Prognostic Factors and Long-Term Survival in Locally Advanced NSCLC with Pathological Complete Response after Surgical Resection Following Neoadjuvant Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Induction Therapy
2.2. Restaging
2.3. Surgery
2.4. Adjuvant Therapy and Surveillance Protocol
2.5. Statistical Analysis
3. Results
3.1. Pattern of Recurrence after Surgery
3.2. Long-Term Outcomes and Prognostic Factors
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Vansteenkiste, J.; Crino, L.; Dooms, C.; Douillard, J.Y.; Faivre-Finn, C.; Lim, E.; Di Rocco, G.; Senan, S.; Van Schil, P.; Veronesi, G.; et al. 2nd ESMO consensus conference on lung cancer: Early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up. Ann. Oncol. 2014, 25, 1462–1474. [Google Scholar] [CrossRef] [PubMed]
- National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 3. 2020). Available online: https://www.nccn.org/ (accessed on 2 July 2020).
- Postmus, P.E.; Kerr, K.M.; Oudkerk, M.; Senan, S.; Waller, D.A.; Vansteenkiste, J.; Escriu, C.; Peters, S.; ESMO Guidelines Committee. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2017, 28, 1–21. [Google Scholar] [CrossRef] [PubMed]
- Biswas, T.; Sharma, N.; Machtay, M. Controversies in the management of stage III non-small-cell lung cancer. Expert Rev. Anticancer. Ther. 2014, 14, 333–347. [Google Scholar] [CrossRef] [PubMed]
- Song, W.-A.; Zhou, N.-K.; Wang, W.; Chu, X.-Y.; Liang, C.-Y.; Tian, X.-D.; Guo, J.-T.; Liu, X.; Liu, Y.; Dai, W.-M. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: An updated meta-analysis of 13 randomized control trials. J. Thorac. Oncol. 2010, 5, 510–516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Paul, S.; Mirza, F.; Port, J.L.; Lee, P.C.; Stiles, B.M.; Kansler, A.L.; Altorki, N.K. Survival of patients with clinical stage IIIA non-small cell lung cancer after induction therapy: Age, mediastinal downstaging, and extent of pulmonary resection as independent predictors. J. Thorac. Cardiovasc. Surg. 2011, 141, 48–58. [Google Scholar] [CrossRef] [Green Version]
- Trodella, L.; Granone, P.; Valente, S.; Margaritora, S.; Macis, G.; Cesario, A.; D’Angelillo, R.M.; Valentini, V.; Corbo, G.M.; Porziella, V.; et al. Neoadjuvant concurrent radiochemotherapy in locally advanced (IIIA-IIIB) non small cell lung cancer: Long term results according to downstaging. Ann. Oncol. 2004, 15, 389–398. [Google Scholar] [CrossRef]
- Decaluwé, H.; De Leyn, P.; Vansteenkiste, J.; Dooms, C.; Van Raemdonck, D.; Nafteux, P.; Coosemans, W.; Lerut, T. Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur. J. Cardio-Thorac. Surg. 2009, 36, 433–439. [Google Scholar] [CrossRef] [Green Version]
- Lococo, F.; Cesario, A.; Margaritora, S.; Dall’Armi, V.; Mattei, F.; Romano, R.; Porziella, V.; Granone, P. Long-term results in patients with pathological complete response after induction radiochemotherapy followed by surgery for locally advanced non-small-cell lung cancer. Eur. J. Cardio-Thorac. Surg. 2013, 43, e71–e81. [Google Scholar] [CrossRef] [Green Version]
- Melek, H.; Çetinkaya, G.; Özer, E.; Yentürk, E.; Sevinç, T.E.; Bayram, A.S.; Gebitekin, C. Pathological complete response after neoadjuvant/induction treatment: Where is its place in the lung cancer staging system? Eur. J. Cardio-Thorac. Surg. 2019, 56, 604–611. [Google Scholar] [CrossRef]
- Kayawake, H.; Okumura, N.; Yamanashi, K.; Takahashi, A.; Itasaka, S.; Yoshioka, H.; Nakashima, T.; Matsuoka, T. Non-small cell lung cancer with pathological complete response: Predictive factors and surgical outcomes. Gen. Thorac. Cardiovasc. Surg. 2019, 67, 773–781. [Google Scholar] [CrossRef]
- Gospodarowicz, M.K.; Brierley, J.D.; Wittekind, C. TNM Classification of Malignant Tumours; Wiley: Hoboken, NJ, USA, 2017. [Google Scholar]
- Lococo, F.; Cesario, A.; Margaritora, S.; Dall’Armi, V.; Nachira, D.; Cusumano, G.; Meacci, E.; Granone, P. Induction therapy followed by surgery for T3-T4/N0 non-small cell lung cancer: Long-term results. Ann. Thorac. Surg. 2012, 93, 1633–1640. [Google Scholar] [CrossRef] [PubMed]
- Scagliotti, G.V.; Pastorino, U.; Vansteenkiste, J.F.; Spaggiari, L.; Facciolo, F.; Orlowski, T.M.; Maiorino, L.; Hetzel, M.; Leschinger, M.; Visseren-Grul, C.; et al. Randomized phase III study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages IB to IIIA non-small-cell lung cancer. J. Clin. Oncol. 2012, 30, 172–178. [Google Scholar] [CrossRef] [PubMed]
- Lardinois, D.; De Leyn, P.; Van Schil, P.; Rami-Porta, R.; Waller, A.D.; Passlick, B.; Zielinski, M.; Junker, K.; Rendina, E.A.; Ris, H.-B. ESTS guidelines for intraoperative lymph node staging in non-small cell lung cancer. Eur. J. Cardiothorac. Surg. 2006, 30, 787–792. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Friedel, G.; Budach, W.; Dippon, J.; Spengler, W.; Eschmann, S.M.; Pfannenberg, C.; Al-Kamash, F.; Walles, T.; Aebert, H.; Kyriss, T.; et al. Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: A single-center study. J. Clin. Oncol. 2010, 28, 942–948. [Google Scholar] [PubMed]
- Cerfolio, R.J.; Bryant, A.S.; Jones, V.L. Pulmonary resection after concurrent chemotherapy and high dose (60Gy) radiation for non-small cell lung cancer is safe and may provide increased survival. Eur. J. Cardiothorac. Surg. 2009, 35, 718–723. [Google Scholar] [CrossRef] [PubMed]
- Martinez-Meehan, D.; Lutfi, W.; Dhupar, R.; Christie, N.; Baker, N.; Schuchert, M.; Luketich, J.D.; Okusanya, O.T. Factors associated with survival in complete pathologic response non-small cell lung cancer. Clin. Lung. Cancer 2020, 21, 349–356. [Google Scholar] [CrossRef] [PubMed]
- Jia, X.-H.; Xu, H.; Geng, L.-Y.; Jiao, M.; Wang, W.-J.; Jiang, L.-L.; Guo, H. Efficacy and safety of neoadjuvant immunotherapy in resectable nonsmall cell lung cancer: A meta-analysis. Lung Cancer 2020, 147, 143–153. [Google Scholar] [CrossRef]
- Milleron, B.; Westeel, V.; Gounant, V.; Wislez, M.; Quoix, E. La réponse complète histologique: Un facteur prédictif de survie après chimiothérapie néoadjuvante dans le cancer bronchopulmonaire [Pathological complete response: A predictive survival factor after neoadjuvant chemotherapy in lung cancer]. Bull Cancer 2016, 103, 66–72. [Google Scholar] [CrossRef]
- Higgins, K.A.; Chino, J.P.; Ready, N.; Onaitis, M.W.; Berry, M.F.; D’Amico, T.A.; Kelsey, C.R. Persistent N2 disease after neoadjuvant chemotherapy for non-small-cell lung cancer. J. Thorac. Cardiovasc. Surg. 2011, 142, 1175–1179. [Google Scholar] [CrossRef] [Green Version]
- Margaritora, S.; Cesario, A.; Cusumano, G.; Dall’Armi, V.; Porziella, V.; Meacci, E.; Lococo, F.; D’Angelillo, R.; Congedo, M.T.; Granone, P. Pneumonectomy with and without induction chemo-radiotherapy for non-small cell lung cancer: Short and long-term results from a single centre. Eur. Rev. Med. Pharmacol. Sci. 2013, 17, 29–40. [Google Scholar]
- D’Amato, T.A.; Ashrafi, A.S.; Schuchert, M.J.; Alshehab, D.S.; Seely, A.J.; Shamji, F.M.; Maziak, D.E.; Sundaresan, S.R.; Ferson, P.F.; Luketich, J.D.; et al. Risk of pneumonectomy after induction therapy for locally advanced non-small cell lung cancer. Ann. Thorac. Surg. 2009, 88, 1079–1085. [Google Scholar] [CrossRef] [PubMed]
- Alifano, M.; Boudaya, M.S.; Salvi, M.; Collet, J.-Y.; Dinu, C.; Camilleri-Broët, S.; Regnard, J.-F. Pneumonectomy after chemotherapy: Morbidity, mortality, and long-term outcome. Ann. Thorac. Surg. 2008, 85, 1866–1872. [Google Scholar] [CrossRef] [PubMed]
- Eberhardt, W.; Wilke, H.; Stamatis, G.; Stuschke, M.; Harstrick, A.; Menker, H.; Krause, B.; Müeller, M.R.; Stahl, M.; Flasshove, M.; et al. Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small cell lung cancer: Mature results of a phase II trial. J. Clin. Oncol. 1998, 16, 622–634. [Google Scholar] [CrossRef] [PubMed]
- Chicas-Sett, R.; Zafra-Martin, J.; Morales-Orue, I.; Castilla-Martinez, J.; Berenguer-Frances, M.A.; Gonzalez-Rodriguez, E.; Rodriguez-Abreu, D.; Couñago, F. Immunoradiotherapy as an effective therapeutic strategy in lung cancer: From palliative care to curative intent. Cancers 2020, 12, 2178. [Google Scholar] [CrossRef]
- Ghysen, K.; Vansteenkiste, J. Immunotherapy in patients with early stage resectable nonsmall cell lung cancer. Curr. Opin. Oncol. 2019, 31, 13–17. [Google Scholar] [CrossRef]
- Chiang, A.C.; Herbst, R.S. Frontline immunotherapy for NSCLC-the tale of the tail. Nat. Rev. Clin. Oncol. 2020, 17, 73–74. [Google Scholar] [CrossRef]
- Predina, J.D.; Haas, A.R.; Martinez, M.; O’Brien, S.; Moon, E.K.; Woodruff, P.; Stadanlick, J.; Corbett, C.; Frenzel-Sulyok, L.; Bryski, M.G.; et al. Neoadjuvant gene mediated cytotoxic immunotherapy for non-small cell lung cancer-safety and immunologic activity. Mol. Ther. 2020, 4. [Google Scholar] [CrossRef]
- Reuss, J.E.; Anagnostou, V.; Cottrell, T.R.; Smith, K.N.; Verde, F.; Zahurak, M.; Lanis, M.; Murray, J.C.; Chan, H.Y.; McCarthy, C.; et al. Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. J. Immunother. Cancer 2020, 8, e001282. [Google Scholar] [CrossRef]
Patients Characteristics | n (%) | Patients Characteristics | n (%) |
---|---|---|---|
Sex (n(%)) | Time between IT and surgery (average ± SD) | 54.91 ± 19.35 | |
Female | 5 (8.1%) | ||
Male | 57 (91.9%) | yTNM (n (%)) | |
0 | 9 (14.5%) | ||
Age (average ± SD) | 62.44 ± 8.76 | IA | 13 (20.9%) |
IB | 0 (0%) | ||
cTNM (n (%)) | IIA | 7 (11.3%) | |
IIB | 3 (4.8%) | IIB | 12 (19.4%) |
IIIA | 28 (45.2%) | IIIA | 9 (14.5%) |
IIIB | 31 (50%) | IIIB | 12 (19.4%) |
cT (n (%)) | Kind of resection (n (%)) | ||
T1 | 5 (8.1%) | Lobectomy | 46 (74.2%) |
T2 | 17 (27.4%) | Pneumonectomy | 12 (19.3%) |
T3 | 25 (40.3%) | Bilobectomy | 4 (6.5%) |
T4 | 15 (24.2%) | ||
Histology (n (%)) | |||
cN (n (%)) | Adenocarcinoma | 30(48.4%) | |
N0 | 6 (9.7%) | Squamous cell carcinoma | 32 (51.6%) |
N1 | 3 (4.8%) | ||
N2 | 53 (85.5%) | Removed nodes (average ± SD) | 9.07 ± 6.2 |
Nodal involvement (n(%)) (N = 31) | Number of removed nodes (n (%)) | ||
Single station | 31 (58.5%) | 1–6 | 16 (25.8%) |
Multiple station | 25 (41.5%) | >6 | 46 (74.2%) |
NAD therapy (num of patients (%)) | Morbidity (n (%)) | ||
CHT | 11 (17.7%) | ||
CHT/RT | 51 (82.3%) | No | 45 (72.6%) |
NAD Protocols (num of patients (%)) | |||
RT (50.4 Gy) | |||
Standard: 180 cGy daily | 16 (31.4%) | ||
Accelerated: 120 cGy twice daily | 35 (68.6%) | Yes | 17 (27.4%) |
CT | |||
Carboplatin | 7 (11.2%) | Adjuvant therapy (n(%)) | |
Cisplatin + Gemcitabine | 46 (74.2%) | None | 29 (46.8%) |
5 FU−Cisplatin | 9 (14.5%) | CT | 22 (30.6%) |
RT | 8 (9.7%) | ||
Toxicity (n (%)) | CT-RT | 3 (12.9%) | |
No | 44 (71%) | ||
Yes | 18 (29%) |
Variations | Local Recurrence n (%) | Distant Recurrence n (%) |
---|---|---|
First relapse site | ||
Brain | - | 14 |
Adrenal Gland | - | 3 |
Liver | - | 3 |
Controlateral Lung | - | 2 |
Bone | - | 1 |
Ipsilateral Lung | 5 | - |
Mediastinal | 2 | - |
Bronchial Stump | 2 | - |
Surgical Approach | ||
Pneumonectomy (n = 12) | 0 (0%) | 6 (50%) |
(Bi)Lobectomy (n = 50) | 9 (18%) | 17 (34%) |
Adjuvant Therapy | ||
None (n = 29) | 5 (17.2%) | 15 (51.7%) |
Chemotherapy alone (n = 22) | 4 (18.2%) | 6 (27.3%) |
Radio-chemotherapy (n = 3) | 0 (0%) | 0 (0%) |
Radiotherapy alone (n = 8) | 0 (0%) | 2 (25%) |
Total | 9 (14.5%) | 23 (37.1%) |
Variation | Overall Survival | Disease-Free Survival | ||||
---|---|---|---|---|---|---|
3 Years (Ns = 36) | 5 Years (Ns = 28) | 3 Years (Ndfs = 33) | 5 Years (Ndfs = 25) | |||
Survival% | Survival% | p-Value | Survival% | Survival% | p-Value | |
Age | ||||||
<60 years (n = 22) | 52% | 52% | 0.280 | 43% | 32% | 0.07 |
60+ years (n = 40) | 66% | 60% | 62% | 54% | ||
Sex | ||||||
Females (n = 5) | 57% | 57% | 0.697 | 60% | 60% | 0.754 |
Males (n = 57) | 60% | 56% | 53% | 44% | ||
cStage | ||||||
IIB (n = 3) | 100% | 100% | 0.564 | 67% | 67% | 0.676 |
IIIA (n = 28) | 58% | 63% | 55% | 50% | ||
IIIB (n = 31) | 58% | 60% | 51% | 37% | ||
cT | ||||||
T1 (n = 5) | 80% | 80% | 0.513 | 60% | 36% | 0.524 |
T2 (n = 17) | 61% | 61% | 62% | 62% | ||
T3 (n = 25) | 62% | 58% | 48% | 38% | ||
T4 (n = 15) | 47% | 36% | 52% | 40% | ||
cN | ||||||
N0 (n = 6) | 83% | 83% | 0.038 | 67% | 67% | 0.026 |
N1 (n = 3) | 0% | 0% | 0% | 0% | ||
N2 (n = 53) | 60% | 55% | 57% | 46% | ||
T-size | ||||||
<50 mm (n = 27) | 65% | 60% | 0.336 | 61% | 48% | 0.385 |
≥50 mm (n = 35) | 56% | 53% | 47% | 43% | ||
Nodal Involvement | ||||||
Single Station (n = 28) | 80% | 80% | 79% | 69% | ||
Multiple Stations (n = 25) | 43% | 32% | 0.001 | 32% | 19%] | 0.001 |
Num. of removed Lymph-Nodes (n (%)) | ||||||
1–6 (n = 16) | 64% | 59% | 60% | 41% | ||
>6 (n = 46) | 63% | 60% | 0.404 | 54% | 54% | 0.555 |
Resection Type | ||||||
Pneumonectomy (n = 12) | 44% | 33% | 0.024 | 29% | 29% | 0.220 |
(Bi)lobectomy (n = 50) | 64% | 61% | 58% | 48% | ||
Histology | ||||||
Adenocarcinoma (n = 30) | 54% | 44% | 0.440 | 48% | 38% | 0.349 |
Squamous Cell Carcinoma (n = 32) | 66% | 66% | 60% | 52% | ||
Adjuvant Therapy | ||||||
No (n = 29) | 43% | 39% | 0.005 | 34% | 29% | 0.013 |
Yes (n = 33) | 75% | 70% | 69% | 57% | ||
Adjuvant Therapy Type | ||||||
None (n = 27) | 38% | 34% | 0.002 | 28% | 23% | 0.004 |
RT alone (n = 2) or CHT alone (n = 32) | 77% | 73% | 71% | 59% | ||
RT-CHT (n = 3) | 67% | 67% | 67% | 67% | ||
Recurrence | ||||||
No (n = 30) | 93% | 93% | 0.000 | |||
Yes (n = 32) | 34% | 28% |
Variables | Mortality | Disease Recurrence | ||
---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
Type of resection | ||||
Pneumonectomy | 2.613 | 0.036 | ||
(1.066; 6.407) | ||||
(Bi)lobectomy | 1 | |||
Adjuvant Therapy | ||||
No | 2.98 | 0.01 | 2.607 | 0.041 |
(1.302; 6.809) | (1.039; 6.542) | |||
Yes | 1 | 1 | ||
N2-multistation disease | 1 | 1 | ||
No | ||||
Yes | 4.37 (1.632; 11.695) | 0.003 | 6.241 (2.305; 16.897) | <<0.001 |
Age > 60 years No | 1 | <<0.001 | ||
Yes | 0.189 | |||
(0.074, 0.483) |
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Lococo, F.; Sassorossi, C.; Nachira, D.; Chiappetta, M.; Petracca Ciavarella, L.; Vita, E.; Boldrini, L.; Evangelista, J.; Cesario, A.; Bria, E.; et al. Prognostic Factors and Long-Term Survival in Locally Advanced NSCLC with Pathological Complete Response after Surgical Resection Following Neoadjuvant Therapy. Cancers 2020, 12, 3572. https://doi.org/10.3390/cancers12123572
Lococo F, Sassorossi C, Nachira D, Chiappetta M, Petracca Ciavarella L, Vita E, Boldrini L, Evangelista J, Cesario A, Bria E, et al. Prognostic Factors and Long-Term Survival in Locally Advanced NSCLC with Pathological Complete Response after Surgical Resection Following Neoadjuvant Therapy. Cancers. 2020; 12(12):3572. https://doi.org/10.3390/cancers12123572
Chicago/Turabian StyleLococo, Filippo, Carolina Sassorossi, Dania Nachira, Marco Chiappetta, Leonardo Petracca Ciavarella, Emanuele Vita, Luca Boldrini, Jessica Evangelista, Alfredo Cesario, Emilio Bria, and et al. 2020. "Prognostic Factors and Long-Term Survival in Locally Advanced NSCLC with Pathological Complete Response after Surgical Resection Following Neoadjuvant Therapy" Cancers 12, no. 12: 3572. https://doi.org/10.3390/cancers12123572