男性の口腔がんはHPVと関連している

 HPVヒトパピローマウイルスは、女性の子宮頚癌の原因となることでよく知られ、連邦政府は11-12才の女子にワクチン接種を薦めている。
画像 多くの口腔がんもこのウイルスと関連しているということがわかりつつある。進行した舌・扁桃がんの40%以上がHPVに感染しているとわかった。年に約28,900人が口腔ガンを発症すると推計されており、18,550人が男性である。全ての思春期の子どもにワクチン接種を考慮すべきであるとミシガン大のDr. Francis P. Wordenは言う。HPVはoral sexにより感染する可能性がある。2月に発行されたJohns Hopkinsの研究者の推計では、口腔の扁平上皮癌の38%がHPVによるとされ、性行動の変化がその原因と疑われている。
 Journal of Clinical Oncologyの2つの論文は、男51女15人の扁桃がんについての研究であるが、治療前に42人の生検が行われその約2/3にあたる27例でHPVが見つかった。男性51人のうち22人が陽性だった。
 最初に化学療法が行われ、50%以下に縮小しなかった12人の患者は手術をうけたが、ほとんどの人は死亡した。残り54人のうち49人が次の治療、化学療法と放射線の併用療法を受けた。78%は手術が不必要で、70%は4年以上生存した。49人のうちの約半数24人がHPV陽性で、うち女性は3人だけだった。HPVが多いと治療に良く反応し、生存率も高かった。
 4つの遺伝子マーカー(EGFR, BCLXL, p53, p16)を調べると治療の効果判定の良い指標となった。女性と喫煙者は治療が上手くいかなかった。
 HPVはガンの原因だが、このタイプのがんは治療に良く反応する。
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HPVによる男性の上咽頭癌の増加
http://kurie.at.webry.info/200802/article_9.html
ZARD坂井泉水死去/子宮頚癌とHPVウイルス(21) 男子にもHPVワクチン
http://kurie.at.webry.info/200802/article_43.html
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Oral Cancer in Men Associated With HPV
http://www.nytimes.com/2008/05/13/health/13canc.html?_r=1&ref=health&oref=slogin

By NICHOLAS BAKALAR
Published: May 13, 2008

The sexually transmitted virus called HPV, for human papillomavirus, is well known to lead to cervical cancer in women ― which is why the federal government recommends that all girls be vaccinated for HPV at 11 or 12, before they become sexually active.

Now researchers are finding that many oral cancers in men are also associated with the virus.

A clinical trial testing therapies for advanced tongue and tonsil cancers has found that more than 40 percent of the tumors in men were infected with HPV. If there is good news in the finding, it is that these HPV-associated tumors were among the most responsive to treatment.

Of an estimated 28,900 cases of oral cancer a year, 18,550 are in men.

“The high risk of HPV-associated cancers in men suggests that vaccinating all adolescents is something that should strongly be considered,” said the lead researcher, Dr. Francis P. Worden, a clinical assistant professor of medicine at the University of Michigan.

HPV can enter the mouth during oral sex. A study published in February by researchers at Johns Hopkins estimated that 38 percent of oral squamous-cell cancers are HPV related, and suggested that their increasing number might be a result of changing sexual behaviors.

The new study, published in two papers in The Journal of Clinical Oncology, included 51 men and 15 women with cancers of the tonsils or the base of tongue. The researchers were able to examine biopsies of 42 of the subjects before treatment. After tests for HPV, the researchers found that 27 tumors, nearly two-thirds, were positive for the virus. Of the 51 men, researchers found 22 with HPV.

Other experts found the results interesting, but said it was unclear what they would mean for treatment. Finding the answer to that question is the next step, said to Dr. Maura L. Gillison, an associate professor of oncology at Johns Hopkins who was not involved in the study.

“Clearly,” Dr. Gillison added, “it should give people optimism that the vaccine that was approved largely for women and for cervical cancer could have broader implications, and also for other cancers that occur in both men and women. All of our clinical trials now will be designed for either HPV-positive or HPV-negative patients. Right now, these patients are treated the same way.”

All the patients in the study were initially treated with induction chemotherapy, that is, an initial course to shrink the tumor. Those whose tumors did not shrink by at least 50 percent, 12 patients, were then treated with surgery. Most of those did not survive their illness.

Of the remaining group, 49 of 54 responded to the next step, combined chemotherapy and radiation. In that group, 78 percent needed no surgery, and 70 percent survived more than four years. Of the 49, almost half, 24, were positive for HPV, and all but 3of those were men.

People with tumors with high HPV levels were significantly more likely to respond to treatment. They were also more likely to survive their cancer and to survive over all.

The researchers also tested these tumors for the presence of four genetic markers: EGFR, a cell receptor associated with various cancers; BCLXL, a repressor of cell death; and the tumor-suppressor proteins p53 and p16. The scientists found that these were also accurate predictors of the success or failure of the treatment. Women and smokers were less likely to be treated successfully.

“Patients who have HPV infections are at higher risk for these cancers,” Dr. Worden said. “But the good news is that if that’s the cause of their cancer, they’re more likely to survive treatment. We still don’t know what the ideal treatment regimens are. For example, these patients may benefit from less intense chemotherapy and radiation.”

Although the researchers acknowledge that the number of patients in their study was small, they conclude that especially in patients with HPV-positive tumors, chemotherapy followed by combined chemotherapy and radiation appears to be an effective treatment.

An author of the papers has an interest in a company that is developing an HPV detection method.

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JCO Early Release, published online ahead of print May 12 2008
Journal of Clinical Oncology, 10.1200/JCO.2007.12.7662

Received May 23, 2007
Accepted October 30, 2007

EGFR, p16, HPV Titer, Bcl-xL and p53, Sex, and Smoking As Indicators of Response to Therapy and Survival in Oropharyngeal Cancer
Bhavna Kumar, Kitrina G. Cordell, Julia S. Lee, Francis P. Worden, Mark E. Prince, Huong H. Tran, Gregory T. Wolf, Susan G. Urba, Douglas B. Chepeha, Theodoros N. Teknos, Avraham Eisbruch, Christina I. Tsien, Jeremy M.G. Taylor, Nisha J. D'Silva, Kun Yang, David M. Kurnit, Joshua A. Bauer, Carol R. Bradford, and Thomas E. Carey*

From the Department of Otolaryngology–Head and Neck Surgery, Department of Periodontics and Oral Medicine, Department of Pathology, Comprehensive Cancer Center, Department of Internal Medicine, Division of Hematology-Oncology, Department of Radiation Oncology, Department of Biostatistics, Department of Pediatrics, and Department of Pharmacology, University of Michigan, Ann Arbor, MI.

* To whom correspondence should be addressed. E-mail: careyte@umich.edu

Purpose: To prospectively identify markers of response to therapy and outcome in an organ-sparing trial for advanced oropharyngeal cancer.

Patients and Methods: Pretreatment biopsies were examined for expression of epidermal growth factor receptor (EGFR), p16, Bcl-xL, and p53 as well as for p53 mutation. These markers were assessed for association with high-risk human papillomavirus (HPV), response to therapy, and survival. Patient variables included smoking history, sex, age, primary site, tumor stage, and nodal status.

Results: EGFR expression was inversely associated with response to induction chemotherapy (IC) (P = .01), chemotherapy/radiotherapy (CRT; P = .055), overall survival (OS; P = .001), and disease-specific survival (DSS; P = .002) and was directly associated with current smoking (P = .04), female sex (P = .053), and lower HPV titer (P = .03). HPV titer was significantly associated with p16 expression (P < .0001); p16 was significantly associated with response to IC (P = .008), CRT (P = .009), OS (P = .001), and DSS (P = .003). As combined markers, lower HPV titer and high EGFR expression were associated with worse OS ({rho}EGFR = 0.008; {rho}HPV = 0.03) and DSS ({rho}EGFR = 0.01; {rho}HPV = 0.016). In 36 of 42 biopsies, p53 was wild-type, and only one HPV-positive tumor had mutant p53. The combination of low p53 and high Bcl-xL expression was associated with poor OS (P = .005) and DSS (P = .002).

Conclusion: Low EGFR and high p16 (or higher HPV titer) expression are markers of good response to organ-sparing therapy and outcome, whereas high EGFR expression, combined low p53/high Bcl-xL expression, female sex, and smoking are associated with a poor outcome. Smoking cessation and strategies to target EGFR and Bcl-xL are important adjuncts to the treatment of oropharyngeal cancer.

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Journal of Clinical Oncology, Vol 26, No 4 (February 1), 2008: pp. 612-619
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.14.1713

Incidence Trends for Human Papillomavirus–Related and –Unrelated Oral Squamous Cell Carcinomas in the United States

Anil K. Chaturvedi, Eric A. Engels, William F. Anderson, Maura L. Gillison

From the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda; and the Johns Hopkins Medical Institutions, Baltimore, MD

Corresponding author: Maura L. Gillison, MD, PhD, Johns Hopkins University, Cancer Research Bldg I, Rm 3M 54A, 1650 Orleans St, Baltimore, MD 21231; e-mail: gillima@jhmi.edu

Purpose: To investigate the impact of human papillomavirus (HPV) on the epidemiology of oral squamous cell carcinomas (OSCCs) in the United States, we assessed differences in patient characteristics, incidence, and survival between potentially HPV-related and HPV-unrelated OSCC sites.

Patients and Methods: Data from nine Surveillance, Epidemiology, and End Results program registries (1973 to 2004) were used to classify OSCCs by anatomic site as potentially HPV-related (n = 17,625) or HPV-unrelated (n = 28,144). Joinpoint regression and age-period-cohort models were used to assess incidence trends. Life-table analyses were used to compare 2-year overall survival for HPV-related and HPV-unrelated OSCCs.

Results: HPV-related OSCCs were diagnosed at younger ages than HPV-unrelated OSCCs (mean ages at diagnosis, 61.0 and 63.8 years, respectively; P < .001). Incidence increased significantly for HPV-related OSCC from 1973 to 2004 (annual percentage change [APC] = 0.80; P < .001), particularly among white men and at younger ages. By contrast, incidence for HPV-unrelated OSCC was stable through 1982 (APC = 0.82; P = .186) and declined significantly during 1983 to 2004 (APC = –1.85; P < .001). When treated with radiation, improvements in 2-year survival across calendar periods were more pronounced for HPV-related OSCCs (absolute increase in survival from 1973 through 1982 to 1993 through 2004 for localized, regional, and distant stages = 9.9%, 23.1%, and 18.6%, respectively) than HPV-unrelated OSCCs (5.6%, 3.1%, and 9.9%, respectively). During 1993 to 2004, for all stages treated with radiation, patients with HPV-related OSCCs had significantly higher survival rates than those with HPV-unrelated OSCCs.

Conclusion: The proportion of OSCCs that are potentially HPV-related increased in the United States from 1973 to 2004, perhaps as a result of changing sexual behaviors. Recent improvements in survival with radiotherapy may be due in part to a shift in the etiology of OSCCs.

Supported by the Intramural Research Program of the National Cancer Institute and the National Institute of Dental and Craniofacial Research.

Presented in part at a Clinical Science Symposium at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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