Practical Approach to the Treatment of Locally Advanced NSCLC: Controversies in Systemic Therapy

November 19, 2008

Lung Cancer is the leading cause of cancer-related death in the United States. Non-small cell lung cancer (NSCLC) accounts for more than 85% of all patients with lung cancer.[1] A third of patients with newly diagnosed NSCLC have locally advanced disease.

Table of Contents

CONTINUING MEDICAL EDUCATION

Activity Release Date: November 15, 2008
Activity Release Date: November 15, 2009

About the Activity


This activity is based on a brief article developed as part of the E-Update Series and posted on the Web. It was developed from an identified educational need for information about practical management issues in the practice of medical, surgical, and radiation oncology. This activity has been developed and approved under the direction of CME LLC.

Activity Learning Objectives

After reading this article, participants should be able to:

1. Demonstrate an understanding of the appropriate role of surgery in the metastatic setting:
• Role of tackling the unexplored mediastinum in patients who have undergone resection
• Role of surgery after chemoradiation in stage IIIA NSCLC

2. Apply into practice the role of radiation therapy post resection in the treatment of N2 NSCLC:
• PORT = Post-Operative Radiation Therapy
• STARBOARD = Sidestepping Trans-Thoracic Adjuvant Radiation Therapy Because One is Averse to Radiation Damage

3. Analyze the efficacy of molecular profiling for cytotoxics and targeted agents

4. Appraise the use of induction therapy versus adjuvant therapy

5. Demonstrate an understanding of the possible role consolidation versus observation after Initial Therapy

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This activity targets physicians in the fields of oncology and hematology.

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Continuing Education CreditAMA PRA Category 1 Credit™
CME LLC designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits™ .
Physicians should only claim credit commensurate with the extent of their participation in the activity

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Financial Disclosures

Dr. Langer has received grant and research support from Bristol-Myers Squibb, ImClone, Pfizer, Lilly, Schering-Plough Research Institute, Sanofi-Aventis, Amgen, Cell Therapeutics Inc, OrthoBiotech, Celgene, Vertex, Genentech, OSI, AstraZeneca, Active Biotech, Medimmune (absorbed by AZ 2008); has served as scientific advisor for Bristol-Myers Squibb, ImClone, Sanofi-Aventis, Pfizer, Intrabiotics, GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca, Novartis, Genentech, Savient, Bayer, Onyx, Abraxis, and Abbott; and has served on the speaker's bureau for Bristol-Myers Squibb, Sanofi-Aventis, Lilly, OrthoBiotech, Genentech, and OSI. Dr. Govindan served as a speaker for Lilly, Genentech, and AstraZeneca.

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Dear Colleague:

As you know well, approximately a third of newly diagnosed patients with non-small cell lung cancer (NSCLC) present with locally advanced disease.  The majority of these patients are treated with definitive chemoradiation alone.  While the promise of consolidation therapy with docetaxel after chemoradiation has not been realized, new agents, particularly cetuximab and other targeted therapies, appear promising and await formal phase III investigation.  Over the past 25 years, the 5-year survival rate for those with unresectable, non-metastatic NSCLC has increased from 5% to 20%–25%.  But further headway is urgently needed.

In our continuing series of E-Updates on the controversies and challenges in the treatment of NSCLC, we are pleased to present a robust discussion on the role of combined modality therapy in locally advanced NSCLC. Dr. Ramaswamy Govindan, an acknowledged expert in this area and current Editor of the ASCO Educational Book, outlines the "state of the art" feature in the treatment of stage III NSCLC in this E-Update entitled "Practical Approach to the Treatment of Locally Advanced NSCLC: Controversies in Systemic Therapy".

I am sure you will find this review very concise and practically useful. Our last issue of these lung cancer E-Updates discussed the current controversies regarding the role of surgery in the treatment of stage III NSCLC. Read back to back, these two issues will address all the practical problems you are likely to face in the treatment of locally advanced NSCLC. I hope you will take time to read these reviews and provide us the all important feedback. As always, please feel free to contact me with your comments and questions at: corey.langer@uphs.upenn.edu.

Hope all of you are having a good and enjoyable autumn.

Best regards,

Corey J Langer MD, FACP
Professor of Medicine
Director of Thoracic Oncology
University of Pennsylvania
Philadelphia, Pennsylvania


Introduction

Lung Cancer is the leading cause of cancer-related death in the United States. Non-small cell lung cancer (NSCLC) accounts for more than 85% of all patients with lung cancer.[1] A third of patients with newly diagnosed NSCLC have locally advanced disease. Locally advanced NSCLC is a heterogeneous group comprised mainly of patients with ipsilateral or contralateral mediastinal lymph node involvement and those with large bulky tumor involving major blood vessels and vertebral bodies. A majority of patients with locally advanced NSCLC are not considered for surgical resection and are treated with definitive chemoradiation. While there are no standard rules about what constitutes resectable locally advanced NSCLC, surgery is reserved only for those with minimal mediastinal lymph node involvement (single station), adequate pulmonary function who are candidates anatomically for lobectomy. This review will focus on the practical issues regarding the systemic therapy of locally advanced NSCLC.



Major Issues in the Systemic Therapy of Patients with Locally Advanced NSCLC

The progress in the treatment of locally advanced NSCLC has been slow since the initial reporting of the seminal Cancer and Leukemia Study Group B (CALGB), demonstrating the advantage of adding chemotherapy to thoracic radiation therapy.[2] Several issues have been addressed over the past two decades with regard to systemic therapy in this setting, including the relative benefits of concurrent chemoradiation versus sequential chemotherapy followed by radiation, the optimal dose and schedule of chemotherapy when administered concurrently with radiation therapy, the role of induction and/or consolidation chemotherapy, and finally the integration of molecularly targeted chemotherapy.[3]



Concurrent versus Sequential Chemoradiation

Several large prospective studies have demonstrated the superiority of concurrent chemoradiation over sequential chemotherapy followed by radiation therapy.[4-13]  It is worth keeping mind that these studies were restricted to patients with good performance status and no significant weight loss. The toxicities of concurrent chemoradiation regimens were higher than those associated with sequential chemotherapy followed by radiation. The most significant and common toxicities are esophagitis and pneumonitis; the incidence rates of esophagitis with concurrent chemoradiation are four- to six-fold higher compared to sequential therapy, although the incidence of severe pneumonitis is no different . Cisplatin (and not carboplatin) has traditionally remained the backbone of the chemotherapy regimens tested in this setting. Despite using an aggressive regimen of chemoradiation, the majority of patients with locally advanced NSCLC who succumb die from distant relapse rather than local recurrence, suggesting a need for better systemic therapy.  Several approaches have been tested in an attempt to improve outcome, beginning with optimal systemic chemotherapy regimen that could be administered safely along with thoracic radiation (second generation versus third generation agents or "low radio sensitizing doses" as opposed to systemically active "full doses" of chemotherapy), use of induction or (and) consolidation therapy and addition of molecularly targeted therapies in this setting.



Optimal Chemotherapy: Low Dose versus High Dose-How Good is the Weekly Paclitaxel, Carboplatin Regimen?

In general, two broad approaches have been pursued in North America with regard to the use of chemotherapy administered in conjunction with thoracic radiation:  (1) one approach employs "low-dose" more frequent chemotherapy to sensitize the effects of radiation, without necessarily exploiting the agents' systemic activity; (2) the second approach employs concurrent "full dose" chemotherapy that could conceivably have systemic anti-cancer activity. While no large prospective studies have compared low dose with full dose chemotherapy, the CALGB 39801 study highlighted the inadequacies of the commonly used low dose chemotherapy option with weekly paclitaxel and carboplatin.[14] The primary objective of this large phase III study was to assess the role of induction chemotherapy in the treatment of locally advanced NSCLC.  This study compared concurrent low dose weekly paclitaxel and carboplatin and thoracic radiation with the same regimen preceded by two cycles of induction chemotherapy with paclitaxel and carboplatin given at full systemic doses for two cycles every 21 days.  While the addition of induction therapy did not improve the outcomes, the most disappointing finding were the poor results observed in both the arms, with the median survival of 12 months without induction therapy and 14 months with induction chemotherapy.  It should be noted, however, that a significant minority of patients enrolled in this study had more than 5% weight loss at baseline.  The Locally Advanced Multimodality Protocol (LAMP) compared sequential chemotherapy followed by radiation therapy alone (sequential) with two study regimens, one with induction chemotherapy followed by concurrent chemoradiation where chemotherapy was administered at low doses on a weekly basis (induction) and the other with the same concurrent chemoradiation regimen followed by consolidation therapy (consolidation).[13]  All patients in this study received paclitaxel and carboplatin. This study was terminated prematurely due to poor accrual. The median overall survival for the sequential (control) arm was 13 months, induction arm 12.7 months and consolidation regimen 16.3 months. It is difficult to draw firm conclusions due to the smaller numbers of patient enrolled in this study.

The CALGB 39801 study raised serious concerns about the adequacy of disease control with the use of a popular regimen of weekly low dose paclitaxel and carboplatin along with thoracic radiation in the treatment of locally advanced NSCLC.  Since the majority of patients with locally advanced NSCLC die from systemic relapse, and the low weekly doses of paclitaxel and carboplatin are likely not systemically active, several investigators have now begun to explore alternative options that would include the use of systemically active doses that can be safely administered along with thoracic radiation.  This sort of practice is similar to the approach used for the treatment of limited stage small cell lung cancer and locally advanced esophageal cancer. What then should be the optimal chemotherapy regimen for locally advanced NSCLC? The largest amount of data now exists for the use of cisplatin and etoposide along with radiation (see below), which can be administered at full dose during RT, which has emerged as the platform regimen for many clinical trials. The Hoosier Oncology Group (HOG) study failed to confirm the value of consolidation therapy (docetaxel in this instance), following concurrent thoracic radiation and two cycles of cisplatin and etoposide, but showed promising survival times of 22 to 24 months for either arm.[15] An alternate strategy is to consider systemically dosed paclitaxel (175 mg/m2) and carboplatin (AUC 5-6) every three weeks with thoracic radiation.[16] Though this is feasible and intuitively attractive since this regimen is systemically active, unfortunately there are only limited data regarding the efficacy of this regimen.



Induction Chemotherapy

Two multicenter studies have addressed the role of induction chemotherapy in the treatment of locally advanced NSCLC here.  CALGB 39801, as discussed previously, did not find any survival improvement with the use of induction chemotherapy.[14] Similar results were observed in a smaller prospective study of 134 patients with locally advanced NSCLC. In this study, patients were randomized to two cycles of induction chemotherapy with cisplatin and gemicitabine (for two cycles) followed by concurrent chemoradiation with cisplatin and paclitaxel or concurrent chemoradiation with cisplatin and paclitaxel.[17] The median overall survival with induction therapy was 12.6 months (95% confidence interval [CI]: 8.6-16.7 months) and with concurrent chemoradiation alone was 18.2 months (95% CI: 11.7-24.8 months, p=.18 months p=.08).  There is significantly less enthusiasm to explore induction chemotherapy given these observations.



Consolidation Chemotherapy

The SWOG 9504 regimen of concurrent chemoradiation with cisplatin and etoposide followed by consolidation docetaxel became very popular, yielding an impressive median overall survival of 26 months and a five-year survival of 29%, even though this was a non-randomized phase II study.[18]  This approach, thought to be rationally designed and scientifically sound and incorporating a " non-cross resistance" drug docetaxel in the consolidation setting following a platinum and etoposide combination, appeared superior to the SWOG's own previous studies.[10]

However, the phase III study conducted by HOG failed to show any survival advantage with the use of consolidation docetaxel.[15]  In this rather small phase III study, 203 patients were enrolled and after receiving cisplatin, etoposide, and thoracic radiation, 147 were randomized to observation or three cycles of consolidation docetaxel.  The study was terminated early by the Data Safety Monitoring Board based on the planned futility analysis. The overall median survival for the entire study population of 203 patients was 21 months.  The addition of docetaxel did not improve the progression free survival or overall survival.  However, treatment-related toxicities and mortality were higher with docetaxel than with observation alone.   Apart from a critical difference with regard to baseline pulmonary function, patient characteristics, treatment delivered, and side effect profile were identical between the HOG study and SWOG 9504. The survival outcomes of all patients enrolled in the HOG study did not differ significantly based on the FEV1 levels at baseline. However, it is not certain whether docetaxel consolidation would have improved the outcomes in optimally selected patients (based on the PFT criteria). Based on this only available phase III study, consolidation with docetaxel or other agents continues to be investigational.



Molecularly Targeted Chemotherapy

It is not surprising that several studies have explored the value of adding molecularly targeted therapy to radiation or chemoradiation in the treatment of locally advanced NSCLC. Epidermal growth factor receptor (EGFR) is commonly expressed in NSCLC and up-regulated in response to radiation injury. EGFR tyrosine kinase inhibitors (TKI) such as gefitinib or erlotinib and monoclonal antibodies to EGFR (cetuximab) have been studied in this setting. The CALGB 30106 study stratified patients with locally advanced NSCLC into two strata: stratum 1 (performance status of 2 or performance status of 0 or 1 with poor risk) or stratum 2 (performance status 0-1).[19] All patients in this study received two cycles of induction therapy with paclitaxel (200 mg/m2) and carboplatin (AUC 6). Patients in stratum 1 received gefitinib (250 mg) once a day along with thoracic radiation. Patients in stratum 2 received concurrent chemotherapy with paclitaxel (50 mg/m2) and carboplatin (AUC 2) along with gefitinib (250 mg daily) and thoracic radiation. This small study showed surprisingly good results in the 20 patients deemed to be at poor risk (assigned to stratum 1) with the median overall survival of 19 months, while median survival was a disappointing 12 months in the good risk stratum despite concurrent chemoradiation and gefitinib, suggesting potential antagonism between chemotherapy and EGFr-TKI in this setting.  A follow-up study is being planned in CALGB substituting erlotinib for gefitinib in the poor risk population. Even more disconcerting were the results of the maintenance therapy with gefitinib, following chemoradiation and consolidation docetaxel. This SWOG study randomized patients to receive maintenance gefitinib or placebo following concurrent chemoradiation (cisplatin and etoposide) and consolidation docetaxel.  While the median overall survival of the entire study cohort was an encouraging 19 months, there was a significant difference in overall survival favoring the placebo arm.[20] SWOG investigators do not feel that treatment-related toxicities led to the poor outcomes.  Molecular correlates from this study are still pending.  A phase I study from the University of Chicago Consortium reported no excess in-field toxicities when erlotinib was added to chemotherapy (paclitaxel and carboplatin or cisplatin and etoposide) and thoracic radiation.

The addition of cetuximab to paclitaxel, carboplatin-based chemotherapy has been studied by the Radiation Therapy Oncology Group (RTOG) and the initial results are encouraging.[21] In this study, 93 good risk patients with locally advanced NSCLC received paclitaxel, carboplatin with thoracic radiation, and cetuximab. The preliminary analysis of 87 evaluable patients revealed a median overall survival of 22.7 months. The RTOG is planning to integrate cetuximab in the ongoing intergroup phase III study investigating the optimal dose of thoracic radiation, with a "two by two" randomized design comparing 74 Gy to 60 Gy using 3-D conformal RT with or without C225. CALGB has just completed the enrollment for a phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab.[22] The combination of cetuximab and chemoradiation was well tolerated in both the CALGB and RTOG studies. Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), improves overall survival when added to paclitaxel and carboplatin when compared with chemotherapy alone in advanced NSCLC. Naturally, several studies have been developed incorporating bevacizumab with thoracic radiation. However, several instances of tracheo-esophageal fistula have been reported not only when bevacizumab was used during chemoradiation, but even when administered a few months after chemoradiation.[23, 24] Given the central role VEGF plays in healing and tissue repair, these isolated observations of TE fistula are concerning enough to lead to early closure of most of the studies testing bevacizumab and thoracic radiation. There are only very limited data regarding the safety of VEGF-TKIs.  There is no role for the use of VEGF inhibitors in combination with thoracic radiation outside the context of a carefully monitored clinical trial setting.



Conclusion

In summary, a third of patients with newly diagnosed NSCLC are diagnosed with locally advanced disease and are not candidates typically for surgical resection. Patients with locally advanced NSCLC who have a good performance status and no significant weight loss should receive concurrent chemoradiation. While there is considerable controversy with regard to the optimal chemotherapy regimen in this setting, our own approach is to use two cycles of cisplatin and etoposide with thoracic radiation. The role of higher than conventional doses of radiation (70 Gy or higher) and molecularly targeted agents in the management of locally advanced NSCLC are being studied with great interest.



 

References


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11. Curran W, Scott CB, Langer CJ, et al: Long-term benefits is observed in a phase III comparison of sequential vs. concurrent chemo-radiation for patients with unresectable NSCLC: RTOG 9410 (abstract 2499). Proc Am Soc Clin Oncol 22:621, 2003.

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13. Belani CP, Choy H, Bonomi P, et al: Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 23(25):5883-5891, 2005.

14. 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 25(13):1698-1704, 2007.

15. Hanna N, Neubauer M, Ansari R, et al: Phase III trial of cisplatin (P) plus etopsoide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel (D) in patients (pts) with inoperable stage III non-small cell lung cancer (NSCLC) HOG LUN01-24/USO-023 (abstract 7512). ASCO Annual Meetings Proceedings J Clin Oncol 25:18S, 2007.

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24. Goodgame, B, Veeramachaneni N, Patterson A, et al: Tracheo-esophageal fistula with bevacizumab after mediastinal radiation. J Thorac Oncol 3(9):1080-1081, 2008.