Advances in the management of recurrent or metastatic squamous cell carcinoma of the head and neck

Most patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) undergo definitive therapy, yet locoregional recurrence and metastasis are common. Most patients ultimately require systemic treatment. Platinum/5‐fluorouracil (5‐FU) has been the standard of care for patients with good performance status (median survival, 6–8 months). Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), significantly improved median survival in combination with platinum/5‐FU compared with chemotherapy alone, establishing it as a new standard for patients with recurrent or metastatic disease. Cetuximab is also active in platinum‐refractory disease. Ongoing trials are exploring other EGFR inhibitors as well as the use of biologic agents in combination (eg, cetuximab + bevacizumab). Predictive biomarkers may help personalize therapy for SCCHN, and it is unclear whether the favorable prognostic effect of p16 or human papillomavirus in locally advanced oropharyngeal cancer is relevant for advanced disease. Head Neck, 2013     

Antibody treatment in colorectal cancer--what the surgeon needs to know

Advances in the medical treatment of colorectal cancer patients have resulted in considerable improvements through the introduction of new cytotoxic drugs. The significant progress in molecular and tumour biology has produced a great number of targeted, tumour-specific, monoclonal antibodies that are now in various stages of clinical development. Two of these antibodies, cetuximab (Erbitux) und bevacizumab (Avastin), directed against the epidermal growth factor receptor (EGFR) and the vascular epithelial growth factor (VEGF), respectively, have recently been approved for use in metastatic colorectal cancer. The combination of well-known and newly developed cytotoxic agents with monoclonal antibodies makes the medical treatment of colorectal cancer patients considerably more complex, but also provides additional therapeutic strategies for patients in advanced stages of disease.     

Aktuelle medikamentöse Therapie des metastasierten Kolonkarzinoms

Medical treatment of metastatic colorectal carcinoma has become more effective in recent years. In addition to an increasing number of cytotoxic drugs (e.g. fluoropyrimidines, irinotecan, oxaliplatin), monoclonal antibodies against VEGF or the EGF receptor have become available. These developments, combined with an increasing number of metastasectomies, have improved the prognosis of patients with metastatic colorectal cancer to a median survival of 24–30 months. Starting with the determination of K-RAS mutations the first molecular markers have found a place in the routine diagnostics i. e. to predict which patients have a higher chance (K-RAS wild type) or very low chance (K-RAS mutation) to respond to EGFR antibody treatment. This information complements important clinical factors for the choice of the therapeutic regimen, such as the treatment target (e.g. neoadjuvant treatment of non-resectable liver metastases), tumor symptoms which urgently require a tumor response and comorbidities.     

Bowel perforation from bevacizumab for the treatment of metastatic colon cancer: incidence, etiology, and management

Avastin (Bevacizumab) is a recently developed monoclonal antibody against vascular endothelial growth factor (VEGF) receptor that increases survival in patients with metastatic colorectal cancer. Bowel perforation is a known risk factor of unknown etiology associated with the use of Avastin. In this report, the incidence, risk factors, typical presentation, and management of patients with this complication is described.     

Treatment of metastatic liver carcinoma: chemotherapy and immunotherapy

The treatment regimens that are considered to be effective against metastatic colorectal carcinoma and available in Japan are levofolinate calcium (Isovorin)/5-fluorouracil (5-FU), irinotecan hydrochloride (Topotecin, CPT-11), and repeated low-dose cisplatin/5-FU. In the USA and Europe, many randomized clinical trials of regimens combining CPT-11 or oxaliplatin (Oxa) with folinate calcium (Leucovorin, LV)/5-FU have been conducted. However, in Japan these three regimens are used sequentially based on the performance status of each patient, and the use of Oxa has not been approved. LV/UFT, and TS-1 will likely be approved soon for colorectal carcinoma. These two regimens may advance the strategy of chemotherapy for colorectal carcinoma. There is no report showing an obvious clinical effect of nonspecific immuno therapy against metastatic colorectal carcinoma. On the other hand, it has been clarified that monoclonal antibodies to the molecular targets such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) show a clear clinical effect when they are used together with chemotherapy. It is important to accumulate further evidence clarifying the best chemotherapy for metastatic colorectal carcinoma. Furthermore, it is important that effective molecular-targeting drugs, including the monoclonal antibody to VEGF bevacizumab, become available in Japan soon.     

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??Progression of targeted therapy for colorectal cancer LIN Feng, LI Yong. Guangdong Provincial People's Hospital ?? Guangdong Province Academy of Medical Sciences, Guangzhou 510080, China
Corresponding author??LIN Feng??E-mail: liyong-lucky@21cn.com
Abstract Colorectal cancer is one of the most common malignant tumors but the results of conventional chemotherapy have been discouraging. The recent successful development of targeted therapy has brought new hope for patients with colorectal cancer. Two monoclonal antibodies, bevacizumab and cetuximab, that block vascular endothelial growth factor and epithelial growth factor receptor are available widely in clinical practice. The addition of cetuximab or bevacizumab to the chemotherapy for metastatic colorectal cancer further improves the outcome. The combination of chemotherapy with cetuximab or bevacizumab has become standard regimens in advanced colorectal cancer and makes a striking step to prolong the survival time in the past few years. The major achievement for the cetuximab targeted therapy of mCRC is the correlation between k-ras status and the efficacy of anti-EGFR therapy. Molecular targeted therapy plays a more important role in treatment for colorectal cancer.     

Cancer colorectal métastatique et thérapies ciblées

Monoclonal antibodies against the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) pathways are the biologic agents that can be use in patients with a metastatic colorectal cancer (MCRC). The median overall survival is now rather than 25 months with biologic agents and standard chemotherapy combination. Although, these drugs have been shown their efficacy in first-, second- and third-line chemotherapy, there is no definitive guideline concerning the most relevant treatment strategy in MCRC. To date, the presence of KRAS mutation has been clearly identified as a predictive marker of resistance to anti-EGFR in MCRC and KRAS genotyping is now systematically required for patient selection. However, no predictive markers have been yet identified in MCRC patients treated with bevacizumab.     

Hepatic Tumor Growth: Target for Angiogenesis Inhibition?

Pathologic angiogenesis induced by a tumor is essential for its survival. The promise of tumor inhibition by targeting angiogenesis over the past several years has translated into numerous ongoing clinical trials. Recently, in a phase III trial involving patients with metastatic colorectal cancer, Bevacizumab (Genentech, Inc, San Francisco, CA), a recombinant humanized monoclonal antibody against vascular endothelial growth factor used in conjunction with standard chemotherapy was shown to increase survival, progression-free survival, response rate, and duration of response compared to chemotherapy alone. Thus far, duration of the increased response remains less than 6 months. The majority of deaths in patients with colorectal cancer are related to hepatic metastases. It is hoped that novel approaches directed at the complex interactions between tumor and microenvironment in the angiogenic process will strengthen the therapeutic armamentarium against hepatic malignancies.     

Small cell lung carcinoma (SCLC): the angiogenic phenomenon

Objectives: Tumor angiogenesis, expressed by the microvessel count (MVC), and its mediators (i.e. vascular endothelial growth factor) significantly correlate with metastases in surgically treated non-small cell lung carcinoma/cancer (NSCLC). SCLC is rarely treated by surgery, as a consequence, few specimens are available to perform a biological characterization. We reviewed our experience in the surgical treatment of SCLC with particular reference to the angiogenetic expression and its correlation to the stage of disease and prognosis. Methods: We retrospectively investigated a homogenous cohort of 87 patients with SCLC, who were primarily operated on and then underwent adjuvant chemotherapy between 1980 and 1998. Their median age was 62 years (range 34–73). All the patients were completely staged. The surgical procedures included: 32 pneumonectomies and 55 lobectomies. There were 46 N0, 17 N1 and 24 N2-disease. The adjuvant chemotherapy consisted of four to six courses of cyclophosphamide, epidoxorubicine and etoposide. The MVC was determined highlighting the microvessels with anti-CD34 monoclonal antibodies. Immunostaining for VEGF was performed using the ABC method with anti-VEGF monoclonal antibodies. The p53 protein expression was assessed by NCL-DO7 anti-p53 monoclonal antibody. Results: With a median follow-up of 109.6 months (range 25–238), 37 patients are alive and well, two are alive with systemic metastases. Forty-four patients died of local (n=5) or systemic (n=39) relapse, while four patients died from other causes. The median MVC was 59 (range 18–145). Among the clinico-pathological parameters, metastatic nodal-involvement (P=0.002) and advanced stage of disease (P=0.005) were associated with a worse overall survival (OS). MVC and VEGF protein expression significantly affected the survival (P<0.001 and P=0.0008, respectively). No statistical association was found between p53 alterations and OS as well as no association was found among p53 alterations, MVC and VEGF expression. On multivariate analysis only the VEGF expression (P=0.003) was an independent prognostic factor. Conclusions: Angiogenesis plays a role in the metastatic process of the SCLC as well as NSCLC. SCLC has a higher vascularization than NSCLC as results from the higher number of microvessels; however, tumor angiogenesis tested by the MVC and the VEGF protein expression correlates with the prognosis also in SCLC. SCLC may be an ideal field to test new antiangiogenic drugs associated to chemotherapy.     

Treatment of metastatic colorectal cancer: an illustration of the changes in the cancer paradigms

Until the 2000 decade, survival gains in metastatic colorectal cancer were due to the addition of new cytotoxic agents with original mechanism of action: fluorouracile, the oxaliplatin and irinotecan and also the improvements of liver surgery. During the 2000 decade, the treatment improvements are related to monoclonal antibodies, directed either against the EGF receptor or the VEGF receptor. The molecular characterization of the tumor, especially the presence or absence of k-ras mutation guides the use of targeted therapy. Finally, changes in habits represents an underestimated way to reduce the risk of recurrence and clinical trials are undergoing to evaluate the impact of changes in nutrition and physical exercice.     

Recent concepts of antiangiogenic therapy

In 2004, a randomized, controlled phase III clinical trial showed that the addition of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)-A, to conventional chemotherapy prolonged the survival of patients with metastatic colorectal cancer. A number of clinical trials are presently underway to test the utility of several angiogenic inhibitors against a variety of malignancies. The original concept of antiangiogenic therapy was the inhibition of outgrowth of new blood vessels; however, it soon became evident that bevacizumab could affect the vasculature through various mechanisms. Recent studies have shown that antiangiogenic agents can normalize the tumor vasculature and prevent the recruitment of endothelial progenitor cells from the bone marrow. Some preclinical studies have also shown that antiangiogenic agents prevent metastasis by modulating the premetastatic niche. Understanding these detailed mechanisms provides the rationale for combination therapy using antiangiogenic agents and cytotoxic chemotherapy, and will lead to more effective treatment strategies. In this review, we summarize the present understanding of the mechanisms of action of antiangiogenic agents and discuss the future prospects of antiangiogenic therapies.     

Targeted biotherapy in metastatic colorectal carcinoma: Current practice

Targeted therapy has become an indispensable tool in the management of metastatic colorectal cancer (mCRC). The combination of monoclonal antibodies with conventional polychemotherapy has proven its efficacy as the median overall survival now exceeds 24 months: these novel molecules act by targeting circulating vascular endothelial growth factor (VEGF) and the receptor of epidermal growth factor (EGFR). At the present time, no factor has been identified to predict the efficacy of bevacizumab, an inhibitor of circulating VEGF. On the other hand, mutation of the KRAS oncogen has been proven to be a factor of non-response, or even of deleterious response to the use of EGFR, therefore limiting its use to patients whose tumors bear the wild type KRAS oncogen. Treatment toxicity for these molecules is moderate, specific, and is not cumulative with chemotherapy-related toxicity. On the other hand, combined targeted therapy (association of several targeted therapy drugs) has not been shown to be of any benefit. Other biotherapies continue to be developed, but there is not yet a consensus of how to best target the tumor nor which anti-tumoral molecules to use in the treatment of mCRC.     

分子靶向药物在胃肠道肿瘤综合治疗中的应用

分子靶向药物在晚期胃肠道肿瘤治疗中,被证实可提高患者的客观缓解率并延长总生存期.因此,其在局部进展期胃肠道肿瘤综合治疗中的价值被逐渐重视.曲妥珠单抗用于HER-2基因阳性的局部进展期胃癌新辅助化疗中的临床研究正在进行中,结果值得期待.大量研究证明,西妥昔单抗联合化疗对于KRAS基因野生型潜在可切除的结直肠癌肝转移患者,能提高手术切除率并延长总生存期;而贝伐珠单抗在KRAS基因突变型结直肠癌肝转移术前转化治疗中的作用正在评估中.对于可切除的结直肠癌肝转移,虽现有的证据显示,分子靶向药物在新辅助治疗中未能带来长期生存益处,但最终结论仍存议甚多.对于局部进展期直肠癌患者,新辅助化疗中的西妥昔单抗在二期临床研究中未能显示治疗获益,贝伐珠单抗的作用同样需要在三期临床研究后进一步证实.与晚期肿瘤单一治疗模式不同,在肿瘤综合治疗中,需要系统评估分子靶向药物与细胞毒药物、手术以及放疗之间可能的相互影响及协同作用,制定出科学并适用于临床实践的综合治疗模式.     

High-risk metastatic urothelial cancer: chances for cure?

The median survival of patients with metastatic bladder cancer treated with methotrexate, vinblastine, adriamycin, and cisplatin chemotherapy is approximately 1 year and long-term survival occurs in a small proportion of patients. Recent efforts to improve the outcome of patients with metastatic transitional cell carcinoma have focused on the identification of new drugs with single agent activity and on their incorporation into platinum-based combination regimens. Paclitaxel, docetaxel, ifosfamide and gemcitabine are among the most active new agents. A large number of phase I/II trials have evaluated these agents in two- and three-drug combination regimens. The response proportion observed with these combinations varies considerably and median survival times range from 8 to 20 months. Because it is known that pretreatment prognostic features have an impact on individual patient outcome, the variation in reported survival in patients treated with chemotherapy may be a consequence of pretreatment patient characteristics. The role of surgery in metastatic bladder cancer is still controversial. After a significant response to chemotherapy, resection of residual resistant disease may be performed with intent to cure in highly selected patients. As obtainment of complete remission is a prerequisite for long-term survival, new therapeutic strategies, such as molecular targeted small molecule therapy and monoclonal antibodies, and new molecular markers predictive of response have the potential to be incorporated into the current treatment strategies, increasing the rate of cure.     

Ischämische Anastomosenperforation im Bereich einer Ileotransversostomie unter Therapie mit Bevacizumab

BACKGROUND: Bevacizumab (Avastin) is a monoclonal antibody against vascular endothelial growth factor (VEGF) receptor that has demonstrated increased overall survival when added to standard chemotherapy regimens in patients with metastatic colorectal cancer. Gastrointestinal perforation is a known risk factor of unknown etiology associated with the use of bevacizumab. OBJECTIVE: We report a 61-year-old woman with adenocarcinoma of the colon ascendens who underwent hemicolectomy and adjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin. Eight months after the operation, we started therapy with bevacizumab combined with irinotecan, 5-fluorouracil, and leucovorin due to disease progression. Two months after completion of this therapy, ischemic anastomotic bowel perforation occurred and a resection of the anastomosis was performed. Because of anastomotic insufficiency 8 days later, a further revision had to be done and the terminal ileum and the colon were brought out through a stoma. DISCUSSION: This case is unusual because the time interval between the primary operation and the application of bevacizumab is regarded as safe with regard to the risk of perforation. An ischemic genesis of the perforation was considered on the basis of the histopathological workup. In case of perforations during therapy with bevacizumab, a safe surgical approach should be preferred, i.e., a transient stoma instead of a primary reconstruction of the bowel passage.     

Le bevacizumab dans les cancers colorectaux métastatiques

Background

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy.

Methods

Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg/kg of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life.

Results

The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P < 0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P < 0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P = 0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P = 0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed.

Conclusion

The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.     

VEGF Expression Predicts Survival in Patients with Peritoneal Surface Metastases from Mucinous Adenocarcinoma of the Appendix and Colon

Background High levels of vascular endothelial growth factor (VEGF) in ovarian cancer metastases are associated with a worse prognosis in patients treated with chemotherapy. VEGF-directed therapy improves survival for those with metastatic colorectal cancer. Patients with mucinous adenocarcinomas metastatic to the peritoneal surfaces can be treated with cytoreductive surgery, and both tumor grade and cytoreduction status are prognostic. We hypothesized that angiogenic indices may be prognostic in patients undergoing cytoreductive surgery for mucinous adenocarcinoma of the appendix and colon. Methods Cytoreductive cases from a 5-year period from the University of Cincinnati peritoneal malignancy database were reviewed. CD 34 counts (blood vessels) and VEGF expression was evaluated by means of immunohistochemistry on specimens from patients undergoing cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP) for mucinous adenocarcinoma. Results A total of 26 males and 9 females, with a mean age of 50 years, underwent cytoreductive surgery and IPHP for mucinous adenocarcinoma of appendiceal (n = 32) or colonic (n = 3) origin. With a mean follow-up of 18 months (range 1–63 months), 23 had disease recurrence and 12 were alive without recurrence. The mean survival was 19 months (range 1–63 months). CD34 counts did not correlate with recurrence or survival; however, average VEGF counts correlated with survival (P = 0.017), and, for patients with recurrence, this correlation was stronger (P = 0.002). Conclusions These results suggest that markers of tumor angiogenesis may predict survival in patients with peritoneal surface metastases from mucinous adenocarcinoma. These findings provoke the hypothesis that antiangiogenic therapies may be effective in patients with this devastating disease. Presented at the 59^th Annual Cancer Symposium, The Society of Surgical Oncology, San Diego, CA, 23-26 March, 2006     

Targeted therapy for non-small cell lung cancer

The overall survival for the treatment of lung cancer patients is less than 15%, despite advances in chemotherapy, radiation therapy, and surgery, due to the inability to control metastatic disease. Over the past three decades, the genetics of lung cancer has been progressively delineated. Small molecule drugs or monoclonal antibodies have been developed that target and inactivate specific cancer-related proteins, such as growth factor receptors or their kinases. This article will review the therapeutic implications of molecular changes associated with non-small cell lung cancer and the status of targeted therapies in its treatment.     

Profile of Plasma Angiogenic Factors Before and After Hepatectomy for Colorectal Cancer Liver Metastases

Background Circulating angiogenic factors in patients with colorectal cancer liver metastases may promote tumor growth and contribute to liver regeneration after partial hepatectomy. Methods We analyzed blood samples from 26 patients with colorectal cancer liver metastases before and after liver resection and used samples from 20 healthy controls as a reference. Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF) were measured, and levels were correlated with recurrence. Results The median preoperative levels of all four factors were significantly higher and more variable in colorectal cancer liver metastasis patients than in controls. HGF and bFGF levels increased significantly 3 days and 1 month after hepatectomy, respectively, and returned to near preoperative levels at 3 months. Postoperative VEGF and EGF levels remained relatively stably increased over 3 months. After a median follow-up of 19 months, 10 patients (42%) experienced recurrence. Higher preoperative VEGF and HGF levels correlated with subsequent recurrence (P = .018 and .021, respectively), and a preoperative adjusted total value of all four factors accurately identified patients at low, moderate, and high risk of recurrence (P = .034). Patients who experienced disease recurrence also had relatively higher bFGF levels 3 months after operation (P = .035). Conclusions Plasma angiogenic factors are increased in patients with colorectal cancer liver metastases and remain increased at least 3 months after partial hepatectomy. Measurement of certain factors before and after hepatic resection can predict recurrence. Targeted biological agents may counteract the tumor-promoting effects of these circulating factors on subclinical disease.     

Hepatic Intra-Arterial Injection of Drug-Eluting Bead, Irinotecan (DEBIRI) in Unresectable Colorectal Liver Metastases Refractory to Systemic Chemotherapy: Results of Multi-Institutional Study

Introduction

Response rates and overall outcome for patients who have failed first-line and in some cases second-line chemotherapy are as low as 12% and 7 months, respectively. The aim of this study is to evaluate the efficacy of hepatic arterial sulfonate hydrogel microsphere (drug-eluting beads), irinotecan preloaded therapy (DEBIRI) in metastatic colorectal cancer refractory to systemic chemotherapy.

Methods

This was a multicenter multinational single-arm study of metastatic colorectal cancer patients who received DEBIRI after failing systemic chemotherapy from 10/2006 to 8/2008. Primary endpoints were safety, tolerance, tumor response rates, and overall survival.

Results

Fifty-five patients who had received prior systemic chemotherapy and who underwent a total of 99 DEBIRI treatments were reviewed. The median number of DEBIRI treatments was 2 (range 1–5), median treatment dose was 100 mg (range 100–200 mg), with total hepatic treatment of 200 mg (range 200–650 mg), with 86% of treatments performed as lobar infusion and 30% of patients treated with concurrent simultaneous chemotherapy. Adverse events occurred in 28% of patients with median grade of 2 (range 1–3) with no deaths at 30 days post procedure. Response rates were 66% at 6 months and 75% at 12 months. Overall survival in these patients was 19 months, with progression-free survival of 11 months.

Conclusions

Hepatic arterial drug-eluting bead, irinotecan (DEBIRI) was safe and effective in treatment of metastatic colorectal cancer (MCC) refractory to multiple lines of systemic chemotherapy. DEBIRI is an acceptable therapy for treatment of metastatic colorectal cancer to the liver.