cetuximab

Facing the facts: HPV-associated head and neck cancers get a second look

Source: www.curetoday.com
Author: Charlotte Huff

Kevin Pruyne knew he didn’t fit the stereotype of a hard drinker or heavy smoker who one day develops an oral cancer.

The 52-year-old mechanic had been working a three-week stint in a remote section of northern Alaska, repairing trucks on an oil field, when he noticed a hard lump beneath his jaw while shaving. For nearly three months, as Pruyne was prescribed antibiotics for a possible infection and then later shuttled between physician specialists, he kept hearing the same thing: the lump could not be cancer.

Pruyne only occasionally consumed alcohol and had never smoked. His wife, Kathy, began researching her husband’s symptoms, which included repetitive throat clearing, a nagging sensation that something was lodged in his throat and ringing in his ears. And the lump, which looked like the top half of an egg, felt solid to the touch.

This wasn’t some inflamed lymph node from a lingering head cold, Kathy Pruyne says. “He had every symptom [of cancer], but nobody would listen to me.”

Pruyne received a diagnosis of stage 4 oral cancer, which started with a tumor at the base of his tongue. He had already begun chemotherapy when he learned that researchers had discovered an association between the human papillomavirus (HPV) and increasing rates of oropharyngeal cancers. He asked that his tissue be tested; the results came back positive. Pruyne says he wanted to know whether his cancer was caused by HPV because “the prognosis is considerably better with HPV-positive cancer.” He adds he “wanted to hear that there was a better chance of a cure.”

An Explosion of Cases

For researchers and clinicians alike, determining appropriate treatment has taken on new urgency: HPV-positive oropharyngeal malignancies—most typically found on the tonsils or at the base of the tongue—increased 225 percent from 1988 to 2004. If current trends continue, HPV-positive oral cancer cases could soon surpass cervical cancer diagnoses, according to a 2011 study published in the Journal of Clinical Oncology.

As researchers have revisited data from prior oral cancer treatment studies, they’re realizing that patients with HPV-positive tumors respond better to chemotherapy and radiation. One study, which retrospectively analyzed treatment outcomes for stage 3 and stage 4 oropharyngeal patients based on their HPV status, found that the three-year overall survival rate was 82.4 percent in patients with HPV-positive tumors. Among those who tested negative, the three-year overall survival rate was 57.1 percent, according to the findings published in 2010 in The New England Journal of Medicine.

With that in mind, research trials are being launched to determine whether treatment can be modified in some way or even dialed back. The goal? To achieve the same survival with fewer of the swallowing difficulties, taste problems and other debilitating side effects.

“For a subset of patients, we’ve actually achieved a pretty high cure rate,” says James Rocco, MD, PhD, a head and neck surgeon at Massachusetts Eye and Ear Infirmary, and director of head and neck cancer research at Massachusetts General Hospital. “And the question is: Can we maintain that cure and reduce some of the major side effects of treatment?”

But researchers and oncologists have only just begun to understand HPV-positive malignancies. “It’s very clear that HPV-positive oropharyngeal cancer is a completely different entity from HPV-negative,” says Stephen Liu, MD, a head and neck cancer specialist, and an assistant professor of medicine at the University of Southern California.

“We think that it’s going to impact treatment in the future,” Liu adds. But, he stresses, outside of a clinical trial, he “would really discourage anyone from receiving less treatment because their tumor is HPV-positive.”

Identifying the Virus

Traditionally, tobacco and alcohol use have been the primary culprits for triggering cancers in the oropharynx and nearby areas of the mouth, as well as other structures in the throat, such as the larynx. Each year, nearly 40,000 Americans develop cancer of the oral cavity or pharynx. Men are more than twice as likely to receive a diagnosis.

But, until recent years, not someone like David Hastings. The certified public accountant was 58 years old, a lean cyclist who rode some 100 miles each week, when he learned six years ago that he had stage 4 oropharyngeal cancer located at the base of his tongue. Clinicians at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., also were puzzled, as the Gulfport resident tells it. “They said the typical oral cancer patient is a man in his 60s or 70s who sits in a bar all day and drinks and smokes.”

The association with HPV emerged from a perplexing conundrum, says Kian Ang, MD, PhD, a professor in the department of radiation oncology at M.D. Anderson Cancer Center in Houston. As cigarette smoking has declined in recent decades, so have head and neck cancers, with the exception of tumors in the oropharynx. (The region encompasses the middle section of the throat, along with the back portion of the tongue, the soft palate and the tonsils.) That statistical anomaly, Ang says, “gave us the first clue that something else might be going on.”

 

Starting with a pivotal study published in 2000, researchers began honing in on the role of HPV. Of the 150-plus strains in the HPV family, more than 40 are believed to be transmitted through sexual contact, including anal, genital and oral, according to the National Cancer Institute. The body’s immune system typically eradicates the viruses in a few years before any symptoms emerge (but, in some cases, the cells remain molecularly altered forever). Several of the HPV strains to date, most frequently HPV type 16, have been linked to oral malignancies.

Increasingly, HPV-16 has become a major player in those oral malignancies, according to last year’s Journal of Clinical Oncology study, which projected an explosion in cases in the decades to come.

When researchers studied 271 tissue samples in previously diagnosed patients, HPV prevalence was identified in only 16.3 percent of those collected between 1984 and 1989. Between 2000 and 2004, 72.7 percent of specimens tested positive, a trend that also perhaps correlates with population-wide increases in oral sex, the researchers wrote.

The analysis also highlighted survival differences. If tumors tested HPV-positive, the median survival was nearly 11 years versus 1.6 years for people whose tumors didn’t carry the virus.

Some of the strides in oral cancer treatment that physicians thought they were achieving can at least be partially explained by the emergence of a less aggressive form of cancer, Ang says. “The other part of the improvement,” he says, “is really due to the addition of chemotherapy and the use of high-precision radiation.”

Multifaceted Treatment

Cancers located in the tonsils or at the base of the tongue can sometimes spread undetected, not becoming visible until they’ve reached the nearby lymph nodes. Some early symptoms include swallowing difficulties or a sudden change or hoarseness in the voice. Like Pruyne, Hastings first became concerned when he felt a mysterious lump while shaving. “Totally painless, no sore throat—nothing,” he says.

Oropharyngeal tumors can be classified as stage 3 or 4 but still be considered localized, as long as they have not spread beyond lymph nodes and structures in the head and neck. Pruyne, whose cancer had migrated to numerous nodes on his neck’s right side, recalls how his oncologist hurried out of the room when his imaging test results became available.

The doctor had already warned Pruyne that he could offer relatively little help if the cancer had spread to his chest. “When he came back up, he was visibly relieved,” Pruyne recalls. “And he said, ‘Your lungs are clear.’”

To thwart oropharyngeal malignancies, cancer specialists may incorporate a mix of treatments, including surgery, radiation and chemotherapy, depending upon the location and the aggressiveness of the tumor involved. Ang estimates that only about one-third of patients will undergo surgery. If the tumor can be removed and there’s no evidence that it’s spread to lymph nodes, radiation may not be needed, he says.

 

But if there’s any concern, patients may receive six weeks of radiation for smaller tumors and seven weeks for larger ones, Ang says. Intensity-modulated radiation therapy (IMRT) is used because it better targets the radiation and thus can limit damage to the salivary glands, reducing dry mouth, as well as damage to other normal tissues, Ang says.

For larger and more aggressive tumors, adding chemotherapy to radiation therapy has been shown to extend survival. One meta-analysis published last year, based on 87 studies involving more than 16,000 patients, analyzed results by tumor location. Researchers found that the combination approach increased five-year overall survival by 8.1 percent in oropharyngeal patients compared with those who didn’t receive any chemotherapy.

The chemotherapy is believed to boost the effectiveness of the radiation, but at a cost—amplified side effects for the patient. The list of potential side effects is lengthy, with so many vulnerable structures and nerves packed into the head and neck area, Liu says. Patients can develop ulcers in their mouth and down their throat, he says. Their salivary glands can generate thick secretions that make it difficult to swallow and to eat.

“The ability to taste, to speak, to salivate,” says Liu, ticking off several more. “Dry mouth. These things can often be permanent. It’s a necessary evil right now because we do what we need to do to cure the cancer.”

Pruyne received two cycles of a cisplatin-based protocol that also included Taxotere (docetaxel) and 5-FU (fluorouracil). Then he started the biologic agent Erbitux (cetuximab) along with hefty doses of IMRT, delivered twice daily for six weeks.

Pruyne’s oncologist warned him that the treatment would be difficult, and it was. He endured radiation burns around the right side of his neck and had to use a feeding tube for two months.

Dialing Back

Although radiation and chemotherapy can be difficult, some patients prefer to take that route, rather than run the risks of surgery, Rocco says. “For advanced local disease, removing the back of the tongue or the soft palate has huge consequences for people,” Rocco says. “They can’t eat. They don’t speak so well.”

But given that patients with HPV-positive tumors are typically diagnosed at a younger age, with potentially decades ahead of them to cope with long-term side effects, the aggressiveness of today’s chemotherapy and radiation regimens are also questionable, he says.

Clinical trials are recruiting patients to answer a question that’s relatively rare in cancer: Can treatment be ramped down? One closely watched phase 3 trial will assess whether Erbitux works as well in HPV-positive patients as the long-standing cisplatin-based chemotherapy regimen.

Cisplatin has been one of the standard drugs used in head and neck cancer, but it’s “very toxic,” says Andy Trotti III, MD, the study’s principal investigator and director of radiation oncology clinical research at Moffitt Cancer Center. The platinum-based drug can impact kidney function and sometimes damage hearing, among other side effects, he says.

Erbitux, which targets the epidermal growth factor receptor (EGFR), primarily affects the skin, Trotti says. In the phase 3 trial, now recruiting HPV-positive patients, the five-year overall survival of patients on Erbitux will be compared with those taking cisplatin. Both groups will receive IMRT.

Another ongoing trial is looking at whether the IMRT regimen can be shortened from six to five weeks, thereby delivering a lower dose of radiation in HPV-positive patients. The patients enrolled in that phase 2 trial, who also will receive cisplatin,  paclitaxel and Erbitux, will be followed for two years.

The study represents a “first step” toward learning whether less radiation can be safely prescribed for HPV-positive patients, Liu says. Since radiation’s effects are cumulative, the extra week of radiation adds “a significant amount of toxicity.”

A New Era in Treatment

Meanwhile, the impact of HPV status on surgical decisions appears to be the subject of some unresolved debate. Given that HPV-positive oropharyngeal malignancies respond well to chemotherapy and radiation, Trotti says, “there has been a real trend away from surgery.”

But new surgical techniques are providing other options for HPV-positive patients who might prefer to limit the long-term side effects of chemotherapy and radiation, says Bert O’Malley, Jr., MD, chairman of the department of otorhinolaryngology of the University of Pennsylvania Health System.

Along with a physician colleague, O’Malley has developed a robotic surgery protocol called TransOral Robotic Surgery. With the assistance of tiny robotic arms and three-dimensional cameras, O’Malley operates through the patient’s mouth, enabling him to remove difficult-to-reach tumors.

A surgery that previously required between six and 16 hours might only take two, he says. Also the approach results in less scarring and fewer surgical complications than the traditional surgery, which may require the jaw to be split, he says.

It’s a new era in HPV-positive treatment, Rocco says. To make his point, he tells of a patient who recently walked in asking to be referred for robotic surgery. The gold standard is still to wait for clinical trial results, but that could take five-plus years, he adds.

HPV-positive patients are frequently “savvy young professionals in the prime of life,” who sort through the latest research online, Rocco points out.

“There are people who are risk-takers,” he says. “They’ll look at the data, and they’ll make a decision, weighing cure and long-term side effects.”

Despite the rigors of treatment, Pruyne was able to resume his job near the Arctic Circle within a few months. He hopes to soon be telling a tale similar to Hastings’, who returned to his biking routine about a year after wrapping up treatment.

Hastings still copes with dry mouth and a reduced ability to taste. But the last time he visited Moffitt for an annual checkup, it felt more like a social call. After some chatting, he quips: “They said, ‘Get out of here. We need to spend more time with people who are sick.’”

 

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.

3.1.17_chart.jpg

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|