Breviar terapeutic al cancerului pulmonar fără celule mici, din perspectiva oncologiei medicale

Introduction

According to the European Society for Medical Oncology (ESMO), primary lung cancer remains the most common malignancy after non-melanocytic skin cancer, and deaths from this type of cancer outweigh those of any other malignancy worldwide. In 2012, lung cancer was the most frequently diagnosed cancer in men, with approximately 1.2 million new cases worldwide. Among women, lung cancer was the leading cause of cancer death in more developed countries and the second leading cause of cancer death in the least developed countries⁽¹⁾. The number of deaths from lung cancer in Europe in 2017 was 1,373,500 compared to 1,333,400 in 2012 (+3%). Lung cancer remains the leading cause of cancer death in men, accounting for 24%, and 15% in women, where it alternates for the first place with breast cancer⁽²⁾.

The most common types of non-small cell lung cancer (NSCLC) are squamous cell carcinoma, large cell carcinoma and adenocarcinoma, but there are a few other types that occur less frequently, and unusual histological variants may occur. Non-small cell lung cancer accounts for 80-90% of lung cancers, while small cell lung cancer (SCLC) has decreased in frequency in many countries in the last two decades⁽³⁾. Over the past 25 years, the distribution of histological types of NSCLC has changed: in the United States of America, squamous cell carcinoma (SCC), the former predominant histotype, has decreased, while adenocarcinoma has increased in both sexes. In Europe, similar trends have occurred in men, while in women, both SCC and adenocarcinoma are on the rise⁽⁴⁾.

References

1. IARC. Cancer Incidence, Mortality and Prevalence Worldwide GLOBOCAN 2012. http://gco.iarc.fr/

2. Malvezzi M, Carioli G, Bertuccio P, et al. European cancer mortality predictions for the year 2017, with focus on lung cancer. Ann Oncol. 2017; 28:1117–1123.

3. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011; 61:69–90.

4. Forman D, Bray F, Brewster D. Cancer Incidence in Five Continents. Lyon: IARC Press 2013.

Histological classification of NSCLC

Non-microcellular malignant epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer, including the following:

• Squamous cell carcinoma (25% of lung cancer).

• Adenocarcinoma (40% of lung cancers).

• Large cell carcinoma (10% of lung cancer).

There are many additional subtypes of decreasing frequency⁽¹⁾.

Histological classification of NSCLC according to WHO/IASLC:

1. Squamous cell carcinoma

• Papillary

• With clear cell

• With small cell

• Basaloid.

2. Adenocarcinoma

• Acinar

• Papillary

• Bronhoalveolary carcimoma

- Nonmucinous

- Mucinous

- Mixt, with mucinous and nonmucinous or un­de­ter­minated

• Solid adenocarcinoma with mucin

• Adenocarcinoma with mixt subtypes

Variants:

- Well diferentiated fetal adenocarcinoma

- Mucinous adenocarcinoma (colloid)

- Mucinous cystadenocarcinoma

- Sealed ring cell adenocarcinoma

- Clear cell adenocarcinoma.

3. Large-cell carcinoma

Variants:

- Large-cell neuroendocrin carcinoma (LCNEC)

- Combined LCNEC

- Basal-cell carcinoma

- Lymphoepithelial carcinoma

- Clear-cell carcinoma

- Large-cell carcinoma with rhabdoid phenotype.

4. Adenosquamous carcinoma.

5. Carcinomas with pleomorphic, sarcomatoid or sarcomatous elements

• Carcinomas with spindle shaped cells and/or giant cells

• Spindle-cell carcinoma

• Giant-cell carcinoma

• Carcinosarcomas

• Pulmonary blastoma.

6. Carcinoid tumor

• Typical carcinoid

• Atypical carcinoid.   

7. Salivary gland carcinomas

• Mucoepidermoid carcinoma

• Adenoid cystic carcinoma.

8. Unclassified carcinoma⁽¹⁾.

AJCC/UICC TNM 8 staging system

Revised International Lung Cancer Staging System

The revised International Lung Cancer Staging System, based on information collected in a clinical database of over 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). The revisions provide greater prognostic specificity for patient groups^(2,3).

References

1. Travis WD, Colby TV, Corrin B, et al. Histological typing of lung and pleural tumours. 3^rd ed., Berlin: Springer-Verlag, 1999.

2. Mountain CF. Revisions in the International System for Staging Lung Cancer. Ches. 1997;111 (6):1710-7.

3. Lung. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8^th ed. New York, NY: Springer, 2017, pp. 431–566.

    Systemic treatment for NSCLC

In the following, we will refer to the stages that require systemic therapy and radiotherapy, the surgery being possible only if the aforementioned therapies would lead to conversion that would allow the surgical intervention.

Standard treatment options for unresectable stage IIIA N2 NSCLC

Radiotherapy. Radiation therapy of locally advanced unresectable tumors: radiation therapy, administered sequentially or concomitantly with chemotherapy, may provide benefits in patients with locally unresectable stage III NSCLC. Radiation therapy with traditional dosing and fractionation sessions (1.8-2 Gy per fraction per day up to 60-70 Gy in 6-7 weeks) provides a long-term survival benefit in 5% to 10% of patients and a significant improvement in symptoms^(1,2). Although patients with nonresectable stage IIIA disease may benefit from radiotherapy, long-term outcomes have generally been poor due to local and systemic recurrence.

Palliative radiotherapy. Radiation therapy may be effective in alleviating local symptoms of NSCLC, such as the following:

• tracheal, esophageal or bronchial compression

• pain

• paralysis of the vocal cords

• hemoptysis

• upper vena cava compression syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructive lesions^(3-10).

Chemoradiotherapy

The addition of sequential and concomitant chemotherapy to radiotherapy has been evaluated in prospective randomized studies and meta-analyses. In general, the concomitant treatment may provide the greatest survival benefit with an increase in toxic effects. Platinum-based chemotherapy concomitantly with radiotherapy may improve the survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal chemotherapy schedule^(11-13). The results of two randomized studies (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concomitant chemoradiotherapy may provide a greater survival benefit, albeit with more toxic effects than sequential chemoradiotherapy^(14-17).

High-dose radiotherapy for concomitant chemoradiotherapy with the improvement of radiotherapy technology in the 1990s, phase I/II studies, demon­strated the feasibility of radiotherapy with increasing the dose to 74 Gy with concomitant chemotherapy^(18-20). However, the phase III study of a conventional 60 Gy dose versus dose escalation to 74 Gy with weekly carboplatin/paclitaxel did not demonstrate improved local control or progression-free survival (PFS), and the overall survival (OS) was poorer with increased dose (HR 1.38; 1.09-1.76; p=0.004). There was an insignificant increase in grade 5 adverse events with radiotherapy with increasing dose (10% versus 2%) and a higher incidence of grade 3 esophagitis (21% versus 7%; p=0.0003). Thus, there is no clear benefit in escalating the radiation dose above 60 Gy for stage III NSCLC⁽²¹⁾.

Concomitant chemoradiotherapy

The randomized phase III PROCLAIM study (NCT00686959) enrolled 598 newly diagnosed patients with stage IIIA/B nonsquamous NSCLC. The main goal was overall survival. The enrollment was stopped early due to negative overall survival outcomes and significant side effects in the study arm⁽²²⁾. Additional systemic therapy before or after concomitant chemoradiotherapy was also studied and the conclusion was that the addition of induction chemotherapy prior to concomitant chemoradiotherapy has not been shown to improve survival⁽²³⁾.

Consolidation immunotherapy – durvalumab

Durvalumab is a selective human IgG1 monoclonal antibody that blocks PD-1 binding to PD-1 and CD80, allowing T cells to recognize and kill tumor cells. The PACIFIC phase III study (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease did not progress after two or more cycles of platinum-based chemoradiotherapy. The patients were randomized to a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months). The median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (HR 0.52; 95% CI; 0.42-0.65; p<0.001). OS was not evaluated in the intermediate analysis⁽²⁴⁾.

Other systemic consolidation therapies

Randomized studies of other systemic strengthening therapies, including docetaxel⁽²⁵⁾, gefitinib⁽²⁶⁾ and tecemotide (MUC1 antigen-centered immunotherapy), did not show an improvement on overall survival.

References

1. Komaki R, Cox JD, Hartz AJ, et al. Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol. 1985;8(5):362-70.

2. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet. 1997;350(9072):161-5. 

3. Miller JI, Phillips TW. Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg. 1990;50(2):190-5. 

4. Ung YC, Yu E, Falkson C, et al. The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy. 2006 Jul-Sep;5(3):189-202.

5. Sundstrøm S, Bremnes R, Aasebø U, et al. Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol. 2004;22(5):801-10, 2004.

6. Lester JF, Macbeth FR, Toy E, et al. Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev. 2006;(4):CD002143.

7. Bezjak A, Dixon P, Brundage M, et al. Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys. 2002;54(3):719-28.

8. Erridge SC, Gaze MN, Price A, et al. Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol). 2005;17(1):61-7.

9. Kramer GW, Wanders SL, Noordijk EM, et al. Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol. 2005;23(13):2962-70.

10. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al. A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer. 2005;92 (6):1038-45.

11. Aupérin A, Le Péchoux C, Pignon JP, et al. Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol. 2006;17(3):473-83.

12. 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;311(7010):899-909.

13. Rowell NP, O’Rourke NP. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev. 2004;(4):CD002140.

14. Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 1999;17(9):2692-9.

15. Fournel P, Robinet G, Thomas P, et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d’Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol. 2005;23(25):5910-7.

16. Curran WJ, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011;103(19):1452-60.

17. Zatloukal P, Petruzelka L, Zemanova M, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer. 2004;46(1):87-98.

18. Rosenman JG, Halle JS, Socinski MA, et al. High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys. 2002;54(2):348-56.

19. Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol. 2008;26(15):2457-63.

20. Bradley JD, Bae K, Graham MV, et al. Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J Clin Oncol. 2010;28(14):2475-80.

21. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187-99.

22. Senan S, Brade A, Wang LH, et al. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34(9):953-62.

23. Vokes EE, Herndon JE, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007;25(13):1698-704.

24. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-29.

25. Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol. 2008;26(35):5755-60.

26. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008;26(15):2450-6.

Treatment of stages IIIB and IIIC

Sequential or concomitant chemotherapy and radiotherapy

 Many randomized studies with unresectable stage III NSCLC patients show that the treatment with cisplatin-based chemotherapy and sequential or concomitant ra­­dio­therapy is associated with improved survival compared to the treatment using radiotherapy alone. Although patients with unresectable stage IIIB or IIIC may benefit from radiotherapy, the long-term outcomes have generally been poor, often resulting in local or systemic recurrence. The addition of sequential or concomitant radiotherapy to chemotherapy has been evaluated in prospective randomized trials^(1,2).

High-dose radiotherapy for concomitant chemoradiotherapy. With the improvement of radiotherapy technology in the 1990s, phase I/II studies demonstrated the feasibility of radiotherapy with increasing the dose to 74 Gy with concomitant chemotherapy^(3-5). However, the phase III study of a conventional 60 Gy dose versus dose escalation to 74 Gy with weekly carboplatin/paclitaxel did not demonstrate improved local control or PFS, and OS was poorer with increased dose (HR 1.38; 1.09-1.76; p=0.004). There was an insignificant increase of grade 5 adverse events in radiotherapy with increasing dose (10% versus 2%) and higher incidence of grade 3 esophagitis (21% versus 7%; p=0.0003)⁽⁶⁾.

Additional systemic therapy before or after chemotherapy and concomitant radiotherapy

Adding induction chemotherapy before simultaneous chemoradiotherapy didn’t show to improve the survival⁽⁷⁾.

Consolidation immunotherapy

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody which blocks the interaction of PD-L1 with PD-1 and CD80 and allows the T cells to recognize and kill tumor cells. The PACIFIC phase III study (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease did not progress after two or more cycles of platinum-based chemoradiotherapy. The patients were randomized to a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months). The median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (HR 0.52; 95% CI; 0.42-0.65; p<0.001). OS was not evaluated in the intermediate analysis⁽⁸⁾.

References

1. Wisnivesky JP, Yankelevitz D, Henschke CI. Stage of lung cancer in relation to its size: part 2. Evidence. Chest. 2005;127(4):1136-9.

2. 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;311(7010):899-909.

3. Rosenman JG, Halle JS, Socinski MA, et al. High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys. 2002;54(2) 348-56.

4. Socinski MA, Blackstock AW, Bogart JA, et al. Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol. 2008;26(15):2457-63.

5. Bradley JD, Bae K, Graham MV, et al. Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J Clin Oncol. 2010;28(14):2475-80.

6. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187-99.

7. Vokes EE, Herndon JE, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol. 2007;25(13):1698-704.

8. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-1929.

First-line treatment of stage IV NSCLC

1. Platinum-based cytotoxic chemotherapy (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, protein-bound paclitaxel or pemetrexed^(1-3).

2. Chemotherapy combined with monoclonal antibodies: bevacizumab, cetuximab, necitumumab.

3. Maintenance therapy after first-line chemotherapy (for patients with stable disease or responding after four cycles of platinum-based combined chemotherapy).

4. Epidermal growth factor receptor (EGFR) receptor tyrosine kinase (TKI) inhibitors (for patients with EGFR mutations): osimertinib, gefitinib, erlotinib, afatinib.

5. Anaplastic lymphoma kinase (ALK) inhibitors (for patients with ALK translocations): alectinib, crizotinib, ceritinib, brigatinib, lorlatinib.

6. BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations): dabrafenib, trametinib.

7. ROS1 inhibitors (for patients with ROS1 rearrangements): entrectinib, crizotinib.

8. Neurotrophic tyrosine kinase inhibitors (NTRK) (for patients with NTRK fusions): larotrectinib, entrectinib.

9. Immune control point inhibitors with or without chemotherapy: pembrolizumab plus chemother­apy, pembrolizumab alone.

10. Local therapies and special situations: endobronchial laser therapy and/or brachytherapy (for obstructive lesions); external beam radiotherapy (EBRT; mainly to alleviate local symptomatic tumor growth); treatment of the second primary tumor; treatment of brain metastases^(4-6).

Second-line therapy of NSCLC

The standard treatment options for patients with progressive, recurrent and recurrent stage IV non-small cell lung cancer (second-line therapy and beyond) include the following:

1. Chemotherapy – docetaxel; docetaxel plus ramucirumab; pemetrexed.

2. Targeted epidermal growth factor receptor (EGFR) therapy. EGFR targeted therapy after first-line chemotherapy: erlotinib, gefitinib, afatinib. Targeted EGFR therapy for EGFR T790M mutations acquired after previous EGFR targeted therapy: osimertinib.

3. ALK inhibitors after first-line chemotherapy – crizotinib, ceritinib, alectinib, brigatinib.

4. BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations) – dabrafenib and trametinib⁽⁷⁾.

5. ROS1 targeted therapy – entrectinib, crizotinib⁽⁸⁾.

6. Neurotrophic tyrosine kinase (NTRK) inhibitors (for patients with NTRK fusions): larotrectinib⁽⁹⁾, entrectinib⁽¹⁰⁾.

7. Immunotherapy – nivolumab, pembrolizumab, atezolizumab.

Conflicts of interests: The authors declare no conflict of interests.