Turmeric makes chemo more effective

Author: staff

Researchers with UCLA’s Jonsson Cancer Center have found that curcumin, the major component in the spice turmeric, when combined with the drug Cisplatin enhances the chemotherapy’s suppression of head and neck cancer cell growth.

In India, women for years have been using turmeric for medicinal purposes, as an anti-aging agent rubbed into their skin, to treat cramps during menstruation, as a poultice on the skin to promote wound healing and as an additive in cosmetics, said scientist Eri Srivatsan, an adjunct professor of surgery and a Jonsson Cancer Center researcher.

Srivatsan, along with Dr. Marilene Wang, a professor of head and neck surgery, lead author of the study and a Jonsson Cancer Center researcher, has been studying curcumin and its anti-cancer properties for six years.

A 2005 study by Wang and Srivatsan first showed that curcumin suppressed the growth of head and neck cancer cells, first in cells and then in mouse models. In the animal studies, the curcumin was applied directly onto the tumours in paste form because it did not dissolve in saline, which would have allowed it to be injected.

In need of a better way to deliver the curcumin, the team collaborated with Dr. Kapil Mehta of M.D. Anderson Cancer Center and found that encapsulating the curcumin in a liposome, an artificially prepared vehicle that enclosed the spice component within its membrane, made the treatment injectable.

The curcumin was injected into the tail vein of a mouse, where it circulated into the blood stream, slowing down and eventually stopping the cancer growth, a study in 2008 found.

“This was a very positive finding, developing an efficient way to deliver the treatment,” Wang said. “Our study also showed that the curcumin was very well tolerated.”

In this study, the team wanted to combine the curcumin with the chemotherapeutic drug Cisplatin, which is very toxic at the doses needed to fight head and neck cancers, damaging kidneys, the ears and the bone marrow. They hoped that if they added curcumin to the mix, they might be able to lower the Cisplatin dose and cause less organ damage. Their finding, that the curcumin made the Cisplatin work better, was very promising, Wang said.

“We knew that both the curcumin and the Cisplatin, when given alone, had an effect against head and neck cancers. This finding that curcumin enhances Cisplatin means that, in the future, we may be able to give this chemotherapy in lower doses.,” Wang said.

The study noted that “the mechanisms of the two agents through different growth signaling pathways suggest potential for the clinical use of sub-therapeutic doses of Cisplatin in combination with curcumin, which will allow effective suppression of tumor growth while minimizing the toxic side effects.”

The study found that curcumin suppressed head and neck cancer growth by regulating cell cycling, Srivatsan said. It binds to an enzyme and prevents the enzyme IKK, an inhibitor of kappa B kinase, from activating a transcription factor called nuclear factor kappa B (NFêB), which promotes cancer growth. Cisplatin”s suppressive action involves a different pathway through the tumor suppressor proteins p16 and p53, both proteins that again inhibit the activity of cancer growth promoter NFêB.

“We needed to know the mechanism to help us translate this from the lab into the clinic. That information will help us make better decisions on how to design therapies,” Wang said.

The study appears in the October issue of the journal Molecular Cancer Therapeutics .

October, 2010|Oral Cancer News|

Lilly presents new data in head and neck cancer – a difficult to treat cancer with poor survival rates

Author: press release

Eli Lilly and Company announced today that its global Phase III trial evaluating Alimta® (pemetrexed for injection) in combination with cisplatin in patients with recurrent or metastatic squamous cell cancer of the head and neck (SCCHN) did not meet its primary endpoint for overall survival. Data were presented for the first time today at the 35th Annual Meeting of the European Society for Medical Oncology (ESMO).

The Phase III study, the largest trial conducted in SCCHN to date, evaluated Alimta in combination with cisplatin compared with placebo plus cisplatin given every three weeks in a total of 795 patients. The primary objective of the study was to determine overall survival. Patient quality of life was also assessed, in addition to several pre-planned sub-group analyses.

The Alimta/cisplatin regimen showed a median overall survival of 7.3 months compared with 6.3 months with cisplatin alone, a result not considered a statistically significant improvement (p=0.082). There was no significant difference in the quality of life scores for patients treated with either ALIMTA/cisplatin or cisplatin alone (p=0.200).

As a result, Lilly will not be submitting marketing authorization applications for Alimta in SCCHN with either the U.S. Food and Drug Administration (FDA) or the European Medicine Agency (EMA).

“The fact that combination treatment with pemetrexed and cisplatin did not improve overall survival in this study is disappointing, although perhaps not surprising given how difficult it can be to effectively treat metastatic or locally advanced head and neck cancer,” said the study’s principal investigator, Professor Susan Urba, M.D., Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, USA. “We did, however, gain valuable information in this large study, which we hope will help us plan even better future trials for head and neck cancer.”

Out of the nine pre-planned subgroup analyses, two showed survival advantage, which may be of clinical interest.

First, in the analysis of 690 patients with ECOG (Eastern Co-operative Oncology Group) performance status of 0 or 1(1), those treated with the Alimta/cisplatin had a longer overall survival than those treated with cisplatin alone (8.4 vs. 6.7 months, p=0.026). These patients represented 87 percent of the total population.

However, for those patients with an ECOG performance status of 2, there was no survival benefit for those treated with the Alimta/cisplatin regimen versus those treated with cisplatin alone (3.5 months vs. 3.3 months, p=0.243).

In another pre-planned analysis evaluating the primary site of disease, the group of 192 patients with oropharyngeal cancer showed improved overall survival when treated with Alimta/cisplatin versus cisplatin alone (9.9 vs. 6.1 months, p=0.002). No survival advantage was seen in patients whose primary site of disease included the oral cavity, hypopharynx, larynx and “other.”

Safety results showed that although the number of deaths on study therapy or within 30 days of treatment discontinuation were similar for Alimta/cisplatin and cisplatin alone (23.5% vs. 24.9%), there were 13 (3.3%) Alimta/cisplatin and one (0.03%) cisplatin-alone related deaths. Drug related serious adverse events were seen more frequently with Alimta/cisplatin than cisplatin alone (febrile neutropenia: 3.1% vs. 0.0%; pneumonia: 1.8% vs. 0.3%; neutropenia: 2.8% vs. 0.3%)

“Trying to improve patient outcomes in difficult-to-treat cancers continues to be a significant challenge. We will, though, continue with Lilly Oncology’s commitment toward finding innovative solutions in this area,” said Richard Gaynor, M.D., vice president of oncology product development and medical affairs at Lilly.

October, 2010|Oral Cancer News|

Organ preservation for advanced resectable cancer of the base of tongue and hypopharynx: a Southwest Oncology Group trial

Source: J Clin Oncol 23:88-95
Author: Susan G. Urba et al.

The Southwest Oncology Group designed a phase II trial for patients with base of tongue or hypopharyngeal cancer to evaluate the complete histologic response rate at the primary site after induction chemotherapy followed by chemoradiotherapy for responders. Secondary end points were the rate of organ preservation and the need for salvage surgery.

Patients and Methods:
Fifty-nine eligible patients were enrolled; 37 had base of tongue cancer, and 22 had hypopharynx cancer. Forty-two percent had stage III disease, and 58% had stage IV disease.
Induction chemotherapy was two cycles of cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/d for 5 days. Patients who had a greater than 50% response at the primary site were treated with radiation 72Gy and concurrent cisplatin 100 mg/m2 for three cycles. Patients with less than partial response at the primary had immediate salvage surgery.

Forty-five patients (76%) had a greater than 50% response at the primary after induction chemotherapy; 43 went on to receive definitive chemoradiotherapy. Thirty-two patients (54%) achieved a histologic complete response at the primary site, and an additional nine patients had a complete clinical response, but biopsy was not done. Seventy-five percent of patients did not require surgery at the primary tumor site. The 3-year overall survival was 64%. The 3-year progression-free survival with organ preservation was 52%.

Patients with base of tongue or hypopharyngeal cancer treated with this regimen of induction chemotherapy followed by definitive chemoradiotherapy have a good rate of organ preservation without compromise of survival.

Susan G. Urba, James Moon, P.G. Shankar Giri, David J. Adelstein, Ehab Hanna, George H. Yoo, Michael LeBlanc, John F. Ensley, and David E. Schuller

Authors’ affilations:
From the University of Michigan Medical Center, Ann Arbor; Wayne State University Medical Center, Detroit, MI; Southwest Oncology Group Statistical Center, Seattle, WA; Eastern Virginia Medical School, Norfolk, VA; Cleveland Clinic Foundation, Cleveland; Ohio State University Medical Center, Columbus, OH; and University of Arkansas for Medical Science, Little Rock, AR.

September, 2010|Oral Cancer News|

HPV-positive oropharnygeal cancer has better prognosis than tobacco-induced cancer

Author: Alice Goodma

Mounting evidence suggests that human papillomavirus (HPV)-positive oropharyngeal cancer has an improved prognosis compared with HPV-negative disease. The most recent supportive evidence comes from an analysis of a Phase III trial presented at the 2009 annual meeting of the American Society of Clinical Oncology.

Our study showed that HPV status is as strong a predictor of outcome as cancer stage for patients with oropharyngeal cancers, even after considering other factors such as age and smoking history, said lead author Maura Gillison, MD, PhD, Professor of Hematology and Oncology, Epidemiology, and Otolaryngology at Ohio State University in Columbus. Dr. Gillison said that tumor HPV status should now be part of the routine workup of patients with oropharyngeal cancers.

Oropharyngeal cancers are mainly attributable to chronic tobacco use and smoking, or to HPV infection. Retrospective analyses, meta-analysis, and small trials have suggested that HPV-positive oropharyngeal cancer is a distinct entity, and the present Phase III study provides the most compelling evidence, she said, because it is the largest study to date.

It is not clear why HPV-associated oropharyngeal cancer has a better prognosis. In the trial, HPV-positive patients were younger, mostly Caucasian, and had improved performance status and smaller tumors. Dr. Gillison said that these factors could have a positive influence on survival.

Survival Benefit

The retrospective correlative analysis of Radiation Therapy Oncology Group (RTOG) 0129, presented by Dr. Gillison, focused on outcome according to HPV status. The randomized study included 206 patients with cancers positive for HPV (96% were HPV 16-positive) and 117 patients with HPV-negative cancers. All patients received radiotherapy plus chemotherapy with high-dose cisplatin. At two years, significantly more patients were alive in the HPV-positive group: 87.9% versus 65.8% in the HPV-negative group. Median two-year progression-free survival was 71.8 months for the HPV-positive group and 50.4 months for the HPV-negative group.

The difference in survival favoring the HPV-positive group increased over time. By five years, a 29% difference favored those who were HPV-positive. Overall five-year survival was greater than 75% in HPV-positive patients versus less than 50% in those who were HPV-negative.

At five years, the HPV-positive group had half the risk of dying compared with the HPV-negative group, even after accounting for the effects of other factors, including type of treatment. The HPV-positive group also had about half the risk for tumor progression at five years. Additional analysis revealed that HPV-positive patients had lower two-year recurrence rates in the radiation field (13.6% vs 24.8%, respectively). At five years, second primary cancers were found in only 9% of the HPV-positive patients versus 18.5% of those who were HPV-negative.

Future trials by the oncology cooperative groups will stratify oropharyngeal cancer patients according to HPV subtype 16 status. HPV-16-positivity on immunohistochemistry was tightly correlated with HPV status and is a valid surrogate marker for HPV status, Dr. Gillison said. Trials may also be designed specifically for HPV-positive or HPV-negative patients, she commented.

A Distinct Entity
Formal discussant of the trial, Barbara Burtness, MD, of Fox Chase Cancer Center in Philadelphia, said that this study adds to the evidence that HPV-positive disease has a better prognosis, with increased sensitivity to both radiotherapy and chemotherapy.

It’s clear that HPV-induced oropharyngeal cancer arises through a different mechanism, has a different biological signature, and responds differently to radiation and chemotherapy, she said. Goals of therapy for HPV-induced oropharyngeal cancer should include increased preservation of speech and safe swallowing, she added.

August, 2010|Oral Cancer News|

ASCO: Second study links HPV to mouth cancer outcomes

Author: Michael Smith, North American Correspondent, MedPage Today

Human papillomavirus (HPV) infection predicts a better chance of survival in patients with oropharyngeal squamous cell carcinoma, researchers said. In a retrospective analysis of a major radiation therapy trial, more than four-fifths of patients whose tumors were HPV-positive were alive three years after treatment, according to Maura Gillison, MD, PhD, of Ohio State University in Columbus, and colleagues.

In contrast, fewer than six of 10 patients with HPV-negative tumors were still alive at the three-year mark, Gillison and colleagues reported online in the New England Journal of Medicine, in an article released to coincide with a presentation at the American Society of Clinical Oncology meeting here.

The study follows a report earlier at the meeting that found a similar pattern among patients enrolled in a chemotherapy trial. The virus is, of course, well known to cause cervical cancer.

The New England Journal study adds to the evidence that “HPV-positive oropharyngeal squamous-cell carcinoma represents a distinct clinicopathological entity associated with a better prognosis than HPV-negative oropharyngeal squamous-cell carcinoma,” said Douglas Lowy, MD, of the NIH, and Karl Munger, PhD, of Brigham and Women’s Hospital in Boston.

Writing in an accompanying editorial, Lowy and Munger argued that if the diseases are distinct, “their treatment or prevention might benefit from different approaches.” One possibility, they said, would be to target HPV proteins to treat the disease in some patients, while prevention might involve vaccination against the virus.

Gillison and colleagues looked at the Radiation Therapy Oncology Group 0129, a randomized study testing accelerated-fractionation radiotherapy against standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck.

Over a median of 4.8 years of follow-up, the study found no significant differences in survival between the two types of radiation therapy, Gillison and colleagues noted.

For this analysis, they looked at the 60.1% of patients — 433 of 721 — who had oropharyngeal cancer. Of those, HPV status was available for 323 patients, they said, including 206 whose tumors were HPV-positive.

Analysis showed that the HPV-positive patients had better three-year rates of overall survival than those with HPV-negative tumors — 82.4% compared with 57.1%. The difference was significant at P<0.001 by the log-rank test.

After adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, those with HPV-positive tumors had a 58% reduction in the risk of death (HR 0.42, 95% CI 0.27 to 0.66).

Tobacco smoking was also a significant predictor of death (at P<0.001), with the risk increasing by 1% for each additional pack-year smoked, the researchers found, and the magnitude of the effect was the same regardless of HPV-status.

One implication of the study, the researchers said, is that future clinical trials of new treatments should be designed to stratify patients on the basis of HPV status.

1. The study was supported by the National Cancer Institute, the National Institute of Dental and Craniofacial Research, and the Oral Cancer Foundation.
2. Gillison is an employee of the National Institute of Dental and Craniofacial Research.
3. The editorial writers reported financial links with Merck, Arbor Vita, and GlaxoSmithKline.

1. Ang KK, et al “Human papillomavirus and survival of patients with oropharyngeal cancer” N Engl J Med 2010.
2. Lowy D, Munger K “Prognostic implications of HPV in oropharyngeal cancer” N Engl J Med 2010.

Docetaxel suppresses invasiveness of head and neck cancer cells in vitro

Source: Cancer Sci, February 22, 2010
Author: Y Kogashiwa et al.

The combination of docetaxel, cisplatin, and fluorouracil significantly enhances the survival of head and neck cancer patients compared to cisplatin and fluorouracil. We hypothesized that docetaxel may affect invasiveness of the head and neck cancer cells in addition to its tumor-killing effect.

Two different head and neck cancer cell lines (HEp-2 and Ca9-22) were treated with docetaxel at IC(10) and IC(50) concentrations. Cell migration and invasive growth was evaluated by wound healing assay and three-dimensional (3D) culture of multicellular tumor spheroids, respectively. Expression levels of possible downstream effectors for cell migration/invasiveness were measured by immunoblotting in conditions with or without docetaxel.

Docetaxel, but not cisplatin, suppressed filopodia formation compared with no treatment (control) condition. Consistent with this, docetaxel suppressed two-dimensional (2D) cell migration and 3D cell invasion compared with control or cisplatin. Only docetaxel treated cells exhibited thick tubulin bundle and had lower activity of Cdc42, a member of the Rho family of small GTPases. In conclusion, Docetaxel treatment suppressed migration and invasiveness of head and neck cancer cells in vitro, which is likely to be mediated by regulating Cdc42 activity.

Y Kogashiwa, H Sakurai, T Kimura, and N Kohno

Authors’ affiliation:
Department of Otolaryngology, Head and Neck Surgery, Kyorin University School of Medicine, Tokyo, Japan

April, 2010|Oral Cancer News|

Pitt researchers receive patent for new head and neck cancer treatment

Author: staff

Researchers from the University of Pittsburgh School of Medicine have been awarded a patent from the U.S. Patent and Trademark Office for the development of a new DNA therapy for head and neck cancers. The therapy targets the epidermal growth factor receptor (EGFR), a protein found on the surface of many types of cancer cells that causes them to multiply.

Standard treatments for head and neck cancers often are ineffective and tend to have debilitating side effects, explained Jennifer R. Grandis, M.D., professor of otolaryngology and pharmacology at Pitt and director of the Head and Neck Program at the University of Pittsburgh Cancer Institute (UPCI). “We set out to develop an alternative approach that is safe and effective for these cancers,” she said.

The new treatment is based on a form of genetic therapy called “antisense,” or AS, in which a synthesized strand of DNA or RNA targets the EGFR genes within a head and neck tumor. The therapy blocks the production of a protein produced by the gene. According to Dr. Grandis, expectations were exceeded in a phase I study of the therapy that was designed primarily to determine the safety and potential toxicity of EGFR AS injections in patients with advanced head and neck cancers.

“Not only were the AS injections well-tolerated, but tumors disappeared or shrank considerably in 29 percent of the patients,” said Dr. Grandis. “These results show that EGFR AS therapy has great potential as a safe, effective treatment.”

A phase II clinical trial evaluating the safety and efficacy of EGFR AS injections in combination with the drug cetuximab and radiation therapy will soon be open for eligible patients. According to Ethan Argiris, M.D., professor of medicine at Pitt and principal investigator of the trial, the study will enroll patients 70 years of age or older with advanced head and neck cancers, who aren’t eligible for cisplatin, the chemotherapy often used to treat head and neck cancers.

Head and neck cancers are a group of biologically similar cancers originating from the upper aerodigestive tract, including the lip, mouth, nasal cavity, paranasal sinuses, pharynx and larynx, that affect more than 45,000 individuals in the U.S. each year. Head and neck cancers are strongly associated with environmental and lifestyle risk factors, including tobacco smoking, alcohol consumption and certain strains of the sexually transmitted human papilloma virus.

About the University of Pittsburgh School of Medicine
As one of the nation’s leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1997 and now ranks fifth in the nation, according to preliminary data for fiscal year 2008. Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region’s economy. For more information about the School of Medicine, see

About UPCI
As the only NCI-designated comprehensive cancer center in western Pennsylvania, UPCI is a recognized leader in providing innovative cancer prevention, detection, diagnosis, and treatment; bio-medical research; compassionate patient care and support; and community-based outreach services. UPCI investigators are world-renowned for their work in clinical and basic cancer research.

January, 2010|Oral Cancer News|

Oropharyngeal cancer, human papilloma virus, and clinical trials

Source: Journal of Clinical Oncology, Vol 28, No 1 (January 1), 2010: pp. 1-3
Author: Danny Rischin

As advances in our understanding of the molecular biology of cancer have evolved in recent years, cancers that were once considered to be relatively homogeneous diseases are now being recognized as comprising distinct subtypes. These subtypes may differ in etiology, molecular profile, sensitivity to treatment, and prognosis. Examples include luminal (mainly estrogen receptor–positive), human epidermal growth factor receptor 2–positive, and basal breast cancer subtypes1; non–small-cell lung cancer associated with EGFR2 or EML4-ALK3 mutations; and melanoma associated with BRAF (V600E)4 or c-KIT mutations.5

In head and neck cancer, we have traditionally combined squamous cell carcinomas of the oral cavity, oropharynx, larynx, and hypopharynx in clinical trials. This has been justified on the basis of similar etiology (tobacco and alcohol) and similar sensitivity to radiotherapy and systemic therapy. However, it has also been recognized that there are differences in clinical behavior, treatment outcome, and prognosis with regard to primary site. Although surgery has remained the primary treatment for oral cavity cancers, organ preservation with primary chemoradiotherapy has been widely used over the last two decades for cancers of the oropharynx, larynx, and hypopharynx. It has become apparent over this same time period that a new subtype of oropharyngeal cancer resulting from human papilloma virus (HPV) has emerged.6 The proportion of HPV-associated oropharyngeal cancer has steadily increased, and in many countries, this subtype now represents the majority of new oropharyngeal cancers.7,8

HPV-associated oropharyngeal cancer differs from other oropharyngeal cancers with regard to risk factors, clinical features, sensitivity to treatment, and prognosis.9 Patients with HPV-associated oropharyngeal cancer have markedly superior survival after chemoradiotherapy compared with those with HPV-negative oropharyngeal cancer.10–12 Preliminary reports of the pattern of failure suggest that this is because of lower rates of locoregional failure, second malignancies, and death as a result of other causes.11,12 There does not seem to be a significant difference between the two in the rate of distant metastasis as site of first failure.

Over the last 5 years, two new treatment options for squamous cell carcinomas of the head and neck—taxane-based induction chemotherapy13,14 and concomitant cetuximab and radiation administration15—have emerged after widely publicized clinical trials. However, the designs of the initial randomized trials of both these approaches did not include comparisons with standard concomitant chemoradiotherapy regimens. We have learned that the regimen of docetaxel, cisplatin, and fluorouracil (TPF) improves overall survival compared with cisplatin and fluorouracil when followed by radiation alone14 or radiation and weekly low-dose carboplatin.13 Although it had been clearly established that induction chemotherapy decreases distant metastases,16 the improvement with TPF, surprisingly, was demonstrated to be a result of improvement in locoregional control.13 The pivotal trial15 showing that the addition of cetuximab to radiation produced superior results compared with radiation alone was first presented in 2005; however, we do not have any results from randomized trials comparing this regimen with a standard concomitant chemoradiotherapy regimen. It is clear that both of these treatment approaches are being widely used in clinical practice, but with the currently available evidence, there remains considerable uncertainty about the relative efficacy and indications of these approaches compared with standard concomitant chemoradiotherapy regimens. Ongoing and recently completed trials should better define the role of induction chemotherapy and epidermal growth factor receptor–targeted therapy concurrent with irradiation.

In this issue of Journal of Clinical Oncology, Kies et al17 report the results of a phase II trial incorporating cetuximab into a short weekly regimen of carboplatin and paclitaxel induction followed by what the authors describe as risk-based local therapy. Although the overall results are good, it is difficult to determine the relative contributions of induction chemotherapy, cetuximab, HPV status, and risk-based local therapy. On the basis of the results of a trial18 involving patients with relapsed or metastatic head and neck cancer, which demonstrated that the addition of concurrent and maintenance cetuximab to chemotherapy improved overall survival and response rates, it was reasonable to anticipate that the addition of cetuximab to induction chemotherapy might also be beneficial. However, Kies et al report that complete response rates achieved with their regimen did not seem to be better than those reported using the same regimen without cetuximab.19 Furthermore, in contrast to the TPF regimen, the weekly carboplatin and paclitaxel regimen, while clearly an active induction regimen, has not been demonstrated to be superior to the cisplatin and fluorouracil regimen.

In the trial by Kies et al,17 the majority of patients had oropharyngeal cancer (41 of 47; 87%). We know that 12 of 26 tumors tested were HPV positive, and this group had a better prognosis than the HPV-negative group, which included four nonoropharyngeal primaries. If we assume that the detected HPV-positive rate of oropharyngeal cancer of 55% was the same in the untested patients, we can estimate that 22 patients (47%) in this trial had HPV-associated oropharyngeal cancer. Because we now know that patients with HPV-associated oropharyngeal cancer have achieved excellent outcomes with standard chemoradiotherapy in multicenter trials, the presence of a high proportion of HPV-positive patients confounds the interpretation of efficacy in phase II trials of novel regimens.

As Kies et al17 note, patients with HPV-associated oropharyngeal cancer frequently present with small primaries (T1-2) and advanced nodal stage. The risk-based approach adopted by the authors, which they suggest may be applicable to HPV-positive patients, involved administering induction chemotherapy to decrease distant metastases and potentially contribute to locoregional control and then decreasing the intensity of local therapy on the basis of stage and site (eg, radiotherapy alone for selected patients with T1-2 disease) to decrease toxicity and improve functional outcomes. However, this induction regimen, which required granulocyte colony-stimulating factor support in 64% of patients, resulted in significant toxicity, with grade 3 rash in 45% of patients, grade 2 neuropathy in 15%, and grade 3 neuropathy in 2%, which in turn precluded use of planned cisplatin during irradiation in several patients. Although radiation alone was administered in 50% of patients after induction chemotherapy, it is noteworthy that 38% of patients received altered fractionation with concomitant boost, a regimen that is associated with an increase in acute and late toxicity.20,21 The authors report good functional outcomes; however, it is unclear whether these outcomes are superior to what could be achieved with concurrent chemoradiotherapy regimens using modern radiotherapy techniques in a similar patient population.

Because we know that advanced nodal stage is a major risk factor for distant metastases,22 one may be inclined intuitively to think that the HPV-positive group with more advanced nodal stage (86% with N2-3 v 65% in HPV-negative group)12 may be more likely to benefit from induction chemotherapy. Enthusiasm for incorporating induction chemotherapy into the treatment of this good-prognosis population should be tempered by the fact that the higher N stage does not seem to be associated with an increased risk of distant metastases compared with HPV-negative patients.11,12 The rates of distant metastasis as site of first failure in HPV-positive oropharyngeal cancer were 9.7% and 5% in recent clinical trials11,12 compared with 13% and 6% in the HPV-negative group, respectively, and did not exceed the locoregional failure rates in the HPV-positive population, which were 13.6% and 6%, respectively. It is possible that longer follow-up may reveal higher rates of isolated distant failure. In HPV-positive oropharyngeal cancer, whether a decrease in distant metastases after induction chemotherapy improves overall survival, which was 88% and 92% at 2 years in these recent trials,11,12 remains an open question.

In view of the excellent survival outcomes in HPV-associated oropharyngeal cancer with standard cisplatin-based chemoradiotherapy regimens, there is considerable interest in exploring less intensive regimens in this group of patients that may decrease both acute and late toxicity while preserving efficacy. Regimens that could be tested in clinical trials include less intensive concomitant chemoradiotherapy regimens, concomitant epidermal growth factor receptor–targeted therapies and irradiation, and radiation alone in selected patients. It is not apparent from the small series reported by Kies et al17 that the strategy of induction chemotherapy and risk-based local therapy improves the therapeutic ratio for patients with HPV-positive oropharyngeal cancer.

Because HPV-associated oropharyngeal cancer is a distinct entity with a much better prognosis than HPV-negative oropharyngeal cancer, the time has come to conduct separate clinical trials in HPV-associated oropharyngeal cancer to define optimal treatment. In randomized trials that do include both HPV-positive and HPV-negative patients, HPV or p16 status should be included as a stratification factor. Recent trials highlighting the good outcomes in HPV-associated oropharyngeal cancer have in turn drawn our attention to the poor prognosis of the HPV-negative group. Future trials of novel and/or intensive chemoradiotherapy strategies intended to improve efficacy should focus on HPV-negative patients.

Author’s 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.

Employment or Leadership Position: None Consultant or Advisory Role: Danny Rischin, Merck Serono (U) Stock Ownership: None Honoraria: None Research Funding: Danny Rischin, Merck Serono, sanofi-aventis Expert Testimony: None Other Remuneration: None

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16. Pignon JP, le Maitre A, Maillard E, et al: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92:4–14, 2009.

17. Kies MS, Holsinger FC, Lee JJ, et al: Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: Results from a phase II prospective trial. J Clin Oncol 28:8–14, 2009.

18. Vermorken JB, Mesia R, Rivera F, et al: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127, 2008.

19. Vokes EE, Stenson K, Rosen FR, et al: Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: Curative and organ-preserving therapy for advanced head and neck cancer. J Clin Oncol 21:320–326, 2003.

20. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7–16, 2000.

21. Trotti A, Fu KK, Pajak TF, et al: Long term outcomes of RTOG 90-03: A comparison of hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 63:S70–S71, 2005 (suppl.)

22. Brockstein B, Haraf DJ, Rademaker AW, et al: Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: A 9-year, 337-patient, multi-institutional experience. Ann Oncol 15:1179–1186, 2004.

Author’s affiliation:
Department of Medical Oncology and Head and Neck Service, Peter MacCallum Cancer Centre; and University of Melbourne, Melbourne, Australia

December, 2009|Oral Cancer News|

Early PET-CT predicts treatment response of head and neck cancer

Author: staff

In patients with advanced squamous cell carcinoma of the head and neck, negative findings on post-treatment positron emission tomography/computed tomography (PET-CT) predict a good treatment response, researchers say.

In 31 patients with clinical stage III and IV tumors treated with cisplatin and concurrent external beam radiotherapy, PET-CT was performed 6 to 8 weeks after therapy was completed, along with a comprehensive physical examination of the head and neck, as reported by Dr. James P. Malone, from the Southern Illinois School of Medicine, Springfield, and colleagues in the November Archives of Otolaryngology — Head and Neck Surgery.

Seventeen patients had evidence of persistent disease on physical exam, CT, and/or PET-CT, and these individuals had surgery for further evaluation. Fourteen patients had complete clinical responses, including no evidence of FDG uptake on PET-CT; these subjects were observed with routine follow-up.

According to the researchers, all but one of these 14 patients remained disease free at the primary tumor site during a median follow-up of 26 months.

Thus, the authors point out, the sensitivity of PET-CT was 83%, and its negative predictive value was “excellent” at 92% for detection of persistent disease at the primary tumor site. Because of a high false-positive rate, specificity was low at 54%, with a positive predictive value of 31%.

Dr. Malone’s group attributes the high false-positive rate to inflammation related to recent treatment.

The investigators also note that 5 of 16 patients with abnormal FDG update developed local disease. “For patients with abnormal FDG uptake at the primary site on early PET-CT and no evidence of local disease on physical examination, we recommend close outpatient follow-up with consideration of repeating PET-CT in 6 to 8 weeks or evaluation under anesthesia and biopsy of the primary tumor site,” they said.

“On the basis of this study, PET-CT performed 6 to 8 weeks after the completion of (chemoradiotherapy) for advanced squamous cell carcinoma of the head and neck is a valuable tool for measuring treatment response and facilitating clinical decision making,” the research team concludes.

November, 2009|Oral Cancer News|

Erbitux® may improve treatment of squamous cell carcinoma of the esophagus

Author: staff

Researchers from Germany have reported that Erbitux® (cetuximab) improves response rate, time to disease progression, and overall survival of patients with metastatic squamous cell carcinoma receiving Platinol® (cisplatin) and 5-FU. The details of this study appeared in the October 2009 issue of Annals of Oncology.[1]

Esophageal cancer is relatively common and is very deadly. It 1998 there were approximately 12,300 new cases of esophageal cancer diagnosed in the United States and nearly 12,000 esophageal cancer deaths, making esophageal cancer one of the most deadly of all cancers. Most cancers of the upper two-thirds of the esophagus arise from squamous cells. Cancers of the lower esophagus most often arise from columnar epithelium and are adenocarcinomas. In the recent past, squamous cell cancers made up more than 80% of all esophageal cancers. Over the past two decades, there has been a dramatic increase in the incidence of adenocarcinomas, which now account for one-third to one-half of all esophageal cancers. However, squamous cell carcinoma of the esophagus remains a major problem and is difficult to treat when metastatic. Usual treatment for metastatic squamous cell carcinoma of the esophagus includes a platinum compound and 5-FU.

Erbitux is a chimeric monoclonal antibody that binds to the outer domain of the epidermal growth factor receptor (EGFR). It is currently approved, in combination with radiation therapy, for the treatment of locally or regionally advanced head and neck cancer, or as a single agent in the treatment of advanced, EGFR-expressing head and neck cancer that has failed prior platinum-based therapies. Early studies have suggested activity for Erbitux for treating squamous cell carcinoma of the esophagus.

The current study randomly allocated 62 patients with metastatic squamous cell carcinoma of the esophagus to treatment with Platinol and 5-FU with or without Erbitux. Toxicity of Erbitux included skin rash and diarrhea. The overall response rate of patients receiving Erbitux was 19% compared with 13% for the chemotherapy-alone group. Disease-control rate was 75% for patients receiving Erbitux and 57% for patients receiving chemotherapy alone. The median progression-free survival was 5.9 months for patients receiving Erbitux and 3.6 months for patients receiving chemotherapy alone. Median survival was 9.5 months for patients receiving Erbitux and 5.5 months for patients receiving chemotherapy alone. No KRAS mutations were identified in 37 specimens.

Comments: Erbitux appears to be active for the treatment of squamous cell carcinoma of the esophagus.

[1] Lorenzen S, Schuster T, Porschen R, et al. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgeminschaft Internistische Onkologie. Annals of Oncology. 2009; 20:1667-1673.

October, 2009|Oral Cancer News|