2006 Aug 10;355(6):570-80.)
** Gene expression profiling. 89 patients learning set, 25 patients from ACOSOG Z0030 and 84 patients from CALGB 9761 as verification set
** Predictive accuracy of recurrence ~75%
** Also identified subset of IA who are at high risk of recurrence
** Since retracted by authors due to questions regarding integrity of the data.

## Lymph Node Staging

* CALGB 9761 PMID 15829324 -- "Poor correspondence between clinical and pathologic staging in stage 1 non-small cell lung cancer: results from CALGB 9761, a prospective trial." (D'Cunha J, Lung Cancer. 2005 May;48(2):241-6. Epub 2005 Jan 4.)
** Prospective. 489 patients with suspected or bx-proven NSCLC, clinical stage I (T1-2N0) by CT scan or cervical mediastinoscopy
** Outcome: Pathologic NSCLC in 86% (others were 2/3 benign, 1/3 malignancy other than NSCLC). Of these, Stage pI 72%, pII 14%, pIII 13%, pIV 1%. Overall, only 62% of clinically suspected Stage I NSCLC had pathologic Stage I NSCLC
** Conclusion: Poor predictive value of current clinical staging

## Lobectomy vs. SBRT

* STARS (NCT00840749) and ROSEL (NCT00687986) Trials - Pooled Analysis of 2 Randomized Trials. (PMID 25981812) Chang JY et al, "Stereotactic ablative radiotherapy versus lobectomyfor operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials" Lancet Oncology. 2015 Jun;16(6):630-7
** 58 total patients with operable T1-2a (<4 cm) N0 M0 non-small cell lung cancer (NSCLC)
** Randomized to lobectomy (total of 27 patients) vs SABR (total 31 patients).
*** At 3 years, SABR associated with improved overall survival (OS) over lobectomy (95% vs. 79%, P=0.037)
*** At 3 years, SABR associated with a decrease in grade ≥3 toxicity (10% vs. 48%)
*** No difference in recurrence free survival at 3 years with SABR (86%) vs lobectomy (80%) (p=0.54)
** Conclusions "Although this study is limited by the small number of enrolled patients and requires validation with larger numbers of patients, our findings strongly support equipoise between surgery and SABR and justify the initiation of large randomised comparisons of surgery versus SABR."
* Editorial (PMID 26244136): Early OS advantages with fractionated radiation over surgery seen in 2 previous RCTs for stage III NSCLC (Albain/Intergroup Lancet 2009 and van Meerbeeck/EORTC JNCI 2007), attributable to difference in treatment-related mortality. But in those trials surgery was associated with better loco-regional control than conventional RT, resulting in a re-approximation of the survival curves over time. By contrast, SABR provides excellent local control, meaning that differences in treatment-related morbidity/mortality may create a "head start effect" allowing for improved OS in studies where SABR can perform at equivalent, or even near-equivalent, oncologic levels to lobectomy.

## Surgery vs. Fractionated RT

* Medical Research Council/Hammersmith Hospital (1954-1958) -- Primary RT vs Primary Surgery
** Randomized. 58 patients, no clinical or radiologic evidence of mediastinal involvement. Biopsy proven carcinoma. Arm 1) RT - using 8 MeV linac, 45 Gy in 4 weeks daily. Target + 2cm + hilar/mediastinal areas; vs. Arm 2) Surgery - pneumonectomy or lobectomy + hilar/mediastinal LND. However 13/30 weren't operable/refused. Histology squamous 64%, adenocarcinoma 3%, small cell/anaplastic 33%
** 1963 PMID not available, doi:10.1016/S0140-6736(63)91444-2 --"THE TREATMENT OF CARCINOMA OF THE BRONCHUS A Clinical Trial to Compare Surgery and Supervoltage Radiotherapy" (Morrison R, Lancet. 1963. Mar 30; 281(7283):683-684)
*** Outcome: 1-year OS RT 64% vs. Surgery 43%; 2-year OS 14% vs. 27%; 4-year 7% vs. 23% (NS). By histology: squamous 6% vs. 30% (SS); small cell 10% both (NS)
*** Conclusion: In squamous cell tumors, surgical resection is significantly better than RT; no difference in small cell.

## Surgery alone
### Type of surgery

* Standard surgery is lobectomy.
* Wedge resection or segmental resection for Stage I disease has been advocated, but in LCSG 821 (see below) wedge (with 2cm margin) shown to have significantly worse recurrence rate (LR 6% vs 18%) without functional improvement
* Nevertheless, CALGB is trying smaller resection again (CALGB 140503) with more modern surgical techniques and smaller tumors
* Criteria:
** Pneumonectomy: FEV1 >80% and >2L, DLCO >50%
** Lobectomy: FEV1 >70% and >1.5L
** Wedge: FEV1 >0.6L
** SBRT/RFA: FEV1 >0.2L
** Post op predictive FEV1 should be 0.7-0.8L (preop FEV1 x # segments remaining/total segments, corrected for lung function)

### ACCP Guidelines

* ACCP; 2007 PMID 17873167 -- "Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition)." (Colice GL, Chest. 2007 Sep;132(3 Suppl):161S-77S.)
* Patients be assessed for curative resection by a multidisciplinary team
* Patients not be denied lung resection surgery on the grounds of age alone
* Patients with major factors for perioperative CV risk to have a preoperative cardiologic evaluation
* If FEV1 >80% predicted or >2L and no evidence of dyspnea on exertion or interstitial lung disease, suitable for pneumonectomy. If FEV1 >1.5L and no evidence of DOE or ILD, suitable for lobectomy
* If evidence of undue dyspnea on exertion or interstitial lung disease, and FEV1 adequate, DLCO is recommended
* If either FEV1 or DLCO <80% predicted, post-op lung function be predicted (PPO = predicted post operative function)
* FEV1 <40% PPO or DLCO <40% PPO indicates increased risk. Patients should undergo pre-op exercise testing
* If product of %PPO FEV1 and %PPO DLCO is <1650% PPO or FEV1 <30%, increased risk. Patients should be counseled about nonstandard approaches
* If VO2max <10 ml/kg, increased risk. Patients should be counseled about nonstandard approaches
* If VO2max <15 ml/kg and both FEV1 and DLCO <40% PPO, increased risk. Patients should be counseled about nonstandard approaches
* If patients walk <25 shuttles on two shuttle walks or less than one flight of stairs, increased risk. Patients should be counseled about nonstandard approaches
* If PACO2 >45 mmHg, not independent risk factor, but further physiologic testing recommended
* If SAO2 <90%, increased risk. Patients should undergo further physiologic testing
* If very poor lung function and lung cancer isn upper lobe emphysema, recommend combined LVRS and lung cancer resection, if both FEV1 and DLCO >20% predicted
* All patients be counselled regarding smoking cessation

### Meta-analysis

* Athens; 2009 PMID 18641014 -- "Does lobectomy achieve better survival and recurrence rates than limited pulmonary resection for T1N0M0 non-small cell lung cancer patients?" (Chamogeorgakis T, Interact Cardiovasc Thorac Surg. 2009 Mar;8(3):364-72. Epub 2008 Jul 18.)
** Meta-analysis; updated analysis done by Nakamura below (PMID 15756281). 3 additional comparative studies identified
** Conclusion: Wedge resection is not comparable to lobectomy; however, segmental resection is comparable to lobectomy for small peripheral tumors
* Shizuoka, Japan; 2005 (1970-2004) PMID 15756281 -- "Survival following lobectomy vs limited resection for stage I lung cancer: a meta-analysis." (Nakamura H, Br J Cancer. 2005 Mar 28;92(6):1033-7.)
** Meta-analysis. 14 articles (1 RCT, 1 matched pair, and 12 retrospective studies), 2790 patients (1887 lobectomy, 903 limited resection)
** Outcome: Survival difference between lobectomy minus limited resection at 1-year 0.7% (NS), 3-years 1.9% (NS), and 5-years 3.6% (NS). However, high inter-study heterogeneity
** Conclusion: Survival after lobectomy or limited resection is comparable; however, interstudy heterogeneity suggests that caution is required to interpret these results

### Sublobar resection

* CALGB 140503 (currently accruing)
** "A Phase III Randomized Trial of Lobectomy versus Sublobar Resection for Small (≤ 2 cm) Peripheral Non-Small Cell Lung Cancer"
** Goal is to determine if lobectomy is necessary for small peripheral tumors that are smaller than those treated 30 yrs ago in LCSG 821.
* SEER data; 2005 (1992-1997) PMID 16002941 -- "Similar long-term survival of elderly patients with non-small cell lung cancer treated with lobectomy or wedge resection within the surveillance, epidemiology, and end results database." (Mery CM, Chest. 2005 Jul;128(1):237-45.)
** SEER analysis. 14,555 patients with Stage I-II NSCLC. Age groups <65 (35%), 65-74 (42%), and >= 75 (23%)
** Outcome: Curative surgery 92% vs. 86% vs. 70% (SS). Limited resection 8% -> 17% (SS). Median OS 5.9 years vs 3.9 years vs 2.3 years (SS). For young patients, lobectomy conferred survival benefit, but no difference for patients >= 71 years
** Conclusion: Lobectomies confer survival benefit over limited resection in young patients but not in for elderly patients
* North American Lung Cancer Study Group 821 (1982-88) -- lobectomy vs. sublobar resection
** Randomized. 247/276 patients with pathologic peripheral pT1N0 (defined on PA and lateral CXR). Middle lobe tumors excluded. Frozen section of LN (at least one node from bronchopulmonary, hilar, and mediastinal) had to be negative, otherwise completion lobectomy prior to randomization. Arm 1) Lobectomy vs. Arm 2) Limited resection (segmental resection or large wedge with 2cm margin). Locoregional recurrence defined as ipsilateral lung or mediastinum; non-local recurrence was DM as well as LR + DM
** Original; 1995 PMID 7677489 — "Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer." (Ginsberg RJ, Ann Thorac Surg. 1995 Sep;60(3):615-22)
*** Locoregional recurrence: limited resection 17% vs. lobectomy 6% (SS, 3x higher). No difference in DM. RFS 69% vs. 82% (SS, p=0.06 in one-sided test with p<0.1); OS 61% vs. 70% (SS, p=0.09 in one-sided test with p<0.1); Deaths due to cancer 62% vs. 55%
*** By tumor volume: lobectomy better, regardless of tumor size (<3 cm3, 3-8 cm3, 8-27 cm3)
*** Toxicity: perioperative morbidity, mortality (1%) comparable. Early post-op pulmonary function significantly better for sublobar resection at 6 months, but no difference at 1 year and 1.5 years.
*** Conclusion: Higher LR and death rate, without improved post-op function
** Update; 1996 PMID 8823141 -- "Lobectomy versus limited resection in T1 N0 lung cancer." (Lederle FA, Ann Thorac Surg. 1996 Oct;62(4):1249-50.)
*** Further update of data, in a letter to editor format. 12 new recurrences identified (7 on sublobar arm and 5 on lobectomy arm). New survival curves
*** Outcome: Overall death-rate-increase improved from 47% in original report to 26% (NS); death due to cancer-rate-increase improved from 47% to 28% (NS); recurrence rate-increase improved from 60% to 39% (NS)
*** Conclusion: Modest corrections, but overall conclusions hold, wth local recurrence rate difference essentially unchanged

### Lobar resection

* Overall 5-year OS for Stage I is ~65%, for Stage II is ~45%
* Tumor size is a prognostic factor, independent of T-stage, with smaller tumors having better survival
* Selected patients with tumors <1.5 cm may have 5-year OS as high as 95%
* Buenos Aires; 2008 (Argentina)(1985-2006) PMID 18758301 -- "Analysis of survival in 400 surgically resected non-small cell lung carcinomas: towards a redefinition of the T factor." (Lyons G, J Thorac Oncol. 2008 Sep;3(9):989-93.)
** Retrospective. 400 patients, pulmonary resection with curative intent. No neoadjuvant chemotherapy. Adeno 61%.
** Outcome: Operative mortality lobectomy 2%, pneumonectomy 18% (SS). Complete resection 85%. For pN0, if tumor <15mm 5-year OS 95% vs. >=15 mm 65% (SS); no impact of age, sex, side, or histology
** Conclusion: Tumors >15 mm associated with shorter 5-year OS
* Modena; 2006 (Italy) PMID 16996167 -- "The prognostic impact of tumor size in resected stage I non-small cell lung cancer: evidence for a two thresholds tumor diameters classification." (Christian C, Lung Cancer. 2006 Nov;54(2):185-91. Epub 2006 Sep 22.)
** Retrospective. 548 patients with Stage I, s/p complete surgical resection
** Outcome: Tumor >5cm had 60% higher probability of death than size 2-5cm, which had 57% higher probability of death than size <2cm
*** Stage IA: 5-year OS 67%, DSS 85%
*** Stage IB: 5-year OS 49%, DSS 53%
** Conclusion: Tumor sizes <2cm, 2-5cm, and >5cm have different prognosis
* Japanese National Chest Hospital Study Group; 2005 PMID 15797041 -- "Impact of large tumor size on survival after resection of pathologically node negative (pN0) non-small cell lung cancer." (Takeda S, Ann Thorac Surg. 2005 Apr;79(4):1142-6.)
** Retrospective. 603 patients with pN0 NSCLC, s/p complete resection.
** Outcome: 5-year OS <=2 cm 80%, 2-3 cm 73%, 3-5 cm 68%, >5 cm 47%
** Conclusion: Tumor size >5cm inversely predicts survival
* MD Anderson; 1995 PMID 7646126 -- "Survival in early-stage non-small cell lung cancer." (Nesbitt JC, Ann Thorac Surg. 1995 Aug;60(2):466-72.)
** Meta-analysis. 10 series
** Outcome: 5-year OS Stage I 65% (55-72%), Stage II 41% (29-51%)
* SEER data; 2004 (1988-2003) PMID 15364754 -- "The effect of tumor size on curability of stage I non-small cell lung cancers." (Wisnivesky JP, Chest. 2004 Sep;126(3):761-5.)
** Population study. 7620 patients, Stage I NSCLC, curative resection.
** Outcome: 12-year OS tumor size 0.5-1.5cm 69%, 1.6-2.5 cm 63%, 2.6-3.5 cm 58%, 3.6-4.5 cm 53%, >4.5 cm 42% (SS)
** Conclusion: Smaller size associated with improved curability
* LCSG 821 - PMID 7677489 - (listed above)
** 5 yr OS for T1N0 s/p lobectomy alone ~65%
** 5 yr OS for T1N0 s/p wedge alone ~45%
* Washington University; 1933 PMID 18591561 -- "Evarts A. Graham and the first pneumonectomy for lung cancer." (Horn L, J Clin Oncol. 2008 Jul 1;26(19):3268-75.)
** Description of the first successful one-stage pneumonectomy for lung cancer performed April 5, 1933

## Pre-op EBRT

* Nijmegen (The Netherlands)(1971-1976) -- Pre-op Mediastinal RT vs Surgery Alone
** Randomized, pilot. 33 patients, clinical T1-2N0 NSCLC, mediastinoscopy LN-. Arm 1) Pre-op RT 20/5 to hilar, subcarinal, tracheo-bronchial, and paraesophageal LNs followed by surgery following Monday vs. Arm 2) Surgery alone. Either lobectomy or pneumonectomy
** 1984 PMID 6378851 -- "Evaluation of short-course preoperative irradiation in the treatment of resectable bronchus carcinoma: long-term analysis of a randomized pilot-study." (Kazem I, Int J Radiat Oncol Biol Phys. 1984 Jul;10(7):981-5.) Minimum F/U 7 years
*** Outcome: 5-year OS pre-op RT 58% vs. surgery alone 43%; 5-year DSS 78% vs. 67% (NS); median OS 6 years vs. 2.5 years. R0 resection in pre-op 57% vs surgery only 28%
*** Subgroup analysis: If lobectomy, RT beneficial only during first year, then no difference. If pneumonectomy, RT beneficial during entire follow-up (5-year OS 66% vs. 42%).
*** Toxicity: 9% operative mortality (all patients in surgery only arm); delayed wound healing comparable
*** Conclusion: Pre-op RT well tolerated, and results are encouraging
* Berlin (East Germany)(1963-1971) -- Pre-op RT vs. Surgery only
** Randomized. 196 operable patients. Arm 1) Pre-op RT 5500 RHD (Co-60) vs. Arm 2) Surgery only
** 1975 PMID 173257 -- "[Results of a controlled clinical trial for evaluation of intensive preoperative irradiation in operable bronchial cancer (author's transl)] - [Article in German]" (Eichhorn HJ, Arch Geschwulstforsch. 1975;45(4):376-84.)
*** Outcome: No difference in annual survival. Significantly reduced LR rate
*** Toxicity: Post-op mortality and complications "a bit more favorable"
*** Conclusion: No difference
* NCI Trial (1963-1966) -- Pre-op RT vs. Surgery only
** Randomized. 17 institutions. 568 patients operable (no carina, no mediastinum/SCV, no chest wall invasion). Arm 1) immediate surgery vs. Arm 2) Pre-op RT, given as >40 Gy supravoltage
** 1975 PMID 171057 -- "Preoperative irradiation of cancer of the lung: final report of a therapeutic trial. A collaborative study." (Warram J, Cancer. 1975 Sep;36(3):914-25.)
*** Outcome: 5-year OS pre-op RT 13% vs. surgery 16% (NS); 5-year RFS 11% vs. 14% (NS)
*** Toxicity: Post-op mortality in surgery alone 11%, not estimated for pre-op RT group
*** Conclusion: No difference

## Post-operative EBRT

* Lung Cancer Study Group trial (LCSG 773) established a benefit for RT in local control, but there was no impact on survival
* PORT Meta-analysis in 1998 analyzed individual data from 9 prospective trials. It concluded that RT had detrimental impact on survival, particularly in N0 and N1 stage. The results for Stage III and N2 disease favored RT, but were not statistically significant
* As a result, clinical use of post-op RT dramatically decreased
* However, radiation oncologists are critical of the meta-analysis conclusions for several reasons, including staging, patient selection, old technology and inappropriate dose/fractionation schedules.
* Retrospective evidence using modern RT techniques suggests a survival benefit for post-op RT in N2 patients, but randomized evidence has not; retrospective SEER data supports benefit for N2 patients, also suggests worse survival for N0-1 patients.
* Similarly, retrospective analysis of data from prospective trial (ANITA) suggest that PORT is detrimental in pN1 patients who undergo treatment with chemotherapy, but it is beneficial in pN1 patients who observed only. There was a benefit for PORT in pN2 patients regardless of whether they received adjuvant chemotherapy or not
* The evidence is stronger for significant benefit in locoregional control. Whether this can ultimately translate into survival (as it did in breast cancer), in N2 patients in a randomized setting appears unlikely.
* The situation is confounded by the fact that adjuvant chemotherapy is becoming widely used, after publication of 3 positive trials (see below)
* Based on the existing data, most recent guidelines (e.g. ASCO 2021) do not recommend routine PORT for pN2 patients.

### Meta-analysis

* PORT Meta-analysis
** 2005 PMID 15846628 -- "Postoperative radiotherapy for non-small cell lung cancer." (PORT Meta-analysis Trialists Group, Cochrane Database Syst Rev. 2005 Apr 18;(2):CD002142.)
*** 10 trials (after 1965), 2232 patients. (Added 1 trial to prior analysis). Median F/U 4.25 years
*** Significant adverse effect of PORT on survival; 3-year OS reduced from 58% to 52% (18% relative increase in risk of death)
*** Subset analysis: effect in Stage I-II, N0-1 disease. No evidence of adverse effect in Stage III, N2 patients
*** Conclusion: PORT is detrimental. Role in N2 tumors may justify further research
*** Comment: most of criticism from 1998 analysis still valid
** 1998 PMID 9690404 — "Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials." PORT Meta-analysis Trialists Group. Lancet. 1998 Jul 25;352(9124):257-63.
*** 2128 pts in 9 randomized trials. Stages I-III.
*** Local control: 24% reduction in local recurrences
*** Survival: Increase in relative risk of death by 21% which corresponds to absolute 7% decrease in 2-year OS with PORT. Detrimental effect confined to Stage I-II. No difference in survival for Stage III.
*** Conclusion: PORT is detrimental and should not be used.
*** Criticism: ~25% patients had T1N0 disease; initial staging inadequate by today's standards; Co-60 used in 4 trials (5-year OS for cobalt 8% vs. 30% for MeV); old techniques including lateral beams; high doses (60 Gy) and fractions (up to 3.0 Gy/fx)

### Surgery +/- EBRT

* Lung ART (France,UK,Germany,Switzerland,Belgium) (2007-18)
** Randomized. 501 patients, pIIIAN2 after lobectomy or greater. Most received adjuvant chemotherapy. Almost all R0 resections; ~25% in each arm with ECE. Most 3DCRT (89%), some IMRT (11%); 91% PET staged preop. Strict tx volume criteria; randomized to PORT (54 Gy, 27-30 fxs) or no PORT. Median follow-up 4.8y.
** 2022 PMID 34919827 – “Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial” (Le Pechoux C et al, Lancet. 2022 Jan;23(1):104-14.)
*** 3-year DFS (primary endpoint): RT 47% vs. 44% (p=0.18); median DFS 31 vs 23 months. Of 296 DFS events, 25% RT patients relapsed in mediastinum vs 46% control; extracranial mets, 49% RT, 47% control.
*** 3-year OS: RT 67% vs. 69% control (p=NS).
*** Early adverse events: RT 89% vs. 74% control. Late: RT 78% vs 62% control.
*** Conclusion: 3D conformal PORT not standard of care in patients with resected IIIAN2 NSCLC.
* Rome (Italy)(1989-1997)
** Randomized. 104 patients with Stage I only. No sublobar resection, hilar-mediastinal radical LND performed (mean 20 LNs). If pN0, randomized to Arm 1) observation vs. Arm 2) RT corrected 50.4/28 to bronchial stump and homolateral hilum only; mean treated area 50 cm2
** 2002 PMID 11830308 -- "Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial." (Trodella L, Radiother Oncol. 2002 Jan;62(1):11-9.)
*** 5-year outcome: OS: RT 67% vs. observation 58% (p=0.048); LR: 2% vs. 23%
*** Toxicity: acute toxicity Grade 1 in 11%; no long term clinical toxicity, 37% radiographic fibrosis
*** Conclusion: RT gave good results in LC, promising OS and DFS
** Comment: In PORT Meta-analysis update from 2005 (PMID 15603857), it is stated that updated results within the meta-analysis are no longer significant (p=0.2). This was attributed to longer follow-up and anomalies in original dataset, which were subsequently corrected
* Slovenia (1988-1992)
** Randomized. 74 patients s/p radical surgery, with N2 disease. +/- RT to hilar/mediastinum 30/10
** 5-years, 1996 PMID 8696724 -- "Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer (NSCLC): randomised clinical study 1988-1992." (Debevec M, Lung Cancer. 1996 Feb;14(1):99-107.)
*** 5-year outcome: no difference in OS; only prognostic factor was number of LN
*** Conclusion: no difference
* Beijing (China) (1982-95)
** Randomized. 366 pts, positive N1 or N2 nodes after surgery. Randomized to RT 60 Gy vs no further therapy. Field included bronchial stump, ipsilateral hilum, and most of the mediastinum; included SCLV for pts with upper mediastinal node involvement; mediastinum down to diaphragm for lower lobe primary. AP/PA 40/20, then obliques 20/10. SCV 50/25
** 2000 PMID 10863061 — "A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial." Feng QF et al. Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):925-9.
*** Outcome: 5-yr OS RT 43% vs control 40% (NS). Trend toward improved OS in T3-4N1 RT 58% vs. control 40% (p=0.09). No difference in N2 RT 23% vs. control 26% (NS)
*** Failure: local 13% vs. 33% (SS), SCV LN 13% vs. 12%, DM 48% vs. 51%
*** Conclusion: Significant benefit on local control, not OS. Trend to survival benefit in T3-4N1
** Comments: More pts with N2 disease in RT group (45% vs 27%)
* GETCB (French/European)(1986-94)
** Randomized. 728 pts (Stage I-III) randomized after resection to RT 60 Gy or observation. 40% N0, 33% N1, 27% N2; Stage I 30%, Stage II 25%, Stage III 45%
** RT: AP/PA 40 Gy (either 40/20 or 40/16 @2.5/fx) to bronchial stump, ipsilateral hilum, upper/middle mediastinum, SCV; then 20 Gy in obliques/laterals to bronchial stump, ipsilateral hilum, mediastinum. SCV dose 40-45 Gy
** 1999 PMID 10421262 — "A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d'Etude et de Traitement des Cancers Bronchiques." Dautzenberg B et al. Cancer. 1999 Jul 15;86(2):265-73. Median F/U 5.7 years
*** 5-yr outcome: OS RT 30% vs control 43%. Excess mortality due to increase in intercurrent deaths (31% vs 8%). More intercurrent deaths for higher dose per fraction. ON subgroup analysis, detrimental effect of RT significant in Stage I-II but not Stage III. No effect on local recurrences or distant mets.
** Critique: included N0 patients, majority treated with Co-60, with fractions up to 2.5 Gy/fx
* Graz (Austria)(1985-1995)
** Randomized. 155 pts, pT1-3 pN0-2. Randomized to RT 50 Gy (if pN0) or 56 Gy (if pN1-2) vs no further treatment. Treatment included the bronchial stump + 2cm margin, ipsilateral hilum, and mediastinum; SCLV included for apical tumors. 2F AP/PA or 3F with off-cord after 42 Gy
** 1997 PMID 9377958 Full text — "Postoperative radiotherapy in radically resected non-small cell lung cancer." Mayer R et al. Chest. 1997 Oct;112(4):954-9.
*** 5-yr outcome: OS: RT 30% vs observation 20% (NS). DFS: 20% vs. 16% (NS). LR 6% vs. 24% (SS)
*** Conclusion: Significant reduction in local recurrences, tendency to OS benefit
* Medical Research Council (1986-93)
** Randomized. 308 pts. Were pN1 or pN2. Randomized after surgery +/- RT 40 Gy in 15 fx.
** 1996 PMID 8761382 — "The role of post-operative radiotherapy in non-small-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease. Medical Research Council Lung Cancer Working Party." Stephens RJ et al. Br J Cancer. 1996 Aug;74(4):632-9.
*** Overall, no survival difference. On subgroup analysis, trend to survival benefit for N2 pts (21% vs 36% at 3 yrs, p=0.18). No benefit in N1 pts.
* France (1985-91)
** Randomized. 163 pts, T2N0. Randomized to RT 60 Gy or no further treatment.
** 1996 PMID 8784014 — "Postresection irradiation for T2 N0 M0 non-small cell carcinoma: a prospective, randomized study." Lafitte JJ et al. Ann Thorac Surg. 1996 Sep;62(3):830-4.
*** No difference in survival, OS 44.2% (survival figures not given for each arm). No difference in local or distant mets.
* Lung Cancer Study Group 773
** Randomized. 230 pts. Resected squamous cell carcinoma, Stage II or III. Randomized to +/- RT 50 Gy to mediastinum.
** 1986 PMID 2877397 — "Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung." The Lung Cancer Study Group. N Engl J Med. 1986 Nov 27;315(22):1377-81.
*** Local recurrences were reduced: 20% vs 1% local failure, but overall treatment failures were the same.
*** Conclusion: Improved LR, but no effect on survival.
* Van Houtte (1966-1975)
** 224 pts. N0. Randomized after resection to RT (60 Gy) vs observation.
*** 1980 PMID 6998936 — "Postoperative radiation therapy in lung cancer: a controlled trial after resection of curative design." Van Houtte P et al. Int J Radiat Oncol Biol Phys. 1980 Aug;6(8):983-6.
*** Survival was worse in the RT group: 5-ys OS 24% vs 43% (NS).

### Surgery + EBRT nonrandomized

* SEER study (1988-2002)
** 2007 PMID 17620279 -- "The risk of death from heart disease in patients with nonsmall cell lung cancer who receive postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database." (Lally BE, Cancer. 2007 Jul 9; [Epub ahead of print])
*** SEER database review. 6148 patients with pneumonectomy/lobectomy, with ipsilateral N+, s/p PORT
*** Outcome: PORT use 1983-1988 HR for cardiac death 1.5 (SS), which is comparable to survival detriment reported by PORT Meta-Analysis; 1989-1993 HR for cardiac death 1.08 (NS)
*** Conclusion: Risk of cardiac death from PORT declined, and no longer significant
** 2006 PMID 16769986 — "Postoperative Radiotherapy for Stage II or III Non-Small-Cell Lung Cancer Using the Surveillance, Epidemiology, and End Results Database." (Lally BE et al. J Clin Oncol 2006 Jul 1; 24(19):2998-3006.)
*** SEER review. 7456 patients with Stage II-III, N0-N2, survival at least 4 months
*** Overall, use of PORT had no impact on survival.
*** Nodal subset analysis: Significant improvement in N2 (HR = 0.855); significant worsening in survival for N0 (HR=1.17) and N1 (HR=1.097) patients
*** Conclusion: significant benefit for N2, disadvantage for N0-1
*** Editorial (PMID 16769984): Recommend risk group stratification, and further exploration of post-op RT
*** Counterpoint (PMID 17264348): Editorialists too optimistic, post-op chemo now standard of care, and randomized CRT trial is badly needed
*** European perspective (PMID 17327597): Design of a multi-national randomized prospective trial (Lung ART), target 700 N2 patients, surgery +/- 3D-CRT, chemo neoadjuvant or adjuvant
* ANITA
** Retrospective analysis of prospective data. Full trial discussed under #Adjuvant chemotherapy below. Patients randomized to surgery +/- chemo, and PORT was recommended for pN+ pts (but not required). 232/840 (28%) received RT 45-60 Gy (8% of N0 pts, 35% of N1, 52% of N2).
** 2008 PMID 18439766 -- "Impact of Postoperative Radiation Therapy on Survival in Patients With Complete Resection and Stage I, II, or IIIA Non-Small-Cell Lung Cancer Treated With Adjuvant Chemotherapy: The Adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial." (Douillard JY, Int J Radiat Oncol Biol Phys. 2008 Apr 24 [Epub ahead of print])
*** pN1: benefit for PORT if no chemo arm (median OS 2.2 years vs. 4.2 years), detriment for PORT if chemo arm (7.8 years vs. 3.9 years)
*** pN2: benefit for PORT regardless of chemo arm; if no chemo (1.1 years vs. 1.9 years), if chemo (2.0 years vs. 3.9 years)
*** Conclusion: Positive effect of PORT in pN2 patients, negative effect in pN1 patients who were treated with chemotherapy
* CALGB 9335 / ECOG (1994-99)
** 2000 ASCO Abstract: "Thorascopic wedge resection and radiotherapy for T1N0 non-small cell lung cancer (NSCLC) in high risk patients: preliminary analysis of a Cancer and Leukemia Group B and Eastern Cooperative Oncology Group Phase II trial" Bogart JA et al. Proc ASCO 19:488a-1907, 2000.
** 2005 PMID 15821648, 2005 update: "Video-assisted wedge resection and local radiotherapy for peripheral lung cancer in high-risk patients: the Cancer and Leukemia Group B (CALGB) 9335, a phase II, multi-institutional cooperative group study." Shennib H et al. J Thorac Cardiovas Surg, 129(4):813-8, 2005
*** Incidence of +margins was 6% in T1N0, 23% in T2N0.
*** Local control was >90%, but there was a 25% incidence of radiation induced pneumonitis.
* U Pennsylvania, 2001 PMID 11579111 -- "Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma." (Machtay M, J Clin Oncol. 2001 Oct 1;19(19):3912-7.)
** Retrospective. 202 patients, most with Stage II-III, 41% positive/close SM. Median RT 55 Gy. Median F/U 2 years, 5.2 years for survivors
** 4-year outcomes: OS 34%; LC 84%; FDM 37%
** Intercurrent disease deaths: 12% (comparable to matched population at 10%). Dose-response: risk of intercurrent death 2% if <54 Gy; 17% if >=54 Gy
** Conclusion: Moderen post-op RT does not increase risk of deaths
* Mayo (1987-93) - N2 disease
** Retrospective. 224 patients. IIIA-N2 completely resected. Post-op RT in 88 patients (40%) to median dose 50.4 Gy. Median F/U 3.5 years for patients alive
** 1997 PMID 9338463 — "The impact of surgical adjuvant thoracic radiation therapy for patients with nonsmall cell lung carcinoma with ipsilateral mediastinal lymph node involvement." Sawyer TE et al. Cancer. 1997 Oct 15;80(8):1399-408.
*** 4-year outcome: OS RT 43% vs. no RT 22% (SS); LR 60% vs. 17% (SS)
*** Conclusion: Adjuvant RT may improve local control and OS
** 1997 PMID 9386711 — "Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks." Sawyer TE et al. Ann Thorac Surg. 1997 Nov;64(5):1402-7.
*** Regression tree analysis to stratify patients into high/intermediate/low risk of LR and death
*** Risk groups: high (both superior (Station 1-6) and inferior (Station 7-9) N2 mediastinum involved), intermediate (positive high OR low N2 mediastinum, AND positive N1 nodes, low (everyone else)
*** Conclusion: Patients at high or intermediate risk for LR and death are likely to benefit from post-op RT

### Post-op RT Technique

* Shanghai, 2014 (2005-11) PMID 24529715 -- "Patterns of Local-Regional Failure in Completely Resected Stage IIIA(N2) Non-Small Cell Lung Cancer Cases: Implications for Postoperative Radiation Therapy Clinical Target Volume Design." (Feng W, Int J Radiat Oncol Biol Phys. 2014 Apr 1;88(5):1100-7.)
** 250 pts with pN2 disease s/p resection who did not receive PORT. 173 of 250 (69%) had disease recurrence. 54 had LRF as first event; of these 48, had recurrence within the proposed PORT CTV.
** Conclusion: "Ipsilateral superior mediastinal recurrences dominated for right-sided tumors, whereas left-sided tumors frequently involved the bilateral superior mediastinum. Most of the LRF sites would have been covered by the proposed PORT CTV. A prospective investigation of patterns of failure after PORT (following our proposed CTV delineation guideline) is presently underway and will be reported in a separate analysis."
* Lung Adjuvant Radiotherapy Trial (Lung ART), 2012 PMID 19560881 -- "Variations in target volume definition for postoperative radiotherapy in stage III non-small-cell lung cancer: analysis of an international contouring study." (Spoelstra FO, Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):1106-13.)
** Contouring study.
** Conclusion: "Even among experts, significant interclinician variations are observed in PORT fields. Inasmuch as contouring variations can confound the interpretation of PORT results, mandatory quality assurance procedures have been incorporated into the current Lung ART study."
* Meta-analysis, 2007 PMID 17507176 -- "Estimating the magnitude and field-size dependence of radiotherapy-induced mortality and tumor control after postoperative radiotherapy for non-small-cell lung cancer: Calculations from clinical trials." (Miles EF, Int J Radiat Oncol Biol Phys. 2007 May 14)
** Model developed to describe field-size effect on OS. Data from trials above that did not include chemo
** Results: RT-induced mortality proportional to cube of field size
** Conclusion: Smaller RT fields, tailored to treat areas at risk, provide highest therapeutic ratio
* Duke, 2006 PMID 16682136 -- "Patterns of failure after resection of non-small-cell lung cancer: implications for postoperative radiation therapy volumes." (Kelsey CR, Int J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1097-105. Epub 2006 May 6.)
** Retrospective, 61 pts s/p resection with negative margins, no RT, with first recurrence at a locoregional site (+/- distant metastasis). Surgery was lobectomy in 69%, wedge in 23%, pneumonectomy in 8%. Most did not receive neoadj/adj chemo (13%).
*** Most pts presented with pathologic Stage I disease (i.e. not PORT candidates).
** 44% presented with LRR without DM. Site of failure was brachial stump / staple line (44%), more common after a wedge resection (79% vs 34%). Mediastinum 70%, ipsi hilum 23%, supraclav 8%. Supraclav involvement more common in those who were pN1-2 vs pN0, whereas mediastinal and hilar involvement did not vary based on pN status.
** Patterns of failure demonstrate a fairly predictable pattern based on the involved lobe.
** Left-sided tumors: more frequent involvement of contralateral mediastinum.
** Small RT fields that cover the surgical stump, ipsi hilum, and lower ipsi mediastinum would encompass at least 60% of failure sites.
** Conclusion: "These data may help clinicians construct postoperative RT volumes that are smaller than ones traditionally utilized, which may improve the therapeutic ratio."

## Limited Surgery + Radiation
### Adjuvant Brachytherapy

* Please see the Lung Brachytherapy page

### Adjuvant External Beam

* CALGB 9335 (1995-1999) PMID 15821648 -- "Video-assisted wedge resection and local radiotherapy for peripheral lung cancer in high-risk patients: the Cancer and Leukemia Group B (CALGB) 9335, a phase II, multi-institutional cooperative group study." (Shennib H, J Thorac Cardiovasc Surg. 2005 Apr;129(4):813-8.)
** Phase II. 58 patients with clinical T1 and poor cardiopulmonary status (FEV1 <40%, DLCO <50%, max O2 consumption <45 mmHg. Treated with VAR + adjuvant RT 56/28. If incomplete resection RT 66/33. Target volume staple line or clip markings + 2cm margin (max field size 7x7 cm)
** Surgery: pathology benign 17%, upstaged to T2+ 28%. Conversion to thoracotomy in 17%. SM+ in 9%. Operative failure 29%.
** Surgery complications: Operative mortality 4%, prolonged air leak 10%
** RT results: 32 pathologic T1, 28 received RT. Median OS 27 months
** RT complications: severe dyspnea 11%, moderate pneumonitis 4%, moderate neurologic 4%
** Conclusion: Clinical staging inaccurate in 45%, VAR high failure rate
** Comment: Adjuvant RT was felt to have too high a rate of persistent severe dyspnea to be clinically worthwhile

## Surgery +/- adjuvant chemotherapy

* Historically, a number of prospective trials was negative
* A meta-analysis in 1995 showed a small (5% at 5 years), but non-significant benefit
* Three out of five trials published in early 2000's were positive, and have markedly impacted clinical practice; however, majority of patients were Stage II-III
* CALGB trial 9633 looking specifically at Stage IB (T2N0) was stopped early since there was a survival benefit on initial analysis, but final results were non-significant. Conversely, a Japanese trial and an Italian trial in Stage I showed a survival benefit
* It is not clear whether adjuvant chemotherapy should be used for Stage IB; data is somewhat murky and discussion in CALGB 9633 paper suggests that while adjuvant chemotherapy should not routinely be used in Stage IB, it can be a treatment option in tumors >= 4cm
* Meta-analysis of cisplatin-based trials using individual patient data (CALGB trial excluded) showed composite OS benefit of 5% at 5 years, consistent with prior meta-analysis. However, hazard ratios for Stage IA and IB were not significantly better
* Cisplatin-vinorelbine combination was used in most of the positive trials, and is thus preferable in absence of clear equivalence data for other agents
Meta-Analysis
* NSCLC Collaborative Group; 2010 PMID 20338627 -- "Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data." ([No Author], Lancet. 2010 Apr 10;375(9722):1267-77.)
** Meta-analysis. 34 trials and 8447 patients, individual data.
** Outcome: Benefit of adding chemotherapy after surgery (HR 0.86, SS) with absolute OS benefit at 5 years of 4% (60% to 64%). Benefit of adding chemotherapy after surgery + PORT (HR 0.88, SS), absolute OS benefit at 5 years of 4% (29% to 33%)
** Conclusion: Addition of adjuvant chemotherapy after surgery improves survival, regardless if post-op RT was used
* LACE Collaborative Group; 2008 PMID 18506026 -- "Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group." (Pignon JP, J Clin Oncol. 2008 Jul 20;26(21):3552-9. Epub 2008 May 27.)
** Individual patient data from 5 trials since last meta-analysis. 4584 patients, treated with cisplatin-based chemotherapy. Median F/U 5.2 years
** Outcome: 5-year OS chemotherapy benefit 5.4% (HR 0.89, p=0.005).
** By Stage: Hazard Ratio for Stage IA 1.4 (NS), IB HR 0.93 (NS), II HR 0.83 (SS), III 0.83 (SS)
** Conclusion: Adjuvant cisplatin-based chemotherapy significantly improves survival in patients with NSCLC
* MRC; 1995 PMID 7580546 — "Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group." BMJ. 1995 Oct 7;311(7010):899-909.
** Alkylating agents alone or with RT reduced OS. Cisplatin/RT was no better than RT alone.
** Cisplatin without RT (compared to observation) resulted in 13% reduction in death, 5% improvement in 5-year OS, but statistically insignificant (p=0.08).
Randomized Evidence
* CHEST (Chemotherapy for Early Stages Trial) (2000-2004) -- preop gemcitabine + cisplatin
** Phase III. 270 pts. Stages I (excluding T1N0), II, or IIIA (T3N1 only). Randomized to: 1) 3 cycles of preoperative gemicitabine + cisplatin followed by surgery, or 2) surgery alone.
** 2012 PMID 22124104 -- "Randomized Phase III Study of Surgery Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non-Small-Cell Lung Cancer." (Scagliotti GV, J Clin Oncol. 2012 Jan 10;30(2):128-131.)
*** Closed early (closed in 2004 after results of 3 randomized trials of adjuvant chemotherapy were released.)
*** Median f/u 3.3 yrs. HR of PFS 0.70 and for OS 0.63, both SS.
*** PFS: 3-yr PFS 52.9% vs 47.9%. No significant benefit for Stages IB/IIA. PFS benefit for Stages IIB/IIIA (HR 0.51), median PFS 4.0 yrs vs 1.1 yr; 3-yr PFS 55.4% vs 36.1%.
*** OS: MS 7.8 yr vs 3.8 yr. 3-yr OS 67.6% vs 59.8%. No benefit for Stages IB/IIA. OS benefit for Stages IIB/IIIA (HR 0.42).
** Conclusion: although the study was terminated early, preop chemotherapy improved OS for stages IIB and IIIA.
* NATCH; Spain -- 3 arm: 1) Surgery alone vs 2) Preoperative Chemo + Surgery vs 3) Surgery + Adjuvant Chemo
** 624 pts, Stage IA(>2cm), IB, II, or T3N1 (IIIA). Randomized prior to surgery. Chemo (neoadj or adj) 3 cycles of carboplatin + paclitaxel.
** 2010 PMID 20516435 -- "Preoperative Chemotherapy Plus Surgery Versus Surgery Plus Adjuvant Chemotherapy Versus Surgery Alone in Early-Stage Non–Small-Cell Lung Cancer" (Felip E, J Clin Oncol. 2010 Jul 1;28(19):3138-45.)
*** Preop: 97% received chemo, Median 3 cycles. Response rate 53.3%. Adjuvant: 66% received chemotherapy.
*** Overall, 94% completed surgery. No differences in surgical procedures or postoperative mortality between groups.
*** Non-significant trend for improved DFS for preop chemo vs surgery alone (5-yr DFS 38.3% v 34.1%; HR 0.92). DFS for adjuvant chemo vs surgery alone, 36.6% vs 34.1%.
*** Conclusions: No statistically significant differences in disease-free survival were found with the addition of preoperative or adjuvant chemotherapy to surgery. More patients were able to receive chemotherapy in the neoadjuvant setting.
** 2007 ASCO Abstract
*** 15% pN2.
* Intergroup MRC LU22/NVALT/EORTC 08012 -- 1) Surgery alone vs 2) Preoperative Chemo + Surgery
** 519 pts (Stage I-61%, Stage II-31%, Stage III-7%). Chemotherapy was platinum based (1 of 6 regimens), 3 cycles.
** 2007 PMID 17544497 -- "Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review." (Gilligan D, Lancet. 2007 Jun 9;369(9577):1929-37.)
*** 75% received all 3 cycles of chemotherapy. Response rate 49%, down-staging in 31%. No differences in surgical procedures or postoperative mortality between groups. No difference in OS (HR 1.02)
*** Update of Meta-analysis: 1507 pts. 12% relative survival benefit with the addition of neoadjuvant chemotherapy (HR 0.88, p=0.07), absolute benefit in survival of 5% at 5 years.
** 2007 ASCO Abstract
** Conclusion: No evidence of difference in overall survival with the addition of neoadjuvant chemotherapy to surgery. However, meta-analysis suggests a 5% improvement in survival at 5 years.
* CALGB 9633 (1996-2003) -- Surgery +/- paclitaxel and carboplatin
** Randomized. Stopped early after interim analysis showed survival benefit. 344 patients (target 500). NSCLC, T2, pN0 by mediastinoscopy, resected with lobectomy/pneumonectomy. Arm 1) adjuvant paclitaxel 200 mg/m2 + carboplatin AUC 6 Q3W x4 cycles vs. Arm 2) observation. Primary endpoint OS
** 2008 PMID 18809614 -- "Adjuvant Paclitaxel Plus Carboplatin Compared With Observation in Stage IB Non-Small-Cell Lung Cancer: CALGB 9633 With the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups." (Strauss GM, J Clin Oncol. 2008 Sep 22. [Epub ahead of print]) Median F/U 6.2 years
*** Outcome: median OS chemo 7.9 years vs. observation 6.5 years (NS); 5-year OS 60% vs. 58% (NS); 5-year DFS 52% vs. 48% (NS). Subgroup analysis: survival difference for tumors >=4cm
*** Toxicity: Grade 3/4 neutropenia in 35%
*** Conclusion: Negative trial, adjuvant chemo should not be standard of care in Stage IB. Survival advantage for large tumors on subset analysis
* International Adjuvant Lung Trial (IALT) (1995-2000) -- Surgery +/- cisplatin and vinca alkaloids
** Randomized. Terminated early due to slow accrual. 1867 patients (target 3300). Stages I-III (Stage I 36%, Stage II 24%, Stage III 40%), complete resection. Arm 1) Adjuvant cisplatin with either etoposide (in 56%) or vinca alkaloid (vinorelbine, vinblastine, vindesine) x3-4 cycles. ~25% also received RT based on institutional preference.
** 2004 PMID 14736927 — "Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer." Arriagada R et al. N Engl J Med. 2004 Jan 22;350(4):351-60. Median F/U 4.7 years
*** Outcome: 5-year OS chemo 44% vs. 40% control (SS); DFS 39% vs. 34% (SS). Also benefit for local control, distant control. However, no OS benefit on Stage I subset analysis (HR 0.95, NS)
*** Toxicity: 1% died due to chemo effects
*** Conclusion: Cisplatin-based adjuvant chemo improves survival
** 2006 PMID 16957145 -- "DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy." (Olaussen KA, N Engl J Med. 2006 Sep 7;355(10):983-91.)
*** Expression of ERCC1. 761 tumors analyzed. 44% positive, 56% negative
*** ERCC1 negative: 5-year OS 47% chemo vs. 39% control (SS). Median OS 56 months chemo vs. 40 months control (14 month benefit)
*** ERCC1 positive: 5-year OS 40% chemo vs. 46% control (NS). Median OS 50 months chemo vs. 55 months control (NS)
*** Conclusion: In completely resected NSCLC, patients with ERCC1- tumors benefit from cisplatin, while ERCC1+ tumors do not. ERCC1+ tumors have a better overall OS
* NCI-Canada JBR.10 / INT (1994-2001) -- Surgery +/- cisplatin and vinorelbine
** Randomized. 482 patients with Stage IB-II (T3 excluded), complete resection. Arm 1) Adjuvant cisplatin 50 mg/m2 and vinorelbine 25 mg/m2 Q4W x4 cycles vs Arm 2) observation. No RT given.
** 5-years; 2005 PMID 15972865 — "Vinorelbine plus Cisplatin vs. Observation in Resected Non–Small-Cell Lung Cancer." Winton T et al. N Engl J Med. 2005 June 23;352(25):2589-2597. Median F/U 5 years.
*** Outcome: Median OS chemo 7.8 years vs 6.1 years (SS); 5-year OS 69% vs 54%. Median RFS 61% vs. 49% (SS). Subgroup analysis showed no benefit for chemotherapy for Stage IB.
** Conclusion: Improvement in overall survival
* Adjuvant Navelbine International Trialist Association (ANITA) (1994-2000) -- Surgery +/- cisplatin and vinorelbine
** Randomized. 840 patients. Stage IB-IIIA (36% IB, 24% II, 39% IIIA), complete resection. Arm 1) Adjuvant Cisplatin 100mg/m2 + Vinorelbine 30mg/m2 x4 cycles vs Arm 2) observation. Post-op RT not mandatory, and done according to each center's policy (given to 28%)
** 6-years; 2006 PMID 16945766 -- "Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial." (Douillard JY, Lancet Oncol. 2006 Sep;7(9):719-27.). Median F/U 6.3 years
*** Outcome: 5-year OS chemo 51% vs observation 43% (SS); decreased death by 21%. Median OS 5.5 years vs 3.6 years (SS). Median RFS 3.0 years vs 1.7 years (SS). No benefit for Stage IB on subgroup analysis (5-year OS 62% vs 64%, NS). For Stage II, 52% vs. 39%; Stage IIIA 42% vs. 26%. If N0, 58% vs. 61% (NS); if N1 52% vs. 36%; if N2 40% vs. 19%
*** Toxicity: neutropenia 92%, febrile neutropenia 9%, toxic deaths 2%
*** Conclusion: Adjuvant vinorelbine/cisplatin extends survival
** See also: Radiotherapy from the ANITA trial (discussed under PORT section)
* Adjuvant Lung Project Italy (ALPI) (1994-1999) -- Surgery +/- MVP
** Randomized, multi-institutional. 1209 patients with Stage I-IIIA. Treated with 1) surgery + adjuvant mitomycinC/vindesine/cisplatin (MVP) vs. 2) Surgery alone. 43% also received RT.
** 2003 PMID 14519751 — "Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer." Scagliotti GV et al. J Natl Cancer Inst. 2003 Oct 1;95(19):1453-61. Median F/U 5.4 years
*** Median OS: no difference; PFS no difference. Elective RT: Arm 1 65% vs. Arm 2 82%
*** Toxicity: only 69% received MVP x3 cycles
*** Conclusion: No difference in outcomes
** Critique: MVP not a good regimen, with pulmonary toxicity of Mitomycin C
* Japan JLCRG (1994-1997) -- Surgery +/- uracil-tegafur (UFT)
** Randomized. 999 patients, pathologic Stage I adenocarcinoma. Arm 1) adjuvant oral uracil-tegafur (tegafur 250 mg/m2) x2 years vs. Arm 2) observation. Primary end point OS
** 2004 PMID 15102997 -- "A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung." (Kato H, N Engl J Med. 2004 Apr 22;350(17):1713-21.) Median F/U 6.1 years
*** Outcome: 5-year OS UFT 88% vs. observation 85% (p=0.047). Stage IA 89% vs. 90% (NS), Stage IB 85% vs. 74% (SS).
*** Toxicity: Grade 3 in 2%
*** Conclusion: Adjuvant chemotherapy improves survival
* Rome Tor Vergata (1988-1994) -- Surgery +/- cisplatin and etoposide
** Randomized. 140 patients, Stage IB (pT2N0), sublobar (34%) or great resection. Arm 1) Adjuvant cisplatin 100 mg/m2 and etoposide 120 mg/m2 Q4W x6 cycles vs Arm 2) observation. Primary endpoint OS
** 2006 PMID 16550600 -- "Postsurgical chemotherapy in stage IB nonsmall cell lung cancer: Long-term survival in a randomized study." (Roselli M, Int J Cancer. 2006 Aug 15;119(4):955-60.) Mean F/U 3.4 years
*** Outcome: 5-year OS chemo 62% vs. observation 42% (SS). If anatomic resection, 75% vs. 50% (SS)); if sublobar resection, 40% vs. 39% (NS)
*** Toxicity: Grade 3 in 18%
*** Conclusion: Adjuvant chemotherapy may improve long-term survival in Stage IB
* Big Lung Trial (Surgical arm)
** 2004 PMID 15200998 — "Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial." Waller D et al. Eur J Cardiothorac Surg. 2004 Jul;26(1):173-82.
** Randomized to chemotherapy vs observation. 3 cycles of chemotherapy q3week. Multiple cisplatin-based regimens.
** No survival benefit.

## Adjuvant chemo vs. adjuvant chemo-RT

* CALGB 9734 - post-op chemo +/- RT
** Randomized. 37/44 patients. Completely resected Stage IIIA. Adjuvant paclitaxel x4 cycles, then 2-4 weeks later +/- RT. Closed early due to slow accrual
** 2007 PMID 17311692 -- "A phase III study of surgical resection and paclitaxel/carboplatin chemotherapy with or without adjuvant radiation therapy for resected stage III non-small-cell lung cancer: Cancer and Leukemia Group B 9734." (Perry MC, Clin Lung Cancer. 2007 Jan;8(4):268-72.)
*** Outcome: Median DFS no RT 1.4 years vs. RT 2.8 years (NS); 1-year OS 72% vs. 74% (NS)
*** Conclusion: Small study, no improvement in outcome
* INT 0115 ECOG EST 3590 / RTOG 91-05 - chemo/RT vs RT
** Randomized. 488 patients. Stage II-IIIA. Cisplatin/etoposide x4 cycles + concurrent RT vs RT alone. Cisplatin 60 mg/m2, etoposide 120 mg/m2. RT 50.4/28
** 2000 PMID 11071672 — "A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer." Keller SM et al. N Engl J Med. 2000 Oct 26;343(17):1217-22.
*** Outcome: median OS 3.2 years vs. 3.2 years (NS). In-field recurrence 13% vs. 12% (NS)
*** Toxicity: treatment-related mortality RT 1.2% vs. CRT 1.6%
*** Conclusion: No difference in recurrence or survival.
Non-Randomized
* RTOG 97-05, 2005 PMID 15908657 -- "Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIA non-small-cell lung cancer: promising long-term results of the Radiation Therapy Oncology Group--RTOG 9705." (Bradley JD, J Clin Oncol. 2005 May 20;23(15):3480-7.)
** Phase II. 88 patients with II-IIIA, surgery + adjuvant paclitaxel/carboplatin + concurrent RT to 50.4/28. Boost of 10.8 Gy for ECE or T3. Median F/U 4.7 years
** Outcomes: median OS 4.7 years; 3-year OS 61%; LF in 15%
** Toxicity: acceptable
** Conclusion: Favorable survival compared to ECOG 3590 (INT 0115 above); suggest PIII trial

## SBRT

* Pooled analysis of STARS (MD Anderson CC) and ROSEL (Dutch) trials; 2015 (2008-2013)) PMID 25981812 -- "Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials" (Chang J et al., Lancet Oncology. 2015 Jun;16(6):630-7)
** Pooled analysis of 2 Phase III studies that both did not meet accrural goals. 58 patients, operable T1-T2a N0 M0 NSCLC, <4 cm diameter, 1:1 randomization SBRT vs surgery. STARS: SBRT 54/3 Gy peripheral, 50/4 Gy central lesions over 5 days; ROSEL: SBRT 54/3 Gy peripheral (5 -8 days), 60/5 Gy central lesions (10-14 days); . Median F/U 3.4 years
** Outcome: 3-year OAS 95% (SBRT) vs 79% (Surgery) (p<0.05)
** Toxicity: SBRT: Grade 3 in 10%, no grade 4/5; Surgery: grade 3/4 44%; 1pt Grade 5
** Conclusion: SBRT is better tolerated than surgery, SBRT might lead to better OAS; SBRT could be an option for operable Stage I NSCLC.
* Washington University; 2010 (2000-2007) PMID 20400121 -- "Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer." (Crabtree TD, J Thorac Cardiovasc Surg. 2010 Apr 16. [Epub ahead of print])
** Retrospective. 462 patients with surgery (2000-2006) and 76 patients with SBRT (2004-2007), clinical Stage IA-IB NSCLC, staged with CT and PET. Surgical patients younger (SS), lower comorbidity (SS), better pulmonary function (SS), but higher stage (IA 63% vs 79%). Final path upstaging in 35%
** Outcome: Unmatched OS surgery 5-years 55% vs SBRT 3-years 32%. 3-year local control IA surgery 96% vs SBRT 89% (SS); no difference in IB local control. No difference in DSS. No difference in local control on propensity analysis 3-years 88% vs 90% (NS)
** Conclusion: Similar rates of local recurrence and disease specific survival on propensity analysis between surgery and SBRT
* William Beaumont; 2010 (2003-2008) PMID 20065181 -- "Outcomes After Stereotactic Lung Radiotherapy or Wedge Resection for Stage I Non-Small-Cell Lung Cancer." (Grills IS, J Clin Oncol. 2010 Jan 11. [Epub ahead of print])
** Retrospective. 127 patients with T1-T2N0 NSCLC treated with wedge resection (54%) or SBRT (46%); all ineligible for lobectomy. SBRT 95% inoperable, 5% refused surgery. Mean FEV1 wedge 1.4 vs SBRT 1.3 (NS), Charlson comorbidity 3 vs 4 (SS), age 74 vs 78 (SS). SBRT T1 48/4 and T2 60/5. Median F/U 2.5 years
** Outcome: Local recurrence wedge 20% vs SBRT 4% (p=0.07), no difference LRR, DM, or FFF. CSS wedge 94% vs SBRT 93% (NS). OS 87% vs 72% (SS). No difference between VATS and open surgery
** Conclusion: Both SBRT and wedge reasonable options for Stage I patients ineligible for lobectomy, with equivalent cancer-specific survival
* RCTs comparing surgery in medically operable early-stage NSCLC:
** ROSEL (Dutch): terminated due to poor accrual
** STARS (Cyberknife): terminated due to poor accrual
** RTOG 1021/ACOSOG Z4099: terminated due to poor accrual

## Review

* 2005 PMID 16000604 -- "Localized non-small cell lung cancer: adjuvant radiotherapy in the era of effective systemic therapy." (Bogart JA, Clin Cancer Res. 2005 Jul 1;11(13 Pt 2):5004s-5010s.)

## Guidelines

* 2007 PMID 17954710 -- "Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline." (Pisters KM,J Clin Oncol. 2007 Dec 1;25(34):5506-18.)