How Important is Histology in Treatment Selection for Non Small Cell Lung Cancer patients?

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1 Cancer Therapy Vol 7, page 324 Cancer Therapy Vol 7, , 2009 How Important is Histology in Treatment Selection for Non Small Cell Lung Cancer patients? Review Article Edgardo S. Santos 1*, Belisario Arango 2, Cesar A. Perez 3, Aurelio B. Castrellon 1, and Luis E. Raez 1 1 Sylvester Comprehensive Cancer Center/University of Miami Miller School of Medicine, Miami, Florida, Department of Internal Medicine, Henry Ford Hospital, 2799 W Grand Blvd., Suite 109, Detroit, MI Internal Medicine/Department of Medicine, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd, North Chicago, IL *Correspondence: Edgardo S. Santos, M.D., FACP, Assistant Professor of Medicine, Associate Director, Hematology/Oncology Fellowship Program, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, 1475 NW 12 th Avenue, D8-4, Miami, FL 33136; Phone: ; Fax: ; esantos2@med.miami.edu Keywords: angiogenesis, bevacizumab, histology, non-small cell lung cancer, pemetrexed, predictive marker, prognostic marker, thymidalate synthase. Received: 26 May 2009; Revised: 29 May 2009 Accepted: 27 May 2009; electronically published: 5 June 2009 Summary Therapy for all non-small cell lung cancers has been non-selective for many decades. This was a blind process due to lack of solid scientific data in terms of tumor biology and molecular medicine focused in this disease. In the last decade, the study of lung cancer genome, molecular analysis, proteomics, and many others have resulted in an avalanche of knowledge which has allowed us to tailor specific treatments based on patients tumor fingerprints ( phenotype ) at the molecular level. Efforts are being conducted to see which available treatments may induce major responses that may translate into survival advantage. As an example, several predictive biomarkers in nonsmall cell lung cancer have been recently elucidated such as DNA repair genes (e.g., ERCC1, RRM1), gene expression profiling, certain gene mutations (e.g. EGFR, K-ras), and others. Recently, the histology of the lung tumors has become a clinical feature driving therapeutic decision. Nowadays, we consider that histology in lung cancer matters and we must secure enough tumor tissue, which can yield not only an accurate pathologic diagnosis but also for further biomarker tests. More research is needed in this arena to define the best treatment selection and therapeutic algorithm for our patients. Many variables besides patient-related factors play a crucial role in the therapeutic decision-making. I. Introduction In the last three years, the median overall survival (OS) of non-small cell lung cancer (NSCLC) has improved due to the introduction of biologic agents in combination with conventional chemotherapy. This novel combination yielded for the first time ever an overall survival (OS) beyond 12 months for advanced/metastatic NSCLC (Sandler et al., 2006). Several questions were raised from the Eastern Cooperative Oncology Group (ECOG) 4599 study which established a new standard of care as front-line treatment in eligible and non-squamous advanced NSCLC: Was there a signaling telling us that non-squamous lung cancer tumors are more susceptible to this targeted treatment against VEGF pathway? Or are histologic subtypes of NSCLC different entities with different clinical behaviors? The latter has had a partial answer from clinical observations many years ago. It is well known that bronchoalveolar carcinoma (a subtype of adenocarcinoma) has most of the time an indolent course different from squamous, large cell or adenocarcinoma of the lung. Bronchoalveolar carcinomas have also been considered non-sensitive to conventional chemotherapy something that has not proven true. In the last 5 years, novel targeted agents has also challenged these concepts but will not be discussed here. The first observations in terms of the importance of histology in NSCLC came from safety issues, which made squamous cell carcinoma patients to be ineligible to receive bevacizumab (Avastin, Genentech, South San Francisco, CA, USA), an anti-vascular endothelial growth 324

2 Santos et al: How Important is Histology in Treatment Selection for Non Small Cell Lung Cancer patients? factor (VEGF) monoclonal antibody (MoAb), due to high risk for life-threatening bleeding (Johnson et al, 2004). Later, a prospective randomized phase III trial which was published recently showed that non squamous cell carcinoma of the lung are more responsive to an antifolate agent known as pemetrexed (Alimta, Eli Lilly & Co, Indianapolis, IN, USA) (Scagliotti et al., 2008). These findings have also been corroborated by other two studies, one being a retrospective analysis and the other a prospective randomized trial (Peterson et al, 2007; Ciuleanu et al., 2008). The cumulative data was conclusive enough to make the United States Food and Drug Administration (US FDA) modified the labeled use of pemetrexed in November Thus, pemetrexed is indicated now for the treatment of non squamous cell carcinomas in both settings first- and second-line, and it is not approved for squamous cell carcinomas any longer. To date, there is a debate in deciding which treatment may offer the best response rate and survival advantage to non-squamous NSCLC. To solve this problem, a large phase III randomized trial has just begun. Herein, more than 900 patients who have stage IIIB/IV will be randomized between carboplatin/paclitaxel/bevacizumab (arm 1) versus carboplatin/pemetrexed/bevacizumab (arm 2). All patients who attain stable disease or objective response will continue on maintenance therapy with bevacizumab alone in arm 1 (as described in ECOG 4599) or pemetrexed/bevacizumab doublet in arm 2 until progression of disease. The trial is seeking if the addition of pemetrexed to bevacizumab enhances further clinical response as well as survival. One of the hypotheses that may explain why pemetrexed is effective in adenocarcinoma or large cell lung cancer is the level of thymidilate synthase (TS) in this particular cancer cells (Ceppi et al, 2006; Scagliotti GV et al, 2009). In the case of antiangiogenesis therapies, the data is more confusing in terms of which one is exactly the target for this therapeutic approach. Overexpression of VEGF has been observed in a variety of cancers and has been associated with a worse relapse-free and OS. Bevacizumab targets the VEGF ligand. However, its clinical efficacy has not been consistently correlated with several biomarkers that have been evaluated. Thus far, there is not a single predictive biomarker for antiangiogenesis. Nowadays, we also recognized that novel targeted agents in which anti-vegf effect is involved also carry with them similar safety issues as it was shown previously by bevacizumab, and perhaps some differences based on histology (Table 1). As an example, sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals, Montville, NJ, USA), a multi-tyrosine kinase inhibitors showed in a large phase III randomized trial (Evaluation of Sorafenib, Carboplatin And Paclitaxel Efficacy in NSCLC, ESCAPE) a worst OS in those patients who had squamous cell histology and received carboplatin/paclitaxel doublet in combination with sorafenib versus those who received only conventional chemotherapy. Moreover, OS showed a trend in favor of non-squamous cell histology patients who received the triplet combination. In summary, the ESCAPE trial reported a negative survival benefit with sorafenib as well as higher mortality among patients with squamous cell histology. Similarly, another small molecule angiogenesis inhibitor, sunitinib (Sutent, Pfizer, New York, NY, USA), was also evaluated in advanced NSCLC patients. In a phase II trial, single-agent sunitinib showed promising efficacy in patients who already have failed a platinumbased chemotherapy. Herein, three deaths were related to hemorrhage (2 were pulmonary hemorrhages in patients with squamous cell histology, and the other was in a patient with adenocarcinoma and central nervous system metastases). To date, bleeding and other toxicity issues may well be a concern with angiogenesis inhibitors as a class in patients with squamous cell histology, and certainly, more studies are warranted to clarify this risk, and define if patients who have squamous cell histology will not receive the antitumor benefits of these novel compounds. We will review the data, which make nonsquamous cell histology a critical clinical factor for selecting treatment in lung cancer. Table 1: Safety data in terms of bleeding adverse events reported with some angiogenesis inhibitors used in NSCLC treatment. Patients; SCC: squamous cell carcinoma; PCS: paclitaxel/carboplatin/sorafenib; PCP: paclitaxel/carboplatin/placebo Agent Study Bleeding AEs reported Bevacizumab Johnson D et al, 2004 (Phase II) Bevacizumab Sandler et al, 2006 (Phase III/ECOG 4599) Sorafenib Hanna et al, 2008 (Phase III/ESCAPE) Sunitinib Socinski et al, 2008 (Phase II; second-line) Epistaxis : 85% grade 1-2 ; 6 pts had lifethreatening bleeding (hemoptysis or hematemesis ; 4 were fatal) 3 pts had CNS hemorrhage grade 4 (0.7%); 3 epistaxis grade 3; 5/8 had grade 5 hemoptysis (1.2%); 2 pts had grade 5 hematemesis (0.5%) 13 pts (1.4%) had grade 5 pulmonary hemorrhage (9 of them had SCC histology-5 in PCS group, 4 in PCP group) 3 hemorrhage-related deaths occurred on study (2 pts had SCC histology). 325

3 Cancer Therapy Vol 7, page 326 II. Biological correlative data supporting differences in NSCLC histology subtypes A. Vascular endothelial growth factor (VEGF) and non-squamous NSCLC histology The clinical benefit of targeting angiogenesis with the anti-vegf MoAb bevacizumab was finally demonstrated with the ECOG 4599 study, when the addition of bevacizumab to paclitaxel plus carboplatin as first-line treatment of NSCLC lead to a significant improvement in OS (Sandler et al, 2006). ECOG 4599 study prompted the approval by the FDA of bevacizumab for the first-line treatment of unresectable NSCLC, increasing thereafter the interest for angiogenesis pathway as a target for therapeutic development and discovery of biomarkers, which could help us to identify those patients more susceptible to this therapeutic approach. The complex process of angiogenesis is tightly controlled by growth factors that stimulate or inhibit the formation of new blood vessels. The VEGF family is composed of the structurally related molecules VEGF-A, VEGF-B, VEGF-C and placental growth factor (PlGF). Among these, VEGF-A is the major mediator of tumor angiogenesis, promoting the proliferation and survival of endothelial cells and increasing vascular permeability (Ferrara, 2004). Furthermore, an increased VEGF expression has been correlated with tumor progression, recurrence, and survival (Crawford et al, 2009). Angiogenesis has also been found to have a possible role in bronchial carcinogenesis, since neovascularization has been found to occur early in high-risk smokers without carcinoma as to nonsmokers (Keith et al, 2000). In NSCLC, neo-angiogenesis has been correlated with the development and progression of the disease, as VEGF overexpression and intratumoral microvessel density (MVD) have been found to be increased in comparison to normal bronchial tissue (Han et al, 2001; Merrick et al, 2005). Plasma VEGF levels has also been found to be elevated in primary lung cancer patients when compared to those of healthy controls (Tamura et al, 2001). Moreover, a significant correlation between plasma VEGF levels and MVD has been found, and also between plasma VEGF and intratumoral VEGF levels (Tamura et al, 2001). Interestingly, serum VEGF level is expressed differently among histological subclasses of NSCLC, being significantly higher in squamous cell carcinoma than in adenocarcinoma (Shimanuki et al, 2005). Hence, considering VEGF as a surrogate marker of lung cancer angiogenesis or even a potential prognosis tool was tempting. Early studies have shown not only an elevated serum VEGF levels in patients with NSCLC when compared to healthy control subjects, but have also revealed a correlation between increased serum levels and poor survival (Han et al, 2001; Niklińska et al, 2001; Shimanuki et al, 2005; Dudek et al, 2005). However, most of these studies found this correlation in either a small number of patients or in a univariate analysis only (without considering all the traditional prognostic variables in lung cancer). Similar findings have been found for tumor cell expression of VEGF, when a correlation with prognosis was only found in a univariate analysis (Donnen et al, 2007; Andersen et al, 2009). Chakra et al. determined the levels of circulating VEGF in the serum by quantitative immunoassay in 451 histologically or cytologically proven and previously untreated NSCLC patients (Chakra et al, 2008). The authors reported that the circulating VEGF distribution differed significantly according to disease stage, nodal status, and performance status (PS), with the highest levels observed in metastatic stage, positive mediastinal nodal status, and poor performance status. Likewise other previous studies, the univariate analysis of survival showed that patients with a high pretreatment circulating VEGF serum level have a shorter OS when compared with patients with a low serum level; however, it was not observed in the multivariate analysis. Going back to ECOG 4599, biological correlative studies were performed to determine if differences in the pretreatment levels of plasma VEGF could predict the response to chemotherapy with or without bevacizumab (Dowlati et al, 2008). The study showed that patients with high levels of baseline plasma VEGF had an increased probability of response to bevacizumab. On the other hand, those patients who expressed low VEGF levels had a similar response rate in both arms of the study. Nonetheless, VEGF levels were again not prognostic for OS. Therefore, we can conclude that high circulating VEGF in serum does not independently determine prognosis of NSCLC, since its elevation only indicates that angiogenesis is certainly increased in this disease and this fact is related with known prognostic factors such as stage, nodal, and performance status. B. Thymidilate synthase overexpression and NSCLC histologic subtypes Pemetrexed, a novel multitargeted antimetabolite, is an antifolate inhibitor of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), with activity against a wide spectrum of tumor cell lines (Taylor et al, 1992; Shih et al, 1997; Haunauske et al, 2001; Calvert et al, 2002; Chattopadhyay et al, 2007). These three enzymes are essential for purine and pyrimidine synthesis. The ability of pemetrexed to deplete cellular nucleotide pools, modulate cell cycle, induce apoptosis, and its toxicity profile makes this drug an attractive cytotoxic agent for polychemotherapy regimens as well as for maintenance treatment in non squamous NSCLC patients. Recent research, involving pemetrexed use in NSCLC, has focused on pharmacogenomic profiling as a method to identify a group of molecular and clinical biomarkers, which may predict tumor response. The ultimate goal of this approach is to create an individualized treatment by selecting those patients who most likely will benefit from a specific therapy, and thus, to enhance response rate which may translate into survival advantage. Resistance to pemetrexed is achieved by upregulation of TS, impaired polyglutamation of 326

4 Santos et al: How Important is Histology in Treatment Selection for Non Small Cell Lung Cancer patients? antifolates, decreased transport into cells, and apoptosis of regulating proteins (Hickman JA, 1996; Shih et al, 1997; Reed JA, 1999; Haunauske et al, 2001). The methylation of dump to dtmp is catalyzed by the enzyme TS which plays an important role in DNA synthesis (Danenberg PV, 1977). TS is elevated in NSCLC tumors (Peters et al, 1991) and is directly proportional to pemetrexed resistance. Several in-vitro studies have documented that exposure to pemetrexed induces further upregulation of TS expression in cancer cells, hence hindering the drug s efficacy (Sigmond et al, 2003; Giovannetti et al, 2005; Giovannetti E et al, 2008). Pemetrexed is transported into the cell by reduced folate carrier (RFC) (Sigmond et al, 2003). Upon entering the cells, pemetrexed is polyglutamated by folylpolyglutamate synthetase (FPGS), which enhances its antitumor activity because they are retained inside the cell for longer periods of time (Hickman JA, 1996; Sigmond et al, 2003). Several studies on leukemic and solid tumor cell lines have also demonstrated an increased resistance to pemetrexed by decreased FPGS and RFC expression in tumor cells (Lu et al, 1995; Drake et al, 1996; Mauritz et al, 2002; Wang et al, 2003). In contrast, increased FPGS and RFC expression in NSCLC cells have been associated with greater chemosensitivity to pemetrexed (Giovannetti E et al, 2008). In the clinical setting, an increased TS expression translates into a higher rate of proliferation in NSCLC cells, and consequently, it is associated with a poor prognosis (Nakagawa et al, 2004). Clinical studies have found a significant correlation between tumor histology and levels of TS expression. As an example, patients with squamous cell carcinomas had higher TS expression level than patients who had non-squamous cell histology, namely adenocarcinoma or large cell carcinomas (Ceppi et al, 2006). Thus, this could be an explanation for the improvement seen in median survival (Scagliotti et al, 2008) or PFS (Ciuleanu et al, 2008) of patients whose tumor s histology has shown either adenocarcinoma or large cell carcinoma and who had received treatment with pemetrexed. To date, an ongoing clinical study (the International TAilored Chemotherapy Adjuvant trial, ITACA) is testing this hypothesis. This is a pharmacogenomic-driven adjuvant therapy assessing two biomarkers: excisional repair cross-complementing enzyme 1 (ERCC1) and TS. Herein, patients whose tumors express low TS levels will be exposed to pemetrexed; those who have high TS levels will be treated with other cytotoxic agents. In addition, pemetrexed has a synergistic interaction with other chemotherapeutic agents such as gemcitabine and erlotinib (Sigmond et al, 2003; Li et al, 2007). Pemetrexed enhances the expression hent1 and dck in NSCLC cell lines, which are two crucial genes in the action of gemcitabine toxicity (Sigmond et al, 2003). A similar effect is seen with erlotinib in which pemetrexed increases EGFR phosphorylation and reduces Akt phosphorylation, and thus, it induces apoptosis (Li et al, 2007). III. Clinical evidence supporting differences between squamous and nonsquamous NSCLC In the phase II trial conducted by Johnson et al., hemorrhagic events appeared to be more related to squamous cell histology. Two distinct clinical patterns of bleeding were observed: minor mucocutaneous hemorrhage and major hemoptysis. The most common mucocutaneous bleeding was epistaxis grade 1 or 2. This was reported in 31% of patients exposed to low-dose of bevacizumab (7.5 mg/kg) and 44% of the patients who received high-dose (15 mg/kg). Unfortunately, 6 patients experienced a major life-threatening bleeding: hemoptysis or hematemesis. Four out of these 6 severe hemorrhages occurred in patients with squamous cell carcinomas. In an exploratory analysis which excluded squamous histology, bevacizumab not only improved response rate but also time to progression (TTP) and survival in non-squamous cell histology subtypes with a small increased risk for serious bleeding event. This became the platform to launch a large phase III study, ECOG 4599 that excluded patients with squamous cell histology. ECOG 4599 clinical trial was the first study to discriminate patients based on histology subtype. Herein, patients were randomized to receive the biologic agent bevacizumab plus carboplatin and paclitaxel or conventional chemotherapy alone. Bevacizumab improved the median survival to 12.3 months surpassing for the first time ever a median survival of more than a year in-patient with metastatic NSCLC (12.3 versus 10.3 months; HR for death: 0.79, P = 0.003). Other endpoints such as PFS and response rate were also statistically significant in favor of the triplet (6.2 versus 4.5 months, P < 0.001, and 35% versus 15%, P < 0.001). Bleeding events were also seen including 5 fatal pulmonary hemorrhages indicating an intrinsic effect of these antiangiogenic agents, however, in lesser extent than those seen in squamous cell histology. Parallel to ECOG 4599, Scagliotti et al. conducted one of the largest clinical trials in advanced NSCLC. In this non-inferiority trial, 1,725 chemotherapy naive patients with ECOG performance status 0-1 were randomized to receive cisplatin plus pemetrexed or cisplatin plus gemcitabine, one of the most common regimens used in Europe and Asia as frontline treatment for metastatic NSCLC. Interestingly, the study had a preplanned subanalysis based on histology subtypes as well as other factors. The treatment schemas consisted of cisplatin 75 mg/m 2 on day 1 and gemcitabine 1,250 mg/m 2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m 2 and pemetrexed 500 mg/m 2 on day 1 (n = 862) every 3 weeks for up to six cycles. Both groups received same premedication as prophylaxis. OS was similar in both arms: 10.3 months (HR: 0.94; 95% CI, 0.84 to 1.05). However, striking differences were seen when the data was analyzed based on histology. In patients with adenocarcinoma, cisplatin/pemetrexed attained an OS of 12.6 months versus 10.9 months for those patients who received cisplatin/gemcitabine (HR =0.84; 95% CI, 0.71 to 0.99; P = 0.03) (Table 2). A larger gap in terms of survival was seen in large-cell histology in which OS was 327

5 Cancer Therapy Vol 7, page versus 6.7 months for cisplatin/pemetrexed and cisplatin/gemcitabine, respectively (HR = 0.67; 95% CI, 0.48 to 0.96; P = 0.03). In the cases of other nonsquamous cell histology and squamous cell histology, the combination of cisplatin and gemcitabine showed to be superior. Interestingly, the group of non-squamous cell other than large cell and adenocarcinoma derived benefit from bevacizumab-based therapy as shown in ECOG 4599 results. Thus, this is the first prospective randomized phase III study conducted in NSCLC patients that has shown survival advantage depending on treatment selection driven by histology. Furthermore, it also corroborates in someway the results from ECOG 4599, which showed differences in terms of safety based on the histology factor. Another large retrospective analysis was performed on the initial registration trial, which compared pemetrexed against docetaxel in the second-line setting (Peterson et al, 2007; Scagliotti G et al, 2009). The analysis showed that non squamous cell carcinomas (n = 399) had a median survival of 9.3 for those treated with pemetrexed versus 8 months for those who received docetaxel (HR = 0.778) (Table 2). Unlikely, patients with squamous cell carcinoma (n = 172) treated with docetaxel had a better median OS (7.4 months) than those treated with pemetrexed (6.2 months). In addition, there was higher response rates noted in the pemetrexed arm than docetaxel group on those patients who had non-squamous cell histology (11.5 % versus 9%) (Scagliotti G et al, 2009). Conversely, response rates favored squamous cell carcinoma histology when treated with docetaxel (8.1% versus 2.8%) (Scagliotti G et al., 2009). In another landmark study, Ciuleanu et al. presented preliminary data in the 2008 annual meeting of the American Society of Clinical Oncology (ASCO) in which patients who were initially treated with systemic chemotherapy (platinumbased) and attained either complete remission, partial remission or stable disease were randomized to immediate pemetrexed versus placebo until progression of disease (Ciuleanu et al, 2008). In this study, there was preplanned subset analysis based also on histology. PFS was superior for non-squamous cell carcinoma that received pemetrexed (4.37 versus 1.84 months; P < ). Among the non-squamous cell carcinoma patients, the bigger difference was found in large cell carcinoma treated with pemetrexed versus placebo (4.53 versus 1.45 months). More interestingly, placebo was superior than pemetrexed in those patients whose tumors were squamous cell carcinoma. A result that certainly establishes and corroborates that histology matters when selecting a therapeutic regimen in NSCLC. OS results are eagerly expected and will be presented at the 2009 annual meeting of ASCO. Similar observations in terms of efficacy of pemetrexed in non-squamous NSCLC histology have been recently published in the second- and third-line treatment settings in smaller studies (Ohe et al, 2008; Lee et al, 2009). IV. Conclusion The oncology field has tremendously evolved in recent years due to novel molecular techniques, which have allowed us to understand more about certain tumorigenesis pathways. However, to do this kind of research, obtain a conclusive pathologic diagnosis, have the opportunity to discover predictive and prognostic markers, and finally, tailor our therapeutic armamentarium, it is necessary to secure enough tumor tissue. A more accurate characterization of NSCLC is necessary as new drugs have shown to be either more effective or safe in certain NSCLC histologic subtypes (Rossi et al, 2009). Table 2: Differences seen in survival or progression-free survival (months) based on histology subtype and treatment selected. MS: median survival; PFS: progression-free survival; OS: overall survival; n= number; NR: not reported; NS: not studied; CP: carboplatin/paclitaxel; CPB: carboplatin/paclitaxel/bevacizumab; CPem: cisplatin/pemetrexed; CG: cisplatin/gemcitabine; Pem: pemetrexed; D: docetaxel; NOS: not otherwise specified. 328