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Meeting Report |
a Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; b University of California at Davis Center, Sacramento, California, USA
Correspondence: Rafael Rosell, M.D., Hospital Germans Trias i Pujol, Crtra Canyet s/n Box 72, 08916 Badalona, Spain. Telephone: 34-93-497-89-25; Fax: 34-93-497-89-50; e-mail: rrosell{at}ns.hugtip.scs.es
Key Words. Non-small cell lung cancer • Translational research
"THINK MOLECULARLY, ACT CLINICALLY."– Martin Edelman
This quote sums up the feeling and goals of the July 1 meeting that was held in Barcelona, Spain. Under the title "Sharing New Approaches to Translational Research in Non-Small-Cell Lung Cancer," Dr. David Gandara and Dr. Rafael Rosell chaired an intense, enthusiastic one-day meeting that may lead to changes in current lung cancer management.
The meeting highlighted the potential benefits of translational research (the clinical application of current molecular discoveries). The day was divided into three major blocks (Figs. 1-3
) which ultimately culminated in an afternoon meeting, the goal of which was to design a clinical trial of customized chemotherapy based on each individual patient's tumor molecular genotype. The result was the Genotypic International Lung Trial (GILT), an innovative trial destined to optimize chemotherapy benefits and reduce unnecessary toxicity and treatment.
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) dealt with current views on non-small cell lung cancer (NSCLC) treatment, and all eight speakers agreed on the urgent need for a novel push to force therapy out of the stagnant pool of 35% one-year survival in metastatic NSCLC and into the rapids of higher survival rates. This novel force could easily be identified as the different molecular markers that are specific to each tumor type, because the challenge facing NSCLC therapy today is to understand and deal with the fact that histologically similar tumors have the ability to behave so differently when treated with the same chemotherapy regimen. The chairpersons, Dr. Rosell and Dr. Gandara, opened the session with their respective talks on "Crossing the Rubicon to the Genomic Era" and "Future Directions for Transatlantic Cooperation." They both mentioned that we need to optimize clinical research of NSCLC and emphasized how we must treat NSCLC as a systemic disease from the onset. They objected to the fact that predictions of response and survival are generally based only on clinical parameters, which are not enough to optimize results with the presently available drugs. But their outlook is hopeful because "today we are on the verge of being able to use our considerable genetic knowledge to draw up molecular profiles on individual cancer patients and develop specific customized chemotherapy regimens that can improve and prolong survival" [1]. Both chairpersons highly emphasized the need to build a stronger, more significant bridge between the laboratory and the clinical setting to help translational research flourish.
Dr. Chandra Belani and Dr. Martin Edelman spoke of the limitations of current chemotherapy. Dr. Belani asked the participants the tough but realistic question, "Have we reached ‘Chemotherapy Efficacy Plateau’?" This question has been in all our minds after seeing the results from Eastern Cooperative Oncology Group 1594, presented at the American Society of Clinical Oncology this past year. He mentioned that we must take chemotherapy to the next level and explore the nonplatinum possibilities, whose efficacy in prolonging survival is still controversial. Moreover, second-line chemotherapy is a highly valid option and must be thoroughly exploited since it has been proven that it improves quality of life and prolongs survival. Dr. Belani emphasized that cisplatin plus a new agent is superior to cisplatin alone, though carboplatin may replace cisplatin (Table 1) [2].
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Dr. Edelman explained that the prevailing approach to treatment has been to continue any single regimen until either a fixed number of cycles has been administered and then hold therapy until progression, or to treat until progression at which time a new agent or combination is introduced. He presented an alternative to these approaches: the utilization of planned sequential chemotherapy. Two models support the concept that sequential administration of chemotherapeutic agents may be superior to concurrent administration. A model described by Day [4] proposes that sequential administration of drugs would result in superior cure rates. Surprisingly, this model also projects that the cure rate may be superior if the weaker drug was utilized first. This finding can be explained if one postulates the existence of several tumor subpopulations with differing patterns of chemosensitivity and resistance. The most important population to eliminate is the one with resistance to the most effective drug. Hence, a drug that eliminates this population, even if it has a lesser degree of effectiveness in terms of cell kill, should be employed first. Norton and Simon [5] have advanced a separate analysis based on kinetic assumptions. Their analysis presumes that the basis for sensitivity and resistance to chemotherapy is heavily influenced by growth kinetics. Sensitive cells grow more rapidly and form the dominant population, while resistant cells grow more slowly and constitute a smaller population at initiation of therapy. This interpretation is consistent with the frequent observation of rapid response to initial therapy followed by rapid regrowth of a resistant population. These two analyses thus converge in that both, for differing reasons, postulate that an effective induction regimen followed rapidly by an effective consolidation treatment will yield optimal results.
The ability to assess an individual patient's susceptibility to treatment and dynamically assess response to therapy will allow us to further develop the paradigm of sequential therapy from a "planned" approach in which decisions regarding therapy and timing of alterations of chemotherapy are guided by characteristics of the disease specific to the individual patient. Recent advances in imaging technology, specifically positron emission tomography scanning, may allow for the determination of tumor response in the individual patient based upon the metabolic activity of the tumor. Another intriguing approach is the assessment of plasma telomerase. Telomerase is the enzyme that repairs the ends of chromosomes and is critical for cell proliferation. Elevated levels of telomerase have been found in most cancers and correlate with tumor aggressiveness. Plasma telomerase is frequently elevated in patients with lung cancer, and levels correlate with response to therapy. Furthermore, elevation of telomerase correlates with disease recurrence/progression, and these elevations frequently precede clinical and radiographic evidence.
A guided sequential approach, that incorporates recent advances in the understanding of the biology of cancer, mechanisms of drug response and resistance, and improvements in response assessment, represents the next step in clinical design.
Dr. Paul J. Hesketh presented the challenge of treating advanced NSCLC patients with a poor performance status (PS = 2), who represent a meaningful percentage of all NSCLC patients. Current multiagent treatment options are associated with considerable toxicity, and the greatest benefits appear to accrue to patients with high functional status. For patients who are still ambulatory but moderately impaired by the neoplasms, the value of conventional chemotherapy is unclear. Poor PS has consistently emerged as one of the most important predictors of inferior tumor response and survival as well as higher toxicity.
The encouraging activity of the new agents (taxanes, gemcitabine, CPT-11) on schedules offering a favorable toxicity profile, such as weekly single agent, may benefit PS 2 patients. These patients would also benefit from a customized chemotherapy that would reduce toxicity.
Dr. Tommaso Martino De Pas spoke about second-line chemotherapy in taxane failures. His group's experience showed reasonable anticancer activity for cisplatin plus vinorelbine in selected patients with NSCLC that is resistant, but not refractory, to a gemcitabine plus paclitaxel combination.
Dr. David Carbone and Dr. Heinz-Josef Lenz provided information on how to improve the outcome of typical clinical trials. Dr. Carbone spoke about using immunotherapy. His group has investigated the mechanisms involved in the inhibition of dendritic cell differentiation by VEGF and tumor cell supernatants. In animal model experiments, they have been able to simulate the effects of tumors by infusing recombinant VEGF at levels seen in tumor-bearing animals, and they have shown that dendritic cell numbers and function can be improved in tumor-bearing animals after treatment with anti-VEGF antibodies. The transcription factor Ikaros is crucial in the development of T cells, and VEGF shuts off Ikaros and causes accelerated thymic involution and a decreased maturation of T cells. They hypothesize that if VEGF can be blocked, then the immune response can be improved. An anti-VEGF plus p53 immunotherapy combination resulted in a 60% cure in these animals.
Dr. Lenz spoke of molecular markers in gastric cancer and how a customized clinical trial based on thymidylate synthase (TS) gene expression is being carried out at Memorial Sloan Kettering Cancer Center (MSKCC). 5-fluorouracil (5-FU) is a widely used chemotherapy regimen in gastric cancers, but only a small proportion of patients responds to 5-FU. We must find which ones will respond. When the gene expression levels of TS are low, there is a response to 5-FU [7]. Gene expression levels of TS, dihydropirimidinedehydrogenase, and thymidine phosphorylase can help to predict chemotherapy responders. The gene expression of ERCC-1 was predictive not only of response to chemotherapy but also of survival of patients treated with neoadjuvant chemotherapy with 5-FU plus cisplatin for gastric and esophageal cancers [6]. Patients with high levels of TS are selected for treatment with CPT-11. The first prospective clinical trial using TS gene expression to stratify chemotherapy is ongoing at MSKCC. Patients with intratumoral relative TS gene expression higher than 4 x 10–3 will be treated with CPT-11, and patients with lower than 4 x 10–3 will be treated with 5-FU. Ultimately, they hope to develop molecular staging criteria, which will then allow them to select the most effective and least toxic chemotherapy regimen based on the molecular characteristics of the tumor.
Identification of molecular profiles associated with a high probability of response to chemotherapy will also revolutionize the design of neoadjuvant strategies.
The second block of the meeting (Fig. 2), termed "New Tools for Response/Survival Assessment and Treatment" dealt with molecular markers that could be used to design specific individualized treatment clinical trials. These included p27 expression, gene methylation, ß-tubulin mutations, microarrays, and antisense oligonucleotides.
Dr. Paul Gumerlock spoke of multiple new antineoplastic agents now undergoing clinical investigation, which represent unique classes of chemical structures and mechanisms of action, unrelated to classic cytotoxic chemotherapy. Included among these are compounds that modulate the cell cycle. It is his group's intention to investigate whether the molecular profile of specific tumor types, or of individual patients, may provide a therapeutic window to individualized cancer therapy. Because p53 is found to be abnormal at a high frequency (>50%) in advanced NSCLC, they are investigating p53-independent pathways to apoptosis. Docetaxel has demonstrated preclinical activity in tumors with disrupted p53, unlike classic DNA-damaging agents. The tumor-suppressor gene p27/KIP1 is a cyclin-dependent kinase inhibitor that functions independently of p53. Loss of p27 protein was demonstrated to be a marker of poor prognosis in several large studies. Conversely, overexpression of p27 induces apoptosis in a variety of human tumor cell lines, suggesting a second function for this tumor suppressor. Docetaxel-induced stabilization of p27 during M-phase is involved in p53-independent apoptosis. Other novel p53-independent anticancer agents have also been shown to increase the levels of p27 following treatment.
The order of the chemotherapy doses is also important in determining outcome. For example, the staurosporine derivative UCN-01 followed by cisplatin induces lower cytotoxicity than the reverse sequence of administration. The combination of flavopiridol and paclitaxel also has this effect. In the paclitaxel-flavopiridol sequence, the apoptosis level is high, since paclitaxel arrests the cell division in the M phase and flavopiridol acts best in M-phase cells. Conversely, with the reverse sequence, the apoptosis rate is low because the cells are in G1 or G2 arrest.
Dr. Peter Danenberg and Dr. Miquel Tarón spoke of methylated genes as genetic landmarks. Tumor DNA is released into the plasma and serum, thus potentially providing a means for early detection of tumors and monitoring clinical procedures. Previous studies had shown that the screening of methylated genes might constitute an effective tumor DNA biomarker. The adenomatous polyposis coli (APC) gene is methylated at a very high frequency (>95%) in esophageal adenocarcinomas. The frequency of detectable methylated APC in the serum of preoperative esophageal cancer patients was 26% but increased to 73% in the serum of recurrent patients. Patients with high levels of methylated APC in their pretreatment serum had a significantly shorter survival time than patients with undetectable or low levels. Recently, Danenberg's group has found that lung tumors also have about a 95% frequency of methylated APC genes, while methylation of other genes, such as p16, is infrequent. Analysis of serum samples from resected lung cancer patients showed that patients with methylated APC levels had poor outcome.
Aurora O'Brate presented information on a study of NSCLC patients that had their ß-tubulin status checked to correlate with response to a taxane regimen. Several research groups have found that mutations in the ß-tubulin gene have conferred resistance to human ovarian cell lines, Chinese hamster ovary cell lines and NSCLC. Mutations were detected in the serum DNA of patients in a frequency similar to p53 mutations. Mutations were found in two regions of exon 4. Mutations found in the GTP-binding site were correlated with worse survival, while mutations in the lower half of the gene were related to a significantly better survival. These results encourage clinical pharmacogenomic trials that customize chemotherapy treatment according to the cluster of mutations each patient harbors, thereby increasing the chances of targeting the specific resistance mechanisms of each cancer cell (Tables 2 and 3). In addition, serum DNA is an important tool that will allow us to establish molecular response as a salient complement to radiographic response in predicting outcome.
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Dr. Miguel Angel Piris and Dr. Carbone presented the microarray technology. Dr. Piris spoke of the Molecular Pathology program in the National Cancer Research Center in Spain, which performs molecular analysis of human tumors to predict the treatment response to commonly used drugs, so that relevant genes in cancer can be identified. He also explained the molecular classification of tumors and the development of a cDNA biochip for the analysis of molecular changes associated with resistance in breast cancer.
Dr. Carbone uses three methods to detect overexpression of certain genes: chromosome translocations, microarrays, and mass spectrometry. They identified an aggressive metastatic lung cancer that has the balanced translocation t(15;19)(q11;p13). The breakpoint on chromosome 19 lies approximately 40 kb upstream from the start site of Notch 3, a member of the notch proto-oncogene family. High levels of Notch 3 expression are found in approximately 25% of the NSCLC tested. Overexpression was highly correlated with translocations involving 19p in these lines [9].
Several ongoing trials were presented at the meeting (Fig. 3). Dr. Axel Hanauske presented clinical studies with ALIMTA, a multitargeted antifolate drug. The dose was 500-600 mg/m2. There were no complete responses with a single agent. The response rate was 20% among previously untreated and 10% in previously treated patients. With cisplatin plus ALIMTA, the response rate was 45% in nontreated and 40% in previously treated patients.
Dr. Tomohide Tamura presented data on how to individualize docetaxel dose according to the CYP3A4 polymorphism by means of a functional assay that measures the degree of the activity of the enzyme.
Several Spanish doctors, Dr. Albert Font, Dr. Alfredo Carrato, Dr. Pilar Garrido, and Dr. Vicente Alberola, presented Spanish ongoing trials. Dr. Font presented a phase I-II weekly docetaxel/CPT-11 study. Dr. Carrato presented a gemcitabine-carboplatin combination as first-line treatment for advanced NSCLC with two schedules, a 21-day and a 28-day schedule. The 21-day schedule was better tolerated. Dr. Garrido spoke of a phase II comparison of sequential versus concurrent chemoradiation with docetaxel in unresectable stage III NSCLC. Dr. Alberola presented a 600-patient phase III trial of the Spanish Lung Cancer Group comparing cisplatin/gemcitabine (CG) versus cisplatin/gemcitabine/ vinorelbine (CGV) versus sequential doublets of gemcitabine/vinorelbine followed by ifosfamide/vinorelbine. The interim analysis of 280 patients yielded the following overall response rates: 40.4% for CG, 33% for CGV, and 19% for sequential noncisplatin doublets.
The GILT trial was the subject of an intense afternoon meeting. The Spanish Lung Cancer Group and Dr. David Gandara are organizing the first pharmacogenomic-oriented trial for the benefit of NSCLC patients on both sides of the Atlantic. The GILT trial aims to prolong survival in NSCLC patients. Serum DNA and RNA from paraffin-embedded tissue at diagnosis will be used to analyze genetic abnormalities that can predict resistance to docetaxel, cisplatin or both drugs, thus allowing us to select the best chemotherapy regimen from the outset. Four hundred patients will be included. The control arm will receive docetaxel and cisplatin for six cycles as a noncustomized treatment. The genotypic arm will have customized treatment based on DNA abnormalities. Patients with only ß-tubulin mutations will receive a nontaxane regimen: gemcitabine and cisplatin for six cycles. Patients with only ERCC-1 overexpression will receive a noncisplatin regimen, since overexpression has been correlated with cisplatin resistance: docetaxel and gemcitabine for six cycles. Patients with both ß-tubulin mutations and ERCC-1 overexpression will receive a nontaxane, nonplatinum regimen: gemcitabine and CPT-11. The cell-free serum DNA and mRNA in peripheral blood can be used to screen for genetic abnormalities related to chemoresistance (Tables 2 and 3).
This meeting gathered together a highly selective group of prominent investigators with great cumulative experience in clinical and molecular research in order to assure the success of this GILT trial. The intense activity of the day was rewarded by a lovely dinner by the Barcelona seaside, although the eager, pioneering mood was still present in the evening. The participants invested a great deal of energy and effort at this meeting, and hopefully the cooperative frame of mind that set the pace for the entire day will carry on with them to ensure the success of the trial.
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