Cisplatin aids survival of high-risk head and neck cancer

Author: Miriam E. Tucker

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.

February, 2012|Oral Cancer News|

Squamous cell subgroups respond differently to treatment

Author: Nancy A. Melville

A long-term follow-up of patients with head and neck squamous cell carcinoma suggests that only certain high-risk subgroups benefit from radiation plus chemotherapy. This information will spare patients who will not benefit from undergoing the additional treatment.

According to the study, presented here at the 2012 Multidisciplinary Head and Neck Cancer Symposium, patients with microscopically involved resection margins and/or extracapsular spread of disease had a lower risk for cancer recurrence with radiation plus chemotherapy 10 years later, whereas those with tumors in multiple lymph nodes did not benefit from combination treatment; they fared better with radiation alone.

“The clinical implication of these findings is that the high-risk group of patients is not as homogenous a group as we believed it was before the study started,” lead author Jay S. Cooper, MD, director of the Maimonides Cancer Center, in Brooklyn, New York, told Medscape Medical News.

Dr. Cooper and his colleagues analyzed 10 years of follow-up data from the Radiation Therapy Oncology Group (RTOG) 9501/Intergroup phase 3 trial, which examined 410 patients with high-risk resected head and neck cancers.

The patients were considered high risk for cancer recurrence because they had microscopically involved resection margins, extracapsular spread of disease, or multiple lymph node involvement.

“The allocation was equally divided [according to treatment regimen] at the beginning of the study; the groups were not intended to be balanced for the different [risk] factors,” Dr. Cooper said. “We thought they were all equally important.”

The treatment regimen was either postoperative radiation therapy (60 Gy in 6 weeks) or identical radiation therapy plus intravenous cisplatin 100 mg/m² on days 1, 22, and 43.

Whereas an earlier follow-up of surviving patients at 45.9 months showed improvements in local-regional control and disease-free survival in the radiation plus chemotherapy group in general, the different responses in risk-factor subgroups was not observed, Dr. Cooper said.

In the 10-year follow-up, however, the analysis showed trends in the subgroups.

The local-regional failure rate with radiation alone was 28.8% and with radiation plus chemotherapy was 22.3% (P = .10). Disease-free survival was 19.1% and 20.1% (P = .25) and overall survival was 27.0% and 29.1% (P = .31), respectively.

In the unplanned subgroups of patients with microscopically involved resection margins and/or extracapsular spread of disease, local-regional failure occurred in 33.1% of the group treated with radiation alone and in 21.0% of the group treated with radiation plus chemotherapy (P = .02).

Disease-free survival in the high-risk subgroups was 12.3% with radiation alone and 18.4% with radiation plus chemotherapy group (P = .05); overall survival was 19.6% and 27.1%, respectively (P = .07).

Patients with tumors in multiple lymph nodes received no benefit from postoperative radiation plus chemotherapy in the longer-term follow-up, compared with radiation alone.

Cause-specific survival rates showed a trend toward improved outcome in patients receiving radiation plus chemotherapy whose death was due to the study cancer, compared with those receiving radiation alone. However, an increased number of deaths related to causes other than the study cancer was observed in patients treated with radiation plus chemotherapy, the authors noted.

“These findings tell us that these subgroups of high-risk patients — who had either a tumor at the margin or extracapsular spread of the disease — do benefit from the addition of chemotherapy in terms of better local control, even at 10-year follow-up. Simultaneously, patients who have multiple node involvement but who don’t have a tumor at the margin or extracapsular spread of the disease do not benefit from chemotherapy,” Dr. Cooper said.

“In a crazy way, it’s a win–win situation, in that we now know how to spare some of the patients we thought were high risk from the toxicity of chemotherapy,” he said.

“For patients we identified as truly high risk, at least in terms of their response to chemotherapy, we now have a better therapy.”

Although similar findings have been observed before, this analysis sheds light on the longer-term response of high-risk patients, said Stuart J. Wong, MD, associate professor of medicine and otolaryngology at the Medical College of Wisconsin in Milwaukee, who moderated the session.

“There was a combined analysis of RTOG 9501 and the EORTC postop study, which had an identical study design,” said Dr. Wong.

“This was a landmark analysis that defines how we currently treat high-risk patients in the postoperative setting.”

“The long-term analysis of RTOG 9501 by Dr. Cooper and colleagues reiterates these findings,” he added. “These key study results are being used in the design of ongoing and future Radiation Therapy Oncology Group (RTOG) studies.”

The study authors and Dr. Wong have disclosed no relevant financial relationships.

Source: 2012 Multidisciplinary Head and Neck Cancer Symposium (MHNCS): Abstract 1. Presented January 26, 2012.

January, 2012|Oral Cancer News|

Distant Metastases in Head-and-Neck Squamous Cell Carcinoma Treated with Intensity-modulated Radiotherapy

Source: International Journal of Radiation Oncology, Biology and Physics (IJROBP Online)

December 2011

PURPOSE: To determine the pattern and risk factors for distant metastases in head-and-neck squamous cell carcinoma (HNSCC) after curative treatment with intensity-modulated radiotherapy (IMRT).

METHODS AND MATERIALS: This was a retrospective study of 284 HNSCC patients treated in a single institution with IMRT. Sites included were oropharynx (125), oral cavity (70), larynx (55), hypopharynx (17), and unknown primary (17). American Joint Committee on Cancer stage distribution includes I (3), II (19), III (42), and IV (203).

There were 224 males and 60 females with a median age of 57. One hundred eighty-six patients were treated with definitive IMRT and 98 postoperative IMRT. One hundred forty-nine patients also received concurrent cisplatin-based chemotherapy.

RESULTS: The median follow-up for all patients was 22.8 months (range, 0.07-77.3 months) and 29.5 months (4.23-77.3 months) for living patients. The 3-year local recurrence-free survival, regional recurrence-free survival, locoregional recurrence-free survival, distant metastasis-free survival, and overall survival were 94.6%, 96.4%, 92.5%, 84.1%, and 68.95%, respectively. There were 45 patients with distant metastasis. In multivariate analysis, distant metastasis was strongly associated with N stage (p = 0.046), T stage (p<0.0001), and pretreatment maximum standardized uptake value of the lymph node (p = 0.006), but not associated with age, gender, disease sites, pretreatment standardized uptake value of the primary tumor, or locoregional control. The freedom from distant metastasis at 3 years was 98.1% for no factors, 88.6% for one factor, 68.3% for two factors, and 41.7% for three factors (p <0.0001 by log-rank test).

CONCLUSION: With advanced radiation techniques and concurrent chemotherapy, the failure pattern has changed with more patients failing distantly. The majority of patients with distant metastases had no local or regional failures, indicating that these patients might have microscopic distant disease before treatment. The clinical factors identified here should be incorporated in future clinical trials.

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

December, 2011|Oral Cancer News|

New Therapies and Prognostic Techniques Highlighted in Head and Neck Cancer

The Asco Post

D. Neil Hayes, MD, MPH, of the University of North Carolina at Chapel Hill, described efforts to position the epidermal growth factor receptor (EGFR) inhibitor cetuximab (Erbitux) in head and neck cancer treatment.

Surprisingly negative results came from the phase III Radiation Therapy Oncology Group (RTOG) 0522 trial (N = 940), which showed no benefit to adding cetuximab to the radiation/cisplatin platform for front-line therapy of advanced head and neck squamous cell carcinoma.1 At 2 years, progression-free survival was approximately 64% in both arms; overall survival was 79.7% with chemoradiation (P = .68) and 82.6% with the addition of cetuximab (P = .17). Rates of locoregional relapse and distant metastases were also similar.

Cetuximab increased grade 3/4 mucositis (43% vs 33%;P < .004), in-field skin toxicity (25% vs 15%;P < .001), and out-of-field skin reactions (19% vs 1%;P < .001), but toxicity beyond 90 days was similar between the arms.

Table 1: After the RTOG 0522 Trial: Where Do We Go from Here?

“RTOG 0522 was the study of the year in head and neck cancer. Unfortunately, it was flat-out negative,” Dr. Hayes noted.

No differential effect emerged by p16 (HPV status). “While 70% of patients had oropharynx tumors (suggesting HPV positivity), tissue collection was lacking in half the patients. Our ability to make inferences with this amount of missing data is very limited,” Dr. Hayes said.

Even as a negative study, RTOG 0522 is practice-changing. “Many physicians have been treating with this regimen, assuming this study would be positive,” he said. “But we now have no data to support this.”

Cetuximab Equivalent to Cisplatin after Induction

The phase II TREMPLIN study (N = 153) evaluated sequential chemoradiotherapy in previously untreated, operable squamous cell carcinoma of the larynx/hypopharynx.2 Patients received induction chemotherapy with docetaxel, cisplatin, and fluorouracil; nonresponders underwent laryngectomy, whereas those with more than a 50% response were randomly assigned to radiotherapy plus either cisplatin or cetuximab.

All endpoints were similar between the arms. Larynx preservation rates at 3 months were 95% with cisplatin and 93% with cetuximab (P = .63). Preservation of larynxfunctionat 18 months (or at death) was seen in 87% and 82%, respectively (P= .68). Overall survival was 92% and 89%, respectively (P = .44), and laryngoesophageal dysfunction-free survival was 79% vs 71% (P = .30). Acute toxicities compromising treatment and late toxicities were more common with cisplatin.

Dr. Hayes concluded, “The take-home message is that these two regimens are equivalent, and that cetuximab plus radiotherapy may be reasonable after induction.”

Laser Treatment Effective for Mucositis

In a phase III randomized trial of 94 patients, upfront use of low-level laser therapy helped prevent oral mucositis associated with chemoradiation.3 Grade 3/4 mucositis was observed in < 7% of the laser therapy group, compared with almost 50% of controls (who received “placebo” laser applications from the same machine but without light), for an 84% reduction (P < .001). Patients receiving active laser therapy also had less pain, narcotic use, and gastrostomia and better quality of life.

“Mucositis, especially grade 3 and 4, may limit treatment and compromise outcomes. While we need confirmatory data, the study shows we can intervene to improve mucositis.”

Future Directions

Key Head and Neck Cancer Findings Presented at Best of ASCO®

An international group developed a 30-gene expression profile that predicted clinical outcomes in primary laryngeal carcinoma.4 Median disease-free survival was 34 months in high-risk patients vs 80 months in low-risk patients (P = .01). Recurrences were four times greater among those in the high-risk group (P = .017).

“This elegant study suggests subgroups of patients can be distinguished according to who will do well and who will do worse. For clinical usefulness, the issue is whether the difference between high- and low-risk groups will be sufficient to change therapy,” Dr. Hayes commented.

Finally, the novel vascular disrupting agent fosbretabulin (CA4P), combined with carboplatin and paclitaxel, tripled survival in the randomized phase II/III FACT trial (N = 80), from 9% at 1 year with chemotherapy alone to 26% (P = .065).5

“There is enthusiasm and excitement over this novel therapy for anaplastic thyroid cancer,” Dr. Hayes commented, urging oncologists to have patients enroll in the upcoming phase III trial.

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

October, 2011|Oral Cancer News|

Palifermin Decreases Severe Oral Mucositis of Patients Undergoing Postoperative Radiochemotherapy for Head and Neck Cancer: A Randomized, Placebo-Controlled Trial



This randomized, placebo-controlled trial found that weekly palifermin was associated with decreased incidence and duration of severe oral mucositis in patients undergoing postoperative chemoradiotherapy for head and neck cancer.


OncologySTAT Editorial Team

Combined chemoradiotherapy (CRT) offers improved outcomes after resection of locally advanced head and neck cancer but also increases the risk of oral mucositis, a debilitating and potentially dose-limiting toxicity of locoregional treatment. Palifermin, an analogue of keratinocyte growth factor, is FDA approved to prevent and treat mucositis in patients undergoing high-dose myelotoxic therapy for hematologic malignancies. In this multicenter, randomized, placebo-controlled trial, Henke et al evaluated whether palifermin reduces severe oral mucositis in patients undergoing CRT after surgical resection of locally advanced head and neck cancer.

Adult patients receiving postoperative CRT for high-risk stage II to IVB head and neck squamous cell carcinoma and with an ECOG performance status of 0 to 2 were enrolled from 38 centers in Europe, Australia, and Canada. Eligible study patients were stratified by tumor location (oral cavity/oropharynx or hypopharynx/larynx) and residual tumor (R0 [complete resection] or R1 [incomplete resection]). Study patients received a radiation dose of 60 Gy (R0 group) or 66 Gy (R1 group) plus cisplatin 100 mg/m2 on days 1 and 22, with the study drug administered 3 days prior to starting CRT and then weekly for 6 weeks. Patients who underwent radiotherapy after 6 weeks received an additional 100 mg/m2 of cisplatin and study drug. Oral saline rinses, topical anesthetics, feeding tubes, and hematopoietic growth factors were permitted; oral anti-inflammatory, antifungal, or antibiotic solutions were not permitted.

Patients initially were randomized to three treatment arms: weekly palifermin 180 µg/kg throughout CRT, weekly palifermin 180 µg/kg for 4 doses followed by weekly placebo through the remainder of CRT, or weekly placebo throughout CRT. However, adverse event monitoring led to a restart of the study after enrollment of the first 17 patients, with subsequently enrolled patients randomized to receive weekly palifermin 120 µg/kg (n = 92) or weekly placebo (n = 94) throughout CRT (for a minimum of 7 weeks); efficacy analyses were based on these 186 patients. The primary endpoint was the incidence of severe oral mucositis (WHO grade 3 or 4). Oral mucosa assessments occurred twice weekly throughout CRT and until resolution of oral mucositis to WHO grade ≤ 2 or week 15, whichever occurred first. Among secondary endpoints were duration of and time to onset of severe oral mucositis, incidence of grade ≥ 2 xerostomia at month 4, and incidence of treatment breaks (≥ 5 missed consecutive radiation fractions; chemotherapy delays or discontinuation). Time to disease progression and overall survival (OS) also were assessed.

Of 186 patients randomized to weekly palifermin 120 µg/kg or placebo, 79 in the palifermin arm (86%) and 82 in the placebo arm (87%) completed all oral evaluations. Patients in the palifermin group received a mean radiation dose of 59.7 Gy in a mean of 43.5 days and a mean cumulative cisplatin dose of 217.1 mg/m2. Patients in the placebo group received a mean radiation dose of 59.8 Gy in a mean of 43.2 days and a mean cumulative cisplatin dose of 206.4 mg/m2. Severe oral mucositis was observed in 47 patients (51%) in the palifermin group and 63 patients (67%) in the placebo group (P = .027). The median duration of severe oral mucositis was 4.5 days in the palifermin group vs 22.0 days in the placebo group (P = .037), and the median time to develop severe oral mucositis was 45 vs 32 days (P = .022), respectively. Incidence of grade ≥ 2 xerostomia at month 4, incidence of treatment breaks, time to disease progression, and OS did not differ significantly between the two groups.

In conclusion, weekly palifermin at a dose of 120 µg/kg was associated with reduced incidence, increased time to development, and decreased duration of severe oral mucositis in patients undergoing postoperative CRT for locally advanced head and neck cancer. However, differences in other efficacy endpoints were not statistically different in patients receiving palifermin. Further study of palifermin in this patient population is needed.

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

September, 2011|Oral Cancer News|

New Study Shows that Fatty Acids Reduces Effectiveness of Chemotherapy


Researchers at University Medical Center Utrecht, the Netherlands, have discovered a substance that has an adverse effect on nearly all types of chemotherapy – making cancer cells insensitive to the treatment. Chemotherapy often loses effectiveness over time. It is often unclear how or why this happens.

It now appears that chemotherapy is made ineffective by two types of fatty acid that are made by in the blood. Under the influence of cisplatin chemotherapy, the stem cells secrete these fatty acids that induce resistance to a broad spectrum of chemotherapies. These substances are referred to by researchers as ‘PIFAs’ which stands for platinum-induced fatty acids. is a type of chemotherapy that is widely used for the , including cancer of the lungs and ovaries.

Tumors under the skin

The researchers studied the effect of PIFA’s in mice and . The mice studied had tumors under the skin. Under normal conditions, the tumors would decrease in size following the administration of chemotherapy. In the study, after administering the fatty acids to the mice, the tumors were found to be insensitive to chemotherapy. The fatty acids were isolated from the medium in which chemotherapy exposed stem cells were grown. But also stem cells in the blood of patients produce the fatty acids that desensitize tumors to chemotherapy.

The fatty acids are also found in commercially-produced containing omega-3 and omega-6 fatty acids as well as in some algae extracts. In the experiments conducted in mice, the tumors became insensitive to chemotherapy after administration of normal amounts of fish oil. Natural products that include fish oil are frequently used by in addition to their regular treatment.

“Don’t use these products”

Professor Emile Voest, a medical oncologist at UMC Utrecht, supervised the research. “Where resistance to chemotherapy is concerned, we usually believe that changes in the themselves have occurred. Now we show that the body itself secretes protective substances into the blood that are powerful enough to block the effect of chemotherapy. These substances can be found in some types of fish oil. While waiting for the results of further research, we currently recommend that these products should not be used while people are undergoing chemotherapy.”

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


September, 2011|Oral Cancer News|

Collaboration of major biomedical centers has shown convergence on a cellular process for head and neck cancers

Author: Broad Institute of MIT and Harvard

Powerful new technologies that zoom in on the connections between human genes and diseases have illuminated the landscape of cancer, singling out changes in tumor DNA that drive the development of certain types of malignancies such as melanoma or ovarian cancer.

Now several major biomedical centers have collaborated to shine a light on head and neck squamous cell cancer. Their large-scale analysis has revealed a surprising new set of mutations involved in this understudied disease.

In back-to-back papers published online July 28 in Science, researchers from the Broad Institute, Dana-Farber Cancer Institute, Johns Hopkins Kimmel Cancer Center, the University of Pittsburgh, and the University of Texas MD Anderson Cancer Center have confirmed genetic abnormalities previously suspected in head and neck cancer, including defects in the tumor suppressor gene known as p53. But the two teams also found mutations in the NOTCH family of genes, suggesting their role as regulators of an important stage in cell development may be impaired.

“This adds a new dimension to head and neck cancer biology that was not on anyone’s radar screen before,” said Levi A. Garraway, a senior associate member of the Broad Institute, an assistant professor at Dana-Farber Cancer Institute and Harvard Medical School, and a senior author of one of the Science papers. “Head and neck cancer is complex and there are many mutations, but we can infer there is a convergence on a cellular process for which we previously did not have genetic evidence. It shows that if you do a genome sequencing project of this size you can gain major new biological insights.”

“The mutational analysis of NOTCH clearly indicated the power of genetic changes determining the function of these genes,” said Kenneth W. Kinzler, professor of oncology and a molecular geneticist at Johns Hopkins, co-director of the Ludwig Center at Johns Hopkins, and an author of one of the Science papers. “It gives us an important clue to start studying their function.”

Head and neck cancer is the sixth most common non-skin cancer in the world, with more than half a million new cases each year. Smokers, drinkers, and people infected with the human papillomavirus (HPV) have the highest risk of developing head and neck cancer, which is the collective name for tumors found in the oral cavity, including the mouth, larynx, and pharynx.

Patients often seek medical care only once they are in the later stages of the disease, when they may be offered surgery, radiation, chemotherapy, or a combination. Treatments can be disfiguring and debilitating, leaving patients unable to speak or swallow. The five-year survival rate of 50 percent has improved little over the past 40 years.

Jennifer R. Grandis, a professor of otolaryngology and pharmacology and chemical biology at the University of Pittsburgh School of Medicine and a senior author of one of the Science papers, bemoaned the dearth of genetic information about head and neck cancer several years ago at a conference where Garraway had given a talk about the genomic landscape of melanoma.

“There was a really big gap in knowledge that was an obstacle to doing the right kind of research” about head and neck cancer, she said. “If we didn’t know the spectrum of the mutations that were in our patients’ tumors, we couldn’t begin to develop more appropriate therapies because we were sort of playing in the dark.”

Grandis and Garraway decided to study a University of Pittsburgh collection of 74 pairs of tumor and normal tissue samples using the Broad’s capacity to perform whole-exome sequencing. The exome represents the tiny fraction of the genome that encodes proteins. Focusing on just these protein-producing genes allows scientists to zero in on mutations that alter key proteins involved in cancer growth. Another collaboration was unfolding among the cancer geneticists, sequencing experts, clinical researchers, and surgical oncologists at Johns Hopkins, MD Anderson, and Baylor College of Medicine to study 32 pairs of head and neck tumor and normal tissue samples by whole-exome sequencing and validate the findings in an additional 88 samples.

Both teams found mutations in the p53 gene in a little more than half of the tumors they studied. The next most common mutation occurred in NOTCH1, which showed up in about 15 percent of tumors.

Normally, NOTCH1 controls how cells differentiate into other kinds of cells, mature, stop dividing, and ultimately die. In head and neck cancer, the scientists saw mutations that turn NOTCH1 off, blocking differentiation and trapping cells in a proliferative, pro-cancer state. Their maturation is arrested, leaving them stuck in an earlier stage, where other damage from smoking or alcohol or even p53 mutations can destabilize the genome.

NOTCH1’s inactivation in head and neck cancer was surprising because in other cancers, such as leukemia, too much NOTCH signaling leads to cancer.

“Our study suggests that a gene’s role can depend on the tumor type. In some cases, a gene can act as a growth promoter in cancer, and in other cases, such as head and neck cancer, the same gene behaves as a growth suppressor,” said Kinzler.

Efforts to combat the mutated p53 tumor suppressor gene with targeted drugs, for example, have so far been unsuccessful.

The next step based on these novel head and neck cancer discoveries, the scientists agree, is to tease out how the genes function in normal cells, whether they form the lining of the larynx, pharynx, or another anatomical site affected by head and neck cancer.

“Both of our studies reveal few clues to the significance of NOTCH mutations. Further studies will be necessary to define its role in prognosis, diagnosis, and/or treatment,” said Nishant Agrawal, a head and neck surgical oncologist at Johns Hopkins and a lead author of one of the Science papers. “The idea is to use these genetic alterations to predict a patient’s prognosis and define personalized treatment strategies tailored to their cancer’s genome.”

Both teams confirmed the role of HPV infection in head and neck cancer, particularly oropharyngeal cancer. Thought to be transmitted by oral sex, the infection has become more prominent. The studies reveal that HPV-positive tumors carried fewer mutations than HPV-negative tumors. Patients with HPV-positive head and neck cancers tend to fare better than patients whose cancers are not caused by the virus.

Translating these discoveries into therapies for patients will take more studies and more time, the scientists all said, but the revelations set a course for the future.

Jeffrey N. Myers, professor of head and neck surgery at M. D. Anderson, said both groups’ work highlights the complexity of the disease and its multiple gene abnormalities.

“It has told us new things that will give us both clinical and scientific opportunities to study in the near and long term,” Myers said. “I think that we’re also in a position to design very specific clinical studies to further understand the significance of these mutations, as well as to begin to think about potentially targeting some of the abnormalities.”

Those studies could include looking at patients with different mutations in addition to p53 and the NOTCH family to see how well they fare.

“The race will be on to figure out the function and particularly the therapeutically relevant function of these mutations,” Grandis said.

Agrawal said the collaborative effort is necessary.

“I think it’s great we are advancing head and neck cancer research this way,” he said. “Unfortunately, the cancer has been beating us. Now it’s time for us to take a permanent lead.”

August, 2011|Oral Cancer News|

Palifermin reduces severe mucositis in head and neck cancer

Author: Janis C. Kelly

Palifermin (Kepivance), which is currently approved for preventing mucositis associated with total-body irradiation and stem-cell transplantation in hematologic malignancies, also prevents oral mucositis in patients with head and neck cancer undergoing radiation and chemotherapy, according to 2 randomized trials published online June 13 in the Journal of Clinical Oncology.

Michael Henke, MD, who led both studies, told Medscape Medical News that “this shows for the first time that radiation-induced mucositis can be ameliorated — and this in a phase 2/3 design!” Dr. Henke is from the Department of Radiation Oncology at University Clinic in Freiburg, Germany. The multicenter studies included researchers from Austria, France, Germany, Hungary, Italy, Poland, Spain, the United Kingdom, and the United States.

The first study was a double-blind randomized placebo-controlled trial of 186 patients with stage II to IVB carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Treatment included radiation, 60 or 66 Gy, after complete or incomplete resection, delivered at 2 Gy per fraction and 5 fractions per week. Treatment also included cisplatin 100 mg/m2 on days 1 and 22 (and on day 43 with incomplete resection).

Patients were randomized to weekly palifermin 120 μg/kg or placebo from 3 days before and throughout radiochemotherapy. The primary end point was the incidence of severe oral mucositis (World Health Organization [WHO] grades 3 to 4).

Palifermin reduced oral mucositis incidence to 51% (41 of 92), compared with 67% (63 of 94) with placebo (P = .027), shortened median mucositis from 22.0 to 4.5 days, and prolonged time to severe mucositis development from 32 to 45 days. Mortality was similar in both groups.

The authors conclude that “palifermin reduced the occurrence of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherapy. Additional clinical exploration of palifermin with postoperative radiochemotherapy would be useful.”

The second study randomized patients scheduled for definitive chemoradiotherapy for locally advanced head and neck cancer to either palifermin (180 μg/kg, n = 94) or placebo (n = 94) before starting chemoradiotherapy, and then once weekly for 7 weeks. Patients received conventionally fractionated radiotherapy (2.0 Gy per day for 5 days per week, to 70 Gy) with cisplatin (100 mg/m2 on days 1, 22, and 43). The primary end point was the incidence of severe oral mucositis (WHO grade 3 to 4).

Palifermin cut the incidence of severe oral mucositis from 69% to 54% (P = .041), delayed median time to severe oral mucositis from 35 to 47 days, and shortened the median duration of severe oral mucositis from 26 to 5 days.

Adverse events, overall survival, and progression-free survival were similar in the 2 treatment groups.

The researchers conclude that “although palifermin reduced severe functional [oral mucositis], its role in the management of locally advanced [head and neck cancer] during chemoradiotherapy remains to be elucidated.”

Dr. Henke said that although several of the end points were not statistically significant after multiplicity adjustment, he thinks that they would have been significant with larger sample sizes.

“Given the proof-of-principle that mucositis is reduced by [palifermin], I am quite positive that its clinical relevance will be proven after adjustment of drug scheduling/dosing,” Dr. Henke said.

He added: “Any means to reduce mucositis will be helpful. It’s really debilitating and makes our patients suffer. One way to go will be smaller phase 2 work on when and at what dose to administer the drug to patients receiving radiation for head and neck cancer.” He also suggested that palifermin might have value in novel radiation techniques sparing normal tissue.

The studies were supported by Amgen. Dr. Henke reports being in employment or leadership positions at Amgen and owning Amgen stock.

Source: J Clin Oncol. Published online June 13, 2011.

Larynx preservation studies should consider treatment impact

Author: Sara Freeman, Internal Medicine News Digital Network

Almost one-quarter of patients who had been given induction chemotherapy before radiotherapy for head and neck cancer experienced long-term swallowing difficulties, with another 15% experiencing voice disabilities that correlated with the mobility of the vocal cords.

Long-term data from the GORTEC (Groupe Oncologie Radiothérapie Tête et Cou) 2000-01 larynx preservation trial also show that approximately two-thirds of long-term head and neck cancer survivors experienced severe problems with sticky saliva and dry mouth, which were in turn linked to nutritional problems.

These findings, reported May 9 at the European Society for Therapeutic Radiation Oncology (ESTRO) Anniversary Conference, further confirm that studies looking at the effects of chemoradiotherapy on the larynx in head and neck cancer need to consider prospective assessment of laryngeal function, rather than just looking at anatomical preservation, according to a French radiation oncologist.

Dr. Gilles Calais of the Centre Hôpitalier Régional et Universitaire de Tours (France) presented data from a prospective analysis of 61 patients who had participated in the original 213-patient GORTEC 2000-01 trial. He also presented updated results from the trial using a recently developed composite end point.

“Larynx preservation can be achieved for most of our [head and neck] patients by using three different strategies: induction chemotherapy, concomitant [chemoradiotherapy], or alternating chemoradiotherapy,” Dr. Calais observed. Indeed, larynx preservation is a possibility in approximately 80% of patients, he said.

However, anatomical preservation does not mean that laryngeal function is maintained, especially with respect to the ability to speak or to swallow normally. This realization recently resulted in the development of new end points for clinical trials that included both survival and laryngeal function. The new end points are laryngoesophageal dysfunction-free survival (LED-FS) and freedom from laryngoesophageal dysfunction (FF-LED).

“So the purpose of this study was to go back to our data of the GORTEC 2000-01 study and evaluate the results according to these new composite end points,” Dr. Calais explained. “In parallel,” he added, “we performed a prospective analysis of voice and swallowing function for long-term surviving patients.”

Published in 2009, the GORTEC 2000-01 study showed that induction chemotherapy with TPF (docetaxel, cisplatin, and 5-fluorouracil) was superior to pf (cisplatin and 5-FU) in terms of 3-year larynx preservation rates (J. Natl. Cancer Inst. 2009;101:498-506). In all, 110 patients had been treated with TPF and 103 with PF, and the published larynx preservation rates were 70.3% and 57.5%, respectively. Anatomical preservation of the larynx was a possibly in 66 patients, and these patients were assessed for voice and swallowing function.

Recalculating survival curves according to the two new end points showed much lower overall values, compared with the anatomical-only end points, Dr. Calais noted. Considering all patients, the 5-year LED-FS was just 28% and the 5-year FF-LED was 50%.

Patients who were treated with the taxane-containing regimen fared better than those who received the cisplatin and 5-FU chemotherapy. The 5-year LED-FS rates were 36% in the TPF arm vs. 21% for the PF arm (P = .007). The 5-year FF-LED rates were 60% and 39%, respectively (P = .005).

“These data can be used as a reference for comparison with future larynx preservation studies,” Dr. Calais said. He noted that it was important to bear in mind that the best treatment to preserve the larynx is not known, referring to the FF-LED rate of 60% with the TPF regimen.

“Of course, [the] patient’s quality of life measure[s used] should be conducted in every future larynx preservation study.”

Dr. Calais declared no financial conflicts of interest.

Turmeric makes head, neck cancer treatment more effective

Author: staff

Researchers at the University of Michigan Comprehensive Cancer Center have found that a compound derived from curcumin helps cells overcome the treatment failure of head and neck cancer. Curcumin is the principal curcuminoid of the popular Indian spice turmeric.

When researchers added a curcumin-based compound, called FLLL32, to head and neck cancer cell lines, they were able to cut the dose of the chemotherapy drug cisplatin by four while still killing tumor cells equally as well as the higher dose of cisplatin without FLLL32.

“This work opens the possibility of using lower, less toxic doses of cisplatin to achieve an equivalent or enhanced tumor kill. Typically, when cells become resistant to cisplatin, we have to give increasingly higher doses. But this drug is so toxic that patients who survive treatment often experience long-term side effects from the treatment,” said senior author Thomas Carey, professor of otolaryngology and pharmacology at the U-M Medical School.

That tumors become resistant to cisplatin is a major reason why head and neck cancer patients frequently see their cancer return or spread. It also plays a big role in why five-year survival for head and neck cancer has not improved in the past three decades.

In the current study, researchers compared varying doses of cisplatin alone with varying doses of cisplatin plus FLLL32 against two sets of head and neck cancer cells: one line that was sensitive to cisplatin and one line that was resistant.

They found that FLLL32 decreased the activation levels of STAT3, sensitizing both resistant and sensitive tumor cells to cisplatin. Further, lower doses of cisplatin with FLLL32 were equally effective at killing cancer cells as the higher doses of cisplatin alone.

The study is detailed in Archives of Otolaryngology-Head and Neck Surgery.