Monthly Archives: December 2009

Vaccines plus screening could end cervical cancer

Author: Fram Lowry

Out with the old and in with the new is a commonly followed maxim in medicine given the rapid pace of developments in diagnosis and treatment. Human papillomavirus vaccines are relative newcomers to the cervical cancer armamentarium, but they cannot be relied on to do the job on their own; screening is still a must.

Richard B. Roden, PhD, from Johns Hopkins University in Baltimore, and Carlos L. Santos, MD, from the Instituto Nacional de Enfermedades Neoplasicas in Lima, Peru, discussed the merits and drawbacks of HPV vaccines and standard screening during a session on female malignancies at ASCO 2009 in Orlando

Long-term protection

The widespread vaccination of adolescents against HPV will be critical to the eradication of cervical cancer, said Dr. Roden, an associate professor in the department of pathology. “HPV virus-like particle [VLP] vaccines are very effective in preventing genital HPV infection and neoplastic disease,” he explained. “Solid protection has been observed for more than six years after vaccination, suggesting vaccine protection is likely to be long-term, although the need for a booster is not out of the question.”

To date, two HPV vaccines are FDA-approved: Gardasil from Merck, produced in yeast, and Cervarix from GlaxoSmithKline, produced in insect cells. In October 2009, Gardasil was approved by the FDA for use in boys and men (aged 9-26) for the prevention of genital warts caused by HPV-6 and HPV-11.

Both vaccines target HPV-16 and HPV-18, the two most common oncogenic HPV types. Gardasil also targets HPV-6 and HPV-11, which cause benign genital warts.

Two types of trials, efficacy trials and immunogenicity bridging trials, have contributed to the licensing of these HPV VLP vaccines. All of the six efficacy trials have been placebo-controlled (randomized 1:1 between vaccine and placebo) and double-blinded, and they have included young women.

“Some of the results from these trials have been confusing to some people, and that reflects the different types of analyses that were done,” Dr. Roden said. The cohorts analyzed were:

• According to protocol (ATP)
• Intention to treat (ITT)
• Modified intention to treat (MITT)

The most clearcut study results came from ATP trials that were conducted with no protocol violations. Also, the endpoints were not counted until the intervention was completed. In ITT, endpoints were counted from the start of enrollment; these trials offer a better estimation of the impact of general use. Finally, in MITT trials, protocol violations were still counted as were endpoints that occurred after one intervention/dose. In the trials with Gardasil and Cervarix, efficacy in the ATP cohort was consistent and impressive, ranging from 96% to 100%. However, the efficacy dropped off in the MITT cohort: between 94% and 100% for the Gardasil trials and between 76% and 94% for Cervarix trials. Based on MITT/ITT analysis for any HPV type, vaccine efficacy came in at 34% in the FUTURE I study, 17% in the FUTURE II study, and 52% in the GSK 001/07 study.

“Why is this efficacy so low? These are really the expected results. The prophylactic vaccine produces somewhat type-restricted protection,” Dr. Roden said. “The vaccine does not induce the regression of established infection. Disease from prevalent infection dominated disease from incident infection in the trials that had a relatively short follow up.” In short, the vaccines are not therapeutic, he added.

The HPV vaccine has been shown to be effective in other groups, Dr. Roden said. ATP data on Gardasil have demonstrated a 90% reduction in HPV-6 and HPV-11 in women aged 24 to 45. It has also been deemed effective in adolescent boys and men (aged 16 to 23), with an approximately 85% reduction in incident, persistent six-month infection and a near 90% reduction in incident external warts caused by the main HPV types.

Finally, immunobridging studies provide rationale for vaccination in groups that were not included in the major trials, such as adolescent girls, he said. Solid protection for more than six years after vaccination suggests that the benefits are long-term.

Screening remains main option in many countries
While the evidence for the efficacy of vaccination may be solid, its widespread, global distribution is less certain at this time. In developing areas with limited resources, vaccination with the current HPV vaccines may not be an option, said Dr. Santos, who is a gynecologic oncologist at his institution. This is particularly problematic because cervical cancer is prevalent in these areas, with the highest incident mortality rates in sub-Saharan Africa, Latin America, and some Asian countries, Dr. Santos said. In half of Latin American countries, cervical cancer is the number one female malignancy.

“Let’s take a look at the development of cervical carcinogenesis in order to understand the place for secondary prevention,” he said. “This is a long-lasting process, starting with HPV infection and ending up in invasive carcinoma capable of killing the host. Fortunately, we have a long period of precancerous or premalignant lesions, usually five to 15 years, and these are easily treatable.”

There are two ways to establish a cervical cancer screening program, Dr. Santos said. An opportunistic program takes advantage of any visit that a female patient makes within her healthcare system as a chance for screening. An organized program is promoted by a central public health institution, which ensures coverage to all at risk.

The standard methodology for screening is cytology, followed by colposcopy if it is deemed necessary, followed by biopsy. This system has proved very effective in industrialized nations, Dr. Santos pointed out. He cited data from Scandinavia as an example. “Sweden and Finland get the best results in terms of reduction of the mortality rate because they have long-standing and very well organized screening programs,” he said. “Norway started screening a bit later compared to its neighbors. In Denmark, there is a mixture of opportunistic and organized screening and their results are not as good.”

Unfortunately, developing nations cannot claim such success rates, Dr. Santos said. Some of the reasons that screening has failed include:

• Failure to reach the population at risk
• Lack of sensitivity of cytologic screening
• Infrequency of repeated screening
• Inadequate management of abnormalities found at screening
• Ineffective treatment

However, some countries are having success with screening programs that work outside the confines of traditional, cytology-based methods. In Peru, a “see and treat” approach has been effective, Dr. Santos said. The 10-minute screening starts with the application of a solution of 5% acetic acid on the cervix, which will demarcate the borders of any lesion in the transformation zone. Any lesions that are found are considered high-grade and are treated immediately with cryotherapy, he said, adding that the advantage of cryotherapy is that it is an outpatient procedure that requires no anesthesia.

While HPV vaccination may not happen in developing nations for some time, HPV DNA testing is coming to the forefront as the primary screening method. HPV DNA testing offers many advantages, according to Dr. Santos. “It has a sensitivity over 95%, although it is less specific than cytology,” he said. “Another virtue of HPV DNA testing is that it has very good predictive value: having a negative HPV test means that there is little or no probability of developing a lesion in the next 10 years.”

The obstacle to using HPV testing in the developing world is cost, with the price tag on an individual test ranging from $70 to $80. But a less expensive reliable test—the careHPV at $5 per test—is on the horizon, Dr. Santos said. “This is the plan for developing countries. Women will be screened with careHPV. Those with negative studies will return in three to five years for follow-up testing. Those with positive results will be triaged the same day to visual inspection, and if necessary, will be treated with cryotherapy.”

Even after HPV vaccination goes global, screening will still be necessary, he said. Women who have been vaccinated will undergo screening with HPV DNA testing or biomarker testing later in life (around age 30), and the interval between screenings may be as long as a decade, Dr. Santos predicted.

December, 2009|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|

microRNA evaluation of unknown primary lesions in the head and neck

Authors: Emma BarkerNilva et al.

Unknown primary malignancy in the head and neck is not an infrequent diagnosis for patients with metastatic cervical lymph nodes. Although linked with a relatively good prognosis following radiation treatment, widespread radiation is coupled with significant morbidity.

Altered microRNA (miRNA) expression has been associated with both cancer progression and metastasis. We sought to determine whether miRNA expression analysis could be used as a diagnostic tool to discover the primary site of malignancy, within the head and neck.

We used quantitative real-time PCR to identify miRNA expression profiles of squamous cell carcinoma of the tonsil, base of tongue and post-nasal space, as well as their corresponding metastatic lymph nodes, from 6 patients. Our results revealed that each cancer maintained its expression profile between the primary site and the nodal metastasis (r= 0.82, p<0.0001).

In addition, each anatomical sub-site maintained a distinct miRNA profile between individual patients (r=0.79, p<0.0001). Finally, between sub-sites, the miRNA profiles were distinct (p<0.0001).

As proof of principle, our study provides an indication that miRNA expression analysis may be useful to compare the primary lesion and local metastatic disease. This may be clinically relevant to predict the primary site of origin of metastatic disease, when the primary site remains obscure.

Emma Barker, Nilva Cervigne, Patricia Reis, Rashmi Goswami, Wei XuIlan Weinreb, Jonathan Irish, Suzanne Kamel-Reid

Source: Molecular Cancer 2009, 8:127

December, 2009|Oral Cancer News|

Doctors using mouthwash to detect head, neck cancer

Author: Jean Enersen

For a patient with head and neck cancer, the cure rate is only 30 percent. That’s because the disease is often detected in the late stages. Now catching the cancer earlier may be as simple as gargling with mouthwash.

Edie Acosta’s niece and nephew gave her the courage to fight neck cancer.

“They cut from here, all the way down here,” she said.

On her neck, the scar marks where a stage four tumor was removed.

“It seemed bigger and bigger ’til it got to the size of a fist, a man’s fist,” she said. “And I couldn’t even move my neck. You feel like a little bird whose wings got cut and you can’t fly anymore. I just, I thought I was really gonna die.”

For patients like Edie, late stage diagnosis makes treating neck cancer more difficult. Now, researchers have developed a quick, inexpensive mouthwash to detect these cancers earlier.

The patient rinses with the saline mouthwash. After they spit it out, doctors add antibodies. In about 48 hours, if there’s cancer detected in the saliva, the molecules show up in color.

“We’ve found that these molecules show up differently in the oral rinses from patients that have cancer compared to patients that don’t have cancer,” said Dr. Elizabeth Franzmann, otolaryngologist, Sylvester Cancer Center at the University of Miami.

In a study that included 102 head and neck cancer patients and 69 patients with benign disease, the oral rinse detected the cancer nearly 90 percent of the time.

For Edie, 30 years of smoking has taken a toll. She hopes this new test helps others catch the cancer before it’s too late.

“I think that would be a miracle,” she said.

If head and neck cancer is caught early, doctors say it has and 80 percent cure rate. Researchers are now working on a version of the mouthwash for home use.

December, 2009|Oral Cancer News|

Emory couples cancer drug with green tea extract to help fight cancers of the head and neck

Author: Kristina Bjoran

Clinical researchers at the Emory University Winship Cancer Institute have discovered that pairing a popular cancer-fighting drug with green tea extract may help reduce the risks for neck and head cancers.

The lead investigator in the trial is Dr. Dong Moon Shin, and he and his team have been working to combine the drug Erlotinib with an extract of green tea to observe the effects. Elrotinib is a drug that has been long used as an effective way to treat certain types of lung and pancreatic cancers.

Green tea may provide hope for those with cancers of the head and neck.

Green tea may provide hope for those with cancers of the head and neck.

Neck and head cancers are more common than many know. The American Cancer Society touts that almost 50,000 Americans will be diagnosed with one of the two cancers this year alone, so this new trial at Emory may provide hope for those with pre-cancerous lesions related to the cancers.

The chemical of interest in the green tea extract is called polyphenon E (PPE), and the lab experiments show that combing PPE with Elrontinib can potentially prevent the development of the cancers by targeting specific cellular activity in the pre-cancerous areas. Shin and his team are focusing on the lesions of the head and neck.

Cancers of the head and neck have relatively low survival rates, and have not seen much of an increase over the past few decades. As the sixth most common type of cancer, this new study provides hope to those in need of a new, effective treatment.

December, 2009|Oral Cancer News|

Best face forward

Author: Lacey Meyer

When 16th-century astronomer Tycho Brahe lost part of his nose in a duel, his options for a prosthesis were limited — he donned a folded metal plate in the shape of a nose to cover his missing anatomy.

Today, patients with head and neck cancer, who may lose bone, skin, teeth or cartilage as a result of cancer surgery, find that the focus is not only on cancer control, but also on facial restoration with specialists who see the process as not only functional but also aesthetic. For past patients, the evolved approach to treatment with a multidisciplinary team of specialists, each concentrating on a certain area within the full scope of maxillofacial prosthetic rehabilitation, can be life-changing.

Joseph Huryn, DDS, says he has patients who were recluses for years, unaware of facial prostheses as a possibility. “It changes their life incredibly,” says Huryn, chief of dental service at Memorial Sloan-Kettering Cancer Center in New York City.

Depending on head and neck cancer location, size and treatment, maxillofacial prostheses can be intra-oral (within the mouth) or extra-oral (outside of the mouth). Maxillofacial prosthodontists can fabricate prostheses ranging from a resection appliance — used to replace part of the lower jaw — to an auricular (ear) prosthesis or an orbital prosthesis replacing the eye and surrounding tissues including the eyelid, socket and sometimes part of the cheek and nose. Professionals in anaplastology — the art and science of creating artificial anatomy — specialize in the fabrication of extra-oral prostheses such as eyes, ears, noses and limbs.

“People who are immersing themselves in facial prosthetics are focused on all those little problems that seem minor, and they can offer something even better the next time a patient comes back,” says Greg Gion, clinical anaplastologist and founder of Medical Art Prosthetics in Dallas.

The Team Approach
A multidisciplinary team works with the patient and surgeon from the beginning, expanding the cancer treatment focus to include rehabilitation and quality of life, according to Betsy Davis, DMD, MS.

“The team approach is critically important because it incorporates a comprehensive treatment with rehabilitation so patients have a better outcome,” says Davis, director of the division of maxillofacial prosthetics at the Medical University of South Carolina.

The Head and Neck Tumor Program at the Medical University of South Carolina involves 30 specialties and 72 practitioners, including head and neck surgeons, radiation oncologists and medical oncologists who determine treatment plans using the latest maxillofacial techniques. “The reconstructive surgeon, the dental/maxillofacial prosthodontist, the oral surgeon, and the speech and swallowing pathologist work as a team on the rehabilitation of the patient,” Davis says.

Building the Prosthesis
Prosthetic rehabilitation, now part of the cancer patient’s surgery and treatment plan, begins with a meeting among the surgeons who remove the tumor and perform the reconstruction, and the maxillofacial prosthodontist. They begin discussing the unique challenges of each patient depending on cancer treatment, surgery, and where and how much tissue is removed. The surgeon removing the tumor and the maxillofacial prosthodondist or the anaplastologist creating the prosthesis determine the best approach before the surgery, deciding whether the prosthesis will be attached with adhesive, anchored to osseointegrated implants (screws placed in the bone beneath the skin) or held in placed by virtue of design.

If the meeting indicates that a patient is a candidate for osseointegrated implants, the surgeon can place them at the time of tumor removal. Then after three to four months of healing time to allow the bone to grow around the implanted screws, the abutments (bar and clip or magnets above the skin to which the prosthesis is attached) can be connected to the implants.

Used in maxillofacial prosthetics for more than a decade, osseointegrated implants offer more secure retention and are easier for patients to use, Huryn says.

“Somebody who’s missing one eye doesn’t have the depth perception and doesn’t have the stereovision very often to apply their orbital prosthesis,” he says. “With magnets on the implants, they basically just have to get in the vicinity of the magnets and they’ll just pull the thing into the proper orientation, so it’s really wonderful.”

However, because of insurance companies’ reluctance to pay for more expensive osseointegrated implants, adhesives remain the most commonly used retention method.

Dallas resident Reva Lee, 74, wears an orbital prosthesis retained with adhesive. “It’s like a walking cane,” she says. “I don’t think I could do without it.”

Lee says that right after she lost her eye, surgeons told her just to put on a black patch. “I was going to stay at home,” she says. But Gion crafted her orbital prosthesis and told her which glasses to wear and how to hold her head so the prosthesis was indiscernible. “I thought I would have a miserable life, and he just turned that around.”

Custom Concerns
For patients who may have difficulty managing adhesives, Gion says he tries to offer other ways of attaching the prosthesis. The prosthetics specialist can create what is called an anatomically/self-retained prosthesis, which stays in place only because of its design and fit. In the case of an orbital prosthesis, the practitioner can design a hollow, balloon-like prosthesis to fit in the eye cavity without needing adhesives or implants if the surgeon has prepared the defect area with well-healed tissues and undercuts in the skin lining the cavity, says Gion.

Customizing a facial prosthesis to match the surrounding skin and tissues presents its own set of issues. The two most challenging aesthetic components of the prosthesis, color and contour, are created using both the newest technology and the oldest, the human hand.

While creating the perfect texture and color depends on artistic ability and experience, advances in the use of computer-aided design and manufacturing (CAD/CAM) technology have led to a less time-consuming fabrication process and more accurate results.

“The coloring is really one thing that remains very low-tech,” Gion says. “All coloring of facial prostheses requires somebody who’s trained or has natural ability with color-matching. The method of coming up with a new color formation differs from provider to provider.” Some people have made up their own system of quantifying color and keep color references for each patient, he says.

The color is mixed into silicone to match the patient’s basic skin tone, then the outside of the prosthesis is hand-painted to perfect pigments and nuances such as freckles and hairs. To ensure aesthetic perfection, Davis says she gives patients two prostheses for the price of one, “because the first time you can get it close, but the second time the color is always better.”

Evolving Technique
Silicone materials used to make external prostheses have remained much the same since the 1960s, Gion says, but methods of mixing the silicone to create softer or firmer textures customized for each patient have been developed. These methods take into account the characteristics of specific tissues and the need for durability.

Meanwhile, the old method of taking an impression of the patient’s head and then carving a wax replica from the mold has been replaced by a three-dimensional scan that collects exact measurements reflecting the anatomy shape and contour. “We have the ability to scan and mill a lot of the form we need using 3D technology, particularly in ear prostheses,” Gion says. “We can take a model of a patient’s left ear, scan and then reverse the data and mill the exact opposite. It saves us a lot of time sculpting, and it gives the patient a much more accurate result.” In addition, most patients have a CT scan made before surgery which can also be used by the computer program (known as Mimics) to create the wax pattern, says Davis.

The CAD/CAM technique uses a process known as rapid prototyping that stores the measurements layer by layer in an electronic file to then mill the intermediate wax pattern. The pattern is retained along with the negative mold to use for fabricating replacement prostheses in the future.

Looking Forward
Davis and Huryn say that tissue engineering and 3D medical imaging with CAD/CAM technology will propel future developments.

“Instead of doing a bone graft from the fibula to reconstruct a jaw,” Huryn says, “it might be possible in the future to encourage the patient’s own bone to grow in this matrix that can be generated on a computer and have the exact shape of preoperative situations. It is amazing. It boggles even me.”

One challenge not yet overcome, Gion says, is how to reattach the prosthesis every day with adhesive and not affect the longevity of the silicone. Because they don’t undergo the wear and deterioration of applying and removing adhesive, implant-anchored prostheses last longer, Gion says, adding that the widespread use of osseointegrated implants to attach facial prostheses will lead to the development of softer, more flesh-like silicone materials.

“I think the implant method, just that technique, has sparked a more professional approach to getting patients really good results,” Gion says. “That technology has fed an interest and kind of heightened practitioners’ desire to come up with even better prostheses to go along with the technique that is much more sophisticated.”

A main purpose of the implants, he says, is so patients don’t have to rely on adhesives and live with the fear of their prosthesis getting loose and falling off. Davis agrees that the secure retention of implants, as well as the overall aesthetics, gives patients additional confidence in their prosthesis.

Davis says that when the prosthesis fits well and the patient can camouflage its existence, it really makes a difference. “I think that it helps patients’ psychological well-being tremendously, because now they can go out in society with confidence.”

Lacey Meyer is an editorial intern for Heal.

December, 2009|Oral Cancer News|

Adverse events associated with concurrent chemoradiation therapy in patients with head and neck cancer

Source: Arch Otolaryngol Head Neck Surg. 2009;135(12):1209-1217
Authors: Daniel J. Givens, BS et al.

To assess toxicities, functional outcomes, and health-related quality of life associated with concurrent chemoradiation therapy (CRT) in patients with head and neck cancer.

Prospective and retrospective outcomes study.

Tertiary care institution.

Participants in the longitudinal Outcomes Assessment Project whose head and neck cancer was treated with CRT between February 1, 2000, and March 1, 2007 (n = 104).

Patients prospectively provided functional and health-related quality of life information, including data from the 1-year and most current follow-up visits. Medical records were reviewed to determine toxicity and survival rates.

Main Outcome Measures:
Well-defined acute and late toxicities; functional outcomes (diet, dentition, tracheostomies); head and neck cancer–specific, general health, and depression outcomes; and survival rates.

Most patients had oropharyngeal or laryngeal tumors (87.5%) and advanced-stage disease (75.0%). Approximately one-half had hematologic toxicities and toxicity-related treatment delays. Approximately one-quarter had neurotoxicities and/or ototoxicites, moist desquamation, pneumonia, nausea and vomiting requiring hospitalization or intravenous fluids, dehydration or malnutrition requiring hospitalization, and mild or moderate fever. Although patients receiving the current intensity-modulated radiation therapy (IMRT) protocol using the Pinnacle3 planning system had more toxicity-related treatment delays, they had fewer toxicities and better functional and health-related quality of life outcomes compared with those receiving conventional lateral opposing-field radiation or the initial IMRT protocol using the Best nomos PEACOCK planning system.

Patients receiving CRT experience a substantial number of treatment-related adverse events, primarily affecting oropharyngeal and laryngeal function, with improvement noted for the current IMRT protocol. Improving dental prosthetic rehabilitation and including evaluations with speech and swallowing pathologists before and during treatment may enhance patient outcomes.

Daniel J. Givens, BS; Lucy Hynds Karnell, PhD; Anjali K. Gupta, MD; Gerald H. Clamon, MD; Nitin A. Pagedar, MD; Kristi E. Chang, MD; Douglas J. Van Daele, MD; Gerry F. Funk, MD

Author Affiliations:
Departments of Otolaryngology–Head and Neck Surgery (Mr Givens and Drs Karnell, Pagedar, Chang, Van Daele, and Funk), Radiation Oncology (Dr Gupta), and Internal Medicine (Dr Clamon), University of Iowa College of Medicine, Iowa City.

December, 2009|Oral Cancer News|

New artificial larynx helps people sound more human

Author: Aaron Saenz

You may have a family member or friend who had throat cancer. Maybe you’ve seen a TV show where a heavy smoker needs an artificial larynx pressed to their neck to speak. Either way, you know the voice that they have to use: robotic, monotone, raspy. It works, but it can leave users unable to express themselves well. Researchers at the University of Witwatersrand in South Africa have developed a new system that measures mouth movement to produce a more “human-like” voice. Their work was on display at the recent International Conference on Biomedical and Pharmaceutical Engineering. By placing a device called a palatometer under the tongue, users can try to speak as normal and have their words synthesized on a speaker. The South African artificial larynx can provide inflection, ending the dreaded monotone and providing the means to indicate you are asking a question. With proper calibration, researchers claim greater than 94% accuracy. That’s good news to those who want to regain a normal speaking voice.

The palatometer, which measures tongue/mouth movements with 118+ pressure sensors, is an older device developed at BYU and produced by Complete Speech. It is most often used by speech therapists in instructing their patients and retails for around $200-$300. You can see a brief presentation of the palatometer after the break. University of Witwatersrand’s innovation comes in developing a selective way of using the mouth movement data to generate toned speech. After cataloging tongue motions, and using predictive-analysis, the team has taught their system to recognize around 50 words with high accuracy. About 18% of the time, however, the new artificial larynx has to skip words it can’t recognize. It also has a 0.3 second delay, leaving users appearing something like a poorly dubbed Godzilla movie. Still, because the palatometer is not an implant (users simply place it in the mouth), it can be easily upgraded as needed. Future versions are likely to improve the accuracy, the vocabulary, and the speed.

December, 2009|Oral Cancer News|

Tongue reconstruction

Author: staff

Tongue cancer accounts for about 25 percent of all oral cancers. According to the National Cancer Institute, about 10,530 cases of tongue cancer will be diagnosed in the U.S. this year. Although the cancer can occur at any age, it’s most commonly diagnosed in older people, with a median age at diagnosis of 61. Men are affected about twice as often as women.

Two important risk factors for tongue cancer are smoking and drinking. For people who smoke and drink, the risk may be up to 100 times that of those who neither smoke nor drink. Another risk factor for tongue cancer is HPV (human papillomavirus) infection. Douglas Chepeha, M.D., Microvascular Reconstructive Surgeon with the University of Michigan, says doctors are also seeing cases of tongue cancer in young and older women who neither smoke nor drink. The reasons for these cases are not clear.

Overall five-year survival rates for tongue cancer are about 59.5 percent. However, the cancer has the potential to spread fairly quickly. If the cancer is detected when the condition is still localized, 5-year survival rates are over 77 percent. Once the cancer spreads regionally, survival rates drop to about 55 percent. Thus, early diagnosis is important. Patients who develop a sore on the tongue that doesn’t heal or bleeds easily should see a physician for evaluation.

Treating Tongue Cancer: Reconstruction After Surgery

Tongue cancer typically occurs on one side of the tongue. The main treatment is surgery, which can require removal of a significant amount of tissue. Chepeha says doctors typically allow the remaining portion of the tongue to heal or place a skin graft over the area. But that can leave patients with trouble speaking, eating and swallowing.

Chepeha and his colleagues are using a reconstructive technique, using a graft from the patient’s own body, to improve the aesthetics and function of the tongue. The natural tongue contains areas of thin and thick tissue. So doctors take tissue from areas of the body that best match the varying degrees of thickness. The most common donor site on the body is the forearm. For very skinny or overweight patients, the abdomen may provide a better match in tissue thickness.

To create the tongue graft, the surgeons look for the area that best matches the size and shape of the original section of tongue. Chepeha compares it to using a fabric pattern to cut out material for a piece of clothing. Once the ideal area is selected, surgeons carefully cut away skin, fat and piece of nerve (no muscle is removed). Then blood vessels and nerve in the graft are connected to those in the mouth. Chepeha says the first 72 hours are the most critical time after the transplant. If the blood vessels are not connected precisely, a clot can form and the transplanted tissue will die.

After the surgery, the nerve in the graft provides some sensation in the transplanted tissue. However, the graft doesn’t have enough muscle control to move on its own. Therefore, patients need to learn how to maneuver the remaining natural half of the tongue for speaking and eating. Taste is not affected much by the surgery because taste buds on the remaining half of the tongue and those located in other areas of the mouth continue to function.

December, 2009|Oral Cancer News|

FDA clears transoral robotic surgery – developed at Penn –for tumors of mouth, throat and voice box

Author: staff

A minimally invasive surgical approach developed by head and neck surgeons at the University of Pennsylvania School of Medicine has been cleared by the U.S. Food and Drug Administration (FDA). The da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, California) has been cleared for TransOral Otolaryngology surgical procedures to treat benign tumors and selected malignant tumors in adults.

Drs. Gregory S. Weinstein and Bert W. O’Malley, Jr. of the University of Pennsylvania School of Medicine’s Department of Otorhinolaryngology: Head and Neck Surgery founded the world’s first TransOral Robotic Surgery (TORS) programat Penn Medicine in 2004, where they developed and researched the TORS approach for a variety of robotic surgical neck approaches for both malignant and benign tumors of the mouth, voice box, tonsil, tongue and other parts of the throat. Since 2005, approximately 350 Penn patients have participated in the world’s first prospective clinical trials of TORS. These research trials compromise the largest and most comprehensive studies of the technology on record.

“TORS has dramatically improved the way we treat head and neck cancer patients, completely removing tumors while preserving speech, swallowing, and other key quality of life issues,” said Bert O’Malley, Jr., MD, professor and chairman of Penn Medicine’s Department of Otorhinolaryngology:Head and Neck Surgery. “It is very exciting that a concept conceived at PENN, evaluated in pre-clinical experimental models at Penn, tested in clinical trials at Penn, and then taught to key surgeons and institutions both within the U.S. and internationally has been officially recognized by our federal governing agencies and peers around the world as a new and improved therapy for select neck cancers and all benign tumors.”

45,000 Americans and approximately 500,000 people worldwide are diagnosed with head and neck cancers each year. Head and neck tumor treatments often involve a combination of surgery, radiation therapy, and chemotherapy. In many cases, surgery offers the greatest chance of cure; yet conventional surgery may require an almost ear-to-ear incision across the throat or splitting the jaw, resulting in speech and swallowing deficits for patients. In comparison, the minimally invasive TORS approach, which accesses the surgical site through the mouth, has been shown to improve long term swallowing function and reduce risk of infection while speeding up the recovery time. When compared to traditional surgeries, after their cancers have been removed successfully, patients have been able to begin swallowing on their own sooner and leave the hospital earlier. TORS outcomes are markedly improved when compared to standard chemotherapy, radiation or traditional open surgical approaches for oropharyngeal cancer.

“Based on our data and patient outcomes, coupled with the national and international enthusiasm and interest for TORS, we are changing the way oropharyngeal cancer and tumors will be treated now and in years to come,” noted Gregory Weinstein, MD, FACS, professor and vice chair of the University of Pennsylvania School of Medicine’s Department of Otorhinolaryngology: Head and Neck Surgery, director of the Division of Head and Neck Surgery and current president of The Society of Robotic Surgery. “We are already collaborating with colleagues in Penn Neurosurgery to investigate TORS for the treatment of other conditions, such as sleep apnea, skull base tumors and cervical spine disease.”

The Penn TORS program developed an international training program that has trained numerous surgical teams from 12 different countries, many of whom have started establishing TORS programs at their respective institutions. With the FDA clearance of the da Vinci System for transoral otolaryngology, Penn Medicine will immediately expand its well established training program to include surgical teams from the United States.

December, 2009|Oral Cancer News|