Paul M. Harari

Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival

BACKGROUND Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival. METHODS Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227. FINDINGS Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002). INTERPRETATION For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash. FUNDING ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

Image guidance for precise conformal radiotherapy

PURPOSE To review the state of the art in image-guided precision conformal radiotherapy and to describe how helical tomotherapy compares with the image-guided practices being developed for conventional radiotherapy. MATERIALS AND METHODS Image guidance is beginning to be the fundamental basis for radiotherapy planning, delivery, and verification. Radiotherapy planning requires more precision in the extension and localization of disease. When greater precision is not possible, conformal avoidance methodology may be indicated whereby the margin of disease extension is generous, except where sensitive normal tissues exist. Radiotherapy delivery requires better precision in the definition of treatment volume, on a daily basis if necessary. Helical tomotherapy has been designed to use CT imaging technology to plan, deliver, and verify that the delivery has been carried out as planned. The image-guided processes of helical tomotherapy that enable this goal are described. RESULTS Examples of the results of helical tomotherapy processes for image-guided intensity-modulated radiotherapy are presented. These processes include megavoltage CT acquisition, automated segmentation of CT images, dose reconstruction using the CT image set, deformable registration of CT images, and reoptimization. CONCLUSIONS Image-guided precision conformal radiotherapy can be used as a tool to treat the tumor yet spare critical structures. Helical tomotherapy has been designed from the ground up as an integrated image-guided intensity-modulated radiotherapy system and allows new verification processes based on megavoltage CT images to be implemented.

Understanding resistance to EGFR inhibitors—impact on future treatment strategies

EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer.

Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members

The epidermal growth factor receptor (EGFR) is a central regulator of proliferation and progression in human cancers. Five EGFR inhibitors, two monoclonal antibodies and three TKIs, have recently gained FDA approval in oncology (cetuximab, panitumumab, erlotinib, gefitinib and lapatinib). These strategies of EGFR inhibition demonstrate major tumor regressions in approximately 10–20% of advanced cancer patients. However, many tumors eventually manifest acquired resistance to treatment. In this study we established and characterized a model to study molecular mechanisms of acquired resistance to the EGFR monoclonal antibody cetuximab. Using high-throughput screening we examined the activity of 42 receptor tyrosine kinases in resistant tumor cells following chronic exposure to cetuximab. Cells developing acquired resistance to cetuximab exhibited increased steady-state EGFR expression secondary to alterations in trafficking and degradation. In addition, cetuximab-resistant cells manifested strong activation of HER2, HER3 and cMET. EGFR upregulation promoted increased dimerization with HER2 and HER3 leading to their transactivation. Blockade of EGFR and HER2 led to loss of HER3 and PI(3)K/Akt activity. These data suggest that acquired resistance to cetuximab is accompanied by dysregulation of EGFR internalization/degradation and subsequent EGFR-dependent activation of HER3. Taken together these findings suggest a rationale for the clinical evaluation of combinatorial anti-HER targeting approaches in tumors manifesting acquired resistance to cetuximab.

Dual-Agent Molecular Targeting of the Epidermal Growth Factor Receptor (EGFR) Combining Anti-EGFR Antibody with Tyrosine Kinase Inhibitor

Molecular inhibition of epidermal growth factor receptor (EGFR/HER1) signaling is under active investigation as a promising cancer treatment strategy. We examined the potency of EGFR inhibition achieved by combining anti-EGFR monoclonal antibody and tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively. We specifically studied the combination of cetuximab (Erbitux, C225; ImClone Systems, New York, NY) with either gefitinib (Iressa, ZD1839; AstraZeneca, Macclesfield, UK) or erlotinib (Tarceva, OSI-774; Genentech, South San Francisco, CA) across a variety of human cancer cells. The combination of cetuximab plus gefitinib or erlotinib enhanced growth inhibition over that observed with either agent alone. As measured by immunostaining, inhibition of EGFR phosphorylation with the combination of cetuximab plus gefitinib or erlotinib was augmented over that obtained with single-agent therapy in head and neck (H&N) cancer cell lines. Phosphorylation inhibition of downstream effector molecules [mitogen-activated protein kinase (MAPK) and AKT] also was enhanced in tumor cells treated with the combination of cetuximab plus gefitinib or erlotinib. Flow cytometry and immunoblot analysis demonstrated that treatment of H&N tumor cells with cetuximab in combination with either gefitinib or erlotinib amplified the induction of apoptosis. Following establishment of cetuximab-resistant cell lines, we observed that gefitinib or erlotinib retained the capacity to inhibit growth of lung and H&N tumor cells that were highly resistant to cetuximab. Treatment with gefitinib or erlotinib, but not cetuximab, also could further inhibit the activation of downstream effectors of EGFR signaling in cetuximab-resistant cells, including MAPK and AKT. These data suggest that tyrosine kinase inhibitors may further modulate intracellular signaling that is not fully blocked by extracellular anti-EGFR antibody treatment. Finally, animal studies confirmed that single EGFR inhibitor treatment resulted in partial and transient tumor regression in human lung cancer xenografts. In contrast, more profound tumor regression and regrowth delay were observed in mice treated with the combination of cetuximab and gefitinib or erlotinib. Immunohistochemical staining, which demonstrated significant reduction of the proliferative marker proliferating cell nuclear antigen in mice treated with dual EGFR inhibitors, further supported this in vivo observation. Together, these data suggest that combined treatment with distinct EGFR inhibitory agents can augment the potency of EGFR signaling inhibition. This approach suggests potential new strategies to maximize effective target inhibition, which may improve the therapeutic ratio for anti-EGFR-targeted therapies in developing clinical trials.

Mechanisms of Enhanced Radiation Response following Epidermal Growth Factor Receptor Signaling Inhibition by Erlotinib (Tarceva)

Erlotinib (Tarceva) is an orally available HER1 (epidermal growth factor receptor, EGFR) tyrosine kinase inhibitor advancing through clinical trials for the treatment of a range of human malignancies. In this study, we examine the capacity of erlotinib to modulate radiation response and investigate specific mechanisms underlying these interactions in human tumor cell lines and xenografts. The impact of erlotinib on cell cycle kinetics was analyzed using flow cytometry, and the impact on apoptosis was evaluated via fluorescein-labeled pan-caspase inhibition and poly(ADP-ribose) polymerase cleavage. Radiation-induced EGFR autophosphorylation and Rad51 expression were examined by Western blot analysis. Radiation survival was analyzed using a clonogenic assay and assessment of in vivo tumor growth was done using a mouse xenograft model system. Microarray studies were carried out using 20 K human cDNA microarray and select genes were validated using quantitative reverse transcription-PCR (RT-PCR). Independently, erlotinib and radiation induce accumulation of tumor cells in G(1) and G(2)-M phase, respectively, with a reduction of cells in S phase. When combined with radiation, erlotinib promotes a further reduction in S-phase fraction. Erlotinib enhances the induction of apoptosis, inhibits EGFR autophosphorylation and Rad51 expression following radiation exposure, and promotes an increase in radiosensitivity. Tumor xenograft studies confirm that systemic administration of erlotinib results in profound tumor growth inhibition when combined with radiation. cDNA microarray analysis assessing genes differentially regulated by erlotinib following radiation exposure identifies a diverse set of genes deriving from several functional classes. Validation is confirmed for several specific genes that may influence radiosensitization by erlotinib including Egr-1, CXCL1, and IL-1beta. These results identify the capacity of erlotinib to enhance radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair. Preliminary microarray data suggests additional mechanisms underlying the complex interaction between EGFR signaling and radiation response. These data suggest that the erlotinib/radiation combination represents a strategy worthy of further examination in clinical trials.

Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale and preliminary clinical results.

The epidermal growth factor receptor (EGFR), a growth factor receptor involved in the regulation of cellular differentiation and proliferation, is highly expressed by many tumor cells. In light of a relationship between overexpression of EGFR and clinically aggressive malignant disease, EGFR has emerged as a promising target for cancer therapy. In recent years, several molecular strategies have been explored to modulate either the EGFR itself, or the downstream signal beyond the cell surface receptor. One of the most promising current strategies involves the use of anti-EGFR monoclonal antibodies (mAbs), either alone or in combination with conventional cytotoxic modalities such as chemotherapy or radiotherapy. This review focuses primarily on recent progress in the development of anti-EGFR mAbs, and examines their potential in the treatment of cancer.

Multi-Institutional Trial of Accelerated Hypofractionated Intensity-Modulated Radiation Therapy for Early-Stage Oropharyngeal Cancer (RTOG 00-22)

PURPOSE To assess the results of a multi-institutional study of intensity-modulated radiation therapy (IMRT) for early oropharyngeal cancer. PATIENTS AND METHODS Patients with oropharyngeal carcinoma Stage T1-2, N0-1, M0 requiring treatment of the bilateral neck were eligible. Chemotherapy was not permitted. Prescribed planning target volumes (PTVs) doses to primary tumor and involved nodes was 66 Gy at 2.2 Gy/fraction over 6 weeks. Subclinical PTVs received simultaneously 54-60 Gy at 1.8-2.0 Gy/fraction. Participating institutions were preapproved for IMRT, and quality assurance review was performed by the Image-Guided Therapy Center. RESULTS 69 patients were accrued from 14 institutions. At median follow-up for surviving patients (2.8 years), the 2-year estimated local-regional failure (LRF) rate was 9%. 2/4 patients (50%) with major underdose deviations had LRF compared with 3/49 (6%) without such deviations (p = 0.04). All cases of LRF, metastasis, or second primary cancer occurred among patients who were current/former smokers, and none among patients who never smoked. Maximal late toxicities Grade >or=2 were skin 12%, mucosa 24%, salivary 67%, esophagus 19%, osteoradionecrosis 6%. Longer follow-up revealed reduced late toxicity in all categories. Xerostomia Grade >or=2 was observed in 55% of patients at 6 months but reduced to 25% and 16% at 12 and 24 months, respectively. In contrast, salivary output did not recover over time. CONCLUSIONS Moderately accelerated hypofractionatd IMRT without chemotherapy for early oropharyngeal cancer is feasible, achieving high tumor control rates and reduced salivary toxicity compared with similar patients in previous Radiation Therapy Oncology Group studies. Major target underdose deviations were associated with higher LRF rate.

Head and neck cancer as a clinical model for molecular targeting of therapy: combining EGFR blockade with radiation.

PURPOSE/OBJECTIVE The primary purpose of this presentation is to develop the concept that molecular blockade of specific growth factor receptors and signal transduction pathways in combination with radiation will prove a valuable cancer therapeutic strategy. More specifically, the rationale for molecular blockade of the epidermal growth factor receptor (EGFR) system in combination with ionizing radiation for epithelial tumors, such as squamous cell carcinomas (SCCs) of the head and neck (H&N), is described. METHODS AND MATERIALS Preclinical experimentation with in vitro and in vivo model systems regarding the capacity of EGFR blockade, using the monoclonal antibody C225, to modulate SCC tumor growth behavior and response to radiation is presented. The rationale for new clinical trials that are currently exploring this concept are presented. RESULTS Blockade of the EGFR system in SCC cell lines with C225 induces G1 cell cycle arrest with an associated decrease in the S-phase fraction. Inhibition of tumor cell proliferation is readily measured following C225 exposure and the corresponding alterations in expression of key regulators of the G1-S cell cycle phase transition are identified. Exposure of SCCs to C225 in culture enhances radiosensitivity following single-dose radiation exposure. Profound augmentation of the in vivo radiation response of SCC tumor xenografts in athymic mice is similarly demonstrated following systemic administration of C225. Preliminary studies are presented regarding potential underlying mechanisms of action for this enhanced tumor response to the combination of C225 and radiation including: (a) proliferative growth inhibition, (b) enhancement of radiation-induced apoptosis, (c) inhibition of damage repair, and (d) downregulation of tumor angiogenic response. Preliminary observations from the Phase III multicenter clinical trial examining C225 plus radiation therapy for advanced H&N cancer patients are provided. CONCLUSION Molecular inhibition of the EGFR signal transduction system in combination with radiation represents a promising investigational area in cancer therapeutics. Epithelial tumors that are rich in their expression of EGFR (e.g., SCC of the H&N) hold special promise for receptor blockade approaches. More broadly, the ultimate therapeutic effect of selected molecular agents which block specific growth factor receptors and signaling pathways may be enhanced when delivered in combination with radiation.

Quality of Life in Head and Neck Cancer Patients After Treatment With High-Dose Radiotherapy Alone or in Combination With Cetuximab

PURPOSE In this randomized, phase III study, quality of life (QoL) was assessed in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) after high-dose radiotherapy alone or in combination with cetuximab. PATIENTS AND METHODS Patients with stage III or IV nonmetastatic and measurable squamous cell carcinoma of the oropharynx, hypopharynx, or larynx were eligible. QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC QLQ Head and Neck Cancer-Specific Module at baseline, week 4, and at months 4, 8, and 12 postbaseline. RESULTS In this study, one of the largest conducted in a population of patients with locoregionally advanced SCCHN, 424 patients received radiotherapy alone (213 patients) or radiotherapy plus cetuximab (211 patients). Radiotherapy/cetuximab significantly improved locoregional control (P = .005) and overall survival (P = .03) compared with radiotherapy alone, without significantly increasing radiotherapy-associated adverse events. The current analysis focused on the impact of cetuximab on the QoL. Compliance with completion of QoL questionnaires was high in both arms. QoL worsened during treatment and improved after cessation of treatment, reaching baseline levels at 12 months. There were no significant differences in QoL scores between the treatment arms. This was particularly notable for global health status/QoL, social functioning, social eating, and social contact. Pretreatment global health status/QoL was identified as a significant prognostic variable in these patients. CONCLUSION The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting QoL.