PTEN loss, PIK3CA mutation predicted resistance to cetuximab in HNSCC

June 2, 2013


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|

Are combination therapies effective for advanced SCCHN?

Author: DrBicuspid Staff

In a recent study, researchers from the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center examined whether the addition of multiple drugs to radiation therapy is superior to the current standard of care therapy with one drug and radiation for locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Their data, published in the Journal of Clinical Oncology, suggests that it does not (March 4, 2013). Standard therapy for SCCHN is a combination of the drug cisplatin and radiotherapy.

This clinical trial compared this combination to the combination with the addition of a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) erlotinib. For the study, 204 patients with locally advanced SCCHN were recruited between December 2006 and October 2011. Participants were assigned to receive either cisplatin and radiotherapy or the same chemoradiotherapy with erlotinab.

EGFR is a therapeutic target for this type of cancer, and at least one other EGFR is approved for multiple uses in treating head and neck cancer, including in combination with radiation. To date, no data have been published on the use of EGFR inhibitors in combination with chemotherapy and radiation.

The goal of the current study was to determine if adding EGRF inhibition improved efficacy when combined with standard of care radiation. Unfortunately, the researchers found that the addition of EGRF did not improve clinical response rate or progression-free survival.

“There has been great enthusiasm and some confusion about the combinations of chemotherapy and biologic therapy such as EGFR inhibitors in conjunction with radiation in the treatment of squamous cell carcinomas of the head and neck,” stated lead author Neil Hayes, MD, MPH, from UNC Lineberger Comprehensive Cancer Center, in a press release. “For the moment, the data are clearly showing no added benefit.”

Future investigations will rely more on patients selected by the molecular tumor characteristics, he added.

Other institutions participating in the study were the University of Washington, Fred Hutchinson Cancer Research Center, Multicare Health Systems, University of New Mexico, Medical University of South Carolina, University of Miami, Coastal Carolina Radiation Oncology, and the University of Tennessee. Funding for the study was provided to the University of Washington by Genentech and Astellas Pharma Global Development.

March, 2013|Oral Cancer News|

Targeted Drugs No Help in Head and Neck Cancer

Author: Charles Bankhead, Staff Writer, MedPage Today
Date: March 05, 2013

The addition of targeted agents to standard chemotherapy failed to improve efficacy in two different trials of advanced head and neck cancer.

In one trial, patients given gefitinib (Iressa) in addition to docetaxel lived about a month longer than those who received docetaxel plus placebo. In the other trial, adding erlotinib (Tarceva) to cisplatin-based chemoradiation did not improve response rate or progression-free survival.

However, neither regimen was associated with increased toxicity compared with standard chemotherapy, investigators reported online in the Journal of Clinical Oncology.

Noting the lack of useful biomarkers to guide the use of targeted agents, the authors of an accompanying editorial said that experience to date suggests current strategies amount to “skimming the surface of a problem that is exceedingly complex.”

“It is unlikely that genomic sequencing alone will represent a panacea to the therapeutic challenges in squamous cell carcinoma of the head and neck,” said Aaron R. Hansen, MBBS, and Lillian L. Siu, MD, of Princess Margaret Cancer Center in Toronto. “Comprehensive characterization that encompasses a broader omics-based molecular evaluation, as well as immune function assessments, is urgently needed.”

The rationale for the gefitinib and erlotinib trials came from evidence that the drugs targeting epidermal growth factor receptors (EGFR) have synergism with conventional chemotherapeutic agents, have radiosensitizing properties, and have demonstrated modest activity as monotherapy in some clinical studies.

Cetuximab (Erbitux), another EGFR inhibitor, has been approved for use with radiation therapy or as monotherapy in selected patients with head and neck cancer.


Preliminary studies of the docetaxel-erlotinib combination showed considerable toxicity that required dose reductions. As a result, the investigators chose to evaluate gefitinib in combination with docetaxel.

“Our hypothesis was that the addition of gefitinib to docetaxel will be synergistic and improve outcomes of previously treated and/or compromised performance status patients with recurrent or metastatic squamous cell carcinoma of the head and neck,” Athanassios Argiris, MD, of the University of Texas Health Science Center at San Antonio, and co-authors wrote.

Eligible patients had recurrent or metastatic disease and Eastern Cooperative Oncology Group (ECOG) performance status 2 or ECOG 0 to 2 and previous exposure to chemotherapy. All patients received weekly docetaxel and were randomized to gefitinib or placebo.

Treatment continued until disease progression, and the primary endpoint was overall survival.

The phase III trial had a patient-accrual goal of 330, but enrollment ended after 270 patients when an interim analysis suggested efforts to demonstrate improvement in the primary endpoint would prove futile.

The results showed a median overall survival of 6 months in the docetaxel-placebo arm and 7.3 months with the docetaxel-gefitinib regimen. An unplanned analysis suggested that patients younger than 65 benefited from gefitinib (7.6 versus 5.2 months median overall survival, P=0.04).

Grade 3/4 toxicity occurred in a similar proportion of patients in both treatment arms, with the exception of diarrhea, which was more common with gefitinib.


The erlotinib trial involved 204 patients with locally advanced squamous cell carcinoma of the head and neck. All patients received cisplatin-based chemoradiation and were randomized to the EGFR inhibitor or no further therapy.

The primary endpoint was complete response rate, and progression-free survival (PFS) was the secondary endpoint, as reported by Renato G. Martins, MD, of the University of Washington in Seattle, and colleagues.

The results showed a complete response rate of 40% without chemoradiation and 52% with chemoradiation plus erlotinib, a difference that did not achieve statistical significance (P=0.08). After a median follow-up of 26 months, PFS also did not differ significantly between the two treatment arms (HR 0.9, P=0.71).

Investigators prospectively evaluated p16 status in 90 patients. A positive result was defined as “strong, diffuse nuclear and cytoplasmic staining in ≥70% of tumor cells.” Patients with p16-positive tumors had significant improvement in the hazard for progression when they received erlotinib (HR 0.39, P=0.04).

Martins and colleagues also evaluated the relationship between development of rash and PFS in patients who received erlotinib. The analysis revealed rash as a significant predictor of improved PFS (HR 0.41 versus erlotinib-treated patients without rash, P=0.03).

“Despite preclinical data suggesting that erlotinib could be synergistic with both chemotherapy and radiotherapy, erlotinib previously failed to improve outcome in metastatic non-small cell lung cancer,” Martins and colleagues noted in their discussion. “Here, erlotinib failed to improve the outcome of locally advanced squamous cell carcinoma of the head and neck when combined with cisplatin-radiotherapy.”

Although disappointing, the results do not represent the end of the line for investigation of targeted agents in head and neck cancer, Ellie Maghami, MD, of City of Hope in Duarte, Calif., told MedPage Today. Echoing the sentiments of Hansen and Liu, Maghami said the true potential of targeted agents in head and neck cancer will not be determined in the absence of accurate biomarkers to guide patient selection.

The gefitinib study was supported by AstraZeneca. The erlotinib study was supported by Genentech.

Argiris disclosed a relationship with AstraZeneca. Co-authors disclosed relationships with AstraZeneca, Boehringer Ingelheim, Genentech, and sanofi-aventis.

Martins disclosed relationships with Genentech and OSI Pharmaceuticals. Co-authors disclosed relationships with XCENDA Amerisource Bergen Consulting Services, Genentech, Intuitive Surgical, and OSI Pharmaceuticals.

Siu disclosed relatinships with Roche, Pfizer, Bristol-Myers Squibb, and Boehringer Ingelheim.

Primary source: Journal of Clinical Oncology
Source reference:
Argiris A, et al “Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: An Eastern Cooperative Oncology Group trial” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.45.4272.

Additional source: Journal of Clinical Oncology
Source reference:
Martins RG, et al “Cisplatin and radiotherapy with or withoout erlotinib in locally advanced squamous cell carcinoma of the head and neck: A randomized phase II trial” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.46.3299.

Additional source: Journal of Clinical Oncology
Source reference:
Hansen AR, Siu LL “Epidermal growth factor receptor targeting in head and neck cancer: Have we been just skimming the surface?” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.47.9220.


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

March, 2013|Oral Cancer News|

Erbitux add-on falls short in esophageal cancer

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|

Ten year results of landmark neck cancer trial published

Author: Gabriel Miller

The latest data from a trial that opened in 1992 confirm that for locally advanced laryngeal cancer, sequential and concomitant chemoradiotherapy each produce similar survival rates, but the concomitant approach more often allows the larynx to be preserved.

When the results of RTOG 91-11 were first published in 2003. “they changed the standard of care treatment for preserving the larynx from the sequential use of chemotherapy then radiotherapy to giving both together,” said lead investigator Dr. Arlene Forastiere of Johns Hopkins University in an email to Reuters Health.

“The results have held up over the last decade,” she said, “…and this exact treatment remains the standard of care today because on average, 15% will ultimately require laryngectomy with the concomitant approach, compared to double that, or 30%, with either giving chemotherapy and radiation in sequence or giving radiotherapy alone.”

“There’s no question that this study has changed the way we approach and treat this disease, so it is truly a landmark study,” said Dr. Chris Holsinger, a head and neck cancer surgeon at MD Anderson Cancer Center in Houston, Texas who wasn’t involved in the research.

Between 1992 and 2000, 547 patients were randomly assigned to three treatment groups: induction chemotherapy followed by radiation; concomitant chemoradiotherapy; and radiotherapy alone.

The induction group received up to three cycles of cisplatin 100 mg/m2 on day one and fluorouracil 1,000 mg/m2 per day for five days, every three weeks. Responders then received up to 70 Gy of radiotherapy in 35 treatments of 2 Gy fractions.

Those in the concomitant chemoradiotherapy group received cisplatin 100mg/m2 on days 1, 22, and 43 of radiation treatments.

Those in the radiotherapy-only group received only 70 Gy of radiation.

All of the patients had stage III or IV squamous cell cancer of the supraglottic or glottic larynx that was considered curable with laryngectomy and radiotherapy. The primary outcome measure was “laryngectomy-free survival,” which was measured after a median of 10.8 years of follow-up in the current report. Late toxicity was also measured.

Overall survival at both five and 10 years was not significantly different between any of the groups, ranging from 54%-58% and 28-39%, respectively.

There was also no significant difference in the cumulative incidence of grade 3-5 toxicities between the groups. At ten years, the rates were 30.6%, 33.3% and 38% for induction chemotherapy followed by radiation, concomitant chemoradiotherapy, and radiotherapy alone, respectively.

However, in terms of larynx preservation, there was a significant advantage for concomitant cisplatin and radiotherapy, with a 54% relative risk reduction for laryngectomy compared to radiotherapy alone (p<0.001) and a 42% reduction compared with induction chemotherapy plus radiotherapy (p=0.005).

This trial was one of the largest and longest in the field to date. But head and neck cancer is a homogenous disease. “For head and neck cancers, in general, and for larynx cancer in particular, we don’t have a fully established standard,” said Dr. Jochen Lorch, a head and neck oncologist at Dana-Farber Cancer Institute in Boston who was not involved in the trial.

“My take would be this shows value in both approaches, induction and concurrent, but I think that you’re not going to get an answer about what’s the best way to treat this disease,” said Dr. Holsinger. “I definitely think that the clear value of the different approaches also opens up the path to studying minimally invasive surgery for this disease, especially neoadjuvant approaches.”

Newer induction regimens have also further clouded the picture.

“The cisplatin and 5-fluorouracil drug combination that was used in sequence with radiation has been replaced with a more effective regimen of three drugs,” said Dr. Forastiere. “We don’t yet know whether this newer induction regimen followed by radiotherapy would be as effective as concomitant treatment. That is a study that needs to be done.”

Full results of the trial were published online November 26 in the Journal of Clinical Oncology.

Source: J Clin Oncol 2012.

November, 2012|Oral Cancer News|

Neoadjuvant chemo does not improve oral cancer survival rates

Author: DrBicuspid Staff

Patients with advanced resectable oral squamous cell carcinoma (OSCC) who undergo surgery do not benefit from improved survival after induction with docetaxel, cisplatin, and fluorouracil (TPF), according to a new study (Journal of Clinical Oncology, November 5, 2012). Study author Zhi-yuan Zhang, MD, PhD, from Shanghai Jiao Tong University School of Medicine, and colleagues assessed 256 patients with resectable locally advanced OSCC.

A total of 222 patients completed the full treatment protocol. They received two cycles of TPF induction chemotherapy (75 mg/m2 of docetaxel on day 1, 75 mg/m2 of cisplatin on day 1, and 750 mg/m2 of fluorouracil on days 1 to 5) followed by radical surgery and postoperative radiotherapy versus upfront radical surgery and postoperative radiotherapy.

The primary end point was overall survival. Secondary end points included local control and safety.

After a median follow-up of 30 months, there was no significant difference in overall survival or disease-free survival between patients treated with or without TPF induction, the study authors noted. Patients in the induction chemotherapy arm with a clinical response or favorable pathologic response had superior overall survival and locoregional and distant control.

“Our study failed to demonstrate that TPF induction chemotherapy improves survival compared with upfront surgery in patients with resectable stage III or IVA OSCC,” the authors concluded.

The lack of survival benefit indicates that TPF induction chemotherapy without selection could not benefit OSCC patients in general, Dr. Zhang told Reuters Health in a news story.

“On the other hand, superior outcomes are seen in responders, as assessed both by clinical and pathologic responses,” he said. “Therefore, induction chemotherapy is likely to be effective for biologically distinct subgroups, and biomarker development might lead to identification of patients whose tumors are likely to respond to a particular treatment.”

November, 2012|Oral Cancer News|

Study will evaluate Panitumumab regimen in advanced SCCHN

Author: staff

Canadian researchers are investigating standard fractionation radiotherapy with concurrent high-dose cisplatin versus accelerated fractionation radiotherapy with panitumumab in patients with locally advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN).

The NCIC Clinical Trials Group has completed accrual for the randomized phase III study, which has a planned sample size of 320 patients with SCC of the oral cavity, oropharynx, larynx, or hypopharynx. The trial was launched in December 2008, and the Data Safety and Monitoring Committee recommended continuing the trial in October 2011.

Patients assigned to arm I will undergo standard fractionation radiotherapy once daily, five days a week, for seven weeks; they will also receive cisplatin intravenously over one hour on days 1, 22, and 43 of radiotherapy.

Participants assigned to arm II will undergo accelerated fractionation radiotherapy once or twice daily, five days a week, for six weeks; they will also receive panitumumab intravenously over 30-90 minutes one week prior to and on days 15 and 36 of radiotherapy.

The primary endpoint is progression-free survival (PFS), while secondary endpoints include overall survival, local and regional PFS, distant metastases, adverse events, swallowing-related quality of life, functional swallowing outcomes, and economic assessments.

The FDA has approved panitumumab under the brand name Vectibix for the treatment of patients with metastatic colorectal carcinoma with disease progression on or following chemotherapy regimens containing fluoropyrimidine, oxaliplatin, and irinotecan. Panitumumab is a human IgG2 kappa monoclonal antibody that binds specifically to human epidermal growth factor receptor (EGFR).

Amgen, which markets Vectibix, has joined the Canadian Cancer Research Society Institute in supporting the trial (NCT00820248).

Waldron JN, Parulekar W, O’Sullivan B, et al. A phase III study of standard fractionation radiotherapy with concurrent high-dose cisplatin versus accelerated fractionation radiotherapy (RT) with panitumumab in patients with locally advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) (NCIC Clinical Trials Group HN.6). J Clin Oncol. 2012;30(suppl; abstr TPS5600)

September, 2012|Oral Cancer News|

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

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.’”


CD4 counts predict chemo response in laryngeal cancer

Author: Miriam E. Tucker

Pretreatment CD4 levels predicted response to induction chemotherapy among 97 patients with advanced laryngeal cancer, but not for 66 patients with advanced oropharyngeal cancer, according to a retrospective analysis of data from two clinical trials.

The two groups of head and neck cancer patients were enrolled in two identical prospective, phase II trials of induction chemotherapy and organ preservation, in which tumor response after one cycle of cisplatin and 5-fluorouracil was used to select those who would undergo surgery or definitive chemoradiation (J. Clin. Oncol. 2006;24:593-8 in laryngeal cancer; J. Clin. Oncol. 2008;26:3138-46 in oropharyngeal cancer).

Several lymphocyte subsets were measured before treatment via routine flow cytometry in peripheral blood in the laryngeal cancer patients, but only CD4 (helper cell) levels were significantly associated with chemotherapy response. Both absolute CD4 counts and CD4 percentages were higher among induction chemotherapy responders than nonresponders (P = .006 and P = .04, respectively).

Investigators also saw a trend for responders to have an increased percentage of CD3 cells (P = .13), decreased percentage of CD8 cells (P = .11), and higher CD4/CD8 ratios.

“Host immune parameters are important factors in treatment outcome, and may be useful in identifying subsets of patients with cancers that are responsive to organ-preserving therapy,” said Dr. Gregory T. Wolf, who presented the data at a head and neck cancer symposium sponsored by the American Society for Radiation Oncology.

“It is likely that immunobiology of head and neck cancers differ significantly by tumor site and predisposing factors,” added Dr. Wolf, a professor in the department of otolaryngology at the University of Michigan, Ann Arbor.

The median length of follow-up in the two studies was 7.9 years for the patients with laryngeal cancer and 6.6 years for those with cancer of the oropharynx. Disease-free survival was 86% at 3 years and 82% at 5 years for laryngeal cancer, and 78% at 3 years and 76% at 4 years for oropharyngeal cancer. The proportions responding to induction chemotherapy were 75% in the laryngeal cancer trial and 82% in the oropharyngeal cancer study.

In an interview, Dr. Wolf said that having two identical treatment trials provided an opportunity to determine whether correlations of pretreatment CD4 levels with chemoresponse differed by tumor site. When the laryngeal and oropharyngeal cancer patient groups were combined, higher CD4 levels were still associated with response, but this was primarily because of the strong correlation among the larynx cancer patients.

Statistical regression testing determined that for patients with oropharyngeal cancer, CD8 cells were more closely associated with chemotherapy response, but the relationship was not as strong as the strong correlation of CD4 levels among laryngeal cancer patients.

There was a trend toward improved survival by both CD4 percentage (P = .36) and absolute CD4 count (P = .15) in the laryngeal cohort, but not in the oropharyngeal cohort. None of the other lymphocyte subsets predicted survival in either group, Dr. Wolf said.

Results for the oropharyngeal cancer patients were further stratified by human papillomavirus status, and were combined with the laryngeal cancer group. Both lower CD4/CD8 ratio and higher CD8 levels were consistent with better prognosis among patients who were HPV positive (P = .02 and P = .06, respectively).

“We combined the results to get the largest sample size and [to see] if the relationship was independent of tumor site, since the biology of these cancers is so different. It was remarkable that the prediction differed by tumor site, with CD4 cells being predictive for larynx and CD8 cells predictive for oropharynx,” Dr. Wolf explained in an interview. This finding likely reflects the major biological differences between these cancers, and is why it was important to also include HPV status, he added.

Note: Dr. Wolf is a consultant for IRX Therapeutics, Inc.

February, 2012|Oral Cancer News|

Cisplatin Aids Survival of High-Risk Head and Neck Cancer

Source: Oncology Report

Adding chemotherapy to radiotherapy improved 10-year survival of resectable head and neck carcinomas among high-risk patients who had microscopically involved resection margins and/or extracapsular spread of disease – but not in high-risk patients who only had tumor in multiple lymph nodes.

The findings come from a long-term update and unplanned subset analysis of 410 evaluable patients from the RTOG (Radiation Therapy Oncology Group) 9501 phase III study, which previously showed no overall survival advantage from the addition of cisplatin chemotherapy to radiation.

The new data are “good news,” according to lead author Dr. Jay Cooper, director of Maimonides Cancer Center in Brooklyn, N.Y.

“We now can eradicate some advanced head and neck tumors that we couldn’t before by adding chemotherapy to radiation therapy. At the same time, we can spare other patients who would not do better with the addition of chemotherapy from its side effects,” he said at a head and neck cancer symposium sponsored by the American Society for Radiation Therapy.

The RTOG 9501 study randomized 459 patients with high-risk, resected head and neck cancers to receive either radiation therapy of 60 Gy in 6 weeks (RT), or identical radiotherapy plus cisplatin at 100 mg/m2 IV on days 1, 22, and 43 (RT+CT).

When reported at a median follow-up of 45.9 months, the locoregional control rate was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for locoregional recurrence, 0.61); disease-free survival was significantly longer with combined therapy (HR for disease or death, 0.78), but overall survival was not (HR for death, 0.84). Moreover, four patients who received combination therapy died as a result of treatment (N. Engl. J. Med. 2004;350:1937-44).

In the current updated analysis conducted 10 years post treatment, none of the primary outcomes differed significantly between the two groups. The evaluable population comprised 208 patients who received RT and 202 given RT+CT. For patients treated by RT vs. RT+CT, the rates were, respectively, 28.8% vs. 22.3% (P = .10) for locoregional failure, 19.1% vs. 20.1% (P = .25) for disease-free survival, and 27.0% vs. 29.1% (P = .31) for overall survival.

In a subset analysis that had not been performed previously, however, statistically significant differences appeared within the 242 patients who had microscopically involved resection margins and/or extracapsular spread of disease. In this group, 115 patients received RT and 127 were given RT+CT. Locoregional failure occurred in 33.1% of the CT group vs. 21.0% of those treated with RT+CT (P = .02). The disease-free survival rate was 12.3% vs. 18.4% (P = .05), and the overall survival rate was 19.6% vs. 27.1% (P = .07), with both end points favoring RT+CT.

That left 168 patients who did not have involved margins or extracapsular extension and were included in the trial solely because they had multiple involved nodes. In this group, 93 received RT and 75 RT+CT, with no significant difference in long-term outcomes.

There was a trend in improved cause-specific survival with RT+CT for patients whose death resulted from head and neck cancer, but more deaths not due to the study cancer were observed in patients treated with concurrent cisplatin. This is a hypothesis-generating finding that needs to be investigated in future trials, Dr. Cooper noted.

In an interview, he explained that the rationale for looking specifically at the patients with microscopically involved resection margins and/or extracapsular spread came from a previous analysis of the raw data from the RTOG trial combined with those of a concurrently published study conducted by the EORTC (European Organisation for Research and Treatment of Cancer).

Although the design of the EORTC 22931 study was similar, the outcome was different. Of a total 167 patients who had been randomized to RT or RT+CT, the rate of progression-free survival at a median follow-up of 60 months was significantly higher in the combined-therapy group than in the group given radiotherapy alone (P = .04) (N. Engl. J. Med. 2004;350:1945-52).

When the data from RTOG and EORTC were combined, it became clear that the main reason for the difference in outcome was in the different entry criteria for the two trials, and that extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of adjuvant chemotherapy-enhanced radiation therapy was significant in both trials (Head Neck 2005;27:843-50).

“What we learned from that analysis is that the patients who got on one of the trials but wouldn’t have qualified for the other trial were not getting much benefit from the study regimen, whereas those who qualified for either study – due to having involved margins and/or extracapsular extension – did better with chemotherapy on all three measures.

“These results were highly significant. But more importantly, the data suggested a subgroup where the big bang for the buck was,” Dr. Cooper said in the interview.

The findings don’t mean that the patients who did not benefit are not “high risk,” Dr. Cooper said. “Would they benefit from other chemotherapy? We don’t know. Would they benefit from different drugs or different regimens? Maybe. But we can now fairly comfortably say that in both the short and long run, if patients are high risk only because of involved lymph nodes, don’t treat them with this combination, and spare them the toxicity.”

Dr. Cooper stated that he has no disclosures, as did nine coauthors. One additional coauthor is an employee of Lilly USA.

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

February, 2012|Oral Cancer News|