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

1. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418–8423, 2003.

2. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139, 2004.

3. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561–566, 2007.

4. Curtin JA, Fridlyand J, Kageshita T, et al: Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147, 2005.

5. Curtin JA, Busam K, Pinkel D, et al: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346, 2006.

6. Gillison ML, Koch WM, Capone RB, et al: Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92:709–720, 2000.

7. Näsman A, Attner P, Hammarstedt L, et al: Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: An epidemic of viral-induced carcinoma. Int J Cancer 125:362–366, 2009.

8. Chaturvedi AK, Engels EA, Anderson WF, et al: Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 26:612–619, 2008.

9. Vidal L, Gillison ML: Human papillomavirus in HNSCC: Recognition of a distinct disease type. Hematol Oncol Clin North Am 22:1125–1142, vii, 2008.

10. Fakhry C, Westra WH, Li S, et al: Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100:261–269, 2008.

11. Gillison ML, Harris J, Westra W, et al: Survival outcomes by tumor human papillomavirus (HPV) status in stage III-IV oropharyngeal cancer (OPC) in RTOG 0129. J Clin Oncol 27:15s; 2009 (suppl; abstr 6003.

12. Rischin D, Young R, Fisher R, et al: Prognostic significance of HPV and p16 status in patients with oropharyngeal cancer treated on a large international phase III trial. J Clin Oncol 27:15s; 2009 (suppl; abstr 6004.

13. Posner MR, Hershock DM, Blajman CR, et al: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357:1705–1715, 2007.

14. Vermorken JB, Remenar E, van Herpen C, et al: Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695–1704, 2007.

15. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578, 2006.

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|

Induction with Docetaxel, Cisplatin, and 5-FU provides survival benefits beyond 5 years in head and neck cancer

Author: Chris Berrie

Induction with docetaxel, cisplatin, and 5-fluorouracil (5-FU) provides sustained significant survival advantages beyond 5 years compared with cisplatin and 5-FU in patients with locally advanced squamous cell cancer of the head and neck.

Jochen Lorch, MD, Head and Neck Oncology Programme, Dana Farber Cancer Institute, Harvard University, Boston, Massachusetts, presented a 5-year follow-up analysis of the multicentre, randomised, open-label, phase 3 Cisplatin and Fluorouracil Alone or With Docetaxel in Head and Neck Cancer (TAX 324) at the joint 15th Congress of the European Cancer Organisation (ECCO) and 34th Congress of the European Society for Medical Oncology (ESMO).

The benefits of docetaxel in combination with cisplatin and 5-fluorouracil (TPF) was shown in the original TAX 324 and TAX 323 studies. Results of the follow-up were presented here on September 22.

TAX 324 included 501 patients with measurable, nonmetastatic stages III and IV squamous cell carcinoma of the head and neck, with a primary tumour location in the oral cavity, oropharynx, larynx or hypopharynx, and unresectable disease. A World Health Organization (WHO) performance status (PS) of 0/1 and no prior chemotherapy or radiotherapy were also specified.

Patients were randomised to induction therapy of TPF (n = 255) or cisplatin plus 5-fluorouracil (PF) on days 1 to 4, every 3 weeks for 3 cycles (n = 246). The induction treatments were followed by chemoradiotherapy with carboplatin area under the curve (AUC) 1.5, weekly and daily radiotherapy (5 days/week).

In the original study, there was a significant 13% improvement (62% vs 49%) in 3-year overall survival (OS) with TPF over PF (P = .006), with median survivals of 71 months versus 30 months.

The current 5-year, long-term follow-up included 440 patients (88%), and showed a significant 10% improvement (52% vs 42%) for TPF over PF (P = .014), with median survivals of 71 months versus 35 months.

According to disease site subgroups here, the median survivals showed, respectively: oropharynx, not reached versus 65 months (P = .045); hypopharynx, 32 versus 20 months (P = .29); larynx, 58 versus 25 months (P = .29); and oral cavity, 37 versus 14 months (P = .70).

However, as Dr. Lorch noted for laryngeal and hypopharyngeal tumours, “If these patients recur, there is a surgical salvage option.” Thus for progression-free survival rather than overall survival, there was indeed a significant benefit for these patients (P = .0365).

According to tumour staging, the beneficial trend for TPF over PF for stage III at 3 years (71 vs 51 months; P = .07) was lost at 5 years (90 vs 65 months; P = .26). In contrast, the main benefit was for stage IV at both 3 years (59 vs 25 months; P = .02) and 5 years (59 vs 25; P = .03).

For toxicity, Dr. Lorch noted that there were no significant differences at 3 years and at 5 years.

1. Funding for this study was provided by Sanofi-Aventis.
2. Presentation tile: Long-Term (Five-Year) Results of TAX324: A Phase III Trial of Sequential Therapy Comparing TPF With PF in Patients With Locally Advanced Squamous Cell Cancer of the Head and Neck. Abstract 8502

September, 2009|Oral Cancer News|

Induction chemotherapy followed by chemoradiotherapy increased time-to-treatment failure compared to chemoradiotherapy alone in patients with unresectable locally advanced head & neck cancer

Author: press release

The Spanish Head and Neck Cancer Cooperative Group (TTCC) announced today that Induction Chemotherapy (IC) delivered prior to standard ChemoRadiotherapy (CRT), a treatment paradigm defined as sequential therapy, compared to upfront CRT alone, significantly prolonged Time-to-Treatment Failure (TTF) for patients with unresectable Locally Advanced Head and Neck Cancer (LAHNC). The endpoint of Time-to-Treatment Failure was defined as a composite of time-to-disease progression, -to-surgery or other cancer-related treatments, -to-drop-out due to an adverse event, and to death from any cause.

Final results (abstract #6009) from the Phase 3 randomized study were presented by Prof. Ricardo Hitt, of the University Hospital 12 de Octubre, Madrid, in an oral presentation at the 2009 annual meeting of the American Society of Clinical Oncology (ASCO). The results of this study have also been selected for inclusion in the Best of ASCO(R) program. The Best of ASCO(R) is an educational initiative that condenses highlights from ASCO’s Annual Meeting, with the objective of increasing global access to cutting-edge science that is relevant and significant in oncology today.

This study enrolled 439 patients with Locally Advanced Head and Neck Cancer with good performance status, who were randomly assigned to receive standard CRT (cisplatin and fractionated radiation) versus the same treatment preceded by IC, which consisted of cisplatin plus 5-fluorouracil (5-FU) with or without Taxotere(R) (docetaxel) Injection Concentrate. The study was designed to compare the results of those patients who received IC prior to CRT (sequential therapy) and patients who received CRT alone.

The sequential therapy of adding IC to CRT improved Time-to-Treatment Failure (TTF) from 5.0 months to 12.5 months (p< 0.0001), a 7.5 month increase. Furthermore, a secondary endpoint of loco-regional control, was observed in 61.5% of the patients treated with the sequential strategy (IC+CRT) compared to 44.5% of those patients treated with CRT alone (p=0.002). The most frequent severe (grade 3-4) adverse reactions were stomatitis (44% for IC+CRT vs. 31% for CRT) and febrile neutropenia (10% for IC+CRT vs. 1% for CRT). Other adverse events included neutropenia and asthenia. "These study results illustrate that this complex disease deserves a rational and comprehensive management strategy to overcome its pathologic mechanism and the inherent possibility of failure of clinical control," said Prof. Ricardo Hitt, MD, PhD, the study principal investigator, from Medical Oncology Service of the University Hospital 12 de Octubre, Madrid, Spain. Every year more than 640,000 people worldwide are diagnosed with head and neck cancer, and an estimated more than 350,000 will die from the disease. Head and neck cancer is a group of tumors that mostly arise in the cells that line the mucosal surfaces, giving rise to squamous cell carcinoma in the head and neck area, such as the mouth, tongue, tonsils, voice box and throat. "This trial showed that adding Induction Chemotherapy to ChemoRadiotherapy increased failure-free survival while significantly increasing local control in patients with advanced unresectable head and neck cancer," said Fadlo Khuri, MD, Professor and Roberto Goizueta Chair of Hematology and Medical Oncology at Emory University, Atlanta, GA, USA. Dr. Khuri, a renowned head and neck cancer expert, also added: "These data may help define and clarify standard approaches to the treatment of patients with advanced unresectable disease."

New platinum-phosphate compounds kill ovarian vancer cells, other cancer cells

Author: staff

A new class of compounds called phosphaplatins can effectively kill ovarian, testicular, head and neck cancer cells with potentially less toxicity than conventional drugs, according to a new study published in the journal Proceedings of the National Academy of Sciences.

The compounds could be less harmful than current cancer treatments on the market such as cisplatin and carboplatin because they don’t penetrate the cell nucleus and attach to DNA, said lead author Rathindra Bose. Conventional drugs can interfere with the functions of the cell’s enzymes, which lead to side effects such as hearing and hair loss and kidney dysfunction.

Though scientists don’t fully understand the mechanism by which the phosphaplatins kill cancer cells, they suspect that the compounds bind to the cell surface membrane proteins and transmit a “death signal” to the interior of the cell, Bose said. The compounds are created by attaching platinum to a phosphate ligand, which can readily anchor to the cell membrane. Future studies will focus on identifying the exact process.

“The findings suggest a paradigm shift in potential molecular targets for platinum anticancer drugs and in their strategic development,” said Bose, a professor of biomedical sciences and chemistry and vice president for research at Ohio University who conducted the work while at Northern Illinois University.

The first drug developed for the treatment of ovarian and testicular cancers, cisplatin, was approved for use in 1982. Though it’s 95 percent effective, it works best during the early stages of the disease, and some patients develop a resistance to it. Two drugs introduced later, carboplatin and oxaliplatin (which is used for colorectal cancer), overcame some of those problems, but their potency can harm the immune system of patients, said Bose, who has been studying alternative compounds and targets for these cancers for 25 years.

Phosphaplatins have the potential to be more efficient, more targeted and create fewer side effects in the patient, Bose said. The new study shows that the phosphaplatins can kill ovarian cells at half of the dosage of conventional drugs, but are just as potent. Unlike cisplatin, which can decompose quickly and create additional toxic side effects through the decomposition products, the new compounds show no signs of degradation after seven days, he added.

A U.S. patent is pending on the work; two provisional patents have been filed. Bose and his colleagues next will test the compounds in mice models.

1. Co-authors of the study are Leila Maurmann of Kansas State University, and Robert Mishur, Linda Yasui, Shefalika Gupta, W. Scott Grayburn, Heike Hofstetter and Tara Milton, all of Northern Illinois University.

November, 2008|Oral Cancer News|

Platinum-based chemotherapy plus cetuximab in head and neck cancer

Source: New England Journal of Medicine, Volume 359:1116-1127, September 11, 2008, Number 11
Authors: Jan B. Vermorken, M.D., Ph.D. et al.

Cetuximab is effective in platinum-resistant recurrent or metastatic squamous-cell carcinoma of the head and neck. We investigated the efficacy of cetuximab plus platinum-based chemotherapy as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck.

We randomly assigned 220 of 442 eligible patients with untreated recurrent or metastatic squamous-cell carcinoma of the head and neck to receive cisplatin (at a dose of 100 mg per square meter of body-surface area on day 1) or carboplatin (at an area under the curve of 5 mg per milliliter per minute, as a 1-hour intravenous infusion on day 1) plus fluorouracil (at a dose of 1000 mg per square meter per day for 4 days) every 3 weeks for a maximum of 6 cycles and 222 patients to receive the same chemotherapy plus cetuximab (at a dose of 400 mg per square meter initially, as a 2-hour intravenous infusion, then 250 mg per square meter, as a 1-hour intravenous infusion per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued to receive cetuximab until disease progression or unacceptable toxic effects, whichever occurred first.

Adding cetuximab to platinum-based chemotherapy with fluorouracil (platinum–fluorouracil) significantly prolonged the median overall survival from 7.4 months in the chemotherapy-alone group to 10.1 months in the group that received chemotherapy plus cetuximab (hazard ratio for death, 0.80; 95% confidence interval, 0.64 to 0.99; P=0.04). The addition of cetuximab prolonged the median progression-free survival time from 3.3 to 5.6 months (hazard ratio for progression, 0.54; P<0.001) and increased the response rate from 20% to 36% (P<0.001). The most common grade 3 or 4 adverse events in the chemotherapy-alone and cetuximab groups were anemia (19% and 13%, respectively), neutropenia (23% and 22%), and thrombocytopenia (11% in both groups). Sepsis occurred in 9 patients in the cetuximab group and in 1 patient in the chemotherapy-alone group (P=0.02). Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade 3 or 4 infusion-related reactions. There were no cetuximab-related deaths.

As compared with platinum-based chemotherapy plus fluorouracil alone, cetuximab plus platinum–fluorouracil chemotherapy improved overall survival when given as first-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck. ( number, NCT00122460)

Jan B. Vermorken, M.D., Ph.D., Ricard Mesia, M.D., Fernando Rivera, M.D., Ph.D., Eva Remenar, M.D., Andrzej Kawecki, M.D., Ph.D., Sylvie Rottey, M.D., Ph.D., Jozsef Erfan, M.D., Dmytro Zabolotnyy, M.D., Ph.D., Heinz-Roland Kienzer, M.D., Didier Cupissol, M.D., Frederic Peyrade, M.D., Marco Benasso, M.D., Ihor Vynnychenko, M.D., Ph.D., Dominique De Raucourt, M.D., Carsten Bokemeyer, M.D., Armin Schueler, M.S., Nadia Amellal, M.D., and Ricardo Hitt, M.D., Ph.D.

Authors’ affiliations:
From Antwerp University Hospital, Edegem (J.B.V.); and Ghent University Hospital, Ghent (S.R.) — both in Belgium; Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona (R.M.); Hospital Universitario Marqués de Valdecilla, Santander (F.R.); and Hospital 12 de Octubre, Madrid (R.H.) — all in Spain; Orszagos Onkologiai Intezet, Budapest (E.R.), and Szabolcs-Szatmar Bereg Megyei Josa Andras Korh, Nyiregyhaza (J.E.) — both in Hungary; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland (A.K.); Institute of Otolaryngology, Academy of Medical Sciences of Ukraine, Kiev (D.Z.); and Sumy Regional Oncology Center, Sumy (I.V.) — both in Ukraine; Ludwig Boltzmann Institute for Applied Cancer Research, Kaiser Franz Josef Spital, Vienna (H.-R.K.); Centre Val d’Aurelle Paul Lamarque Service d’Oncologie, Montpellier (D.C.); Centre Antoine Lacassagne, Nice (F.P.); and Centre François Baclesse, Caen (D.D.R.) — all in France; Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy (M.B.); and Universitaetskrankenhaus Hamburg-Eppendorf, Hamburg (C.B.); and Merck, Darmstadt (A.S., N.A.) — both in Germany.

September, 2008|Oral Cancer News|