cetuximab

Head and neck cancer presentation highlights

Source: www.dailyrx.com
Author: Travis Giddings

The field of head and neck cancer from ASCO 2012

A recent presentation at the American Society of Clinical Oncology expanded on several molecular breakthroughs concerning head and neck cancers, and a team of doctors gave an overview of recent conclusions from their respective fields.

The newly identified molecular pathway for cancers of the head and neck that involves the epidermal growth factor receptor (EGFR) led to developments of highly effective drugs specific for the cancerous cells, EGFR inhibitors.

Soon afterwards, scientists discovered the increasingly important role that the human papillomavirus (HPV) played in the development of cancers in the head and neck.

Following the explosion of research in the field of molecular pathways involved in head and neck cancers, doctors quickly found that the cancer was a lot more complicated than previous believed. Additional research continues as scientists try to make sense of the data.

Approaching the treatment of head and neck cancer from their perspectives from surgery, radiology, and oncology, doctors on the panel discussed the difficulties the field currently faced.

The director of Johns Hopkins’ Head and Neck Cancer Research department, oncologist David Sidransky, MD, opened the meeting.

“The genetic and epigenetic alterations in human tumors are becoming increasingly important for devising and implementing personalized oncology approaches,” said Dr. Sidransky. “Unlike in some other cancers, in head and neck cancer the common mutations that have been identified have not been very helpful for treatment.”

The chair of the conference was held by Ezra E.W. Cohen, MD, of The University of Chicago, who mentioned that the molecular differences involved in all the different kinds of this classification of cancer was quite challenging.

“We are learning a lot more about the biology of this disease and are beginning to understand just how heterogeneous it is when it comes to molecular profiling, even within HPV-positive and HPV-negative tumors,” Dr. Cohen explained.

As a board-certified surgeon, Robert L. Ferris, MD/PhD, from the University of Pittsburgh Cancer Institute, spoke on the importance of further development in immunotherapies. He stated that research in the use of monoclonal antibodies could hold the key to successful treatment, as so much of the cancer involved a key point of immune system dysfunction.

“T cells are drawn into tumors through chronic antigen stimulation,” Dr. Ferris explained. “They are chronically stimulated and often driven into an exhausted state through chronic antigen exposure.”

With the successful development of targeted antibodies, doctors could learn how to turn off that immune reaction that makes cancers of the head and neck so difficult to treat. Similar to what Dr. Ferris said, treatment with monoclonal antibodies including cetuximab are one of the few glimmers of hope in the research, but results have been underwhelming so far.

Quynh-Thu Le, MD, a radiologist at Stanford University, spoke about the current treatments in use. Radiation therapy has shown some success on its own, but she hopes to take it to the next level by involving the molecular therapies against EGFR. While studies have discussed evidence linking how aggressive head and neck cancers are by identifying low levels of oxygen in tumor sites, finding a solid mathematical relationship has been difficult. Dr. Le also outlined the lack of success that researchers have had in using secondary drugs such as bevacizumab to change blood vessels, theoretically increasing the amount of chemotherapy received by the tumors.

“The thought was that if we could normalize tumor vasculature with antiangiogenic therapy, we could increase oxygen and chemotherapy delivery, thereby enhancing treatment in these tumors,” Dr. Le explained. Unfortunately, testing of the theory showed this was not the case.

The presentation concluded with an appeal by Jill Gilbert, MD, an oncologist at the Vanderbilt Ingram Cancer Center requesting for more doctors currently practicing to become involved in front-line research, sending solid data back to research teams discussing what therapies had shown success.

“This will require us [to] partner with physician–scientists in a broad array of arenas and [to] encourage patient participation and buy-in, because, without them, we are not going to see improvements in these areas,” stated Dr. Gilbert.

Note:
1. Material presented at the conference was given as expert-level evidence only rather than a presentation of data from a formal study.

Epidermal Growth Factor Receptor and the Changing Face of Oropharyngeal Cancer

Source: Journal of Clinical Oncology

To the Editor:

In their article, Chaturvedi et al1 document the rise in human papillomavirus (HPV) –associated cancers as a proportion of squamous cell carcinomas of the oropharynx over the last 25 years. The contemporary figures are mirrored by two recent British studies2,3 demonstrating that the majority of oropharyngeal cancers are now HPV related.

In the accompanying editorial,4 Mroz et al rightly highlight the importance of evaluating HPV vaccination for both men and women in the light of these data and lament the lack of significant improvement in the outcomes for non–HPV-associated head and neck cancers. However, they also suggest that the benefit of targeting epidermal growth factor receptor (EGFR) through concurrent cetuximab may be confined to HPV-associated tumors. Although EGFR expression per se does not correlate closely with response to cetuximab, there is increasing evidence of an inverse correlation between p16INK4A expression (as a marker of HPV association) and EGFR expression shown by immunohistochemistry.5,6 Though suppressed by viral oncogenes, HPV-associated tumors retain wild-type P53,7 and patients with this tumor type have demonstrated excellent survival with existing protocols such as concurrent chemoradiotherapy or surgery with postoperative radiotherapy. Conversely, non-HPV tumors, harboring a range of mutations,8 may respond less well to DNA-damaging agents, but patients with these tumors might benefit from the addition of concurrent EGFR blockade to radiotherapy. Data from the recent SPECTRUM (Study of Panitumumab Efficacy in Patients With Recurrent and/or Metastatic Head and Neck Cancer) study of adding another EGFR-targeting monoclonal antibody, panitumumab,9 suggest that in the metastatic setting at least, only patients with HPV-negative tumors benefit from a combination of palliative chemotherapy and an anti-EGFR strategy. If confirmed in sample sets containing non-HPV tumors treated with EGFR-targeting agents in combination with radiotherapy, this could open the door to the improvements urgently needed in HPV-negative oropharyngeal cancers, where an older demographic and greater burden of comorbidities make the uncomplicated and complete delivery of concurrent chemoradiotherapy challenging.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

March, 2012|Oral Cancer News|

Use of carbon nanoparticles paves way to customized cancer therapy

Source: www.azonano.com
Author: Cameron Chai

A research study by Jeffrey Myers from the University of Texas MD Anderson Cancer Center and James Tour from the Rice University has reported that a combination of carbon nanoparticles and existing drugs has the capability to improve head-and-neck cancer treatment, particularly when coupled with radiation therapy.

 

The novel technique encapsulates chemotherapeutic drugs using carbon nanoparticles, which sequester the drugs until their delivery into the targeted cancer cells, opening the door to develop customized therapies based on the requirements of individual patients.

The researchers have developed a simple technique to mix Cetuximab, a targeting agent, and paclitaxel, a hydrophobic active chemotherapy agent marketed as Taxol, with hydrophilic carbon clusters that are functionalized with polyethylene glycol or PEG-HCC. According to the researchers, Cetuximab, paclitaxel and PEG-HCC ingredients combine easily and form a water-soluble compound that targets tumors more effectively than Taxol, while eliminating the toxic effects of Cremophor EL and paclitaxel on neighboring healthy cells.

Cremophor EL is a carrier based on castor oil that makes the hydrophobic paclitaxel into a water-soluble compound and delivers it to patients intravenously. Tour commented that the novel technique utilizes a very small quantity of chemotherapy drug. Myers informed that tests involving the use of Cetuximab, paclitaxel and PEG-HCC ingredients and radiation therapy on mice demonstrated a substantial increase in destroying tumors. The researchers’ hypothesis is paclitaxel detects the tumor cells to the radiation effects and Cetuximab and PEG-HCC augment the delivery of paclitaxel into the cancer cells, Myers explained.

Tour stated that the functionalized carbon clusters are nontoxic. Myers commented that this research has demonstrated the principle that carbon nanoparticles are capable of linking a chemotherapeutic drug non-covalently with a targeting antibody, which can supply the drug to target-specific cancer cells. This principle can be applied for delivering other drugs to other kinds of cells via target-specific cell surface receptors as a way of augmenting the therapeutic ratio, Myers concluded.

February, 2012|Oral Cancer News|

Fatal Infusion Reactions to Cetuximab: Role of Immunoglobulin E–Mediated Anaphylaxis

Source: Journal of Clinical Oncology

To the Editor:

In Journal of Clinical Oncology, Tronconi et al1 report a fatal hypersensitivity reaction to cetuximab in a 63-year-old patient with metastatic colon cancer and outlined a 0.1% incidence of death in the literature. We greatly acknowledge the authors’ desire to communicate the risk of fatal anaphylactic reaction with cetuximab. Over the past 2 years in our center in Tours, France, four instances of grade 4 anaphylactic reactions occurred in patients treated for head and neck cancer (locally advanced or metastatic), with one immediately fatal; another patient died within 5 days (unpublished data). Seven lethal anaphylactic reactions were registered in a pharmacovigilance survey in France, based on spontaneous declarations (Grandvuillemin et al, manuscript in preparation). Anaphylaxis to cetuximab is a problem that merits serious clinical attention.

In the authors’ words, “the pathogenic mechanisms underlying the development of this phenomenon remain to be elucidated.”1 They raise the hypothesis of immunoglobulin E (IgE) –independent mechanisms, even in the context of a paradoxic atopic history. Moreover, Tronconi et al suggest that the field “search for reliable risk factors that can facilitate the safe selection of patients as candidates for cetuximab-based treatment.”1

These comments are quite surprising, because they do not integrate major contributions that have been previously published. Indeed, it has been known for 3 years that anaphylaxis to cetuximab is the result of antidrug IgE antibodies present in patient serum before therapy.2 These IgE antibodies are directed against galactose-α-1, 3-galactose (α3Gal) residues, present in the Fab portion of this monoclonal antibody.3 Because humans do not express this glycan, anti-α3Gal IgM and IgG antibodies spontaneously develop, whereas the appearance of IgE is only occasional. The observation that most of the patients developed reactions to cetuximab during their first infusion supports this hypothesis and is consistent with an IgE-mediated event. Environmental factors, such as bites by ectoparasitic ticks, probably explain the heterogeneous proportion of individuals displaying anti-α3Gal IgE and the heterogeneous incidence of anaphylactic reactions to cetuximab among studies and geographic areas. 2,46 History of atopy, age, race, additional therapy (ie, chemotherapy or radiotherapy), sex, and head and neck cancer (rather than colorectal cancer) have also been proposed as factors favoring anaphylaxis to cetuximab, but they remain controversial.2,4,5

Therefore, instead of searching for reliable risk factors, it seems more straightforward to detect the presence of anti-α3Gal IgE before treatment. Since the first studies, several academic groups and companies around the world have developed such assays (Pointreau et al, manuscript in preparation),2,7 and the recent international congress held in Tours dedicated to anaphylaxis to cetuximab provided us with the opportunity to discuss this relevant strategy.8

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

January, 2012|Oral Cancer News|

Third Head and Neck Indication for Erbitux

Source: The ASCO Post, January 1, 2012, Volume 3, Issue 1, Matthew Stenger

 

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.Cetuximab (Erbitux) was recently approved by the FDA for use in combination with platinum-based therapy plus fluorouracil (5-FU) for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck.1-3 Cetuximab has prior indications in combination with radiation therapy in locally or regionally advanced squamous cell head and neck cancer and in recurrent or metastatic head and neck cancer that has progressed after platinum-based therapy. It also has indications in colorectal cancer.

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The most recent approval is based primarily on results of a study conducted outside the United States in 442 patients with metastatic or locally recurrent squamous cell carcinoma of the head and neck who were not suitable for curative treatment with surgery or radiation. The study used a European Union (EU)-approved cetuximab rather than the U.S.-approved cetuximab (Erbitux). Erbitux provides approximately 22% higher exposure than the EU-approved cetuximab; these pharmacokinetic data, together with the results of the study conducted in Europe and other data using Erbitux establish the safety and efficacy of Erbitux at the recommended dose.In this trial, the addition of cetuximab (n = 222) to platinum-based therapy plus 5-FU (n = 220) significantly increased median overall survival from 7.4 to 10.1 months, representing a 20% reduction in risk of death (HR = 0.80, P = .034), and significantly increased median progression-free survival from 3.3 to 5.5 months, representing a 43% reduction in risk of disease progression (HR = 0.57, P < .0001). Objective response rates were 35.6% in the cetuximab group and 19.5% in the chemotherapy-alone group (P = .0001).


3.1.17_ofnote-1.jpg

How It Works

Cetuximab is an IgG1 monoclonal antibody that inhibits ligand-binding to the epidermal growth factor receptor (EGFR) on both normal and tumor cells. Binding of cetuximab to EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased production of matrix metalloproteinase and vascular endothelial growth factor. In cells with activating KRAS mutation, however, the KRAS proteins are continuously active and are independent of EGFR regulation. Cetuximab also stimulates antibody-dependent cell-mediated cytotoxicity and enhances the activity of a number of chemotherapeutic agents, including cisplatin.

How It Is Given

For the new indication, the recommended dose is 400 mg/m2 as a 120-minute IV infusion, with a maximum rate of 10 mg/min, on the day that platinum-based therapy plus 5-FU is started. The infusion must be completed 1 hour prior to beginning platinum-based therapy plus 5-FU. The subsequent weekly dose is 250 mg/m2 over 60 minutes until disease progression or unacceptable toxicity.Patients should be premedicated with an H1 antagonist (eg, diphenhydramine, 50 mg) IV 30 to 60 minutes before the first dose of cetuximab; premedication for subsequent doses depends on clinical judgment and presence/severity of prior infusion reactions. The infusion rate should be reduced by 50% for grade 1 or 2 or nonserious grade 3 infusion reactions. Cetuximab should be immediately and permanently discontinued for severe infusion reactions.In cases of severe acneiform rash, administration should be delayed by 1 to 2 weeks, and cetuximab discontinued at the fourth occurrence. The weekly dose should be reduced to 200 mg/m2 after the second occurrence and 150 mg/m2 after the third.Cetuximab should be administered via infusion pump or syringe pump and through a low protein-binding 0.22-micrometer in-line filter.

Safety Profile

Cetuximab carries a boxed warning for infusion reactions and cardiopulmonary arrest. Serious infusion reactions occurred in approximately 3% of patients in clinical trials, with fatal outcome in less than 1 in 1,000 cases. In patients with squamous cell carcinoma of the head and neck receiving cetuximab, cardiopulmonary arrest or sudden death occurred in 2% of those receiving radiotherapy and in 3% of those receving platinum-based therapy plus 5-FU. Serum electrolytes, including magnesium, potassium, and calcium, must be carefully monitored during and after cetuximab administration.In the trial supporting the current indication, the most common adverse reactions (≥ 25%) in patients in the cetuximab group were nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia; conjunctivitis occurred in 10%. Other adverse reactions, sometimes severe, caused by cetuximab included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia. Death attributed to cardiovascular event or sudden death was reported in 3.2% of the patients in the cetuximab group and in 1.9% in the chemotherapy alone group.

 This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

January, 2012|Oral Cancer News|

FDA Approves Cetuximab for Late-Stage Head and Neck Cancer

Source: The Oncology Report

The Food and Drug Administration on Nov. 7 approved cetuximab as an initial treatment of late-stage head and neck cancer in combination with chemotherapy.

Cetuximab, marketed as Erbitux by Bristol-Myers Squibb, is an epidermal growth factor receptor (EGFR) antagonist, administered as an intravenous infusion. Previously, it was approved in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma. It was also approved for use alone in patients with recurrent locoregional disease or metastatic disease whose disease has progressed following platinum-based chemotherapy.

The newly approved indication is for the treatment of these recurrent or metastatic patients as an initial therapy in combination with platinum-based therapy with 5-fluorouracil (5-FU), a BMS spokesperson said. (At press time, the company had not yet issued a statement on the approval.)

Erbitux was initially approved in 2004 to treat EGFR-positive late-stage colon cancer after patients stopped responding to chemotherapy and was approved in 2006 for the treatment of head and neck cancer. The newly approved indication is for “recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with 5-FU,” according to the revised label, posted on the FDA Web site.

The two previously approved indications for head and neck cancer were for “locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy,” and for “recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy.

“Erbitux’s ability to extend the lives of patients with head and neck cancers is an important tool for oncologists who often rely on a multitreatment approach for patients,” Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research said in the statement. “Given the aggressive nature of head and neck cancers that cannot be treated with surgery and radiation, it is important that patients have as many treatment options available as possible,” he added.

The approval was based on a multicenter study of 442 patients who had metastatic or recurrent head and neck cancer, which was inoperable or widespread, and of those who had not been treated with chemotherapy. The study was conducted outside of the United States and used a version of cetuximab that is not approved in the United States, the statement said.

The median overall survival among patients who were treated with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil) combination was 10.1 months, compared with 7.4 months among those who received chemotherapy alone cisplatin or carboplatin and 5-fluorouracil, the FDA statement said.

The most common adverse events reported by patients in the cetuximab plus chemotherapy arm were rash; pruritus; nail changes; headache; diarrhea; and respiratory, skin, and mouth infections, according to the FDA.

Other adverse effects that have been associated with cetuximab include low serum levels of magnesium, potassium, and calcium; and potentially fatal infusion reactions and myocardial infarctions. Sun exposure should be limited during treatment.

Cetuximab available in the United States provides about 22% greater exposure than the European Union–approved cetuximab that was used in this study, but this pharmacokinetic data along with the results of this study “and other clinical trial data establish the efficacy of Erbitux at the recommended dose,” according to the revised prescribing information posted on the FDA Web site.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

November, 2011|Oral Cancer News|

US FDA approval for expanded use of Erbitux

Source: www.pharmabiz.com
Author: staff

The US Food and Drug Administration (FDA) has approved Erbitux (cetuximab), in combination with platinum-based chemotherapy with 5-fluorouracil (CT), for the first-line treatment of recurrent locoregional or metastatic squamous cell carcinoma of the head and neck (SCCHN).

The approval, which is based on data from the landmark EXTREME (ErbituX in first-line Treatment of REcurrent or MEtastatic head & neck cancer) trial, makes Erbitux plus CT the first treatment regimen approved in 30 years with extended overall survival in patients with recurrent locoregional or metastatic SCCHN.

Erbitux (cetuximab) is a monoclonal antibody (IgG1 Mab) designed to inhibit the function of a molecular structure expressed on the surface of normal and tumour cells called the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1). In vitro assays and in vivo animal studies have shown that binding of ERBITU Erbitux GFR blocks phosphorylation and activation of receptor-associated kinases, resulting in induction of apoptosis (cell death), inhibition of cell growth, and decreased matrix metalloproteinase and vascular endothelial growth factor production. In vitro, Erbitux can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that Erbitux inhibits the growth and survival of tumour cells that express the EGFR. No anti-tumour effects of Erbitux were observed in human tumour xenografts lacking EGFR expression.

EXTREME, which was previously published in the New England Journal of Medicine, was a phase III open label, randomized, multi-centre, controlled trial. This study was conducted outside the US by Merck KGaA, Darmstadt, Germany, and used European Union (EU)-approved cetuximab. Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab used in the EXTREME trial; these pharmacokinetic data, together with the results of the EXTREME trial and other clinical trial data establish the efficacy of Erbitux at the recommended dose. EXTREME showed that cetuximab plus CT in the first-line treatment of recurrent locoregional or metastatic SCCHN resulted in superior efficacy across clinically meaningful endpoints, including overall survival, progression-free survival, and objective response rate compared to CT. Cetuximab plus CT significantly extended patients’ median overall survival by 36% compared to patients who received CT alone (10.1 months vs. 7.4 months, respectively) [HR: 0.80; 95% CI: 0.64-0.98; p=0.034]. Cetuximab plus CT also significantly increased median progression-free survival by 67% (5.5 vs. 3.3 months, respectively) [HR: 0.57; 95% CI: 0.46-0.72; p<0.0001] compared to CT alone. A significant improvement in objective response rate was also demonstrated (36% vs. 20%, odds ratio, 2.33 [95% CI: 1.50-3.60]; p=0.0001).

Serious infusion reactions occurred with the administration of Erbitux in approximately 3 per cent of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Healthcare providers should immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. Cardiopulmonary arrest and/or sudden death occurred in 2 per cent of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with Erbitux and radiation therapy and in 3 per cent of patients with squamous cell carcinoma of the head and neck treated with EU-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in the EXTREME trial. Healthcare providers should closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration.

Bristol-Myers Squibb and Lilly are committed to supporting patient access to ERBITUX and have put in place a number of programmes to help patients and providers. Destination Access, which is a Reimbursement Support Program, helps patient access by providing benefits investigation support, prior authorization assistance, appeals assistance and patient assistance.

November, 2011|Oral Cancer News|

FDA Approves Cetuximab for Metastatic Head and Neck Cancer

Source: MedScape News Today

The US Food and Drug Administration (FDA) has approved cetuximab (Erbitux, Bristol-Myers Squibb ) for use in combination with chemotherapy for the treatment of metastatic head and neck cancer.

Data show that when combined with cisplatin-based chemotherapy, cetuximab improved overall survival, compared with chemotherapy alone. According to the researchers, this is the first time in 3 decades — since cisplatin was first used in head and neck cancer — that any regimen has improved on its success. The improved survival that was seen after cetuximab was added to the regimen (at a median of 2.7 months) is “therefore notable.”

Cetuximab was approved in the United States in 2004 for the treatment of epidermal growth-factor receptor–positive late-stage colon cancer in patients who no longer responded to chemotherapy. In 2006, it was approved for use in combination with radiation therapy for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. This latest approval expands on that to cover metastatic head and neck cancer.

The ability of cetuximab “to extend the lives of patients with head and neck cancer is an important tool for oncologists, who often rely on a multitreatment approach for patients,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, in a statement.” Given the aggressive nature of head and neck cancers that cannot be treated with surgery and radiation, it is important that patients have as many treatment options available as possible.”

EXTREME Trial

The safety and effectiveness of cetuximab for this indication is based on the results of a multicenter clinical study — the Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) trial. The results of this study were first reported at the 2007 meeting of the American Society of Clinical Oncology. At the time, experts in the field predicted that they would change clinical practice. The results were subsequently published in 2008 (N Engl J Med. 2008;359:1116-1127).

Cetuximab was granted approval by the European Commission in November 2008 for the treatment of first-line recurrent and/or metastatic head and neck cancer on the basis of the EXTREME study.

The trial involved 442 patients with untreated recurrent or metastatic squamous cell carcinoma of the head and neck; approximately 60% of the cohort had not received any previous chemotherapy. All patients received chemotherapy with a platinum agent (cisplatin or carboplatin, chosen by the investigator) plus infusional 5-fluorouracil. Half of the patients were randomized to also receive cetuximab.

On average, patients who received cetuximab plus chemotherapy survived longer than those who received chemotherapy alone (10.1 vs 7.4 months; hazard ratio [HR] for death, 0.80; P = .04).

The addition of cetuximab also significantly improved median progression-free survival (3.3 vs 5.6 months; HR for progression, 0.54; P < .001) and increased the response rate (20% vs 36%; P < .001).

“I think these data support the notion that we have a new standard treatment for patients with recurrent and/or metastatic head and neck cancer,” lead researcher Jan Vermorken, MD, PhD, professor of oncology at Antwerp University Hospital, in Ghent, Belgium, told Medscape Medical News when the study was published. “I would recommend that every patient with recurrent head and neck cancer who is not a candidate for radiation or surgery now receive platinum-based chemotherapy plus cetuximab, if their condition allows them to tolerate this.”

Higher Risk Adverse Events

The most commonly reported adverse events in patients who received cetuximab included rash, pruritus, nail changes, headache, diarrhea, and respiratory, skin, and mouth infections. The addition of cetuximab also increased the rate of sepsis, which occurred in 9 patients treated with chemotherapy plus cetuximab but in only 1 patient treated with chemotherapy alone (P = .02).

Cetuximab has also been known to cause low serum magnesium, potassium, and calcium; in this study, the incidence of hypomagnesemia also increased (11 patients treated with chemotherapy plus cetuximab and 3 treated with chemotherapy alone; P = .05). Other adverse events, such as neutropenia, were reported at similar rates in both groups, and the authors note that these adverse effects are consistent with the adverse-effect profile of cetuximab.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

November, 2011|Oral Cancer News|

New Therapies and Prognostic Techniques Highlighted in Head and Neck Cancer

The Asco Post

D. Neil Hayes, MD, MPH, of the University of North Carolina at Chapel Hill, described efforts to position the epidermal growth factor receptor (EGFR) inhibitor cetuximab (Erbitux) in head and neck cancer treatment.

Surprisingly negative results came from the phase III Radiation Therapy Oncology Group (RTOG) 0522 trial (N = 940), which showed no benefit to adding cetuximab to the radiation/cisplatin platform for front-line therapy of advanced head and neck squamous cell carcinoma.1 At 2 years, progression-free survival was approximately 64% in both arms; overall survival was 79.7% with chemoradiation (P = .68) and 82.6% with the addition of cetuximab (P = .17). Rates of locoregional relapse and distant metastases were also similar.

Cetuximab increased grade 3/4 mucositis (43% vs 33%;P < .004), in-field skin toxicity (25% vs 15%;P < .001), and out-of-field skin reactions (19% vs 1%;P < .001), but toxicity beyond 90 days was similar between the arms.

Table 1: After the RTOG 0522 Trial: Where Do We Go from Here?

“RTOG 0522 was the study of the year in head and neck cancer. Unfortunately, it was flat-out negative,” Dr. Hayes noted.

No differential effect emerged by p16 (HPV status). “While 70% of patients had oropharynx tumors (suggesting HPV positivity), tissue collection was lacking in half the patients. Our ability to make inferences with this amount of missing data is very limited,” Dr. Hayes said.

Even as a negative study, RTOG 0522 is practice-changing. “Many physicians have been treating with this regimen, assuming this study would be positive,” he said. “But we now have no data to support this.”

Cetuximab Equivalent to Cisplatin after Induction

The phase II TREMPLIN study (N = 153) evaluated sequential chemoradiotherapy in previously untreated, operable squamous cell carcinoma of the larynx/hypopharynx.2 Patients received induction chemotherapy with docetaxel, cisplatin, and fluorouracil; nonresponders underwent laryngectomy, whereas those with more than a 50% response were randomly assigned to radiotherapy plus either cisplatin or cetuximab.

All endpoints were similar between the arms. Larynx preservation rates at 3 months were 95% with cisplatin and 93% with cetuximab (P = .63). Preservation of larynxfunctionat 18 months (or at death) was seen in 87% and 82%, respectively (P= .68). Overall survival was 92% and 89%, respectively (P = .44), and laryngoesophageal dysfunction-free survival was 79% vs 71% (P = .30). Acute toxicities compromising treatment and late toxicities were more common with cisplatin.

Dr. Hayes concluded, “The take-home message is that these two regimens are equivalent, and that cetuximab plus radiotherapy may be reasonable after induction.”

Laser Treatment Effective for Mucositis

In a phase III randomized trial of 94 patients, upfront use of low-level laser therapy helped prevent oral mucositis associated with chemoradiation.3 Grade 3/4 mucositis was observed in < 7% of the laser therapy group, compared with almost 50% of controls (who received “placebo” laser applications from the same machine but without light), for an 84% reduction (P < .001). Patients receiving active laser therapy also had less pain, narcotic use, and gastrostomia and better quality of life.

“Mucositis, especially grade 3 and 4, may limit treatment and compromise outcomes. While we need confirmatory data, the study shows we can intervene to improve mucositis.”

Future Directions

Key Head and Neck Cancer Findings Presented at Best of ASCO®

An international group developed a 30-gene expression profile that predicted clinical outcomes in primary laryngeal carcinoma.4 Median disease-free survival was 34 months in high-risk patients vs 80 months in low-risk patients (P = .01). Recurrences were four times greater among those in the high-risk group (P = .017).

“This elegant study suggests subgroups of patients can be distinguished according to who will do well and who will do worse. For clinical usefulness, the issue is whether the difference between high- and low-risk groups will be sufficient to change therapy,” Dr. Hayes commented.

Finally, the novel vascular disrupting agent fosbretabulin (CA4P), combined with carboplatin and paclitaxel, tripled survival in the randomized phase II/III FACT trial (N = 80), from 9% at 1 year with chemotherapy alone to 26% (P = .065).5

“There is enthusiasm and excitement over this novel therapy for anaplastic thyroid cancer,” Dr. Hayes commented, urging oncologists to have patients enroll in the upcoming phase III trial.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.


October, 2011|Oral Cancer News|

Researchers find potential new therapeutic strategy for head and neck cancer

Source: www.uab.edu
Author: Beena Thannickal

Shih-Hsin (Eddy) Yang, M.D., Ph.D., an assistant professor in the UAB Department of Radiation Oncology and associate scientist in the experimental therapeutics program at the UAB Comprehensive Cancer Center, found a way to prevent head and neck cancer cells from repairing damage to DNA as they grow.

The findings, published by the Public Library of Science, showed that using the drug cetuximab can induce a DNA repair defect in head and neck cancer cells, and subsequently render the tumors susceptible to PARP inhibitors, which block enzymes that repair some types of DNA damage. This method prevents cancer cells from repairing the damage to the DNA as they grow, ultimately leading to cancer inhibition.

Poly ADP-ribose polymerases, or PARPs, are enzymes that repair some types of damage done to DNA. If they are inhibited, a backup repair pathway is initiated. Cetuximab, which inhibits the epidermal growth factor receptor signaling pathway of cancer cells, blocks this backup pathway and thus induces cancer cell death.

“The novelty of this finding is that we use targeted agents like cetuximab, in combination with a PARP inhibitor, ABT-888, both of which have already been tested to be safe in humans, to selectively kill tumors defective in DNA repair while potentially minimizing side effects,” says Yang.

Cetuximab was pioneered by James Bonner, M.D., chair of the UAB Department of Radiation Oncology, in a landmark multi-institutional clinical trial in head and neck cancer patients.

Because head and neck cancers are frequently aggressive, outcomes for patients are currently poor.

“This new potential therapeutic strategy may improve outcomes while keeping a favorable side effect profile,” says Yang.

September, 2011|Oral Cancer News|