Met in lung cancer

Receptor tyrosine kinases play important roles in the biology of many tumor cell types. In approximately 10% of non-small cell lung cancer (NSCLC) patients mutational activation of the epidermal growth factor receptor (EGFR) results in tumor cells that are exquisitely addicted to signaling by this receptor.¹ Thus expression of mutant active EGFR but in general not wild-type EGFR predisposes NSCLC cells to inhibitors of EGFR/ErbB2. Use of EGFR inhibitory agents such as gefitinib for this subset of NSCLC patients causes tumor regression and disease stabilization for 12–18 mo, after which tumor cells become resistant to the drug.² Initial studies identified a second mutation within the EGFR, which results in the resistance of the tyrosine kinase to gefitinib, as a major cause of reduced tumor control.³ This has resulted in the development of newer EGFR inhibitors, e.g., afatinib, which inhibited double mutant EGFR.⁴ In a subset of these patients, however, resistance to gefitinib was not associated with EGFR mutations.⁵ Clearly, other mechanisms of gefitinib resistance must be at play.     

Macropinocytosis: mechanism and targeted therapy in cancers

Macropinocytosis is a form of endocytosis which provides an effective way for non-selective uptakes of extracellular proteins, liquids, and particles. The endocytic process is initiated by the activation of the growth factors signaling pathways. After activation of the biochemical signal, the cell starts internalizing extracellular solutes and nutrients into the irregular endocytic vesicles, known as macropinosomes that deliver them into the lysosomes for degradation. Macropinocytosis plays an important role in the nutritional supply of cancer cells. Due to the rapid expansion of cancer cells and the abnormal vascular microenvironment, cancer cells are usually deprived of oxygen and nutrients. Therefore, they must transform their metabolism to survive and grow in this harsh microenvironment. To satisfy their energy needs, cancer cells enhance the activity of macropinocytosis. Therefore, this metabolic adaptation that is used by cancer cells can be exploited to develop new targeted cancer therapies. In this review, we discuss the molecular mechanism that actuates the process of macropinocytosis in a variety of cancers, and the novel anti-cancer therapeutics in targeting macropinocytosis.     

A dual-targeted molecular therapy of PP242 and cetuximab plays an anti-tumor effect through EGFR downstream signaling pathways in colorectal cancer

BackgroundEpidermal growth factor receptor (EGFR) and its downstream Ras-mitogen-activated protein kinase kinase (MAPKK, MEK)-extracellular regulated protein kinase (ERK) signaling pathway and phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway play important roles in the pathogenesis of colorectal cancer (CRC). The combination therapy of anti-EGFR and anti-mTOR needs to be explored.MethodsHere we combined the anti-EGFR monoclonal antibody cetuximab (CTX) with the mTOR inhibitor PP242 in CRC cell lines and mouse xenograft models and discussed the changes of EGFR downstream signaling pathways of CRC cell lines.ResultsIn HT-29 cells and Caco-2 cells, combined application of CTX and PP242 significantly inhibited the proliferation of CRC cells in vivo and in vitro. In BRAF wild-type Caco-2 cells, combined application of CTX and PP242 inhibited the activation of the EGFR and its downstream signaling pathways.ConclusionsOur research further demonstrates the effectiveness of the combined application of CTX and PP242 in inhibiting CRC cell lines from the perspective of cell proliferation, cell cycle, apoptosis, and mouse xenografts. We revealed that the combined application of CTX and PP242 can inhibit tumor growth and proliferation by inhibiting the phosphorylation of key molecules in EGFR downstream MEK-ERK and MEK 4/7 (MKK)-c-Jun N-terminal kinase (JNK) signaling pathways in BRAF wild-type CRC cells. In addition, we found that in BRAF mutant CRC cells, the monotherapy of PP242 resulted in negative feedback increased EGFR phosphorylation rates, accompanied by significant up-regulation of downstream MEK and ERK phosphorylation.     

Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4-phenylenebis(methylene)selenocyanate in human prostate cancer cells

Preclinical studies and clinical analyses have implicated the mammalian target of rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that the synthetic organoselenium compound, p-XSC, effectively inhibits viability and critical signaling molecules (e.g., androgen receptor, Akt) in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. On the basis of its inhibition of Akt, we hypothesized that p-XSC modulates mTORC2, an upstream regulator of the kinase. We further hypothesized that combining p-XSC with rapamycin, an mTORC1 inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer. The effects of p-XSC and rapamycin, alone or in combination, on viability and mTOR signaling were examined in AR LNCaP prostate cancer cells and AI C4-2 and DU145 cells. Phosphorylation of downstream targets of mTORC1 and mTORC2 was analyzed by immunoblotting. The interaction of mTORC1- and mTORC2-specific proteins with mTOR was probed through immunoprecipitation and immunoblotting. p-XSC inhibited phosphorylation of mTORC2 downstream targets, Akt and PCKα, and decreased the levels of rictor, an mTORC2-specific protein, coimmunoprecipitated with mTOR in C4-2 cells. The combination of p-XSC and rapamycin more effectively inhibited viability and mTOR signaling in C4-2, LNCaP and DU145 cells than either agent individually.     

Targeted therapy for non-small-cell lung cancer: past,present and future

Therapy for advanced non-small-cell lung cancer has developed significantly with new awareness of histologic subtype as an important factor in guiding treatment and the development of targeted agents for molecular subgroups harboring critical mutations that spur on cancer growth. In this comprehensive review, we look back at developments in targeted therapy for advanced non-small-cell lung cancer, reviewing in detail efforts, both successful and in some cases less so, to target EGFR, VEGF and ALK. This review provides an overview of where the field stands at present and the areas we feel are most likely to provide challenges and potential successes in the next 5 years including immune checkpoint inhibition, epigenetic therapy and driver mutation targeting.     

A new era in prostate cancer therapy: new targets and novel therapeutics

The results of two phase III trials demonstrating a significant prolongation of survival with docetaxel-based chemotherapy has fueled interest in expanding therapeutic development in prostate cancer. This coupled with improved understanding of the mechanisms responsible for prostate cancer development and progression has lead to discovery of several biologic targets that can be exploited using novel therapeutics in what has been referred to as the era of “targeted therapy.” Several of these therapies have shown promise either as single agents or in combination with proven chemotherapeutic agents. This review focuses upon some of the more promising targeted therapies under investigation for the treatment of hormone refractory prostate cancer and highlights some of challenges faced in therapeutic development.     

Vemurafenib and panitumumab combination tailored therapy in BRAF-mutated metastatic colorectal cancer: A case report

As the knowledge on cancer genetic alterations progresses, it fosters the need for more personalized therapeutic intervention in modern cancer management. Recently, mutations in KRAS, BRAF, and PIK3CA genes have emerged as important mechanisms of resistance to EGFR-targeted therapy in metastatic colorectal cancer (mCRC). Here we report the first case of a mCRC patient whose disease had progressed on standard lines of treatment and for which we devised a personalized therapeutic approach consisting of vemurafenib (Zelboraf^TM) and panitumumab (Vectibix^TM), based on the following molecular profile: BRAF^V600E-mutant, amplified EGFR (double positive) and WT KRAS, WT PIK3CA, not-amplified HER2 (triple negative). This new combination therapy was well tolerated and resulted in a strong control of the disease. In particular, the vemurafenib-panitumumab combination appears to limit the typical toxicity of single agents, since no cutaneous toxic effects typically associated with vemurafenib were observed. Here we report the first clinical evidence that the combination of an anti-EGFR (panitumumab) and an inhibitor of BRAF^V600E (vemurafenib) is well tolerated and results in a strong disease control in an extensively pretreated mCRC patient.     

Antitumor activity of pimasertib,a selective MEK 1/2 inhibitor,in combination with PI3K/mTOR inhibitors or with multi‐targeted kinase inhibitors in pimasertib‐resistant human lung and colorectal cancer cells

The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti‐cancer therapies. The in vitro and in vivo anti‐tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi‐targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib‐sensitive (IC₅₀ for cell growth inhibition of 0.001 µM) or pimasertib‐resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up‐regulated in pimasertib‐resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK‐ and AKT‐dependent signaling pathways in pimasertib‐resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition.     

Targeted therapy for hepatocellular carcinoma: novel agents on the horizon

Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers. In the last decade it has become one of the most frequently occurring tumors worldwide and is also considered to be the most lethal of the cancer systems, accounting for approximately one third of all malignancies. Although the clinical diagnosis and management of early-stage HCC has improved significantly, HCC prognosis is still extremely poor. Furthermore, advanced HCC is a highly aggressive tumor with a poor or no response to common therapies. Therefore, new effective and well-tolerated therapy strategies are urgently needed. Targeted therapies have entered the field of anti-neoplastic treatment and are being used on their own or in combination with conventional chemotherapy drugs. Molecular-targeted therapy holds great promise in the treatment of HCC. A new therapeutic opportunity for advanced HCC is the use of sorafenib (Nexavar). On the basis of the recent large randomized phase III study, the Sorafenib HCC Assessment Randomized Protocol (SHARP), sorafenib has been approved by the FDA for the treatment of advanced HCC. Sorafenib showed to be able to significantly increase survival in patients with advanced HCC, establishing a new standard of care. Despite this promising breakthrough, patients with HCC still have a dismal prognosis, as it is currently the major cause of death in cirrhotic patients. Nevertheless, the successful results of the SHARP trial underscore the need for a comprehensive understanding of the molecular pathogenesis of this devastating disease. In this review we summarize the most important studies on the signaling pathways implicated in the pathogenesis of HCC, as well as the newest emerging drugs and their potential use in HCC management.     

Systemic therapy in recurrent ovarian cancer: current treatment options and new drugs

Most patients with ovarian cancer relapse despite aggressive surgery and platinum–taxane-based primary chemotherapy. Further treatment depends on prior response and progression-free interval. Monotherapy is indicated in patients with so-called platinum-resistant or -refractory ovarian cancer. The standard treatment for patients with platinum-sensitive recurrent ovarian cancer is platinum-based combination chemotherapy. Cytoreductive surgery is also a treatment option in such patients. Actual treatment options and strategies in recurrent ovarian cancer will also be discussed. Furthermore, this review focuses on new drugs in the treatment of primary and recurrent ovarian cancer.     

A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy.The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with.     

Microcalcifications in breast cancer: novel insights into the molecular mechanism and functional consequence of mammary mineralisation

Background:

Mammographic microcalcifications represent one of the most reliable features of nonpalpable breast cancer yet remain largely unexplored and poorly understood.

Methods:

We report a novel model to investigate the in vitro mineralisation potential of a panel of mammary cell lines. Primary mammary tumours were produced by implanting tumourigenic cells into the mammary fat pads of female BALB/c mice.

Results:

Hydroxyapatite (HA) was deposited only by the tumourigenic cell lines, indicating mineralisation potential may be associated with cell phenotype in this in vitro model. We propose a mechanism for mammary mineralisation, which suggests that the balance between enhancers and inhibitors of physiological mineralisation are disrupted. Inhibition of alkaline phosphatase and phosphate transport prevented mineralisation, demonstrating that mineralisation is an active cell-mediated process. Hydroxyapatite was found to enhance in vitro tumour cell migration, while calcium oxalate had no effect, highlighting potential consequences of calcium deposition. In addition, HA was also deposited in primary mammary tumours produced by implanting the tumourigenic cells into the mammary fat pads of female BALB/c mice.

Conclusion:

This work indicates that formation of mammary HA is a cell-specific regulated process, which creates an osteomimetic niche potentially enhancing breast tumour progression. Our findings point to the cells mineralisation potential and the microenvironment regulating it, as a significant feature of breast tumour development.     

Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer

Despite recent advances in the management of colorectal cancer, metastatic disease remains challenging, and patients are rarely cured. However, a better understanding of the pathways implicated in the evolution and proliferation of cancer cells has led to the development of targeted therapies, that is, agents with action directed at these pathways/features. This approach is more specific to cells within which these pathways, such as epidermal growth factor receptor (EGFR), are overactive; this is in contrast to the relatively indiscriminate mechanism by which cytotoxic chemotherapy tends to affect rapidly dividing cells, regardless of their role. Although factors unique to a given patient, such as the location of the primary tumor (sidedness) or the presence of mutations that confer resistance, may limit the utility of these agents, targeted therapies are now a part of the treatment paradigm for metastatic colorectal cancer, and survival outcomes have significantly improved. This review provides an overview of the role of targeted therapy in the management of patients with colorectal cancer metastases as well as a discussion of issues in patient selection, with a focus on inhibitors of angiogenesis, EGFR-targeted therapy, BRAF mutation–targeted therapies, and other novel strategies, including immunotherapy.     

免疫检查点抑制剂联合治疗实体瘤的疗效和安全性的Meta分析

目的:旨在评价免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合治疗在实体瘤患者中的安全性和有效性,为临床实践提供参考依据。方法:计算机检索 PubMed,EMBASE,Cochrane Library数据库和ClinicalTrials.gov网站符合条件的随机对照试验（randomized controlled trials,RCTs）。根据PICOS（患者类型,干预,对照,结果和研究设计）原则确定纳入标准。结果:包含6 616名患者的17项随机对照试验纳入此项Meta分析。结果显示,ICI联合治疗可显著改善实体瘤患者的总体反应率（overall response rate,ORR）［RR=1.56（95％CI 1.24,1.96）,P=0.000 1］,延长无进展生存期（progression free survival,PFS）［HR=0.69（95％CI 0.59,0.81）,P<0.000 01］和总生存期（overall survival,OS）［HR=0.76（95％CI 0.67,0.87）,P<0.000 1］。亚组分析结果表明,接受ICI联合治疗的黑色素瘤患者的OS［HR=0.64（95％CI 0.58,0.72）,P<0.000 01］显著延长,但小细胞肺癌（small cell lung cancer,SCLC）［HR=0.94（95％CI 0.82,1.08）,P=0.40］和非小细胞肺癌（non-small cell lung cancer,NSCLC）［HR=0.92（95％CI 0.79,1.07）,P=0.26］患者OS无显著改善。此外,ICI联合治疗可增加疲劳、皮疹、腹泻和转氨酶升高等不良反应发生风险。结论:本研究结果表明,ICI联合治疗在未来的临床实践和研究设计中极具前景。ICI联合治疗在恶性黑色素瘤患者中有临床应用价值。然而,目前的研究结果暂不支持ICI联合治疗在NSCLC和SCLC患者中大规模临床应用。     

Patient‐reported symptoms and stepwise symptom management in patients on epidermal growth factor inhibitors: A retrospective,descriptive cohort study

Adverse events (AEs) of epidermal growth factor inhibitors (EGFRi) influence well‐being with a risk to dose modifications (DMs). Hereby, clinical benefit of treatment might be affected. This retrospective cohort study was set up to gain insight into the suitability and added value of a patient‐reported outcome measurement tool (PROM), together with a stepwise intervention management plan for EGFRi‐related AEs in daily practice. The primary objective was to gain insight into total treatment duration and DMs, and the secondary objective to gain insight into patient‐reported symptoms and well‐being as well as healthcare professional‐reported AEs. Sixty‐eight patients on cetuximab and 19 on panitumumab treatment were included for analysis; 69% had squamous cell carcinoma of head and neck (SCCHN) and 26% metastatic colorectal carcinoma. DMs due to AEs occurred in 39% of the patients and dose discontinuations in 22%. Especially anorexia, dysphagia, oral pain and skin changes led to a decreased well‐being. In patients on EGFRi, application of PROMs together with a stepwise symptom management plan enhances early recognition of symptom burden, pro‐active symptom management and effect evaluation of interventions performed whereby well‐being recovers. Since only SCCHN patients discontinued treatment due to AEs, patient‐centred care focused on radiotherapy‐related AEs, creates opportunities for amelioration.     

Atrasentan: a novel and rationally designed therapeutic alternative in the management of cancer

Endothelin axis deregulation triggers a series of events that ultimately activate proliferation, invasion, escape from programmed cell death, new vessel formation, abnormal osteogenesis and alteration of nociceptive stimuli. Atrasentan is a novel agent that effectively targets this pathway and is able to inhibit and/or reverse several of those events. Biologic and clinical activity in patients with prostate cancer has been demonstrated in a Phase III, placebo-controlled setting by the suppression of markers of biochemical prostate cancer progression and a delay in time to disease progression. Atrasentan represents a new therapeutic option in the management of prostate cancer, especially in those patients with bone metastases. However, its precise role in other diseases such as ovarian cancer is yet to be defined.     

Safety profile of combined therapy inhibiting EFGR and VEGF pathways in patients with advanced non‐small‐cell lung cancer: A meta‐analysis of 15 phase II/III randomized trials

The efficacy of combined vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibition in patients with advanced non‐small‐cell lung cancer (NSCLC) was well studied. However, few studies focused on the risk and adverse events (AEs) of combined targeted therapy. The aim of this meta‐analysis was to evaluate the safety profile of combined targeted therapy against EFGR and VEGF in patients with advanced NSCLC. A comprehensive literature search in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ASCO Abstracts and ESMO Abstracts was conducted. Eligible studies were randomized clinical trials (RCTs) that compared safety profile of combined therapy inhibiting EFGR and VEGF pathways with control groups (placebo, single EGFR or VEGF inhibition therapy, chemotherapy or a combination of them) in patients with advanced NSCLC. The endpoints included treatment discontinuation, treatment‐related deaths and AEs. The search identified 15 RCTs involving 6,919 patients. The outcomes showed that three of four pairwise comparisons detected more discontinuation due to AEs in combined targeted therapy, with odds ratio (OR) compared with the control groups ranged from 1.97 to 2.29. Treatment with combined inhibition therapy was associated with several all‐grade and grade 3 or 4 AEs (e.g. rash, diarrhea and hypertension). Also, there was a significantly higher incidence of treatment‐related deaths in combined inhibition using vandetanib versus single EGFR inhibition therapy (OR = 1.97, 95% CI 1.19–3.28). In conclusion, combined inhibition therapy against EGFR and VEGF in patients with advanced NSCLC was associated with increased toxicity. Increased AEs hinder patient compliance and reduce their quality of life, leading to dose reduction or discontinuation.     

D-1553: A novel KRASG12C inhibitor with potent and selective cellular and in vivo antitumor activity

D-1553 is a small molecule inhibitor selectively targeting KRAS^G12C and currently in phase II clinical trials. Here, we report the preclinical data demonstrating antitumor activity of D-1553. Potency and specificity of D-1553 in inhibiting GDP-bound KRAS^G12C mutation were determined by thermal shift assay and KRAS^G12C-coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRAS^G12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRAS^G12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRAS^G12C mutation. Compared to the KRAS WT and KRAS^G12D cell lines, D-1553 selectively inhibited cell viability in multiple KRAS^G12C cell lines, and the potency was slightly superior to sotorasib and adagrasib. In a panel of xenograft tumor models, D-1553, given orally, showed partial or complete tumor regression. The combination of D-1553 with chemotherapy, MEK inhibitor, or SHP2 inhibitor showed stronger potency on tumor growth inhibition or regression compared to D-1553 alone. These findings support the clinical evaluation of D-1553 as an efficacious drug candidate, both as a single agent or in combination, for patients with solid tumors harboring KRAS^G12C mutation.     

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer

Background and purpose:Docetaxel is an active agent in thetreatment of metastatic breast cancer. We evaluated the feasibility ofdocetaxel-based sequential and combination regimens as adjuvant therapies forpatients with node-positive breast cancer. Patients and methods:Three consecutive groups of patients withnode-positive breast cancer or locally-advanced disease, aged 70 years,received one of the following regimens: a) sequential A T CMF:doxorubicin 75 mg/m² q 3 weeks × 3, followed by docetaxel 100mg/m² q 3 weeks × 3, followed by i.v. CMF days 1 + 8 q 4weeks × 3; b) sequential accelerated A T CMF: A and T wereadministered at the same doses q 2 weeks; c) combination therapy: doxorubicin50 mg/m² + docetaxel 75 mg/m² q 3 weeks × 4,followed by CMF × 4. When indicated, radiotherapy was administeredduring or after CMF, and tamoxifen started after the end of CMF. Results:Seventy-nine patients have been treated. Median age was48 years. A 30% rate of early treatment discontinuation was observedin patients receiving the sequential accelerated therapy (23% duringA T), due principally to severe skin toxicity. Median relativedose-intensity was 100% in the three treatment arms. The incidence ofG3–G4 major toxicities by treated patients, was as follows: skintoxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%;b: 20%; c: 3%. The incidence of neutropenic fever was a:30%; b: 13%; c: 48%. After a median follow-up of 18months, no late toxicity has been reported. Conclusions:The accelerated sequential A T CMFtreatment is not feasible due to an excess of skin toxicity. The sequentialnon accelerated and the combination regimens are feasible and under evaluationin a phase III trial of adjuvant therapy.