cisplatin

Ten year results of landmark neck cancer trial published

Source: www.modernmedicine.com
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

Source: www.drbicuspid.com
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

Source: http://www.onclive.com/
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).

Source:
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

Source: www.curetoday.com
Author: Charlotte Huff

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

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

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

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

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

An Explosion of Cases

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

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

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

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

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

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

Identifying the Virus

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

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

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

 

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

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

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

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

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

Multifaceted Treatment

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

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

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

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

 

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

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

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

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

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

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

Dialing Back

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

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

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

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

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

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

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

A New Era in Treatment

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

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

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

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

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

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

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

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

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

 

CD4 counts predict chemo response in laryngeal cancer

Source: www.oncologyreport.com/
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|

Cisplatin aids survival of high-risk head and neck cancer

Source: www.oncologyreport.com
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

Source: www.medscape.com
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|