Current progress of cancer chemotherapy The Fifteenth International Symposium of the Hiroshima Cancer Seminar, October 2005

The Fifteenth International Symposium of the Hiroshima Cancer Seminar (HCS) Foundation was held on 30 October 2005 at the International Conference Center, Hiroshima. The symposium consisted of 11 special lectures and 28 free paper presentations for poster session. Approximately 238 people were present and actively discussed ‘Current Progress of Cancer Chemotherapy’. Prior to this symposium, an open lecture to the public by HCS and the Japan Society for Dying with Dignity was held on 29 October. Yutaka Hirokawa (Hiroshima Cancer Patient Support Network, Hiroshima) and Toshihiko Asahi (Kagawa Prefectural Central Hospital, Kagawa) spoke about ‘Second Opinion’, ‘Informed Consent’ and ‘How to Tell the Truth for Cancer Therapy’ to more than 473 people. At the beginning, Eiichi Tahara (HCS Foundation), Chairman of the Organizing Committee of the Fifteenth International Symposium and Chairman of the HCS Foundation, gave an opening address. Tahara introduced a brief background and the purpose of this series of symposia. In addition, Tahara, as ex-Chief of Research of the Radiation Effect Research Foundation, pointed out that deaths from solid cancers are significantly increasing among atomic bomb survivors even though 2005 marks the 60th anniversary of the atomic bombing. Since the establishment of the HCS Foundation in 1992, annual international symposia are organized to create an opportunity for basic scientists and clinical researchers to exchange ideas for cancer research, cancer prevention and cancer therapy. In 2005, the organizing committee planned to explore the important issue of ‘Current Progress of Cancer Chemotherapy’. Advances in diagnostics and treatment have enabled us to offer excellent long-term survival for early cancer, but prognosis of advanced cancer still remains poor. Recently, promising anticancer drugs, including molecular targeting agents, have been developed and response rates are improving with their combination. The molecular mechanism of drug resistance has been uncovered and molecular markers of therapeutic response have been identified. The participants will be able to profit by exchanging and learning ideas from the informative presentations and discussions, and will contribute to future development in cancer treatment. Jaffer A. Ajani (University of Texas MD Anderson Cancer Center, USA) opened the symposium by describing the advances in therapy of localized and metastatic gastric cancer in the Western world. The advances in improving the outcome of gastric cancer patients have lagged considerably compared to those achieved in other malignancies. The lack of significant advances in gastric cancer may be predominantly due to our focus on empirical approaches in the current investigative processes. Increased emphasis should be placed on molecular understanding of the cancer and genetics of a patient. The combination of the two, to include genomics, proteomics, genotyping and phenotyping, can possibly result in selection of patients for specific therapy. Nevertheless, the contemporary approaches have brought about some advances. In patients with localized (high-stage) gastric cancer, preoperative approaches are appealing, and one randomized trial showed benefit when compared to patients taken to surgery. Preoperative chemoradiation is another avenue being explored. For patients with advanced gastric cancer, the advances have been slow. Currently, the only promising agents are taxotere, S-1, oxaliplatin, and targeted agents. Ajani presented the results of individual agents and their combination regimens. Atsushi Ohtsu (National Cancer Center Hospital East, Chiba) described the current status of chemotherapy for gastric cancer in Japan. Recently, four promising agents; irinotecan (CPT-11), S-1, docetaxel (TXT) and paclitaxel (TXL), have been commercially available for treatment of gastric cancer in Japan. In the single agent registration studies, S-1 showed the highest response rate of 45%. Various attempts by combination regimens including CPT-11 + cisplatin (CDDP), S-1 + CDDP, and S-1 + CPT-11 have yielded high response rates. Taxanes also have promising activity as a second-line treatment and their combinations are now being investigated as a front-line treatment. Survival advantages of these new generation regimens are being evaluated in various randomized controlled trials. The Japanese Clinical Oncology Group (JCOG) has initiated three arm randomizations (JCOG9912) comparing 5-fluorouracil (5-FU) alone with a combination of CPT-11/CDDP and with S-1 alone. The second study is a post-marketing randomized trial comparing S-1 alone with S-1 + CDDP. The other studies are also designed to make S-1 the reference arm: S-1 versus 5-FU/leokovorin (LV) and S-1 versus S-1/CPT-11. S-1 is under investigation as an adjuvant or neoadjuvant chemotherapy. A large randomized trial comparing no adjuvant therapy with S-1 treatment after curative resection for stage II–III disease is also underway. Another randomized study comparing surgery alone with neoadjunvant chemotherapy of S-1/CDDP is now being planned for patients with resectable scirrhous type carcinoma. These studies will clarify the true impact of newer generation regimens in the treatment of gastric cancer. Molecular targeting agents is another topic in this field and some are now under investigation for gastric cancer. Trastuzumab in combination with fluorouracil and cisplatin will be evaluated in an international randomized trial, with patients mainly from Asian countries. EMD 72000, humanized monoclonal antibody against EGF-R, and GW 572016, dual (her 1 & 2) inhibitor, are the other candidates to be investigated. For evaluating these new agents, more collaboration with other countries is needed. Claus-Henning Köhne (Städtisches Klinikum gGmbH, Oldenburg, Germany) gave a talk on recent progress in the treatment of metastatic colorectal cancer. One of the most dramatic improvements in the treatment of cancer has been achieved for patients with colorectal cancer. By sequential use of FOLFIRI or FOLFOX or vice versa, a median survival time approaching or above 20 months is now regarded as a reference. The choice of the chemotherapy regimen depends on the toxicity profile. Recently, monoclonal antibodies directed against the EGFR, such as cetuximab, have been found to be active. Cetuximab in combination with CPT-11 in patients who have failed a CPT-11 regimen is superior to cetuximab alone and is a third-line option. Currently, its value in first-line treatment is being tested in randomized trials. The vascular endothelial growth factor antagonist, bevacizumab, was proven to improve the antineoplastic activity of the IFL regimen. Patients treated with a combination had a significantly higher response rate, a longer progression-free and median overall survival. Thus, bevacizumab is regarded as an important combination for first-line treatment. The higher response rates observed with combination chemotherapy alone or in combination with a monoclonal antibody led to surgical candidates for liver metastases in patients who had unresectable metastatic disease. The probability of having a secondary resection depends on careful patient selection and the activity of the used chemotherapy regimen. Thus, the median overall survival for patients with metastatic disease has been substantially improved over the last 20 years, with the possibility of cure in some patients suitable for secondary resection. Further studies are necessary to identify both the cohort of patients most suitable for such a strategy and the regimen most efficacious in this clinical situation. Morito Monden (Osaka University, Osaka) reported the mechanisms involved in a combination therapy using 5-FU and interferon-alpha (IFN-alpha) for hepatocellular carcinoma (HCC). The prognosis of HCC is generally poor, and the 5-year survival rate is limited to 25% to 49% after surgery. Conventional therapies, such as transcatheter arterial embolization and microwave coagulation therapy, are not generally indicated for advanced HCC. Over half of the HCC patients with tumor emboli die within 1 year even after curative surgery, and the prognosis of patients with unresectable HCC is much worse. In general, HCCs are resistant to anticancer drugs. However, recent studies showed an excellent clinical response to the combination therapy of IFN-alpha and 5-FU in HCC patients complicated with severe portal tumor emboli. It has been reported that IFN-alpha enhances the expression of thymidine phosphorylase, which converts 5-FU to an active metabolite and enhances the DNA damage by 5-FU. Several in vitro studies have provided some explanations about the synergistic effects of the combination of IFN and 5-FU, however, there are a few studies on fundamental cell biology in HCC cells. Recently, Monden's group demonstrated that: (i) combination therapy inhibited cell growth and induced apoptosis of HCC cells in a dose- and time-dependent manner; (ii) the Bcl-2 family plays a key role in combination therapy–related apoptosis; (iii) inhibition of cell growth and induction of apoptosis were synergistic or additive but not antagonistic; (iv) IFNR expression was frequently observed on HCC cells; (v) upregulation of p27 and the expression of IFN receptor were the direct mechanisms of combination therapy–mediated antitumor effects. The indirect effect of this combination therapy, such as TNF-related apoptosis-inducing ligand (TRAIL), was also discussed. Robert S. Kerbel (Sunnybrook and Women's College Health Sciences Centre, Canada) described markers and mechanisms for antiangiogenic low-dose metronomic chemotherapy. The recent approval of the targeted antiangiogenic drug has stimulated renewed interest in antiangiogenic based therapeutics. In this regard, there is thought to be a number of anticancer drugs, in part, by inhibiting tumor angiogenesis. This antiangiogenic ‘side-effect’ of chemotherapy is heavily dependent on dosing and scheduling. One of the advantages of metronomic chemotherapy regimens in preclinical models is that they can be far more efficacious than the corresponding maximum tolerated dose (MTD) of the same drug. Promising is a sequential combination approach in which therapy is initiated with a short course of MTD chemotherapy, followed by long-term maintenance type metronomic chemotherapy regimens, even using the same drug. Recent evidence suggests that an indirect mechanism may be involved, namely, systemic induction of endogenous inhibitors of angiogenesis, such as thrombospondin-1, in antiangiogenesis. There are a number of advantages to metronomic chemotherapy regimens. To determine the optimal biological dose for a given metronomic chemotherapy regimen, there is an urgent need to develop surrogate biomarkers to monitor the antiangiogenic efficacy of metronomic chemotherapy, and more importantly, to help establish optimal biological dose ranges. Kerbel's group have had considerable success in preclinical studies in this respect by using circulating vascular endothelial growth factor (VEGF) receptor-2 positive cells in the peripheral blood, some of which may be endothelial progenitor cells derived from the bone marrow, and as such a biomarker. Using this approach, they designed combination metronomic chemotherapy protocols for the treatment of advanced and widespread metastatic breast cancer in preclinical models. One such model involves a highly metastatic breast cancer cell line (MDA-MB-231) injected orthotopically into immunodeficient mice, which are then treated with a combination of oral metronomic cyclophosphamide and uracil/ftorafur (UFT). Masahiro Fukuoka (Kinki University, Osaka) introduced current perspectives of targeted therapy in lung cancer. In spite of significant progress in cancer therapy, prognosis of lung cancer patients is still poor. Recently, novel targeted therapeutics have been developed. The first targeted agents against lung cancer are epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib (Iressa) and erlotinib (Tarceva). Randomized phase II trials of gefitinib or erlotinib in patients with advanced non-small cell lung cancer (NSCLC) who had relapsed following previous platinum-based chemotherapy revealed a response rate of about 10–20% and a median survival of 6–8 months. A randomized placebo-controlled phase III trial of a single agent of erlotinib in patients with advanced NSCLC, who had received previous chemotherapy regimens, showed significantly superior survival compared to placebo. Among patients with NSCLC, a greater likelihood of response and survival in monotherapy of EGFR-TKIs has been found in female, adenocarcinoma, Asian patients, and non-smokers. Somatic mutations in the region of the TK domain of the EGFR gene are found in patients with dramatic response to gefitinib or erlotinib. These mutations were more frequently observed in Asian patients, females, adenocarcinoma and non-smokers. The second targeted therapeutics are VEGF targeted agents. Bevacizumab (Avastin), a monoclonal antibody directed against the VEGF receptor, has shown promise in treating NSCLC. Recently, the addition of bevacizumab to standard chemotherapy of carboplatin and paclitaxel has demonstrated a significantly longer survival compared with chemotherapy alone in advanced non-squamous NSCLC. ZD6474, a small molecule that inhibits tyrosine kinases of VEGF receptor and EGFR, is also promising in the treatment of NSCLC, and an obvious response was observed in NSCLC patients in a phase I trial. Robert B. Diasio (University of Alabama at Birmingham, USA) described new insights of dihydropyrimidine dehydrogenase (DPD) deficiency, especially the cause, population distribution and methods for detection. DPD deficiency is an autosomal codominantly inherited pharmacogenetic syndrome associated with a variable phenotype, ranging from partial to complete loss of DPD enzyme activity. The clinical impact of DPD deficiency has been dramatically demonstrated by studies showing that 43–60% of patients with severe toxicity (including death) following administration of standard doses of 5-FU or related drugs are partially or profoundly DPD deficient. Previous population studies have shown the prevalence of partial and profound DPD deficiency to be 3% and <0.1% in the American population, respectively. The availability of new methods to rapidly phenotype using a 13C-Uracil Breath Test (UraBT) and genotype using denaturing high-performance liquid chromatography (DHPLC) have permitted studies of populations of healthy volunteers as well as patients who experienced toxicity with 5-FU or related prodrugs. Using these methods, new mutations were discovered in the coding region of the gene (DPYD) coding for DPD, as well as alterations in the DPYD promoter that are associated with decreased DPD enzyme activity and abnormal UraBT consistent with DPD deficiency. Population studies in more than 100 African Americans demonstrated a normal distribution, but with a range of DPD activity that was lower than that of the Caucasian control population. The overall frequency of DPD deficiency appeared higher in African Americans (approximately 8%) than in Caucasians (<2%). An update on the sensitivity and selectivity of the UraBT as a screening method for detecting both DPD deficiency from an ongoing population study in normal volunteers and patients being treated with 5-FU was presented. Toshiaki Saeki (Saitama Medical School, Saitama) gave a talk on drug resistance in chemotherapy for breast cancer. Although recent development of chemotherapy for breast cancer improved the survival of patients, non-responders against conventional anticancer agents still remained. Expression of P-glycoprotein (P-gp) encoded by the multidrug resistance 1 (MDR1) gene in tumors is associated with certain clinical drug resistance. Because P-gp appeared to be involved in both acquired and congenital MDR in human cancers, P-gp could be an important target to improve efficacy of chemotherapy. Dofequidar fumarate (Dof) is a novel, orally active quinoline derivative that reverses multidrug resistance. The inhibition of doxorubicin resistant cancer cell lines was observed in the presence of Dof + doxorubicin. A randomized, placebo-controlled trial including Dof + cyclophosphamide (C), doxorubicin (A) and 5-FU therapy (F) was conducted for advanced or recurrent breast cancer patients. Overall response rate was 42.6% for CAF alone versus 53.1% for Dof + CAF. Dof significantly improved performance status (PFS) in patients who were premenopausal, who had no prior therapy or patients with advanced primary tumor. Dof was well tolerated and displayed promising efficacy in patients who had not received prior therapy. Tamoxifen (TAM) and toremifene (TOR), anti-estrogens, may possibly moderate the P-gp related drug resistance in vitro. TOR demonstrated a synergistic effect in combination with paclitaxel on various breast cancer cell lines including a multidrug resistant cell line, and this effect was more potent in combination with TOR than was TAM. Preliminary data obtained by a pharmacokinetic study of TOR and paclitaxel combination treatment for patients who had received paclitaxel monotherapy were presented. Masahiko Nishiyama (Hiroshima University, Hiroshima) described molecular markers of therapeutic response to 5-FU chemotherapy. 5-FU and its analogs are key agents in the treatment of a large spectrum of cancers, but the response to the drugs varies significantly among patients. Among a variety of predictive markers identified to date, DPD has been the most extensively investigated for individual response to 5-FU. DPD in cancer cells is widely recognized as an important determinant of sensitivity to 5-FU and could be a novel and critical predictor of 5-FU response. DPD phenotype is controlled, at least in part, by some transcriptional mechanisms. AP-1 is probably one of the key factors in the transcriptional regulation of the DPYD gene in cancer cells. Aberrant methylation of the DPYD promoter region acted as one of the repressors of DPYD expression and affected the sensitivity to 5-FU in cancer cells. These findings may lead to a more precise understanding of the molecular basis of 5-FU response and contribute to the development of personalized medicine. Conversely, drug sensitivity is determined by multiple genes. To develop an accurate prediction system for treatment efficacy, using cDNA microarray, Nishiyama's group sorted out genes which were correlative in the expression levels with cytotoxicities of the eight anticancer drugs (5-FU, CDDP, mitomycin C, doxorubicin, CPT-11, SN-38, TXL, and TXT), and finally selected 12 genes. Then, they fixed eight prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order to predict the efficacy of the drugs using multivariate regression analysis. In an investigation using clinical samples, this model was found to be of predictive value in terms of survival, time to treatment failure and tumor growth. Kazuhiro Yoshida (Hiroshima University, Hiroshima) described the current status of combination chemotherapy of S-1 and TXT and their synergistic mechanisms in gastric cancer. S-1, an oral fluorouracil antitumor drug, has been identified as an effective agent for the treatment of gastric cancer. This drug has gradually come to be accepted as the front-line regimen for the treatment of gastric cancer in Japan. Recently, the combination therapies with S-1 and new agents including taxanes, CDDP and CPT-11 have been of great interest. For the phase II trial of the combination of S-1 and TXT, patients with advanced or recurrent gastric cancer, who had not received any chemotherapy except one regimen, were eligible and were treated with docetaxel 40 mg/m2 1 h i.v. infusion on day 1 and S-1 at a full dose of 80 mg/m2/day for 2 weeks every 3 weeks. The overall response rate (CR + PR) was 56.2% (95% confidence interval [CI] 38–66%) and the tumor control rate (CR + PR + SD) was 93.8% (95% CI 83–98%). The study of growth inhibitory effects and the expression profiles of metabolic enzymes of 5-FU in vitro and in vivo revealed striking synergistic effects on growth inhibition. The combination of S-1 and TXT exhibited a greater growth-inhibitory effect than the former combination. The combination of TXT and 5-FU increased the expression of apoptosis related genes. Expression of thymidylate synthase (TS) and DPD were decreased whereas that of orotate phosphorybosyl transferase was increased, suggesting the biochemical modulation of the two drugs. These results strongly indicate that the combination chemotherapy of TXT and S-1 is active on gastric cancers and this may be a good candidate as a standard chemotherapy. Makoto Tahara (National Cancer Center Hospital East, Chiba) reported the result of a phase I study of concurrent chemoradiotherapy with S-1 and CDDP in patients with unresectable, locally advanced squamous cell carcinoma of the head and neck. Concurrent platinum-based chemotherapy and radiotherapy is the standard treatment of unresectable, locally advanced squamous cell carcinoma of the head and neck. S-1 has shown high activity for head and neck cancer with a response rate of 34%. The aim of this study was to determine MTD of S-1 in combination with CDDP and radiotherapy. Patients with adequate organ function and no prior chemotherapy were enrolled. Chemotherapy consisted of administration of S-1 twice daily on days 1–14 at 40, 60 and 80 mg/m2/day, and 2-h infusions of CDDP at 20 mg/m2/day on days 8–11, repeated twice with a 5-week interval. Once daily radiotherapy of 70 Gy in 35 fractions was given concurrently, starting on day 1. Two additional cycles of S-1 and CDDP were planned 4 weeks after the completion of chemoradiotherapy. Dose-limiting toxicities were defined as neutropenic fever lasting for 4 days, grade 4 thrombocytopenia, and grade 3 non-hematological toxicities except mucositis, dysphagia, anorexia, nausea, vomiting, and infection due to mucositis. The MTD was reached at 80 mg/m2/day of S-1, with some patients experiencing neutropenic fever lasting for 4 days. Of the patients treated with 60 mg/m2/day of S-1, one of seven developed grade 3 diarrhea, and another developed neutropenic fever lasting for 2 weeks. Of the 16 patients studied, 13 experienced a complete response according to response criteria in solid tumor (RECIST). In conclusion, S-1 at 60 mg/m2/day for 14 days and CDDP at 20 mg/m2/day for 4 days are recommended. Although data are preliminary, the response rate was very promising and this approach warrants further investigation. Active discussion was made in the poster session with 28 presentations concerning cancer chemotherapy. The papers entitled ‘Down-regulation of MAD1 (mitotic arrest deficiency 1) in human gastric carcinoma’ by Mitsuhiko Osaki (Tottori University, Yonago), and ‘Localization of the PP2A B56γ regulatory subunit at the Golgi role in and by University, were the poster Jaffer A. of the organizing made presentations concerning current progress of cancer chemotherapy were of cancer therapy including chemotherapy, molecular targeting therapy, drug resistance and molecular markers of therapeutic response were discussed at the of preclinical and clinical will lead cancer patients to a of long-term survival with a high of

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