cisplatin

Sensitization of Head and Neck Cancer to Cisplatin Through the Use of a Novel Curcumin Analog

Source: EthiconEndo-Surgery.com

Objective To determine whether a novel small molecule inhibitor derived from curcumin (FLLL32) that targets signal transducer and activator of transcription (STAT) 3 would induce cytotoxic effects in STAT3-dependent head and neck squamous cell cancer (HNSCC) cells and would sensitize tumors to cisplatin.

Design Basic science. Two HNSCC cell lines, UM-SCC-29 and UM-SCC-74B, were characterized for cisplatin [cis-diammineplatinum(II) dichloride] sensitivity. Baseline expression of STAT3 and other apoptosis proteins was determined. The FLLL32 50% inhibitory concentration (IC50) dose was determined for each cell line, and the effect of FLLL32 treatment on the expression of phosphorylated STAT3 and other key proteins was elucidated. The antitumor efficacy of cisplatin, FLLL32, and combination treatment was measured. The proportion of apoptotic cells after cisplatin, FLLL32, or combination therapy was determined.

Results The UM-SCC-29 cell line is cisplatin resistant, and the UM-SCC-74B cell line is cisplatin sensitive. Both cell lines express STAT3, phosphorylated STAT3 (pSTAT3), and key apoptotic proteins. FLLL32 downregulates the active form of STAT3, pSTAT3, in HNSCC cells and induces a potent antitumor effect. FLLL32, alone or with cisplatin, increases the proportion of apoptotic cells. FLLL32 sensitized cisplatin-resistant cancer cells, achieving an equivalent tumor kill with a 4-fold lower dose of cisplatin.

Conclusions FLLL32 monotherapy induces a potent antitumor effect and sensitizes cancer cells to cisplatin, permitting an equivalent or improved antitumor effect at lower doses of cisplatin. Our results suggest that FLLL32 acts by inhibiting STAT3 phosphorylation, reduced survival signaling, increased susceptibility to apoptosis, and sensitization to cisplatin.

 

 

 

HPV and EGFR are hottest topics in head and neck cancer

Source: www.medscape.com
Author: Zosia Chustecka

The hottest topic in head and neck cancers is the role of human papillomavirus (HPV) in the disease, although there is also a lot interest in treatment with EGRF inhibitors, especially the second-generation products, according to an expert here at the European Society for Therapeutic Radiology and Oncology 11th Biennial Conference.

HPV has only been associated with head and neck cancer in the last few years, but it is now clear that patients who are positive for the virus have a better prognosis, said Cai Grau, MD, DMSC, professor of oncology at Aarhus University Hospital, Denmark. He chaired a session during which both hot topics were discussed.

“These patients have a better prognosis, irrespective of treatment, and their risk of a second cancer is virtually zero,” added session participant Lisa Licitra, MD, medical oncologist at the Istituto Nazionale per lo Studio e la Cura dei Tumori in Milan, Italy.

However, there is a difference between patients in the United States and those in Europe with regard to risk, she told meeting attendees.

For American patterns, Dr. Licitra cited the analysis published last year in the New England Journal of Medicine (2010;363:24-35), which reported a risk model for death from oropharyngeal squamous cell carcinoma on the basis of HPV status, pack-years of tobacco smoking, and tumor and nodal stage. In this 266-patient cohort, 43% were low risk, 30% were intermediate risk, and 27% were high risk.

Dr. Licitra reported that when she performed the same analysis on a cohort of 120 patients at her institution, the percentages were different — among the Italian patients, 22% were low risk, 38% were intermediate risk, and 40% were high risk.

“There were more high-risk and fewer low-risk patients,” she pointed out, and speculated in an interview that this might be because of higher rates of smoking in Italy.

These differences in risk estimates might account for differences in outcomes between European and American patients in international trials of head and neck cancer, Dr. Licitra said. For instance, this was seen in a trial by Bonner et al (N Engl J Med. 2006:354;567-578), which showed that the EGRF inhibitor cetuximab (Erbitux) added to radiotherapy was an effective option in head and neck cancer.

The European patients in the Bonner trial fared worse than the American patients, and there has been a lot of speculation as to why, she noted in an interview. There were suggestions that radiotherapy improved outcomes in the United States, for example. But the new data reported by Dr. Licitra suggest another potential explanation: the European patients might have had worse outcomes because more were negative for HPV and at higher risk for recurrence. “We now appreciate that the patient population is different,” she explained.

However, she emphasized that this is speculation; the participants of the Bonner trial were not tested for HPV status.

Going forward, clinical trials of patients with head and neck cancer are now stratifying for HPV status, Dr. Licitra and Dr. Grau both noted.

Less Intense Therapy?

One of the issues being explored is whether the management should be different for head and neck cancer patients who are positive for HPV. There is a suggestion that, because of their better prognosis, these patients could undergo less intense therapy.

However, so far “the scientific evidence for this is not strong,” Kevin Harrington, FRCP, FRCR PhD, senior lecturer at the Institute of Cancer Research, and honorary consultant oncologist at the Royal Marsden Hospital, London, United Kingdom, told meeting attendees.

Standard treatment for head and neck cancer is chemoradiation, which is supported by level 1a evidence from controlled randomized clinical trials, he noted. The gold standard is single-agent cisplatin with radiotherapy.

There are data that show that HPV-positive patients have a significantly better outcome than HPV-negative patients, deriving about 35% greater benefit, he said. “But it is difficult to suggest abandoning chemoradiation,” he said. There might be a case for replacing cisplatin with a less toxic chemotherapeutic and/or deescalating the radiation dose, he added.

EGFR inhibitors such as cetuximab offer another therapy option. Clinical trials so far have added cetuximab to radiotherapy (as the Bonner trial did) and added cetuximab to chemoradiotherapy. This option is attractive because these drugs are oral and less toxic than chemotherapy such as cisplatin. As a result, there has been a separate trend within head and neck cancer to assess tumors for EGRF-receptor expression.

Initially, there was hope that the patients with HPV-positive tumors, who have a better prognosis, would be the patients who would respond best to treatment with EGRF inhibitors, and thus avoid chemotherapy, Dr. Grau explained.

However, there appears to be little interaction between HPV and EGFR inhibitors, Dr. Harrington said. “We were looking to see if HPV and EGFR are talking to one another,” he said, but “there is no evidence in the medical literature that they are interacting at a molecular or mechanistic level.”

The data do not support the notion that patients who have HPV-positive tumors are good candidates for treatment with EGFR inhibitors, he said.

Currently, chemoradiation with single-agent cisplatin remains the gold standard treatment for head and neck cancer. This is the treatment against which all new options will be measured, Dr. Harrington noted.

An ongoing trial (NCT00820248) is the first head-to-head trial to test the standard treatment of cisplatin with radiotherapy against a newer option — radiotherapy combined with the second-generation EGRF inhibitor panitumumab, he said.

Note:
1. Zosia Chustecka is the News Editor for Medscape Oncology.

Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells’ Sensitivity to Cisplatin and Radiation In Vivo and In Vitro

Abstract

Purpose: We investigated whether vandetanib, an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma (HNSCC).

Experimental Design: OSC-19 and HN5 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib, cisplatin, and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model. Treatment effects were assessed using clonogenic survival assay, tumor volume, bioluminescence imaging, tumor growth delay, survival, microvessel density, tumor and endothelial cell apoptosis, and EGFR and Akt phosphorylation data.

Results: Vandetanib plus cisplatin radiosensitized HNSCC cells in vitro and in vivo. The combination treatment with vandetanib, cisplatin, and radiation was superior to the rest of treatments (including the double combinations) in antitumoral effects, prolonging survival, decreasing cervical lymph node metastases in vivo. It also increased both tumor and tumor-associated endothelial cell apoptosis and decreased microvessel density in vivo. An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo. All vandetanib-containing treatments inhibited EGFR and Akt phosphorylation in vitro and in vivo.

Conclusion: The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC. Further study of this regimen in clinical trials may be warranted. Clin Cancer Res; 17(7); 1815–27. ©2011 AACR.

April, 2011|Oral Cancer News|

Three-drug combination shows long-lasting survival benefit in head and neck cancer patients

Source: www.medicalnewstoday.com
Author: staff

Adding a third drug (docetaxel) to a standard two-drug initial chemotherapy regimen significantly improves the long-term survival of patients with head and neck cancer, reducing the likelihood of dying by 26% over 6 years. The long-term results of the TAX 324 trial published Online First in The Lancet Oncology, confirm that this three-drug regimen should become the standard of care for patients who are suitable for induction therapy.

Every year, cancers of the head and neck are diagnosed in more than 40 000 people in the USA. Standard treatment for these patients involves combining radiotherapy and chemotherapy with or without surgery, and the addition of induction chemotherapy has been shown to prolong survival. However, the best ways of combining these treatments remains unclear.

In recent years, cisplatin plus fluorouracil (PF) has become a standard induction chemotherapy combination and has been shown to significantly prolong survival.

The TAX 324 trial was designed to establish whether the addition of docetaxel to initial chemotherapy with cisplatin and fluorouracil (PF) might help patients with locally advanced head and neck cancer live longer. Between May 1999 and December 2003, 501 patients were recruited from 55 centres across the USA, Canada, Argentina, and Europe.

In 2007, initial results (minimum follow-up 2 years) showed that induction chemotherapy with docetaxel, cisplatin, and fluorouracil (TPF) significantly improved survival compared with PF.

To establish the durability of this survival benefit, Jochen Lorch from the Dana-Farber Cancer Institute, Boston, USA and colleagues evaluated the long-term follow-up of patients from the TAX 324 trial.

Over 6 years, the survival advantage was sustained and the addition of docetaxel reduced the risk of death by 26%.

Overall survival was significantly better in the TPF group (70.6 months) than in the PF group (34.8 months). Survival at 5 years was 52% in the three-drug combination group and 42% in the two-drug group.

Additionally, progression-free survival was significantly longer for patients receiving the TPF than those on PF (median 38.1 months vs 13.2 months).

Further analyses showed that patients with hypopharyngeal and laryngeal cancers had significantly prolonged PFS from treatment with the three-drug regimen compared with the two-drug regimen, and oropharyngeal cancers treated with TPF showed an overall survival benefit.

Long-term toxic effects (measured by the use of tracheostomy and dependence on gastric feeding tubes) did not differ between the treatment groups.

The authors say: “The updated results of our study suggest that the survival benefit of sequential therapy with TPF continues well beyond the 2 years of the original analysis and was sustained at the same level.” They conclude: “Patients who are candidates for induction chemotherapy should be treated with TPF.”

In a Comment, June Corry and Danny Rischin from the Peter MacCallum Cancer Centre, Melbourne, Australia, say that the role of induction chemotherapy in advanced head and neck cancer is still unclear: “Use of TPF requires a subsequent compromise in dose intensity of the chemotherapy that can be given concomitantly with radiation…[as such] there are concerns that subjecting patients to a protracted course of treatment might compromise the delivery of the concomitant component, which has been shown to have the largest effect on locoregional control and overall survival.”

They add: “Hopefully, other completed or ongoing trials will provide the answers we need to determine whether there is a role for TPF-induction chemotherapy.”

Source: The Lancet Oncology

January, 2011|Oral Cancer News|

Panitumumab Plus Platinum Chemo Misses Mark in Advanced Head and Neck Cancer

Source: Internal Medicine News Digital Network
By: Patrice Wendling

MILAN – Panitumumab plus chemotherapy with cisplatin and 5-fluorouracil proved clinically active, but failed to boost overall survival significantly in first-line recurrent or metastatic head and neck cancer in the global, phase III SPECTRUM trial.

The primary end point of median overall survival showed a statistically insignificant increase from 9.0 months with chemotherapy alone to 11.1 months with the addition of panitumumab (Vectibix) (hazard ratio, 0.87; log-rank P = .14).

Subgroup analysis revealed, however, that the effect of panitumumab, an anti–epidermal growth factor receptor (EGFR) monoclonal antibody, was not the same for all patients in the international study, lead author Dr. Jan Vermorken said at the annual congress of the European Society for Medical Oncology.

Regional differences were observed, suggesting a greater benefit in patients from North/South America (HR, 0.69) and Western Europe (HR, 0.73) than in those in Eastern Europe (HR, 1.11). Asian Pacific patients fell somewhere in the middle (HR, 0.99).

About 45% of patients in each arm used some form of subsequent antitumor activity once off the study protocol, but differences cropped up here as well. The use of cytotoxic chemotherapy was imbalanced at 30% in the panitumumab arm vs. 25% in the chemotherapy arm, while twice as many patients in the chemotherapy arm (12% vs. 6%) received subsequent targeted systemic therapy driven largely by the use of anti-EGFR monoclonal antibodies, observed Dr. Vermorken of the Antwerp University Hospital in Edegem, Belgium.

“It’s clear this is the first analysis shown to you, and it’s also very clear that further analyses need to be done to identify subgroups that may have greater benefit than others with the combination of panitumumab with platinum-based chemotherapy,” he said.

SPECTRUM was conducted at 120 sites in 26 countries, and randomized 657 patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck to six 21-day cycles of cisplatin 100 mg/m2 on day 1 plus 5-FU 1,000 mg/m2 on days 1-4 with or without panitumumab 9 mg/kg on day 1.

Carboplatin was substituted for cisplatin because of severe neurotoxicity or a decrease in creatinine clearance in 21% of the 327 panitumumab patients and 26% of the 330 chemotherapy patients. Also, 33% of patients in the experimental arm opted to remain on panitumumab 9 mg/kg every 3 weeks, for a median of 11 weeks.

The median time to disease progression was significantly longer in patients receiving panitumumab at 5.8 months vs. 4.6 months with chemotherapy alone (log-rank P = .004, descriptive only; HR, 0.78), Dr. Vermorken said.

The objective response rate was 36% in the experimental arm vs. 25% in the control arm (P = .007, descriptive only). A complete response was achieved by 2% of patients in the experimental and control arms; partial responses in 35% and 24%, respectively; and stable disease in 46% and 47%.

The disease control rate also favored panitumumab at 82%, vs. 72% for chemotherapy alone (P = .004, descriptive only).

The safety profile of the experimental arm was in line with other trials of panitumumab and comparable with the use of other monoclonal antibodies in combination with chemotherapy, Dr. Vermorken said. Grade 3 and 4 events occurred in 31% and 15% of the panitumumab group, and in 18% and 8% of the chemotherapy group. Infusion reactions of any grade occurred in 3% of the panitumumab group and 2% of the chemotherapy group.

“The utility of this [triplet] appears significant,” said Dr. Marshall Posner, who was invited to discuss the late-breaking abstract. “The toxicity appears to be manageable, there are no infusion reactions, and the every three-week dosing makes this a somewhat easier agent to give than cetuximab.”

He suggested that the lack of survival advantage with panitumumab may be due to limited accessibility in some populations, notably the Eastern Europeans, to anti-EGFR antibodies, particularly cetuximab (Erbitux). In addition, cultural and regional differences in their cancer and the management of their care may have confounded survival.

What is not known is whether the oropharyngeal site, which has proved to do better in several other trials, did better in SPECTRUM and how well the triplet will work in second-line monotherapy, said Dr. Posner, medical director of the head and neck medical oncology program and cancer clinical trials office at Mount Sinai Medical Center in New York.

Amgen Inc. supported the trial. Dr. Vermorken reported participating in advisory boards for and receiving honoraria from Amgen, Merck-Serono, Lilly, Boehringer-Ingelheim, and Sanofi-Aventis. Two coinvestigators reported employee/stockholder relationships with Amgen. Dr. Posner disclosed consulting for several pharmaceutical companies.

October, 2010|Oral Cancer News|

The Major Component In Tumeric Enhances The Effect Of Chemotherapy In Suppressing Head And Neck Cancers

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, researchers with UCLA’s Jonsson Cancer Center have found.

A naturally occurring spice widely used in South Asian and Middle Eastern cooking, Turmeric has long been known to have medicinal properties, attributed to its anti-inflammatory effects. Previous studies have shown it can suppress the growth of certain cancers, said Dr. Marilene Wang, a professor of head and neck surgery, lead author of the study and a Jonsson Cancer Center researcher.

“Head and neck cancers, particularly cases diagnosed in a later stage, are terrible cancers that often require very radical surgeries and chemotherapy and radiation,” Wang said. “They often don’t present until late, and the structures in the head and neck are so vital that our treatments often cause disfigurement and severe loss of function. So using non-toxic curcumin as a treatment was a very appealing idea.”

The study, done in cells in Petri dishes and then in mouse models, appears in the October issue of the journal Molecular Cancer Therapeutics.

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 who, along with Wang, 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 tumors 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.

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

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 (NFκB), 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 NFκB.

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

The next step in the clinical setting is to give patients oral curcumin prior to surgery and, after surgery, study the excised tumors to determine curcumin’s effect on tumor markers, specifically whether there is reduced expression of markers such as growth promoting NFκB. They also will be monitoring to determine if the curcumin results in any side effects. After that, the team would give curcumin to patients also getting chemotherapy and radiation to see if the tumor suppression found in the cells lines and mouse models can be replicated in humans.

Although turmeric is used in cooking, the amount of curcumin needed to produce a clinical response is much larger, about 500 milligrams. Expecting a positive effect through eating foods spiced with turmeric is not realistic, the researchers said.

Curcumin also has a suppressive effect on other cancers, Wang said, including breast, colon and pancreatic cancers. However, the mechanism of suppression in those cancers has not yet been uncovered. It also may be effective against Alzheimer’s and aging, Wang said.

The study was funded by the VA Greater Los Angeles Surgical Education Research Center, UCLA Academic Senate, the National Institutes of Health and the Veterans Administration.

Source:
UCLA’s Jonsson Comprehensive Cancer Center

October, 2010|Oral Cancer News|

Turmeric makes chemo more effective

Source: timesofindia.indiatimes.com
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

Source: www.prnewswire.com
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.

Purpose:
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.

Results:
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%.

Conclusion:
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.

Authors:
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

Source: www.enttoday.org
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|