Individualized Treatment Selection in Patients With Head and Neck Cancer – Do Molecular Markers Meet the Challenge?

  • 6/30/2008
  • web-based article
  • Bhuvanesh Singh and David G. Pfister
  • Journal of Clinical Oncology, Vol 26, No 19 (July 1), 2008: pp. 3114-3116

Integrated chemotherapy and radiation therapy have become the standard of care for most patients with advanced stage laryngopharyngeal cancers. The concurrent administration of these two modalities is the approach recommended by most experts at present.1 This strategy achieves higher rates of locoregional control compared to when chemotherapy is given as induction treatment before, or as an adjuvant after, radiation therapy.2-6 However, the benefits from concomitant chemoradiotherapy treatment are tempered by higher rates of treatment-related sequelae, especially in the short term. This issue is of particular concern in patients that fail to respond and who have to endure the adverse effects of treatment.

Based on observations that response to chemotherapy predicts radiation response, initial combined modality trials used response to induction chemotherapy to select patients for subsequent organ preservation treatment with definitive radiation, reserving laryngectomy for chemoresistant patients.5,6 However, with a shift to concomitant administration of chemotherapy and radiation therapy, the opportunity for treatment selection based on initial response was lost.3 To maximize the potential value of induction chemotherapy in terms of patient selection while minimizing the delay in the start of concomitant treatment, Urba et al has promulgated an approach in larynx cancer in which one cycle of neoadjuvant chemotherapy is delivered to select patients for subsequent concomitant chemoradiotherapy.7 Their published work suggests that this approach offers advantages for survival improvement over historical controls. The group recently expanded their observations to oropharyngeal cancers, reporting 3-year overall survival of 67% (95% CI, 53.5% to 80.6%) and disease-free survival of 80.5% (95% CI, 68.9% to 92.1%) that was superior to historical controls.8

The use of induction chemotherapy primarily in select patients for subsequent therapy is not without issues. For example, the results of Radiation Therapy Oncology Group trial 91-11 demonstrated that among patients who had less than a partial response at the primary site to induction chemotherapy but refused recommended total laryngectomy, durable disease control was still possible with radiation therapy alone. Similarly, it can be difficult to assess response after just one cycle of chemotherapy, raising the possibility that patients who would have done well with radiation-based treatment alone are triaged to unnecessary surgery.9 Finally, newer triplet induction chemotherapy regimens combining cisplatin and fluorouracil with a taxane have proven to be more efficacious than cisplatin and fluorouracil alone.10-12 By focusing on a short course of induction therapy for patient selection purposes, the potential therapeutic benefit of a more prolonged course on distant control may be compromised.

Not surprisingly, there has been a growing interest in defining molecular subgroups that predict disease behavior to select treatment. The work from Kumar and colleagues13 reported in this issue of the Journal aims to define pretreatment molecular markers that predict response to chemotherapy in a clinical trials data set. This well designed study has the clear benefit of identifying markers that may be clinically applicable. The investigators chose to look at established markers individually and in combination based on biologic principles, leading to the identification of prognostically significant molecular predictors.

The genetic analysis of cancers reached a crescendo with the completion of the Human Genome Project along with the development of high throughput genome-wide analytic techniques. These analyses have helped to shape our understanding of human malignancies generally, and head and neck cancers specifically. Global genomic analyses have identified molecular subsets of head and neck squamous cell carcinoma (HNSCC), which may have prognostic implications.14-21 The challenge has been to reproduce prognostic gene signatures. For example, two independent groups have reported gene signatures that predict outcome in breast cancers using gene arrays, one including 70 genes and the other 76 genes.22-25 Interestingly, although both sets of genes have been validated in independent patient cohorts, there is relatively little overlap between the gene sets. Similarly, the use of individual and combined markers to predict outcome in HNSCC has shown conflicting results, as is well illustrated by the variable correlation between p53 status and outcome reported by different investigators.26-32

Divergent findings are not uncommon when assessing individual molecular markers, reflecting the genetic complexity of HNSCC. To overcome these issues, several studies have attempted to define molecular prognostic groups based on global genomic profiles. Several studies have used comparative genomic hybridization (CGH) to categorize prognostic subgroups in HNSCC. Three of these studies define individual prognostic markers among a background of complex genetic aberrations identified by CGH using well defined statistical methods.14,21,33 These studies identified amplifications at 11q13 and 3q26-27 as markers of outcome. The 11q13 amplification has been well studied, with well characterized oncogenes including cyclin D1, EMS1, and TAOS1 as putative targets for 11q13 amplification.34,35 Amplification at 3q26.3 has also been a topic of significant analysis, with several putative genes (including PIK3CA, PKC-, LAMP3, and eIF-5A2) identified at this locus.36-40 Similarly, gene array studies have delineated putative prognostic subsets that predict outcome.15-17,29 Overall, studies using DNA-based assessment have been more reproducible than those that profile using mRNA-based gene arrays. Moreover, even though they are provocative, none of these studies have been validated sufficiently to allow use in routine clinical practice.

Given the significance of response to chemotherapy in HNSCC, several studies have used this as a surrogate end point for defining molecular markers. Predictably, the literature on genome-based assessment of factors predicting response to platinum-based treatment is limited. Studies using CGH suggest that increased chromosomal instability may contribute to tumors containing or acquiring genetic changes that confer treatment resistance in HNSCC, but do not reproducibly identify specific events that predict treatment response. Gene expression array analyses have identified factors that may predict response to chemotherapy. In an interesting study, 45 genes were identified that predicted cisplatin response.18 The accuracy of these markers was 83%, with a positive predictive value of 78% and a negative predictive value of 100% in ovarian and lung cancers. Other studies have also identified prognostic signatures, but there is limited overlap between studies in the gene sets, calling their significance into question.41,42 Moreover, limited information is available for gene sets predicating chemoresponse in HNSCC.15,29

In contrast to specific or combined molecular markers, the definition of patient subgroups by biologic parameters has been much more reliable in predicting outcome. In vitro chemosensitivity testing has been shown by some investigators to be an independent predictor of outcome,43-45 although a technology assessment done by the American Society of Clinical Oncology would suggest that chemopredictive assays are not ready for routine use.46 The presence of human papillomavirus (HPV) in oropharyngeal cancers also predicts outcome. Like cervical cancers, HPV appears to play a causative role in the development of HNSCC.47 A meta-analysis of published trials, including 5,046 HNSCC cancer specimens, shows a 26% prevalence of HPV, with the vast majority being HPV type 16 (HPV-16).48 The predominant location of HPV-associated tumors is in the oropharynx, with a predilection for nonsmokers (up to 50% of cases). Similar to cervical cancers, detection of HPV in HNSCC is associated with sexual history, implicating direct exposure as a cause for infection.49 In addition, immunosuppression has been suggested to increase the risk for infection and development of HPV-related HNSCC.50 Of specific interest, HPV-positive tumors have improved outcomes relative to HPV-negative cases.51 The outcome advantage is maintained in patients treated with chemoradiotherapy, suggesting that HPV status may be a predictor of treatment response.52 This assertion is validated by the studies from Worden et al54 and Kumar et al,13 suggesting that HPV status should be considered in the selection of patients for concomitant chemoradiotherapy. Recent work indicates that the genetic composition of HPV-positive and HPV-negative cancers may be different, suggesting putative molecular markers that may have predictive value.20,53 Kumar and colleagues report an association between p16 and HPV status, suggesting that p16 may serve as a surrogate marker for HPV infection.13,54 Weinberg and colleagues combined the HPV status with the p16 expression level to develop a prognostic categorization for oropharyngeal tumors and showed that it was a treatment response predictor.52,55

Despite these promising findings, the key question that remains is whether any of the putative predictors can be used to individualize treatment selection. Unfortunately, unlike the example of kinase mutations in other solid tumors, the predictive value of individual or combined molecular markers remains insufficient for routine clinical use in HNSCC. Even more importantly, the inherent genetic differences that predict response to chemotherapy remain unidentified, which may not only serve as treatment selectors, but also as therapeutic targets. The current work suggests that combining the epidermal growth factor receptor (EGFR) expression status with HPV status may predict chemoradiotherapy treatment response. Given the success of EGFR targeting in combination with radiation in HNSCC, could targeting EGFR in HPV-negative, EGFR overexpressing cases improve control? These and other possibilities merit investigation.

1. published online ahead of print at on May 12, 2008
2. The author(s) indicated no potential conflicts of interest.

1. National Comprehensive Cancer Network Practice Guidelines: Head and Neck Cancer (v.1.2007).

2. Pfister DG, Laurie SA, Weinstein GS, et al: American Society of Clinical Oncology clinical practice guideline for the use of larynx-preservation strategies in the treatment of laryngeal cancer. J Clin Oncol 24:3693-3704, 2006

3. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003

4. Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data: MACH-NC Collaborative Group: Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355:949-955, 2000

5. Wolf GT, Fisher SG: Effectiveness of salvage neck dissection for advanced regional metastases when induction chemotherapy and radiation are used for organ preservation. Laryngoscope 102:934-939, 1992

6. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preservation in pyriform sinus cancer: Preliminary results of a European Organisation for Research and Treatment of Cancer phase III trial: EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 88:890-899, 1996

7. Urba S, Wolf G, Eisbruch A, et al: Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: A new treatment paradigm. J Clin Oncol 24:593-598, 2006

8. Worden FP, Urba S, Bradford C, et al: One cycle of induction chemotherapy (IC) in advanced oropharyngeal cancer (SCCOP) to select patients for organ preservation (OP). J Clin Oncol 23:503s, 2005 (abstr 5512)

9. Pfister DG, Ridge JA: Induction chemotherapy for larynx preservation: Patient selection or therapeutic effect? J Clin Oncol 24:540-543, 2006

10. 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

11. 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

12. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al: Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 23:8636-8645, 2005

13. Kumar B, Cordell K, Lee DJ, et al: EGFR, p16, HPV titer, BCLXL and p53, sex and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 26:3128-3137, 2008

14. Bockmuhl U, Schluns K, Kuchler I, et al: Genetic imbalances with impact on survival in head and neck cancer patients. Am J Pathol 157:369-375, 2000

15. Akervall J: Genomic screening of head and neck cancer and its implications for therapy planning. Eur Arch Otorhinolaryngol 263:297-304, 2006

16. Belbin TJ, Singh B, Barber I, et al: Molecular classification of head and neck squamous cell carcinoma using cDNA microarrays. Cancer Res 62:1184-1190, 2002

17. Chung CH, Parker JS, Karaca G, et al: Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 5:489-500, 2004

18. Hsu DS, Balakumaran BS, Acharya CR, et al: Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer. J Clin Oncol 25:4350-4357, 2007

19. O’Regan EM, Toner ME, Smyth PC, et al: Distinct array comparative genomic hybridization profiles in oral squamous cell carcinoma occurring in young patients. Head Neck 28:330-338, 2006

20. Smeets SJ, Braakhuis BJM, Abbas S, et al: Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus. Oncogene 25:2558-2564, 2006

21. Wreesmann VB, Shi W, Thaler HT, et al: Identification of novel prognosticators of outcome in squamous cell carcinoma of the head and neck. J Clin Oncol 22:3965-3972, 2004

22. Foekens JA, Atkins D, Zhang Y, et al: Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer. J Clin Oncol 24:1665-1671, 2006

23. Wang Y, Klijn JG, Zhang Y, et al: Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671-679, 2005

24. van de Vijver MJ, He YD, van’t Veer LJ, et al: A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002

25. van ‘t Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002

26. Bradford CR, Zhu S, Ogawa H, et al: P53 mutation correlates with cisplatin sensitivity in head and neck squamous cell carcinoma lines. Head Neck 25:654-661, 2003

27. Bradford CR, Zhu S, Poore J, et al: p53 mutation as a prognostic marker in advanced laryngeal carcinoma: Department of Veterans Affairs Laryngeal Cancer Cooperative Study Group. Arch Otolaryngol Head Neck Surg 123:605-609, 1997

28. Bradford CR, Zhu S, Wolf GT, et al: Overexpression of p53 predicts organ preservation using induction chemotherapy and radiation in patients with advanced laryngeal cancer: Department of Veterans Affairs Laryngeal Cancer Study Group. Otolaryngol Head Neck Surg 113:408-412, 1995

29. Ganly I, Talbot S, Carlson D, et al: Identification of angiogenesis/metastases genes predicting chemoradiotherapy response in patients with laryngopharyngeal carcinoma. J Clin Oncol 25:1369-1376, 2007

30. Homma AA, Furuta YY, Oridate NN, et al: Prognostic significance of clinical parameters and biological markers in patients with squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy. Clin Cancer Res 5:801-806, 1999

31. Lavertu PP, Adelstein DDJ, Myles JJ, et al: P53 and Ki-67 as outcome predictors for advanced squamous cell cancers of the head and neck treated with chemoradiotherapy. The Laryngoscope 111:1878-1892, 2001

32. Osman I, Sherman E, Singh B, et al: Alteration of p53 pathway in squamous cell carcinoma of the head and neck: Impact on treatment outcome in patients treated with larynx preservation intent. J Clin Oncol 20:2980-2987, 2002

33. Ashman JN, Patmore HS, Condon LT, et al: Prognostic value of genomic alterations in head and neck squamous cell carcinoma detected by comparative genomic hybridisation. Br J Cancer 89:864-869, 2003

34. Huang X, Gollin SM, Raja S, et al: High-resolution mapping of the 11q13 amplicon and identification of a gene, TAOS1, that is amplified and overexpressed in oral cancer cells. Proc Natl Acad Sci U S A 99:11369-11374, 2002

35. Rodrigo JP, Garcia LA, Ramos S, et al: EMS1 gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. Clin Cancer Res 6:3177-3182, 2000

36. Singh B, Reddy PG, Goberdhan A, et al: p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas. Genes Dev 16:984-993, 2002

37. Eder AM, Sui X, Rosen DG, et al: Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci U S A 102:12519-12524, 2005

38. Kanao H, Enomoto T, Kimura T, et al: Overexpression of LAMP3/TSC403/DC-LAMP promotes metastasis in uterine cervical cancer. Cancer Res 65:8640-8645, 2005

39. Regala RP, Weems C, Jamieson L, et al: Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol Chem 280:31109-31115, 2005

40. Brass N, Heckel D, Sahin U, et al: Translation initiation factor eIF-4gamma is encoded by an amplified gene and induces an immune response in squamous cell lung carcinoma. Hum Mol Genet 6:33-39, 1997

41. Kerley-Hamilton JS, Pike AM, Li N, et al: A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embryonal carcinoma. Oncogene 24:6090-6100, 2005

42. Dressman HK, Berchuck A, Chan G, et al: An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J Clin Oncol 25:517-525, 2007

43. Singh B, Li R, Xu L, et al: Prediction of survival in patients with head and neck cancer using the histoculture drug response assay. Head Neck 24:437-442, 2002

44. Ohie S, Udagawa Y, Aoki D, et al: Histoculture drug response assay to monitor chemoresponse. Methods Mol Med 110:79-86, 2005

45. Furukawa T, Kubota T, Hoffman RM: Clinical applications of the histoculture drug response assay. Clin Cancer Res 1:305-311, 1995

46. Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology Technology Assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22:3631-3638, 2004

47. 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

48. Kreimer AR, Clifford GM, Boyle P, et al: Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review. Cancer Epidemiol Biomarkers Prev 14:467-475, 2005

49. D’Souza G, Kreimer AR, Viscidi R, et al: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356:1944-1956, 2007

50. Kutler DI, Wreesmann VB, Goberdhan A, et al: Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients.J Natl Cancer Inst 95:1718-1721, 2003

51. Fakhry C, Gillison ML: Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 24:2606-2611, 2006

52. Weinberger PM, Yu Z, Haffty BG, et al: Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 24:736-747, 2006

53. Strati K, Pitot HC, Lambert PF: Identification of biomarkers that distinguish human papillomavirus (HPV)-positive versus HPV-negative head and neck cancers in a mouse model. Proc Natl Acad Sci U S A 103:14152-14157, 2006

54. Worden F, Kumar B, Lee J, et al: Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: Response an survival positively associated with HPV16 copy number. J Clin Oncol 26:3138-3146, 2008

55. Weinberger P, Kountourakis P, Sasaki C, et al: Oropharyngeal squamous cell cancers (OSCC) bearing transcriptionally active human papillomavirus (HPV) display distinct protein expression profile. J Clin Oncol 24:, 2006 (abstr 10028)

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Knowledge and opinions regarding oral cancer among Maryland dental students

  • 6/30/2008
  • Bethesda, MD
  • S Boroumand et al.
  • J Cancer Educ, June 1, 2008; 23(2): 85-91

Most oral cancers are diagnosed at late stages. Health care providers, particularly dentists, play a critical role in early detection of oral cancers and should be knowledgeable and skillful in oral cancer diagnosis. In this study, we assessed knowledge and opinions regarding oral cancer among dental students in Maryland.

A cross-sectional survey was conducted among Maryland dental students in 2005.

The response rate was 59.6%. Knowledge of oral cancer was low among freshmen and significantly different from other classes. There was no statistically significant difference between 2nd-, 3rd- and 4th-year students in terms of level of oral cancer knowledge. The results revealed inadequate confidence among junior and senior students with regard to oral cancer examination and lymph node palpation.

Findings from this study identify areas that need reinforcement in Maryland dental school’s curriculum regarding oral cancer education. This survey approach could be a model for other dental schools in the United States or overseas.

S Boroumand, AI Garcia, RH Selwitz, and HS Goodman

Authors’ affiliation:
National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA

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Prognostic factors of survival in head and neck cancer patients treated with surgery and postoperative radiation therapy

  • 6/30/2008
  • Clichy, France
  • C Le Tourneau et al.
  • Acta Otolaryngol, June 1, 2008; 128(6): 706-12

Given that radiation therapy (RT) is currently initiated as soon as possible after surgery, our results indicate that the main prognostic factors of survival are pT and pN stages in patients treated with surgery and postoperative RT for locally advanced head and neck squamous cell carcinoma (HNSCC).

To determine the prognostic factors for survival in patients treated with surgery and postoperative RT for locally advanced HNSCC. Patients and methods. A retrospective study was performed on 308 consecutive patients treated from 1990 to 1998 with surgery and postoperative RT. In addition to histological factors, time-related factors were considered.

The median age of the whole cohort was 56 years (range 35-83). Median follow-up was 98 months. Median interval from surgery to the start of RT was 44 days (range 18-157), while median RT duration was 52 days (range 22-115). From univariate analysis of overall survival, statistically significant prognostic factors were pT stage (p<0.0001), pN stage (p=0.008), RT duration (p=0.01) and total treatment time (p=0.02). Perineural invasion, perivascular invasion, extranodal spread and positive resection margins did not appear to be related to survival. From multivariate analysis, the only statistically independent prognostic factors appeared to be pT and pN stages.

C Le Tourneau, GM Jung, C Borel, G Bronner, H Flesch, and M Velten

Authors’ affiliation:
Department of Medical Oncology, Beaujon University Hospital Clichy

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Chemoselection As a Strategy for Organ Preservation in Advanced Oropharynx Cancer

  • 6/30/2008
  • Ann Arbor, MI
  • Francis P. Worden et al.
  • Journal of Clinical Oncology, Vol 26, No 19 (July 1), 2008: pp. 3138-3146

Response and Survival Positively Associated With HPV16 Copy Number

To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome.

Patients and Methods:
Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m2) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m2/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m2 or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV.

Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008).

Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.

Supported in part by Grants No. R01 DE13346 and P30 DC 05188 from the National Institutes of Health (NIH) NIDCR; Head and Neck Cancer SPORE Grant No. P50 CA97248; Cancer Center Support Grant No. P30 CA46592; and Grants from the state of Michigan.

Francis P. Worden, Bhavna Kumar, Julia S. Lee, Gregory T. Wolf, Kitrina G. Cordell, Jeremy M.G. Taylor, Susan G. Urba, Avraham Eisbruch, Theodoros N. Teknos, Douglas B. Chepeha, Mark E. Prince, Christina I. Tsien, Nisha J. D’Silva, Kun Yang, David M. Kurnit, Heidi L. Mason, Tamara H. Miller, Nancy E. Wallace, Carol R. Bradford, Thomas E. Carey

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

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Genetically engineered viruses battle cancer

  • 6/29/2008
  • Washington, DC
  • Robert Boyd

Viruses aren’t always the bad guys. Sure, they can cause colds, measles, AIDS and other miseries. But with some tinkering, these tiny organisms may become a new and better way to treat cancer.
In the last few years, scientists have been genetically engineering various viruses so they attack cancer cells but leave healthy cells alone. These “oncolytic” — cancer-destroying — viruses are being tested in hundreds of terminally ill patients for whom surgery, radiation and chemotherapy have failed.

Several of these experimental viruses target malignant brain tumors, like the incurable glioma that’s afflicting Sen. Edward Kennedy, D-Mass.

“The past two years have seen several major advances in oncolytic virotherapy,” David Kirn, the president of Jennerex Biotherapeutics Inc., a biotechnology firm in San Francisco, reported in the journal Gene Therapy in April. “A large number of clinical trials have been carried out. Safety in humans has been demonstrated in more than 800 patients.”

So far, no cancer-killing virus has received U.S. government approval for general use in humans, but dozens of clinical trials are under way to determine their safety and effectiveness.

Some could be ready for doctors to use in the next two or three years, said Dr. Frank McCormick, a cancer researcher at the University of California-San Francisco. He cautioned, however, that many hurdles remain to be overcome before viral therapy will be part of usual medical practice.

Ways must be found to defeat the body’s natural immune system, which is primed to destroy invading viruses. Early results show that viruses can shrink a local tumor, but stopping cancer from spreading, or metastasizing, is much harder, McCormick said.

“The real need is systemic treatment for metastatic disease,” McCormick said. “We’re not there yet with this technology.”

Despite the doubts, at least six species of viruses are candidates for cancer therapy.

For example, researchers are working with a harmless virus that sits in the lungs and intestines of most people. It’s called a “reovirus,” short for respiratory enteric orphaned virus.” A Canadian company, Oncolytics Biotech, fiddles with reovirus genes to produce Reolysin, a virus that attacks a wide variety of cancers.

In a trial headed by Dr. James Markert, a neurosurgeon at the University of Alabama in Birmingham, 44 patients with brain cancer received injections of Reolysin. Preliminary results are encouraging, Markert said. “We’re very optimistic that viral therapy will be one of our weapons in the fight against cancer. It could be a major piece of the puzzle.”

Drs. Monica Mita and Francis Giles, at the University of Texas Health Science Center in San Antonio, are testing reovirus against bone and lung cancer.

The cancer in one of Mita’s experimental patients, Kenneth Scott, has remained stable since he received an experimental injection of Reolysin a year ago.

According to Mita, the side effects of reovirus are similar to a mild cold, compared with the more serious impacts of chemotherapy.

There are multiple strategies for a virus to attack cancer, Kirn said. The virus can worm its way inside a cancer cell, multiply and kill the cell. It can act as a tiny truck or “Trojan horse,” sneaking cancer-killing substances into the target cell. It can gum up the environment around a tumor so that the cancer can’t spread.

Other viruses being tested as weapons against cancer include: — The common herpes virus, the source of cold sores and genital lesions.

A modified herpes virus called HSV1716 has passed preliminary tests for safety and effectiveness against brain tumors and melanoma. It’s undergoing an advanced clinical trial in Great Britain.

Markert and colleagues are testing another herpes virus, known as G207, against brain cancer. “Some patients had remarkable successes,” Markert said.

Vaccinia, the first vaccine against smallpox, which Edward Jenner, an English country doctor, discovered in 1796. Also known as poxvirus, it’s the basis of JX-594, an anti-cancer product developed by Jennerex in San Francisco.

In a preliminary trial, 14 end-stage liver and lung cancer patients were injected with the JX-594 virus. Half of them survived for more than eight months, well past their life expectancies of three to four months, Kirn told a meeting of the American Gene Therapy Association in Boston in May.

A modified cold virus, called H101, which the Chinese government approved in 2005 for use against head and neck cancers.

“This is the first oncolytic virus product approved by a governmental agency for human use,” Kirn reported.

China is “more open-minded about trying these novel biological therapies than people here,” McCormick said. China requires only that a drug reduce the size of a cancerous tumor, not necessarily prove that it prolongs a patient’s life.

“Getting approval based on patient survival is very different than just showing a shrinking of tumors,” McCormick said. “Rightly, our FDA would not approve that sort of thing.”

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Researchers from University of Minnesota publish findings in oral cancer

  • 6/25/2008
  • Minneapolis, MN
  • staff
  • NewsRX (

According to a study from the United States, “Whole human saliva possesses tremendous potential in clinical diagnostics, particularly for conditions within the oral cavity such as oral cancer. Although many have studied the soluble fraction of whole saliva, few have taken advantage of the diagnostic potential of the cells present in saliva, and none have taken advantage of proteomics capabilities for their study.”

“We report on a novel proteomics method with which we characterized for the first time cells contained in whole saliva from patients diagnosed with oral squamous cell carcinoma. Our method uses three dimensions of peptide fractionation, combining the following steps: preparative IEF using free flow electrophoresis, strong cation exchange step gradient chromatography, and microcapillary reverse-phase liquid chromatography. We determined that the whole saliva samples contained enough cells, mostly exfoliated epithelial cells, providing adequate amounts of total protein for proteomics analysis. From a mixture of four oral cancer patient samples, the analysis resulted in a catalogue of over 1000 human proteins, each identified from at least two peptides, including numerous proteins with a role in oral squamous cell carcinoma signaling and tumorigenesis pathways. Additionally proteins from over 30 different bacteria were identified, some of which putatively contribute to cancer development. The combination of preparative IEF followed by strong cation exchange chromatography effectively fractionated the complex peptide mixtures despite the closely related physiochemical peptide properties of these separations (pI and solution phase charge, respectively). Furthermore compared with our two-step method combining preparative IEF and reverse-phase liquid chromatography, our three-step method identified significantly more cellular proteins while retaining higher confidence protein identification enabled by peptide pi information gained through IEF,” wrote H.W. Xie and colleagues, University of Minnesota.

The researchers concluded: “Thus, for detecting salivary markers of oral cancer and possibly other conditions of the oral cavity, the results confirm both the potential of analyzing the cells in whole saliva and doing so with our proteomics method.”

1. Xie and colleagues published their study in Molecular & Cellular Proteomics (Proteomics analysis of cells in whole saliva from oral cancer patients via value-added three-dimensional peptide fractionation and tandem mass spectrometry. Molecular & Cellular Proteomics, 2008;7(3):486-498).

2. For more information, contact T.J. Griffin, University of Minnesota, Dept. of Biochemistry Molecular Biology & Biophysics, School Dental, 321 Church St. SE, 6-155 Jackson Hall, Minneapolis, MN 55455, USA.

3. Publisher contact information for the journal Molecular & Cellular Proteomics is: American Society Biochemistry Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814-3996, USA.

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Treatment of Patients with Clinically Lymph Node-negative Squamous Cell Carcinoma of the Oral Cavity

  • 6/24/2008
  • Seoul, South Korea
  • Won Il Jang et al.
  • Japanese Journal of Clinical Oncology 2008 38(6):395-401

To evaluate treatment outcome and to determine optimal treatment strategy for patients with clinically lymph node-negative (N0) oral cavity squamous cell carcinoma (SCC).

Two hundred and twenty-seven patients with oral cavity SCC received radiotherapy with curative intent. We retrospectively analyzed 69 patients with clinically N0 disease. Forty-three patients were treated with surgery followed by radiotherapy (S+EBRT) and 26 with radiotherapy alone (EBRT). The median doses administered were 63.0 Gy for S+EBRT and 70.2 Gy for EBRT.

The rates of occult metastasis were 60% for T1, 69% for T2, 100% for T3 and 39% for T4, respectively, among patients who underwent neck dissection. A contralateral occult metastasis occurred only in two patients. The median follow-up was 39 months (range, 6–170 months). The 5-year overall survival (OS), disease-free survival (DFS), local control (LC) and regional control (RC) rates for all patients were 56, 50, 66 and 79%, respectively. The 5-year OS, DFS, LC and RC rates were 67/39% (P < 0.01), 66/24% (P < 0.01), 87/30% (P < 0.01) and 73/89% (P = 0.11) for S+EBRT/EBRT, respectively.

The risk for occult neck metastasis is high in patients with oral cavity SCC; therefore, elective neck treatment should be considered. Excellent RC for subclinical disease can be achieved with radiotherapy alone. However, external beam radiotherapy alone to primary tumor resulted in poor LC and combined treatment with surgery and radiotherapy appeared to be a better treatment strategy.

Won Il Jang1, Hong-Gyun Wu1,4,5, Charn Il Park1,4,5, Kwang Hyun Kim2, Myoung-Whun Sung2, Myung-Jin Kim3, Pill-Hoon Choung3, Jong-Ho Lee3 and Jin-Yong Choi3

Authors affiliations:
1 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul
2 Department of Otolaryngology and Head and Neck Surgery, Seoul National University College of Medicine, Seoul
3 Department of Oral and Maxillofacial Surgery, Seoul National University College of Dentistry, Seoul
4 Cancer Research Institute, Seoul National University College of Medicine, Seoul
5 Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea

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Clinical Trials for the Prevention of Mucositis in Patients With Cancer of the Head and Neck

  • 6/24/2008
  • Los Angeles, CA
  • press release
  • Fox Business (

Canopus BioPharma, Inc. is pleased to announce that the South African Medicines Control Council has granted approval for a Phase II study in 30 cancer patients evaluating the protective effect of CB1400 on the gastrointestional tract from radiation-induced mucositis. This new trial is an important step forward in the development of CB1400 as a novel, preventative, anti-mucositis agent.

Oral and gastrointestinal (GI) mucositis is a painful, debilitating, and sometimes fatal, side-effect of radiation therapy and cancer chemotherapy. No preventative mucositis medicines are available, and few treatments are effective. With some cancer therapies, oral mucositis can develop in over 90% of patients. Consequently, it is a widespread problem with considerable economic and healthcare implications. There is a real need for an effective and well-tolerated mucositis prophylactic. The US market for a preventative mucositis agent is estimated to be over $1 billion per annum.

In work carried out on behalf of Canopus, CB1400 has already been shown to have protective and antimutagenic effects when tested in an animal model of mucositis. Complete protection of the GI tract was seen in gamma-radiated mice pre-treated with oral CB1400 (100 mg/kg/day). Even with high doses of radiation (10Gy), there was no evidence of mucositis: weight gain was observed in the CB1400 pre-treated groups; all mice treated with placebo died.

Canopus BioPharma Inc. has applied to undertake further clinical studies with leading oncologists in Australia, South Africa and the USA, investigating CB1400 as a preventative mucositis agent in head and neck cancer patients who are receiving radiation and/or chemotherapy.

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Imrt Reirradiation of Head and Neck Cancer-Disease Control and Morbidity Outcomes

  • 6/23/2008
  • web-based article
  • Erik P Sulman et al.
  • Int J Radiat Oncol Biol Phys, June 13, 2008

Institutional and cooperative group experience has demonstrated the feasibility of reirradiation for head and neck cancer. Limited data are available regarding the use of intensity-modulated radiotherapy (IMRT) for this indication. We reviewed our initial experience using IMRT for previously irradiated head and neck cancer patients.

Methods and Materials:
Records of 78 consecutive patients reirradiated with IMRT for head and neck cancer between 1999 and 2004 were reviewed; 74 cases were analyzed. Reirradiation was defined as any overlap between original and new radiation treatment volumes regardless of the time interval between initial and subsequent treatment. Severe reirradiation-related toxicity was defined as toxic events resulting in hospitalization, corrective surgery, or patient death. Longitudinal estimates of survival were calculated by Kaplan-Meier technique.

Twenty (27%) patients underwent salvage surgical resection and 36 (49%) patients received chemotherapy. Median follow-up from reirradiation was 25 months. Median time interval between initial radiation and reirradiation was 46 months. Median reirradiation dose was 60 Gy. Median lifetime radiation dose was 116.1 Gy. The 2-year overall survival and locoregional control rates were 58% and 64%, respectively. Severe reirradiation related toxicity occurred in 15 patients (20%); one treatment-related death was observed.

The use of IMRT for reirradiation of recurrent or second primary head and neck cancers resulted in encouraging local control and survival. Reirradiation-related morbidity was significant, but may be less severe than previously published reports using conventional techniques.

Erik P Sulman, David L Schwartz, Thuy T Le, K Kian Ang, William H Morrison, David I Rosenthal, Anesa Ahamad, Merril Kies, Bonnie Glisson, Randal Weber, and Adam S Garden

Authors’ affiliation:
Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX

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Mouth cancer checks DO happen, say dentists

  • 6/23/2008
  • London, England
  • staff

A report revealing an alarming number of dental patients going without mouth cancer checks has prompted a tide of protest from dentists throughout the UK. The survey revealed that 71% of people said their dentist had never checked them for the condition. And 87% said their dentist had never even spoken to them about it.

Dr Nigel Carter, chief executive of the British Dental Health Foundation (BDHF), said: ‘Mouth cancer is a very serious condition.

‘It kills more than cervical cancer and testicular cancer combined, and yet a staggering 23% of people have never even heard of it.

‘The problem here appears to be twofold. First, not enough dentists are carrying out the checks, and second, those that do carry them out are failing to communicate this to their patients, missing a perfect opportunity to educate them on the dangers of mouth cancer.

‘NHS dentists are expected to carry out dental check-ups in a very short space of time, and it appears that many do not feel they have the time to carry out this important activity.’

The National Mouth Cancer Survey questioned 500 adults across 10 UK cities in April 2008 and was coducted by the BDHF and Medicash.

However, Mr Gill, a partner at Dean Road Dental Practice in South Shields, said: ‘It is something that is done, but not said.

‘When having a good look around the mouth, we look for these things. It is what we do. It is part of our job.’

Mr Gill has only come across three cases of mouth cancer in the 15 years he has been qualified.

He added: ‘It is not something you see often, but it is on the increase due to alcohol and smoking, and that is a concern. We check every patient, full stop.’

Dr Amarjit Gill, who works at a practice in Nottingham, said: ‘I’m sure dentists are checking, but maybe just not telling the patient.

‘The important thing for patients is to feel empowered and ask if they are worried about anything.

‘When you use the word ‘cancer’ with people, it sends shockwaves.’

Dr Gill said all his patients knew he checked for the disease and made them aware of it.

Mouth cancer kills one in two people that develop the condition but with early detection survival chances increase to nine out of ten.

Dentists are trained to spot the early signs of mouth cancer that can include ulcers that do not heal, lumps and red or white patches in the mouth.

Self-examination can also be beneficial.

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