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24.05.2011: Third CECOG Consensus on the Systemic Treatment of Non Small Cell Lung Cancer.

T. Brodowicz1, 3, T. Ciuleanu4, J. Crawford5, M. Filipits2, J.R. Fischer, V. Georgoulias7, C. Gridelli8, F. R. Hirsch9, J. Jassem10, 3, P. Kosmidis11, M. Krzakowski12, 3, Ch. Manegold13, J.L. Pujol14, R. Stahel15, N. Thatcher16, J. Vansteenkiste17, C. Minichshofer1, , S. Zöchbauer-Müller1, R. Pirker1 and C. Zielinski1,3 for the Central European Cooperative Oncology Group (CECOG)*

1Clinical Division of Oncology, and
2Institute of Cancer Research, Department of Medicine I, General Hospital-Medical University Vienna, Vienna, Austria,
3Central European Cooperative Oncology Group, www.cecog.org
4Institute of Oncology, Cluj-Napoca, Romania
5Duke Medical Center, Durham, USA  
6Clinic of Medicine II Oncology, Clinic Löwenstein, Germany
7Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete, Greece
8S.G. Moscati Hospital Department, Division of Medical Oncology, Contrada Amoretta, Italy
9Department of Pathology, University of Colorado, Aurora, Colorado, USA.
10Dept. of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland
11Department of Medical Oncology, Hygeia Hospital, Athens, Greece
12Department of Lung and Thoracic Tumours, Warsaw, Poland
13Department of Thoraxoncology, University of Heidelberg Medical Faculty Mannheim, Mannheim, Germany
14Hopital Arnaud de Villeneuve, Montpellier, France
15Laboratory for Molecular Oncology, Clinic and Policlinic for Oncology, University Hospital Zurich, Zurich, Switzerland
16Christie Hospital NHS Trust in Manchester, Manchester, United Kingdom
17Respiratory Oncology Unit (Pulmonology), University Hospital Gasthuisberg, Leuven, Belgium
Short title: CECOG Consensus on Systemic Treatment of NSCLC


Organizing Institution
Central European Cooperative Oncology Group (CECOG),
Headoffice: Schlagergasse 6, A-1090 Vienna, Austria
(www.cecog.org)

Supporting Institution
Clinical Division of Oncology, Department of Medicine I / Cancer Center
General Hospital - Medical University Vienna
18-20 Währinger Gürtel, A-1090 Vienna, Austria (www.meduniwien.ac.at/krebszentrum)




 
ABSTRACT
The current third consensus on the systemic treatment of NSCLC builds upon and updates similar publications on the subject by the Central European Cooperative Oncology (CECOG) which has published such consensus statements in the years 2002 and 2005 ³. The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree 4. This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables 3,4.
Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy of NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated which readdresses previous disease-related issues, but also expands towards recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages in the light of a rapidly expanding array of individual therapeutic options.

Key words: CECOG, chemotherapy,  NSCLC,  targeted therapy,

Abbreviations: CECOG – Central European Cooperative Oncology Group; NSCLC – non-small cell lung cancer; QoL – quality of life; IHC – immunohistochemistry; FISH - fluorescence in situ hybridization; IHC – immunohistochemistry; PFS – progression-free survival; OS – overall survival; TTP – time to progression; ORR – objective response rate; EGFR – epidermal growth factor receptor; VEGF – vascular endothelial growth factor; VEGFR – vascular endothelial growth factor receptor; TKI – tyrosine kinase inhibitor; BSC – best supportive care; ESA – erythropoiesis-stimualting agent; CSF – colony-stimulating factor; ERCC1 - excision repair cross-complementation group 1; B-RAF - Raf proto-oncogene serine/threonine-protein kinase; RR – response rate; EMEA – European Medicines Agency; SWOG – Southwestern Oncology Group; CRC – colorectal cancer; FDA – US Food and Drug Administration; PS – performance status; BAC – bronchioalveolar carcinoma; Her2 - human epidermal growth factor receptor 2; RRM-1 - ribonucleotide reductase M1.

INTRODUCTION

Lung cancer is one of the most frequently occurring malignancies in the world and represents the leading cause of cancer-related deaths in Western countries. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancer cases. In 2006, lung cancer was in incidence the third most common cancer in Europe amounting to 386.300 cases and 12.1% of all incident cases 1. In the same year and geographic area, lung cancer was the most frequent reason for death caused by a malignancy 1. Age-standardised incidence rates per 100.000 were 75.3 in men and 18.3 in women, whereas the corresponding mortality rates were 64.8 in men and 15.1 in women 1. Smoking has been unequivocally and very strongly shown to be tightly associated with disease occurrence representing the causative factor for about 90% of all lung cancers 2. Environmental tobacco smoke is a scientifically documented concern and results in an increased risk for the development of lung cancer 2.


Systemic therapy (chemotherapy and targeted therapy) constitutes an essential element of multimodality therapy of NSCLC. In early NSCLC, more than 80% of recurrences occur within two years from the time of radical surgery. However, over 70% of patients have locally advanced or metastatic disease already at presentation and thus require systemic treatment.






 
1. ADJUVANT AND NEOADJUVANT CHEMOTHERAPY
1.1 Adjuvant chemotherapy
Despite of surgery and complete surgical resection of NSCLC, up to about 60% of patients experience recurrence of disease 5-7. Thus, adjuvant chemotherapy in these patients with completely resected NSCLC has been proposed based on the assumption that distant micrometastases present at the time of diagnosis constitute the reason for recurrence of NSCLC in a considerable proportion of patients. Several adjuvant chemotherapy trials have been performed 8-12. A metaanalysis of five cisplatin-based trials revealed an increase of the 5-year survival rate following adjuvant chemotherapy by 5.3% 13.

Adjuvant cisplatin-based doublet chemotherapy (three to four cycles) should be offered to patients with stage II and III disease  and may be considered for selected patients based on tumor size with stage IB disease with adequate postoperative recovery, absence of clinically relevant comorbidity and good performance status within two months after surgery. Cisplatin should be preferred over carboplatin and combined with a third generation cytotoxic drug, preferentially vinorelbine. This is based upon the LACE metaanalysis - prespecified in the statistical plan – in which superior survival was obtained by the combination of cisplatin with vinorelbine, as compared to other cisplatin-based doublets (overall test of interaction - p = 0.04; HR 0.80, 95% CI 0.70-0.91, p <0.001 for LACE-vinorelbine and HR 0.95, 95% CI 0.86-1.05, p = 0.33 for LACE-other). Importantly, patients randomised to cisplatin-vinorelbine constituted the largest (41%) and the most homogeneous subgroup in terms of cisplatin dose. Although grade 3-4 toxicity was more common, the LACE  preplaned subanalysis confirmed a survival benefit in NSCLC of stages II and III in patients receiving cisplatin with vinorelbine 14.

1. 2 Neoadjuvant (induction) chemotherapy
*available online

Conclusion
1. Surgery remains the mainstay of treatment for early NSCLC [I,A].
2. Adjuvant chemotherapy after complete tumor resection should be offered to patients with stage II and III [I, A] disease and may be considered for selected patients based on tumor size with stage IB disease. Chemotherapy should consist of cisplatin plus a third generation cytotoxic drug, preferentially vinorelbine [I,B].
3. Neoadjuvant (induction) chemotherapy may be considered in stage III disease [II,B].
 
2. SYSTEMIC THERAPY FOR ADVANCED DISEASE

2.1 First-line Therapy

A. Platinum-based chemotherapy
Chemotherapy improves survival, quality of life (QoL) and tumor-related symptoms in patients with good performance status 19. The evidence of efficacy is best documented for platinum-based regimens. Therefore platinum-based doublet combinations are recommended in patients with performance status 0 or 1.

According to a meta-analysis, cisplatin is preferred over carboplatin under consideration of different toxicities of the two drugs 20, 21. Cisplatinum-based treatment should be delivered in combination with preferentially third generation cytotoxic drugs 22. There is no evidence that a cisplatin dose of >75 – 80 mg/m² delivered every 3-4 weeks might ameliorate treatment outcome 23. First-line cytotoxic chemotherapy should be administered for four to six cycles, but should be stopped at disease progression. Non-platinum based therapy can be considered in patients who have contraindications to platinum treatment and in unfit elderly patients

Three randomized phase III trials have indicated that pemetrexed exerts optimal activity in non-squamous-NSCLC 24-26: The pivotal trial 26 was a non-inferiority study including 1.700 chemonaive patients with stage IIIB-IV NSCLC and a performance status of 0 or 1. Patients were randomized to cisplatin in combination with either gemcitabine or pemetrexed for up to six cycles. OS was similar in both arms. However, when analysed by histology, patients with adenocarcinoma and large cell carcinoma showed significantly superior OS with cisplatin / pemetrexed, as compared to cisplatin / gemcitabine. The inverse was true for patients with squamous cell carcinoma. Based on these results, cisplatin / pemetrexed was approved by EMA in patients with non-squamous NSCLC.

Selection of first-line chemotherapy may thus be based on clinical criteria 27, 28 histological subtype 27-29, and on epidermal growth factor (EGFR) mutation status 29.

Conclusion
1.    Cisplatin-based doublets containing a third generation cytotoxic drug is the treatment of choice in patients with advanced NSCLC, unless platinum is contraindicated [I,A].
2.    Non-squamous histology is a prerequisite for pemetrexed efficacy [I,B].
3.    Cisplatin doses of <75 – 80 mg/m² every 3-4 weeks are recommended [I,B].
4.    Chemotherapy should be given for four to six cycles, but stopped at disease progression [II,B].

B. Targeted therapies

B.1 Bevacizumab
Two randomized studies indicated efficacy of the anti-angiogenesis compound bevacizumab 27, 28. The design of the pivotal intergroup trial foresaw the continuation of bevacizumab after the termination of chemotherapy until disease progression or unacceptable toxicity 28. This phase III trial which randomly analyzed treatment efficacy by the addition of bevacizumab to paclitaxel and carboplatin found a statistically significant increase of OS as well as for PFS in the bevacizumab-containing (bevacizumab dose: 15mg/kg q. 3 weeks) treatment arm 28. Another phase III trial (AVAIL) on the efficacy of bevacizumab (7.5mg/kg or 15mg/kg q. 3 weeks) combined with gemcitabine and cisplatin confirmed the PFS benefit in patients randomized to bevacizumab plus chemotherapy, but did not confirm an improvement of OS 27.


Based on presently available data, the use of bevacizumab is not indicated in patients with squamous cell histology in whom an increased rate of hemorrhages was observed 27, 28 .

Conclusions
The addition of bevacizumab in first-line chemotherapy (either carboplatin/paclitaxel or cisplatin/gemcitabine) of advanced nonsquamous NSCLC provides benefit in patients with good performance status and age <70 [I,B]. The dose of bevacizumab may be either 7.5mg/kg or 15mg/kg every three weeks depending on the chemotherapeutic backbone.


B.2 Cetuximab
In a large pivotal trial (FLEX), NSCLC patients with EGFR - positive advanced NSCLC (assessed by IHC) were randomly assigned to receive cisplatin plus vinorelbine with or without cetuximab. Cetuximab was given weekly until progression of disease 30. Patients assigned to the cetuximab group demonstrated a modestly longer median OS (11.3 months vs 10.1 months; HR 0.871 [95% CI 0.762–0.996]; p=0.044) and a higher response rate (RR), whereas there was no difference in PFS. Most common cetuximab related side-effects were acne-like skin rash, diarrhoea and infusion-related reactions. The cetuximab-induced benefit was independent of histology subtype, gender or smoking status. Similarly, K-RAS mutation status was not predictive for cetuximab efficacy, whereas early acne-like rash of any grade was associated with better outcome 32, 33. In another phase III study (BMS-099), the addition of cetuximab to carboplatin plus a taxane failed to improve the primary endpoint of PFS 34.
In a recent metaanalysis based on individual data of 2018 patients from four randomized phase II or III trials, the median OS in patients who received cetuximab in addition to chemotherapy was 10.3 months, as compared to 9.4 months in the chemotherapy-only arm (HR 0.878 [95%CI 0.795-0.969]; P=0.01) corresponding to an absolute benefit of 4.8% at one year 35. PFS was also more favorable for chemotherapy plus cetuximab (HR 0.89 [95%CI 0.81-0.99]; P=0.03).

Conclusion
Despite these results, the US Food and Drug Administration (FDA) label for cetuximab does not yet include NSCLC, and the European Medicines Agency (EMA) did not grant its use in this indication owing to modest benefits and associated toxicity. Nevertheless addition of cetuximab to a platinum based chemotherapy regimen is a treatment option in advanced NSCLC [I,B].

B.3 EGFR – TKIs
Four trials examined the efficacy of EGFR-TKIs erlotinib or gefitinib in combination with cytotoxic chemotherapy doublets in the first-line setting 36-39. All four trials found no improvement in OS, PFS or RR with the addition of an EGFR-TKI to chemotherapy. Therefore, erlotinib or gefitinib should not be used in combination with cytotoxic chemotherapy as first-line treatment in unselected patients.

In contrast, the first-line use of gefitinib as single agent has shown efficacy in patients with activating EGFR-mutations in a large randomized phase III trial (IPASS) comparing gefitinib given until disease progression with chemotherapy consisting of paclitaxel plus carboplatin as first-line treatment in a population specific to East Asia 29. The primary endpoint of PFS was significantly longer with gefitinib. OS - a secondary endpoint – did not differ. Hematotoxicity, alopecia, neuropathy and nausea were more pronounced in the chemotherapy arm, whereas diarrhea and skin toxicity were more frequent in the gefitinib arm. Patients with EGFR activating mutation experienced a better outcome with gefitinib, whereas patients without mutations had more benefit from chemotherapy.

Conclusion
1.    It is strongly recommended to test for EGFR activating mutations [I,A].
2.    In the absence of EGFR-activating mutations, chemotherapy remains the treatment of choice [I,A].
3.    In patients with EGFR activating mutations, treatment with gefitinib is the preferred treatment option [I,A].

C. ECOG Performance Status (PS) 2
Available data support the use of single agent chemotherapy in patients with PS of ECOG 2. However, data are still insufficient to make a recommendation for or against using a combination of two cytotoxic drugs for patients with PS of 2 19, 40-43.

D. Treatment in the Elderly
*available online
Conclusion:
Single agent therapy remains a reasonable option for unfit elderly patients  [I,B]55, 56, although clinical evidence does not support selection of a specific first-line chemotherapy drug or combination based on age alone. However, the need for enhanced supportive care should be emphasized in this patient population

2.2 Maintenance therapy
*available online
Conclusion
1.    The administration of pemetrexed immediately after first-line platinum-based, non-pemetrexed-containing chemotherapy constitutes a registered option in patients with non-progressing non-squamous NSCLC [I,B].
2.    Maintenance therapy with erlotinib administered  in patients with  NSCLC who experienced SD by first-line chemotherapy or with an activating EGFR mutation is also registered for this indication [I,B].

2.2 Second-Line Systemic Therapy

In patients treated with first line chemotherapy   for advanced NSCLC, disease progression usually occurs within 3-5 months. Second-line therapy at progression palliates tumor-related symptoms and improves survival 66. The benefit of second line therapy is more likely in patients who have responded to first-line chemotherapy and who have a good performance status 67.

Efficacy of second-line chemotherapy was first demonstrated   in a phase III trial of docetaxel against best supportive care (BSC). This trial showed significant benefit for OS and QoL achieved by the administration of docetaxel despite the risk of toxicity 68.

A. Chemotherapy
Docetaxel has been established as a first standard in squamous NSCLC 68, 69. However, pemetrexed showed similar efficacy, but a more favorable toxicity profile, as compared to docetaxel in a study originally designed to prove non-inferiority 25. In a post hoc analysis, the benefit achieved by pemetrexed was found to occur in patients with non-squamous tumors and this subsequently resulting in a limitation change of the pemetrexed label.

B. Targeted agents

B.1 EGFR-TKIs
 Erlotinib and gefitinib were investigated for efficacy in pretreated patients71-72. A phase III study (BR21) comparing erlotinib to placebo in stage IIIB or IV NSCLC patients who had received one to two prior combination chemotherapy regimens and were not candidates for further cytotoxic treatment, demonstrated significant, albeit moderate clinical benefit of erlotinib (median OS of 6.7 months and 4.7 months for erlotinib and placebo, respectively (HR 0.70 [0.58-0.85]; P<0.001) 71. Patients treated with erlotinib had also improvements in pain, cough, and dyspnoea. The most common side effect of erlotinib was acneiform rash and diarrhoea (75% and 55%, respectively) although grades 3 to 4 toxicity occurred in less than 10% of patients. High EGFR gene copy number by FISH was the strongest predictive marker for clinical benefit from erlotinib 73.
A similarly designed phase III trial (ISEL) evaluating gefitinib versus placebo in advanced NSCLC patients who failed one or two prior chemotherapy regimens did not reach significant OS superiority with (HR 0.89 [95%CI 0.77-1.02]; p=0.087) 72. However, in preplanned subgroup analyses, OS was significantly longer with gefitinib in never-smokers and patients of Asian ethnicity.  Similarly to the BR 21 study, the clinical benefit obtained from gefitinib was associated with high EGFR gene copy number 74.
In a large non-inferiority randomized study (INTEREST) comparing gefitinib versus docetaxel in previously treated advanced NSCLC patients, gefitinib was equivalent to chemotherapy for survival as primary endpoint OS and superior for the secondary endpoint QoL 70.


Conclusions
1.    The data from randomized trials on second-line therapy are sufficient to recommend either a cytotoxic agent (docetaxel for squamous NSCLC [II,B] or pemetrexed for non-squamous NSCLC [II,B]) or the EGFR-TKI erlotinib [I,B].  
2.    An EGFR-TKI should be considered in patients with  EGFR-activating mutations in their tumours who have not received it as first-line treatment [II,B]. Sequencing of chemotherapy after EGFR TKIs has not been defined and remains an important open issue.



3. Supportive Care
*available online




4.1 Targeted Treatment Options
A. EGFR-related biomarkers for prognosis
A metaanalysis of several studies failed to show a consistent correlation between EGFR expression levels and survival 85. Most studies have shown no prognostic effect of EGFR expression or a slight detrimental effect. The results for activating EGFR  mutations are strikingly different. Nearly all studies reported that patients with these mutations have a better outcome compared to those without these mutations, irrespective of tumor stage and treatment 84-87.

Prediction of outcome of EGFR-targeted therapy

About 10% of NSCLC patients in a Western population and 30-50% in East Asia have EGFR-activating mutations. A randomized phase II study showed that in patients with EGFR activating mutations, the median PFS was 18.2 months with erlotinib compared to 4.9 months with the alteration of chemotherapy and erlotinib. In contrast, the chemotherapy arm had a better median PFS in patients without an EGFR activating mutation 88. There is no evidence that EGFR activating mutations predict for superior outcome following cetuximab therapy 33.

While K-RAS mutation has been demonstrated to be a negative predictor in EGFR inhibition in patients with metastatic colorectal cancer (CRC), its role in NSCLC patients is still under debate.

B. ALK/EML4 FUSION
The fusion gene ALK/EML4 was first reported in NSCLC only a few years ago 89. A clinical dose escalation phase I study with an oral MET and ALK inhibitor, PF-02341066 showed for NSCLC patients with tumors harboring an activating ALK gene fusion, an objective response rate of of 64% and  a disease control rate of 90% 90.Although, the ALK- fusion either with EML4 or other fusion partners are relatively infrequent in NSCLC (4-5%), there still is a substantial number of patients, who might have a significant clinical benefit from this well tolerated therapy 91.
Conclusions
1. EGFR mutations predicts a better response to EGFR-TKIs (i.e. gefitinib) compared to chemotherapy as 1st line therapy in advanced NSCLC. Thus, EGFR mutation testing should be encouraged before treatment decision [I,A].
2. K-RAS mutation predicts a low response to EGFR-TKIs, but a significant association with survival was demonstrated for neither EGFR-TKI nor antibody therapy. Testing should not be recommended as a basis for treatment decisions in routine practice.
3. Patients with ALK/EML4 fusion tumours benefit  from specific targeted therapy against ALK-fusion. The role of routinely performed ALK-fusion testing for clinical practice is awaiting the results from ongoing clinical trials.

Acknowledgements
CECOG wants to thank all the authors, who are not listed on the paper:
Martin Filipits, Clinical Division of Oncology and Institute of Cancer Research, Dep of Medicine I, Medical University of Vienna, Austria
Vassilis Georgoulias, Department of Medical Oncology, University General Hospital of Heraklion, Greece
Cesare Gridelli, S.G. Moscati Hospital Department, Division of Medical Oncology, Contrada Amoretta, Italy
Paris Kosmidis, Department of Medical Oncology, Hygeia Hospital, Athens, Greece
Sabine Zöchbauer-Müller, Clinical Division of Oncology and Institute of Cancer Research, Dep of Medicine I, Medical University of Vienna, Austria

The panel wants to thank Ms. Ursula Fischer for expert help in managing the infrastructure and organisation of the conference and Dr. Katarzyna Elandt for support during the conference.
The meeting was made possible by educational grants from Eli Lilly, Merck-Serono and Amgen to the Central European Cooperative Oncology Group to further support its educational activities.



Appendices
Supplementary data
1. 2 Neoadjuvant (induction) chemotherapy
Neoadjuvant (induction) chemotherapy has been studied in early-stage NSCLC. The conclusions from these trials have been limited because of low numbers of patients included into clinical trials and/or their premature closure due to the increased use of adjuvant chemotherapy. Large trials failed to demonstrate a statistically significant improvement in overall survival (OS) by neoadjuvant chemotherapy in patients with early stage NSCLC 16-18. Thus neoadjuvant chemotherapy is not standard, but may be considered in selected patients - particularly those with stage IIIA (N2) disease- in order to obtain resectability of the malignancy. Favourable results of induction chemo- or chemo radiotherapy in patients with stage III NSCLC are particularly seen in patients who experience down-staging of mediastinal lymph nodes and complete tumour resection.

Neoadjuvant (induction) therapy followed by surgery has also been attempted in patients with stage IIIB disease, but no final conclusions about the prolongation of survival can be drawn.

With regard to the type of induction chemotherapy 14, cisplatin should be preferred over carboplatin and combined with a third generation cytotoxic drug. In general, the decision on the use of neoadjuvant (induction) chemotherapy followed by surgery should always be based on a thorough discussion in a multidisciplinary team.
Conclusion
Neoadjuvant (induction) chemotherapy may be considered in stage III [I,B] disease.

D. Treatment in the Elderly
Four randomized controlled trials 41, 44-46, two subgroup analysis 43, 47, one retrospective analysis 53 and one pooled analysis 49 have been reported since 2003.

Statistics examined the optimal first-line treatment for patients older than 65 to 70 years. Several analyses found no differences in survival between patients defined as elderly and younger patients. In addition, in terms of survival there was no evidence that one regimen would be superior over another. However, there was more toxicity reported for doublet versus single agent therapy.

Therefore, in order to avoid unacceptable toxicity, single agent therapy remains a reasonable option for unfit elderly patients [I,B]50, 51, although clinical evidence does not support selection of a specific first-line chemotherapy drug or combination based on age alone. However, the need for enhanced supportive care should be emphasized in this patient population.

2.2 Maintenance therapy

Definition: The prolongation of duration of systemic therapy by the administration of additional drugs after the end of a defined number of cycles of initial chemotherapy is referred to as “maintenance therapy” 52, 53.

The terms “maintenance”, “consolidation” or “early second-line” treatment are often used interchangeably.

In the absence of significant toxicity, maintenance chemotherapy with either a drug included in the induction regimen or another, non-cross-resistant agent used in sequence aiming at the amelioration of treatment outcome may be continued until disease progression. Different series demonstrated that an increasingly large population of patients will receive second-line treatment. Maintenance therapy could provide the opportunity of active treatment deferring progression and ultimately leading to an improvement in OS.

Older studies failed to show a survival benefit for prolonged administration of platinum-based therapy in NSCLC 54-57. These results led different groups such as ESMO 58 and ASCO 19 to recommend limiting first-line treatment. Due to the availability of newer, active and less toxic agents the concept of “maintenance” therapy was recently revisited by exploring different approaches in the maintenance setting.
A. Continuation with an agent used in the initial combination
Maintaining the least toxic agent from the initial combination gave mixed results. Maintenance with paclitaxel did not improve outcome 59. Maintenance with gemcitabine resulted in an improved time to progression (TTP), but the study was not powered to show an improvement in OS 60.
B. Maintenance therapy with an agent different from the ones used in the initial combination
With the advent of several effective second-line drugs (such as docetaxel, pemetrexed, erlotinib) which improved survival after progression, the next logical step was to analyze whether maintenance with such non–cross-resistant drugs immediately after completion of first-line therapy would improve OS.
Immediate use of docetaxel versus its use at the time of  progression improved PFS, but failed to improve OS, and proved to be too toxic for prolonged use 61.
Sequential maintenance with pemetrexed following four cycles of a platinum doublet (with either gemcitabine or docetaxel or paclitaxel) in non-progressing patients resulted in a 40% reduction in the risk of progression and a 21% reduction in the risk of death in the intent-to-treat population, and was well tolerated even at longer exposure 24. An unprecedented 5.2 months OS benefit (15.5 vs. 10.3 months) in patients with non-squamous NSCLC recommended its use as maintenance agent in patients with non-squamous histology. Drug-related grade 3 or 4 toxicities were slightly higher for pemetrexed (16% versus 4%), particularly concerning fatigue (5% vs. 0.5%) and neutropenia (2.9% vs. 0%).

At the present time, there are no data to show whether maintenance with pemetrexed after first line therapy pemetrexed plus platinum in patients with non-squamous NSCLC would also improve OS. Data from an on-going randomized trial will answer this question.

In a placebo-controlled randomized clinical study (SATURN study), sequential maintenance with erlotinib following first line therapy with a platinum based doublet resulted in a modest statistically significant benefit survival regarding PFS (HR=0, 71) 62,64,94. The benefit was shown in unselected patients irrespective of gender, race, histology, smoking and EGFR status. The highest benefit in terms of OS was seen in patients with SD after induction chemotherapy (HR=0, 72). Toxicity was as expected for this drug with no safety concerns 94.

The addition of erlotinib to bevacizumab after 4 cycles of chemotherapy plus bevacizumab significantly improved PFS (HR 0.722; ATLAS study)63. This improvement was seen across multiple subgroups, including those defined by gender, histology, age, and smoking status. No new safety signals were observed. No significant difference in OS was observed 65.

Conclusion
1.    The administration of pemetrexed immediately after first-line platinum-based, non-pemetrexed-containing chemotherapy constitutes a registered option in patients with non-progressing non-squamous NSCLC [I,B].
2.    Maintenance therapy with erlotinib administered in patients with NSCLC who experienced SD by first-line chemotherapy or with an activating EGFR mutation is also registered for this indication [I,B].
Controlled clinical trials comparing maintenance therapy versus second-line therapy at relapse are lacking.


3. SUPPORTIVE CARE

Supportive care should be an integral part of the treatment plan for all patients with NSCLC.  Disease-related symptoms include fatigue, cachexia, pain, cough, dyspnea, neurologic impairment from brain metastasis or spinal cord compression, and electrolyte abnormality such as hypercalcemia and hyponatremia. The majority of these symptoms are best approached by cancer treatment, in conjunction with supportive care approaches. In addition Surgery, radiotherapy, chemotherapy and targeted therapy all have significant toxicities which also need to be recognized and addressed proactively. Treatment-related symptoms include emesis, hair loss, mucositis, cutaneous toxicity, neuropathy and myelosuppression. While all of these areas are worth of discussion, they are beyond the scope of these guidelines and are reviewed elsewhere 76.

A. Anemia and the Role of Erythropoiesis Stimulating Agents (ESAs)
Anemia commonly occurs in patients with NSCLC. Particularly in patients receiving platinum-based chemotherapy, as many as 90% may develop anemia.  After evaluation for reversible causes of anemia in cancer patients, the primary intervention historically has been the administration of red blood cell transfusions for symptomatic anemia.  In the early 1990’s, ESAs were first approved for use in reducing transfusion requirements in patients with chemotherapy-related anemia.  The currently available ESAs include epoetin alpha, epoetin beta, and darbepoietin alpha.  While all three of these agents have biochemical differences and differ in frequency of administration, all three agents have a similar efficacy and side effect profile and no single agent can be considered superior to others.

A metaanalysis has documented a reduction in transfusion requirement with ESAs, but with an associated 1.6-fold increased risk in thromboembolic events 77. With the improvement in anemia, the majority of studies have documented an improvement in patient-reported QoL measures. While the need for transfusion is very patient-dependent based on cardiovascular symptoms, fatigue and other factors, the majority of patients will require transfusion with a hemoglobin of less than 8 g/dl and many patients will be transfused even in the range of a hemoglobin between 8 and 10 g/dl. Thus, maintenance of the hemoglobin level above 10 g/dl is generally adequate to avoid transfusion.

In recent years, randomized trials evaluated the role of raising hemoglobin levels above 12 g/dl in hopes of improving therapeutic benefit. However, eight of these studies have reported on an opposite effect of reduced survival. Four of these were in the setting of chemotherapy, 2 in the setting of radiation therapy alone and 2 in the setting of supportive care alone, one of which was a small trial in NSCLC. When all very different types of trials were brought together in a metaanalysis, there was an overall increased mortality with the use of ESAs 78. However, when the analysis was restricted to patients receiving chemotherapy only, this hazard risk was no longer significant. A metaanalysis restricted to patients with lung cancer did not show evidence of increased mortality risk either 79. Another recent metaanalysis looked at the effect of baseline hemoglobin at the time of inclusion in chemotherapy-induced anemia trials on survival outcomes: the negative signal was limited to studies with a mean entry hemoglobin >12 g/dl, and not present in all others entering patients with hemoglobin below 12 g/dl. While the negative survival signals were thus generated from studies targeting higher than the standard hemoglobin levels, some regulatory bodies, nonetheless, requested a large international trial in advanced NSCLC, randomizing patients to ESA versus placebo with transfusion in both arms, as needed. Such a trial is currently ongoing with darbepoietin alpha.

Conclusions
1. The use of ESAs should be restricted to patients receiving cancer chemotherapy [I,A].
 2. The primary goal for ESA therapy should be the avoidance of transfusion.  Therefore, the initiation of therapy as the hemoglobin approaches <10 g/dl can be considered and ESAs should be titrated to maintain the hemoglobin level between 10 and 12 g/dl [II,B].
3. All patients receiving ESAs should be informed of the increased relative risk of thromboembolism and uncertainties about impact of ESAs on survival in certain settings.
4. Transfusion itself remains an acceptable strategy for management of patients with anemia related to cancer chemotherapy. Transfusions carry risks that must be explained to the patient, as does untreated anemia when it is severe.  Until more information is available, transfusion should be the preferred strategy for patients in the curative setting [I,A].

B. Neutropenia
Neutropenia is the major dose-limiting toxicity of myelosuppressive chemotherapy in patients with NSCLC across all stages of treatment. Among solid tumor patients, lung cancer patients are at highest risk for the consequences of neutropenia and infection because of a higher risk for pneumonia and infections of other tissues, causes related to cancer itself as well as to co morbidity (e.g. chronic obstructive pulmonary disease).  Early recognition of the danger of infection due to neutropenia and induction of treatment with antibiotics is vital in reducing both the morbidity and mortality.  Prior to the advent of colony stimulating factors (CSFs), the only preventive approach has been dose reduction or delay of chemotherapy. It is worth noting that in a pooled analysis of three clinical trials, a strong correlation of the development of neutropenia with the likelihood of a clinical benefit from chemotherapy in advanced stages of NSCLC was found 80.

Among patients receiving chemotherapy for solid tumors or lymphoma, the prophylactic use of antibiotics (mainly quinolones such as levofloxacin) has been shown to reduce the incidence of fever, infection and hospitalization 81, although this strategy is not unequivocally accepted 82.



Conclusions
1. Guidelines generated by ASCO, EORTC, ESMO and NCCN have all recommended prophylactic use of CSFs if chemotherapy-associated risk of febrile neutropenia is >20% [I,A].
2. The standard regimens used for the management of patients with NSCLC are not normally associated with a risk of febrile neutropenia of greater than 20%. Therefore, the routine use of primary prophylaxis with a CSF is not warranted [I,A].
3. However, in the setting of special patient circumstances including an advanced stage tumour, advanced patient age, risk for pneumonia, presence of co morbidities, poor performance status, prior chemotherapy or significant radiation treatment, primary prophylaxis may be considered [III,C].
4. For secondary prophylaxis relating to patients who had neutropenia or a neutropenic event following a prior cycle of chemotherapy, the decision between the reduction of chemotherapy dose and the use of a CSF should depend upon the clinical benefit the patient is supposed to receive from chemotherapy under the consideration of chemotherapy-related toxicity.
5. Prophylactic antibiotics have shown an ability to reduce the risks of fever, infection, and hospitalization, but their use after standard-dosed chemotherapy has to be weighed against the concern on the development of antibiotic resistance.

4. Molecular Markers

4.2 Prediction of outcome to chemotherapy
Platinum-based doublets remain the standard of treatment for patients with NSCLC.  However, it should be noted that response and outcome varies significantly between patients highlighting the need for molecular predictive markers for these therapeutic combinations.

A.  ERCC1 as a predictor of clinical benefit from platinum-based therapy
Nucleotide excision repair is a highly versatile pathway for DNA damage removal and is often dysfunctional in NSCLC. Excision repair cross-complementation group 1 (ERCC1) performs an essential late step in the nucleotide excision repair process, where it nicks the damaged DNA strand at the 5′ site of the helix-distorting cisplatin lesion. ERCC1 might also play several other important roles in the DNA repair process.

In the large randomized study, IALT (International Adjuvant Lung Cancer Trial), 761 NSCLC patients were assessed for ERCC1 protein expression by IHC 15. ERCC1 was found to be positive in 44% of patients and negative in 56% of patients. The absence of ERCC1 was associated with a benefit from cisplatin-based adjuvant chemotherapy. The ERCC1-negative tumors had an adjusted HR of 0.65 (95% CI 0.50–0.86, P=0.002) compared with a HR of 1.14 (95% CI 0.84–1.55, P=0.40) for ERCC1-positive patients. Among patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors (adjusted hazard ratio for death, 0.66; 95% CI, 0.49 to 0.90; P=0.009). It was concluded that patients who had NSCLC with completely resected ERCC1-negative tumors were stronger candidates for adjuvant cisplatin-based chemotherapy than those who had resected ERCC1-positive tumors 15.

A joint Spanish–US study has observed longer OS and a trend towards improved response in NSCLC patients with stage IV disease and low ERCC1 mRNA levels who were treated with gemcitabine plus cisplatin 92. In another study from the Spanish Lung Cancer Group, 444 patients with NSCLC (stage IV disease) were prospectively randomized based on ERCC1 mRNA levels 93. In the genotyped treatment arm, the response rate was 50.7% compared with 39.3% in the control arm (P=0.02). The study demonstrated that assessment of ERCC1 mRNA expression is feasible in the clinical setting, and predicts response rates to docetaxel plus cisplatin but not survival. Ceppi et al 96 have also shown, in a retrospective study of 70 patients, that a low level of ERCC1 as measured by IHC predicts longer survival under cisplatin-based chemotherapy.
Based on these results, there is a high probability that cisplatin-based chemotherapy could be selected according to ERCC1 expression in tumor tissue in the near future. Nevertheless, additional studies are warranted to standardize and optimize methodologies for ERCC1 analysis in tumor tissue in order to define a biomarker profile for predicting outcome.

Future Perspectives
Therapy based on molecular biomarkers seems to move into lung cancer management very quickly.  It is estimated that about 20-25% of patients with advanced NSCLC might benefit from molecular testing and associated molecular targeted therapies therapy: EGFR mutations (10-15%), ALK-fusion (4-5%), c-MET amplification (3%), and HER2 amplification/mutation (3%). For chemotherapy, several potential biomarkers have shown encouraging results, e.g. ERCC1 (for cisplatin), RRM1 (for gemcitabine) and Thymidylate Synthase (for pemetrexed). Ongoing and future prospective studies need to validate the biomarkers’ predictive and prognostic values as well as standardization of assays.