Targeted radiation, drug therapy combo less toxic for recurrent head, neck cancers

Source: medicalxpress.com
Author: University of Pittsburgh Schools of the Health Sciences

Patients with a recurrence of head and neck cancer who have previously received radiation treatment can be treated more quickly, safely and with fewer side effects with high doses of targeted radiation known as Stereotactic Body Radiation Therapy (SBRT) in combination with a drug that also carefully targets cancerous tumors. These findings from a UPMC CancerCenter study were presented today at the American Society of Radiation Oncology (ASTRO) annual meeting in San Francisco.

SBRT uses concentrated radiation beams in high doses to destroy tumors in difficult or hard-to-reach areas. The treatment is noninvasive, which minimizes damage to surrounding healthy tissue and organs. Clinicians at UPMC CancerCenter, partner with the University of Pittsburgh Cancer Institute (UPCI), used SBRT in combination with the drug cetuximab for patients who had a recurrence of squamous cell carcinoma of the head and neck after going through radiation.

“The prognosis for patients who have a recurrence of head and neck cancer that cannot be surgically removed is already poor. Traditional treatments can be associated with significant side effects so severe that patients give up on the therapy altogether,” said Dwight E. Heron, M.D., vice chairman of radiation oncology at UPCI and director of Radiation Oncology Services at UPMC CancerCenter. “By taking these patients through an abbreviated course of targeted drug and SBRT, we minimize the side effects of treatment.”

Doctors treated 48 patients with the combination therapy between July 2007 and March 2013. All of the patients were able to complete the treatments, which were administered in a span of about two weeks compared to traditional therapies which can take up to nine weeks. Severe toxicity was reported at 12 percent using the combination therapy, compared to upwards of 85 percent using conventional therapies.

“The good news here is that we improved their quality of life and did it safely,” said John Vargo, M.D., a radiation oncology resident at UPMC CancerCenter and one of the lead authors of the study.

“Unfortunately, outcomes using this approach are still challenging so the next part of our research will concentrate on continuing to find ways to improve outcomes by integrating additional novel systemic agents.”

September, 2014|Oral Cancer News|

Docetaxel regimen tops cisplatin in head and neck cancer

Source: www.cancernetwork.com
Author: Anna Azvolinsky, PhD

A phase II study has demonstrated that combining docetaxel-based chemoradiotherapy and the antibody cetuximab postoperatively in patients with high-risk squamous cell carcinoma of the head and neck led to improved disease-free and overall survival, with no unexpected toxicities. The results of the study were published in the Journal of Clinical Oncology.

Two-hundred and thirty-eight stage III and IV patients were randomized to receive radiation therapy (60 Gy) plus cetuximab and either cisplatin (30 mg/m2) or docetaxel (15 mg/m2) once per week as part of the Radiation Therapy Oncology Group (RTOG) 0234 clinical trial.

The 2-year overall survival (OS) was 69% in the cisplatin treatment arm and 79% in the docetaxel treatment arm. The 2-year disease-free survival (DFS) was 57% and 66% in the cisplatin and docetaxel arms, respectively.

Previously, two large phase III trials, the RTOG 9501 and the European Organisation for Research and Treatment of Cancer (EORTC) 22931 trials, both showed a small but significant survival benefit for postoperative head and neck cancer patients who received adjuvant radiation and chemotherapy concurrently, resulting in the incorporation of cisplatin in an adjuvant regimen for high-risk patients. The drawback was that adding cisplatin to radiation therapy increased toxicity. Many of these patients are not candidates for the combination therapy due to poor performance status, older age, and renal insufficiency. The purpose of the current trial was to test whether combining a molecular therapy such as cetuximab with chemotherapy would improve survival with a better toxicity profile, compared with radiation therapy plus chemotherapy.

After a median follow-up of 4.4 years, 48 patients in the cisplatin arm had a DFS event compared with 51 patients in the docetaxel arm. Cisplatin patients had a 24% reduction (P = .05) and docetaxel patients had a 31% reduction (P = .01) in the DFS failure rate compared with a historical control arm (the RTOG 9501 trial).

Patients who had p16-positive oropharynx tumors (43 of 54 patients) had improved survival compared with those who had p16-negative oropharynx disease.

The most common high-grade non-hematologic adverse events were mucositis, dysphagia, and skin rash, seen in both the cisplatin and docetaxel treatment arms. Patients in the cisplatin arm had a greater frequency of high-grade hematologic toxicities compared with those in the docetaxel arm (27.8% vs 14.2%, respectively). More patients in the docetaxel arm had toxicities deemed unacceptable by those conducting the trial (12.3% in the docetaxel arm vs 9.3% in the cisplatin arm).

Cetuximab is a chimeric human monoclonal antibody against the epidermal growth factor receptor (EGFR).

“The delivery of postoperative chemoradiotherapy (using cisplatin or docetaxel once per week plus 60 Gy radiation) with concurrent once-per-week cetuximab for patients with SCCHN [squamous cell carcinoma of the head and neck] who have high-risk pathologic features is feasible and tolerated with predictable toxicity. The radiation-docetaxel-cetuximab regimen shows particularly promising outcome with improvement in DFS and OS relative to RTOG historical controls and appears worthy of further investigation in high-risk patients with SCCHN,” concluded the authors.

Because the conclusions of this trial rely on a historical control comparison, these results need to be further validated in a phase III control-arm clinical trial. The docetaxel plus cetuximab regimen is currently being tested in a phase II/III clinical trial.

In an editorial, Amanda Psyrri, MD, PhD, and Urania Dafni, MD, both of the University of Athens in Greece, noted that, “In an era when next-generation sequencing is becoming increasingly available, identification of mutations that predict therapeutic response or resistance would be a major advance. Therefore, it seems mandatory that we focus our efforts at identifying an ‘EGFR sensitivity signature.’ Until then, it would seem wise not to conduct large phase III studies with cetuximab in unselected patient populations.”

An effective and well-tolerated strategy in recurrent and/or metastatic head and neck cancer: successive lines of active chemotherapeutic agents

Source: 7thspace.com
Author: staff

The combination platinum, 5-fluorouracil (5-FU) and cetuximab is the standard first-line regimen of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). Due to the toxicity of this treatment, alternative therapies are often offered to patients.

The aim of this study was to evaluate the overall survival obtained with a first line chemotherapy adapted to patients functional status and the administration of all active drugs within successive lines of chemotherapy.

Methods: This series included a total of 194 patients with recurrent and/or metastatic HNSCC treated from 2006 to 2011 in a single institution where the administration of successive lines of chemotherapies has been the standard clinical approach. Treatment was administered according to clinical practice guidelines.

Results: Most patients received at least two treatment lines.

Only 11 patients (6%) were treated with a combination of cisplatin, 5-FU and cetuximab in front line, but most patients received at least one platinum-based regimen (n = 154 patients, 78%); 162 (82%) received taxanes, 36 (18%) received 5-FU, 27 (14%) received capecitabine, 67 (34%) received methotrexate and 134 (68%) received cetuximab. The median overall survival was 9.8 months (95% CI: 8.1-11.4 months) and reached 13.1 months among the subgroup of 131 patients eligible for inclusion in a clinical trial.

Conclusion: The survival outcomes of patients treated in the first-line setting with chemotherapy regimens adapted to their functional status, followed by several subsequent regimens were comparable with published outcomes of patients treated by platinum, 5-FU and cetuximab.

Credits/Source: BMC Cancer 2014, 14:504

Lower radiation dose may be given to HPV-positive head and neck cancer patients

Source: Vanderbilt University
Published: June 19, 2014
By: Dagny Stuart


A new study suggests that lowering the dose of radiation therapy for some head and neck cancer patients may improve outcomes and cause fewer long-term side effects.

The research was presented by lead author Anthony Cmelak, M.D., professor of Radiation Oncology at Vanderbilt-Ingram Cancer Center, during the 50th annual meeting of the American Society of Clinical Oncology (ASCO), held May 30 to June 3 in Chicago.

The study focused on patients with newly diagnosed oropharyngeal cancers related to the human papilloma virus (HPV). More than two-thirds of new head and neck cancer patients have HPV-positive tumors and the number of these patients is on the rise. Cmelak’s prior study found that patients with HPV-positive oropharyngeal cancer have significantly longer survival rates than patients whose tumors are HPV negative.

For the new study, 80 HPV-positive patients with stage III, or IVa,b squamous cell cancer of the oropharynx received induction chemotherapy, including paclitaxel, cisplatin and cetuximab.

After chemotherapy, 62 of the patients showed no sign of cancer and were assigned to receive a 25 percent lower dose of intensity-modulated radiation therapy (IMRT) — an advanced technology that targets the radiation beam more accurately to treat the tumor without harming surrounding tissue. The rest of the patients received a standard IMRT dose. The drug cetuximab was also given to both groups of patients along with the IMRT treatment.

Two years after treatment, the survival for the low-dose IMRT patients was 93 percent. Those who did not have complete resolution of cancer following induction and went on to get full-dose radiation had an 87 percent two-year survival. Eighty percent of the low-dose patients and 65 percent of standard IMRT patients also showed no evidence of tumor recurrence. Ninety-six percent of those who had minimal or no smoking history had no evidence of tumor recurrence after two years following treatment, and long-term side effects were minimal.

The investigators concluded that patients with HPV-positive cancer who had excellent responses to induction chemotherapy followed by a reduced dose IMRT and cetuximab experienced high rates of tumor control and very low side effects, particularly for those with a minimal smoking history.

Treating tumors in the delicate head and neck region often causes side effects that can be troublesome and long-lasting, including difficulty swallowing, speech impairment, dry mouth, problems with taste and thyroid issues, so any therapy option that reduces these side effects can have an impact on patient quality of life.

“Treatment for head and neck cancer can be quite grueling, so it’s very encouraging to see we can safely dial back treatment for patients with less aggressive disease and an overall good prognosis, particularly for young patients who have many years to deal with long-term side effects,” said Cmelak.

He noted that lower-dose IMRT is not recommended for patients with HPV-negative cancer or larger tumors.

The authors note that further studies of reduced-dose IMRT in HPV-positive patients are warranted.

Funding was provided by The National Cancer Institute, a division of the National Institutes of Health (CDR0000665170).

* This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.


June, 2014|Oral Cancer News|

Low-dose IMRT may be safe for patients with HPV-positive head and neck cancer

Source: www.oncologypractice.com
Author: Laura Nikolaides

Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.

Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.

Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.

However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. “I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial,” he said. “This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities,” he added.

“We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors,” commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. “Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer,” he added.

Experimental EGFR inhibitor added nothing but rash

Source: www.oncologypractice.com
Author: Neil Osterweil, Oncology Report Digital Network

The addition of the experimental targeted agent zalutumumab to primary curative chemoradiation for head and neck cancers did not improve locoregional control, disease-specific survival, or overall survival at 3 years of follow-up.

The only thing that zalutumumab added to therapy was a skin rash in the large majority of patients who received it, reported Dr. Jens Overgaard, of the department of experimental clinical oncology at Aarhus University, Denmark.

Response to zalutumumab, a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR), was not related to tumor human papillomavirus 16 (HPV/p16) status or to chemoradiotherapy, Dr. Overgaard reported at the Multidisciplinary Head and Neck Cancer Symposium.

The results of the DAHANCA 19 trial echo those of the RTOG (Radiation Oncology Therapy Group) trial 0522, which found no benefit from the addition of the EGFR inhibitor cetuximab (Erbitux) to accelerated cisplatin-based chemoradiotherapy, said Dr. Paul Harari, an invited discussant from the University of Wisconsin, Madison.

“Where I think we have a lot of unanswered questions is acknowledging how little we actually understand about EGFR biology, despite now 40 years of progressive knowledge,” Dr. Harari said.

“We’re now seeing very clearly in molecular and clinical correlate studies that the more we suppress the EGFR, the more we see collateral overexpression of additional RTKs [receptor tyrosine kinases], including members of the HER family, such as HER-3, that enable an escape mechanism for tumors that become resistant to EGFR inhibition,” he said.

Dr. Overgaard and his colleagues in the Danish Head and Neck Cancer Group conducted an open-label, phase III trial in which 619 patients with nonmetastatic squamous cell carcinomas of the larynx, oropharynx, hypopharynx, or oral cavity were randomly assigned to received 66-68 Gy of accelerated radiotherapy with or without zalutumumab 8 mg/kg weekly, with the first dose given a week before the start of radiation. The radiation was given concomitantly with the radiosensitizer nimorazole and, in patients with involved lymph nodes, cisplatin.

A total of 301 patients who received zalutumumab and 307 controls were included in the final intention-to-treat analysis.

At 3-year follow-up, there were no significant differences in either the primary endpoint of locoregional control (76% in zalutumumab-treated patients and 77% of controls) or in the secondary endpoints of disease-specific survival (82% and 85%, respectively) or overall survival (72% and 79%), Dr. Overgaard reported at the symposium, cosponsored by the American Society for Radiation Oncology and the American Society of Clinical Oncology.

Overall, patients who were positive for the HPV/p16 biomarker fared better than p16-negative patients, with an odds ratio for the probability of local control in negative patients of 0.52 (95% confidence interval, 0.36-0.73; P value not reported).

However, regardless of HPV 16 status, the addition of zalutumumab made no difference in the primary endpoint.

In a proportional hazard analysis, factors significantly associated with worse outcomes included worse World Health Organization performance status, higher disease stage, nodal involvement, and HPV/p16 negative status.

Although zalutumumab was generally well tolerated, 94% of patients who received it developed a rash, and of this group, 29% had grade 3 or 4 rash. In all, 11% of patients assigned to zalutumumab had to stop the drug because of rash.

The trial was sponsored by the Danish Head and Neck Cancer Group. Dr. Overgaard reported having no financial disclosures. Dr. Harari has received research funding from Amgen.

March, 2014|Oral Cancer News|

PTEN loss, PIK3CA mutation predicted resistance to cetuximab in HNSCC

June 2, 2013
Source: Helio.com


CHICAGO — PTEN loss or PIK3CA mutation predicted resistance to treatment with cisplatin plus cetuximab in a cohort of patients with head and neck squamous cell carcinoma, according to phase 3 study results presented at the ASCO Annual Meeting.

“Cetuximab is the only targeted therapy in use in head and neck cancer, and although it prolongs survival, the effects are modest. For patients who receive [cetuximab] in the setting of metastatic or recurrent disease, median survival remains less than 1 year,” Barbara Burtness, MD, a medical oncologist at Fox Chase Cancer Center who specializes in head and neck cancers and a HemOnc Today Editorial Board member, said in an interview. “In colon cancer, patients are tested for KRAS mutations to detect patients with upfront resistance to cetuximab, but KRAS mutation is rare in head and neck cancer, and we haven’t had a biomarker to separate the sensitive from resistant patients.”

Burtness and colleagues compared cisplatin plus placebo vs. cisplatin plus cetuximab (Erbitux, Eli Lilly) in 117 patients. The researchers also assessed PIK3CA mutations and loss of PTEN expression in the cohort.

Results indicated that 34% of tumors studied had a loss of PTEN expression and 4% had PIK3CA mutations in the three hotspots studied.

Researchers did not observe any statistically significant differences in OS, PFS or overall response rates.

However, among patients with PIK3CA and PTEN expression, median PFS was 4.2 months for those assigned to cetuximab vs. 2.9 months for those assigned to placebo (adjusted P value=.07). Among patients with PIK3CA mutations but without PTEN expression, median survival was 4.6 months for those assigned to cetuximab and 3.5 months for those assigned to placebo.

“This study was limited by the small size of the original clinical trial, as well as by the fact that specimens were not available for all the patients, so the results are of borderline statistical significance,” Burtness said. “But if these data are corroborated in larger cohorts of cetuximab-treated patients, they would suggest that PTEN loss together with PIK3CA mutation could serve as a signature to identify patients who will not benefit from cetuximab therapy as it is currently given. The advent of PIK3 inhibitors could give us a new treatment strategy for these patients, potentially in combination with cetuximab.”


* This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.


June, 2013|Oral Cancer News|

Erbitux add-on falls short in esophageal cancer

Source: www.medpagetoday.com
Author: Charles Bankhead, Staff Writer, MedPage Today

The addition of a targeted agent to definitive chemoradiation failed to improve survival in an unselected population with esophageal cancer, a randomized trial showed. In fact, patients who received cetuximab (Erbitux) with chemoradiation had significantly worse overall survival (OS) reflected in a 50% increase in the hazard versus chemoradiation alone, reported Thomas Crosby, MD, of Velindre Hospital in Cardiff, Wales, and colleagues.

Investigators could not find any subgroup of patients who benefited from cetuximab, they said in a presentation at the Gastrointestinal Cancers Symposium.

“The addition of cetuximab cannot be recommended to standard definitive chemoradiotherapy in the treatment of unselected patients with esophageal cancer,” Crosby said.

“The use of high-quality definitive chemoradiotherapy in the treatment of localized, poor-prognosis esophageal cancer was associated with excellent survival compared with previous radiotherapy and surgical series,” he added.

Randomized trials have shown that definitive (or primary) chemoradiation improves survival in localized esophageal cancer compared with a single treatment modality. In England, definitive chemoradiation has been used primarily for patients with localized disease that is unsuitable for surgery, Crosby said.

Add-on therapy with cetuximab has improved outcomes in other cancers, notably head and neck cancer and colorectal cancer. The findings provided a rationale for evaluating the addition of cetuximab to primary radiation therapy for localized esophageal cancer.

Crosby presented results of a randomized trial wherein patients with localized (stage I-III) esophageal cancer (less than 10 cm). Patients were excluded if they had celiac lymph-node involvement.

The patients received cisplatin-capecitabine (Xeloda) chemotherapy with or without cetuximab. After 6 weeks of chemotherapy, patients underwent definitive conformal radiation therapy at a total dose of 50 Gy in 25 fractions.

The trial had two stages. The first stage had a primary endpoint of treatment failure-free survival (TFFS), defined as alive at 6 months with no residual cancer in biopsy specimens and no evidence of disease progression outside the radiation therapy field. Secondary endpoints were toxicity, quality of life, overall survival (OS), and feasibility of recruitment. The first stage of the trial had an accrual target of 180 patients.

The trial’s second stage had a primary endpoint of OS and accrual to 420 patients.

However, the trial never reached second stage, but ended after a planned stage one analysis convinced the independent review committee that continued accrual to meet the primary endpoint would be futile.

Treatment and follow-up continued with enrolled patients, and the final analysis included 258 patients who had completed the 6-month assessment of disease status.

Crosby reported that patients randomized to conventional chemoradiation without cetuximab had a TFFS of 77% whereas the cetuximab group had a TFFS of 66%. All survival outcomes favored omission of cetuximab:

Median OS: 25.4 months versus 22.1 months
2-year survival: 56% versus 43.1%
Median progression-free survival: 19.4 months versus 15.9 months
The analysis showed a marked difference in median OS between patients who met the TFFS goal at 6 months and those who did not: 26.7 months versus 8.3 months.

Comparison of OS in the two arms yielded hazard ratio of 1.53 for the cetuximab arm versus chemoradiation only (P=0.035).

In addition to the inferior outcomes with cetuximab, addition of the targeted agent added to the toxicity burden. The cetuximab arm had an 81.4% incidence of grade 3 to 5 toxicity compared with 72.9% without cetuximab.

Patients who received cetuximab in addition to chemoradiation had significantly more grade 3 to 5 dermatologic toxicity (21.7% versus 3.9%, P<0.001) and metabolic/biochemical toxicity (24.0% versus 10.9%, P=0.005).

Additionally, the analysis revealed a trend toward more cardiac adverse events in the cetuximab arm (6.2% versus 1.6%, P=0.053).

The addition of cetuximab also adversely affected adherence to the treatment protocol. Patients in the cetuximab arm were significantly less likely to receive full doses of cisplatin (76.7% versus 89.9%, P=0.005), capecitabine (69.0% versus 85.3%, P=0.002), and radiation therapy (75.2% versus 86.0%, P=0.027).

Additionally, almost a third of patients did not receive the prescribed dose of cetuximab.

“Future strategies to improve the outcome of definitive chemoradiotherapy in esophageal cancer must focus on developing evidence-based biomarkers to select treatments and incorporating newer radiotherapy technologies and targeted systemic treatment to safely intensify treatment, including a higher radiotherapy dose,” Crosby said.

January, 2013|Oral Cancer News|

Scientists find new way to boost cancer drugs

Source: www.drbicuspid.com
Author: DrBicuspid Staff

Shutting down a specific pathway in cancer cells appears to improve the ability of common drugs to wipe those cells out, according to new research from scientists at Fox Chase Cancer Center (Cancer Discovery, January 2013, Vol. 3:1, pp. 96-111).

The new approach appears to enhance the tumor-killing ability of a commonly prescribed class of drugs that includes cetuximab (Erbitux), used to treat head and neck cancers. These drugs work by blocking the activity of the epidermal growth factor receptor (EGFR), which sits on the cell surface and senses cues from the environment, telling cancer cells to grow and divide, according to co-author Igor Astsaturov, MD, PhD, an attending physician in the department of medical oncology at Fox Chase.

In 2010, Dr. Astsaturov and his colleagues identified a pathway in the cell that, when blocked, completely suppressed EGFR activity. Interestingly, the pathway consists of a series of enzymes that, when working in concert, synthesize new molecules of cholesterol.

Working with cancer cells in the lab, the researchers inactivated a key gene in the cholesterol synthesis pathway, and found the cells became more vulnerable to treatment with cetuximab. The same was true in mice that lacked this particular pathway, according to Dr. Astsaturov.

“Most tumors are only moderately sensitive to inhibitors of EGFR, but when these tumors lack an essential gene in the cholesterol pathway, they become exquisitely sensitive to the anti-EGFR drugs,” he said. “The cancers literally melt away in mice.”

The researchers then removed one of the cholesterol genes from the mouse genome and saw that mice developed patchy, scaly skin. When they biopsied this affected skin, they saw no activity of the EGFR protein, reaffirming that shutting down cholesterol synthesis interrupts EGFR.

When the cholesterol biosynthesis pathway is blocked, the normal chain of events that creates a cholesterol molecule is interrupted, and cells accumulate intermediate products of cholesterol that block the normal movement of substances around the cell, according to the researchers. This cellular traffic jam makes it difficult for the cell to transport important components, such as EGFR, which has to move between the inside of the cell and its surface to function properly.

Eventually, researchers can design drugs or look for existing ones that block this cholesterol synthesis pathway, Dr. Astsaturov noted. For now, his lab is trying to uncover more details of how the pathway works, the role of each protein that is involved, and whether if, by blocking a protein, they can wipe out tumors in humans that evade current therapies.

January, 2013|Oral Cancer News|

Facing the facts: HPV-associated head and neck cancers get a second look

Source: www.curetoday.com
Author: Charlotte Huff

Kevin Pruyne knew he didn’t fit the stereotype of a hard drinker or heavy smoker who one day develops an oral cancer.

The 52-year-old mechanic had been working a three-week stint in a remote section of northern Alaska, repairing trucks on an oil field, when he noticed a hard lump beneath his jaw while shaving. For nearly three months, as Pruyne was prescribed antibiotics for a possible infection and then later shuttled between physician specialists, he kept hearing the same thing: the lump could not be cancer.

Pruyne only occasionally consumed alcohol and had never smoked. His wife, Kathy, began researching her husband’s symptoms, which included repetitive throat clearing, a nagging sensation that something was lodged in his throat and ringing in his ears. And the lump, which looked like the top half of an egg, felt solid to the touch.

This wasn’t some inflamed lymph node from a lingering head cold, Kathy Pruyne says. “He had every symptom [of cancer], but nobody would listen to me.”

Pruyne received a diagnosis of stage 4 oral cancer, which started with a tumor at the base of his tongue. He had already begun chemotherapy when he learned that researchers had discovered an association between the human papillomavirus (HPV) and increasing rates of oropharyngeal cancers. He asked that his tissue be tested; the results came back positive. Pruyne says he wanted to know whether his cancer was caused by HPV because “the prognosis is considerably better with HPV-positive cancer.” He adds he “wanted to hear that there was a better chance of a cure.”

An Explosion of Cases

For researchers and clinicians alike, determining appropriate treatment has taken on new urgency: HPV-positive oropharyngeal malignancies—most typically found on the tonsils or at the base of the tongue—increased 225 percent from 1988 to 2004. If current trends continue, HPV-positive oral cancer cases could soon surpass cervical cancer diagnoses, according to a 2011 study published in the Journal of Clinical Oncology.

As researchers have revisited data from prior oral cancer treatment studies, they’re realizing that patients with HPV-positive tumors respond better to chemotherapy and radiation. One study, which retrospectively analyzed treatment outcomes for stage 3 and stage 4 oropharyngeal patients based on their HPV status, found that the three-year overall survival rate was 82.4 percent in patients with HPV-positive tumors. Among those who tested negative, the three-year overall survival rate was 57.1 percent, according to the findings published in 2010 in The New England Journal of Medicine.

With that in mind, research trials are being launched to determine whether treatment can be modified in some way or even dialed back. The goal? To achieve the same survival with fewer of the swallowing difficulties, taste problems and other debilitating side effects.

“For a subset of patients, we’ve actually achieved a pretty high cure rate,” says James Rocco, MD, PhD, a head and neck surgeon at Massachusetts Eye and Ear Infirmary, and director of head and neck cancer research at Massachusetts General Hospital. “And the question is: Can we maintain that cure and reduce some of the major side effects of treatment?”

But researchers and oncologists have only just begun to understand HPV-positive malignancies. “It’s very clear that HPV-positive oropharyngeal cancer is a completely different entity from HPV-negative,” says Stephen Liu, MD, a head and neck cancer specialist, and an assistant professor of medicine at the University of Southern California.

“We think that it’s going to impact treatment in the future,” Liu adds. But, he stresses, outside of a clinical trial, he “would really discourage anyone from receiving less treatment because their tumor is HPV-positive.”

Identifying the Virus

Traditionally, tobacco and alcohol use have been the primary culprits for triggering cancers in the oropharynx and nearby areas of the mouth, as well as other structures in the throat, such as the larynx. Each year, nearly 40,000 Americans develop cancer of the oral cavity or pharynx. Men are more than twice as likely to receive a diagnosis.

But, until recent years, not someone like David Hastings. The certified public accountant was 58 years old, a lean cyclist who rode some 100 miles each week, when he learned six years ago that he had stage 4 oropharyngeal cancer located at the base of his tongue. Clinicians at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., also were puzzled, as the Gulfport resident tells it. “They said the typical oral cancer patient is a man in his 60s or 70s who sits in a bar all day and drinks and smokes.”

The association with HPV emerged from a perplexing conundrum, says Kian Ang, MD, PhD, a professor in the department of radiation oncology at M.D. Anderson Cancer Center in Houston. As cigarette smoking has declined in recent decades, so have head and neck cancers, with the exception of tumors in the oropharynx. (The region encompasses the middle section of the throat, along with the back portion of the tongue, the soft palate and the tonsils.) That statistical anomaly, Ang says, “gave us the first clue that something else might be going on.”


Starting with a pivotal study published in 2000, researchers began honing in on the role of HPV. Of the 150-plus strains in the HPV family, more than 40 are believed to be transmitted through sexual contact, including anal, genital and oral, according to the National Cancer Institute. The body’s immune system typically eradicates the viruses in a few years before any symptoms emerge (but, in some cases, the cells remain molecularly altered forever). Several of the HPV strains to date, most frequently HPV type 16, have been linked to oral malignancies.

Increasingly, HPV-16 has become a major player in those oral malignancies, according to last year’s Journal of Clinical Oncology study, which projected an explosion in cases in the decades to come.

When researchers studied 271 tissue samples in previously diagnosed patients, HPV prevalence was identified in only 16.3 percent of those collected between 1984 and 1989. Between 2000 and 2004, 72.7 percent of specimens tested positive, a trend that also perhaps correlates with population-wide increases in oral sex, the researchers wrote.

The analysis also highlighted survival differences. If tumors tested HPV-positive, the median survival was nearly 11 years versus 1.6 years for people whose tumors didn’t carry the virus.

Some of the strides in oral cancer treatment that physicians thought they were achieving can at least be partially explained by the emergence of a less aggressive form of cancer, Ang says. “The other part of the improvement,” he says, “is really due to the addition of chemotherapy and the use of high-precision radiation.”

Multifaceted Treatment

Cancers located in the tonsils or at the base of the tongue can sometimes spread undetected, not becoming visible until they’ve reached the nearby lymph nodes. Some early symptoms include swallowing difficulties or a sudden change or hoarseness in the voice. Like Pruyne, Hastings first became concerned when he felt a mysterious lump while shaving. “Totally painless, no sore throat—nothing,” he says.

Oropharyngeal tumors can be classified as stage 3 or 4 but still be considered localized, as long as they have not spread beyond lymph nodes and structures in the head and neck. Pruyne, whose cancer had migrated to numerous nodes on his neck’s right side, recalls how his oncologist hurried out of the room when his imaging test results became available.

The doctor had already warned Pruyne that he could offer relatively little help if the cancer had spread to his chest. “When he came back up, he was visibly relieved,” Pruyne recalls. “And he said, ‘Your lungs are clear.’”

To thwart oropharyngeal malignancies, cancer specialists may incorporate a mix of treatments, including surgery, radiation and chemotherapy, depending upon the location and the aggressiveness of the tumor involved. Ang estimates that only about one-third of patients will undergo surgery. If the tumor can be removed and there’s no evidence that it’s spread to lymph nodes, radiation may not be needed, he says.


But if there’s any concern, patients may receive six weeks of radiation for smaller tumors and seven weeks for larger ones, Ang says. Intensity-modulated radiation therapy (IMRT) is used because it better targets the radiation and thus can limit damage to the salivary glands, reducing dry mouth, as well as damage to other normal tissues, Ang says.

For larger and more aggressive tumors, adding chemotherapy to radiation therapy has been shown to extend survival. One meta-analysis published last year, based on 87 studies involving more than 16,000 patients, analyzed results by tumor location. Researchers found that the combination approach increased five-year overall survival by 8.1 percent in oropharyngeal patients compared with those who didn’t receive any chemotherapy.

The chemotherapy is believed to boost the effectiveness of the radiation, but at a cost—amplified side effects for the patient. The list of potential side effects is lengthy, with so many vulnerable structures and nerves packed into the head and neck area, Liu says. Patients can develop ulcers in their mouth and down their throat, he says. Their salivary glands can generate thick secretions that make it difficult to swallow and to eat.

“The ability to taste, to speak, to salivate,” says Liu, ticking off several more. “Dry mouth. These things can often be permanent. It’s a necessary evil right now because we do what we need to do to cure the cancer.”

Pruyne received two cycles of a cisplatin-based protocol that also included Taxotere (docetaxel) and 5-FU (fluorouracil). Then he started the biologic agent Erbitux (cetuximab) along with hefty doses of IMRT, delivered twice daily for six weeks.

Pruyne’s oncologist warned him that the treatment would be difficult, and it was. He endured radiation burns around the right side of his neck and had to use a feeding tube for two months.

Dialing Back

Although radiation and chemotherapy can be difficult, some patients prefer to take that route, rather than run the risks of surgery, Rocco says. “For advanced local disease, removing the back of the tongue or the soft palate has huge consequences for people,” Rocco says. “They can’t eat. They don’t speak so well.”

But given that patients with HPV-positive tumors are typically diagnosed at a younger age, with potentially decades ahead of them to cope with long-term side effects, the aggressiveness of today’s chemotherapy and radiation regimens are also questionable, he says.

Clinical trials are recruiting patients to answer a question that’s relatively rare in cancer: Can treatment be ramped down? One closely watched phase 3 trial will assess whether Erbitux works as well in HPV-positive patients as the long-standing cisplatin-based chemotherapy regimen.

Cisplatin has been one of the standard drugs used in head and neck cancer, but it’s “very toxic,” says Andy Trotti III, MD, the study’s principal investigator and director of radiation oncology clinical research at Moffitt Cancer Center. The platinum-based drug can impact kidney function and sometimes damage hearing, among other side effects, he says.

Erbitux, which targets the epidermal growth factor receptor (EGFR), primarily affects the skin, Trotti says. In the phase 3 trial, now recruiting HPV-positive patients, the five-year overall survival of patients on Erbitux will be compared with those taking cisplatin. Both groups will receive IMRT.

Another ongoing trial is looking at whether the IMRT regimen can be shortened from six to five weeks, thereby delivering a lower dose of radiation in HPV-positive patients. The patients enrolled in that phase 2 trial, who also will receive cisplatin,  paclitaxel and Erbitux, will be followed for two years.

The study represents a “first step” toward learning whether less radiation can be safely prescribed for HPV-positive patients, Liu says. Since radiation’s effects are cumulative, the extra week of radiation adds “a significant amount of toxicity.”

A New Era in Treatment

Meanwhile, the impact of HPV status on surgical decisions appears to be the subject of some unresolved debate. Given that HPV-positive oropharyngeal malignancies respond well to chemotherapy and radiation, Trotti says, “there has been a real trend away from surgery.”

But new surgical techniques are providing other options for HPV-positive patients who might prefer to limit the long-term side effects of chemotherapy and radiation, says Bert O’Malley, Jr., MD, chairman of the department of otorhinolaryngology of the University of Pennsylvania Health System.

Along with a physician colleague, O’Malley has developed a robotic surgery protocol called TransOral Robotic Surgery. With the assistance of tiny robotic arms and three-dimensional cameras, O’Malley operates through the patient’s mouth, enabling him to remove difficult-to-reach tumors.

A surgery that previously required between six and 16 hours might only take two, he says. Also the approach results in less scarring and fewer surgical complications than the traditional surgery, which may require the jaw to be split, he says.

It’s a new era in HPV-positive treatment, Rocco says. To make his point, he tells of a patient who recently walked in asking to be referred for robotic surgery. The gold standard is still to wait for clinical trial results, but that could take five-plus years, he adds.

HPV-positive patients are frequently “savvy young professionals in the prime of life,” who sort through the latest research online, Rocco points out.

“There are people who are risk-takers,” he says. “They’ll look at the data, and they’ll make a decision, weighing cure and long-term side effects.”

Despite the rigors of treatment, Pruyne was able to resume his job near the Arctic Circle within a few months. He hopes to soon be telling a tale similar to Hastings’, who returned to his biking routine about a year after wrapping up treatment.

Hastings still copes with dry mouth and a reduced ability to taste. But the last time he visited Moffitt for an annual checkup, it felt more like a social call. After some chatting, he quips: “They said, ‘Get out of here. We need to spend more time with people who are sick.’”