GARDASIL-9 FOR PREVENTION OF HEAD-NECK CANCER

The US Food and Drug Administration (FDA) has expanded the indication for the Gardasil-9 (Merck) vaccine to include prevention of oropharyngeal and other head and neck cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58.

This new indication is approved under the FDA's accelerated approval program and is based on the vaccine's effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial, which is currently underway.

"At Merck, working to help prevent certain HPV-related cancers has been a priority for more than two decades," said Alain Luxembourg, MD, director, clinical research, Merck Research Laboratories, in a statement. "Today's approval for the prevention of HPV-related oropharyngeal and other head and neck cancers represents an important step in Merck's mission to help reduce the number of men and women affected by certain HPV-related cancers."

This new indication doesn't affect the current recommendations that are already in place. In 2018, a supplemental application for Gardasil 9 was approved to include women and men aged 27 through 45 years for preventing a variety of cancers including cervical, vulvar, vaginal, and anal cancer as well as genital warts. But cancers of the head and neck were not included.

The original Gardasil vaccine came on the market in 2006, with an indication to prevent certain cancers and diseases caused by HPV types 6, 11, 16, and 18. It is no longer distributed in the United States.

In 2014, the FDA approved Gardasil 9, which extends the vaccine coverage for the initial four HPV types as five additional types (31, 33, 45, 52, and 58), and its initial indication was for use in both men and women between the ages of 9 through 26 years.

Head and Neck Cancers Surpass Cervical Cancer

More than 2 decades ago, researchers first found a connection between HPV and a subset of head-and-neck cancers (Curr Opin Oncol. 1999;11(3):191-199). The cancers associated with HPV also appeared to have a different biology and disease pattern, as well as a better prognosis, compared with those that were unrelated. HPV is now responsible for the majority of oropharyngeal squamous cell cancers diagnosed in the United States.

A study published last year found that oral HPV infections were occurring with significantly less frequency among sexually active female adolescents who had received the quadrivalent vaccine, as compared with those who were unvaccinated.

These findings provided evidence that HPV vaccination was associated with a reduced frequency of HPV infection in the oral cavity, suggesting that vaccination could decrease the future risk of HPV-associated head and neck cancers.

The omission of head and neck cancers from the initial list of indications for the vaccine is notable because, according to data from the Centers for Disease Control and Prevention (CDC), oropharyngeal cancers are now the most common malignancy caused by HPV, surpassing cervical cancer.

Who Will Benefit?

An estimated 14 million new HPV infections occur every year in the United States, according to the CDC, and about 80% of individuals who are sexually active have been exposed at some point during their lifetime. In most people, however, the virus will clear on its own without causing any illness or symptoms.

In a Medscape videoblog, Sandra Adamson Fryhofer, MD, MACP, FRCP, helped clarify the adult population most likely to benefit from the vaccine. She pointed out that the HPV vaccine doesn't treat HPV-related disease or help clear infections, and there are currently no clinical antibody tests or titers that can predict immunity.

"Many adults aged 27-45 have already been exposed to HPV early in life," she said. Those in a long-term mutually monogamous relationship are not likely to get a new HPV infection. Those with multiple prior sex partners are more likely to have already been exposed to vaccine serotypes. For them, the vaccine will be less effective."

Fryhofer added that individuals who are now at risk for exposure to a new HPV infection from a new sex partner are the ones most likely to benefit from HPV vaccination.

Confirmation Needed

The FDA's accelerated approval is contingent on confirmatory data, and Merck opened a clinical trial this past February to evaluate the efficacy, immunogenicity, and safety of the 9-valent HPV vaccine in men 20 to 45 years of age. The phase 3 multicenter randomized trial will have an estimated enrollment of 6000 men.

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ASCO 2020-WEEKLY CDDP ADDED TO RT FOR ADJUVANT TREATMENT OF HEAD-NECK CANCER-A NEW STANDARD OF CARE

For the first time, weekly cisplatin plus radiotherapy (CDDP+RT) has been shown to be not only less toxic than dosing once every three weeks but also achieves better outcomes in patients with postoperative squamous cell carcinoma of the head and neck (SCCHN), say Japanese researchers.

Consequently, the results of the JCOG1008 trial suggest that the weekly schedule should become the new standard of care in these patients, potentially settling what has been a "contentious" issue.

The research was presented the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.

Lead author Naomi Kiyota, MD, PhD, Medical Oncology and Hematology, Cancer Center, Kobe University Hospital, Japan, said that the study involving more than 160 high-risk patients with SCCHN demonstrated comparable overall survival in the weekly and three-weekly CDDP+RT groups.

Moreover, it showed that the weekly schedule was associated with better relapse-free and local relapse-free survival, and, in line with previous studies, had a more favorable safety profile.

"This phase II/III study is the first to show that weekly CDDP+RT is non-inferior to three-weekly CDDP+RT [and] is a new standard treatment option for these patients," Kiyota said.

Study discussant Hisham M. Mehanna, MD, PhD, Warwickshire Head and Neck Clinic, University of Birmingham, UK, described the study as a "significant achievement" that answers "an important question that we’ve been asking for a very long time."

He said that, despite three-weekly CDDP+RT being the standard treatment in the postoperative setting for SCCHN, there have been "lingering concerns," as 40% of patients don’t get all three CDDP cycles "and it is toxic."

Weekly CDDP is, on the other hand, "widely used, although the evidence for it is not as strong," and has a number of advantages, including that it can be delivered in the outpatient setting and it may be less toxic.

Mehanna said that there was "a surprise" to the current study, in that it was terminated early because it crossed the boundary for non-inferiority because  weekly CDDP has better survival than the three-weekly dose; notably, however, superiority was not achieved.

Mehanna also expressed some reservations over imbalances in the treatment groups that could have meant the three-weekly cohort had an unfavorable prognosis, and said questions remain over longer-term toxicity.

"Contentious Issue"

In a highlights session, Nabil F. Saba, MD, director of the Head and Neck Onology Program at Emory University's Winship Cancer Institute in Atlanta, Georgia, said that the dosing of CDDP in these patients has been "a contentious issue."

One issue has been whether scheduling of CDDP or the cumulative dose achieved is the key determinant of clinical outcome, and he suggested that the superior results seen in the current study can be attributed to the high cumulative dose that the investigators achieved in their patients compared with previous investigations.For Saba, the take-home message of the trial is that weekly cisplatin "is now, finally, an accepted standard of care in the postoperative high-risk setting, which is a major change at this ASCO meeting."

Presenting the trial, Kiyota said, in a recent study from the Tata Memorial Hospital, weekly CDDP at 30 mg/m² plus radiotherapy failed to achieve non-inferiority to a three-weekly regimen, "albeit with fewer toxicities."

He suggested that this could be because it was a single center trial, the use of two different treatment strategies, the majority of primary sites being in the oral cavity, and the dose being insufficient.

His team, on the other hand, undertook a randomized trial in which patients with postoperative high-risk SCCHN were recruited from 28 institutions.

The participants, who were aged 20 to 75 years and had ECOG performance status 0 to 1, all had pathological stage III/IV disease and a microscopically positive margin and/or extranodal extension.

They were randomly assigned to 100 mg/m² CDDP once every three weeks or weekly 40 mg/m² CDDP, plus radiotherapy at 66 Gy over 33 fractions.

For the intention-to-treat efficacy analysis, 132 patients received three-weekly CDDP+RT and 129 had weekly CDDP+RT, while the per protocol safety analysis included 129 and 122 patients, respectively.

The median age of the patients was 61 to 62 years and 110 patients in both treatment groups were male. Although there was a similar distribution of primary sites and high-risk factors in the two groups, more patients in the weekly group had pathological stage T2 disease (40) than in the three-weekly group (26).

The dose targets were met in both treatment groups. In the 3-weekly group, the cumulative dose of CDDP achieved was 280 mg/m² and in the weekly group it was 239 mg/m².

The second planned interim analysis showed that, over a median follow-up of 2.2 years, three-year overall survival was estimated at 71.6% in the weekly group vs 59.1% in the three-weekly group (hazard ratio [HR], 0.69).

As this was below the one-sided P value for non-inferiority, the data and safety monitoring committee recommended terminating the trial early.

The researchers also found that the 3-year relapse-free survival was higher with weekly CDDP+RT, at 64.5% vs 53.0% with three-weekly dosing (HR, 0.71).

Local relapse-free survival was also better with weekly dosing, at a three-year rate of 69.6% vs 59.5% for patients in the three-weekly group (HR, 0.73).

On a planned subgroup analysis, weekly CDDP+RT was nonsignificantly superior to the three-weekly schedule on almost every measure, whether looking at patient age, ECOG performance status, and primary site.

There were also differences in the occurrence of hematologic toxicities between the two groups, with fewer patients given the weekly schedule experiencing grade 3/4 neutropenia than those on the three-weekly dosing; however, there were more cases of any grade thrombocytopenia for patients getting the weekly dosing.

The weekly CDDP+RT regimen demonstrated its lower toxicity when looking at acute nonhematologic adverse events, with fewer occurrences of any grade dysphagia, nausea, hyponatremia, renal impairment, and hearing impairment vs the three-weekly schedule.

The weekly dosing schedule was also associated with lower rates of grade 3/4 dysphagia, nausea, and infection.

The study was funded by the National Cancer Center Research and Development Fund, Japan Agency for Medical Research and Development Fund.

Kiyota reports honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb Japan, Chugai Pharma, Eisai, Merck Serono, MSD, and Ono Pharmaceutical; speakers bureau fees from AstraZeneca, Bayer, Bristol-Myers Squibb Japan; Eisai, Merck Serono, MSD, and Ono Pharmaceutical; and receiving research funding from AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), and Roche (Inst). Other study authors report potential conflicts of interest. The full list can be found here.

Mehanna reports stock and other ownership interests in Warwickshire Head and Neck Clinic; honoraria from AstraZeneca; speakers bureau fess from Merck, MSD, and Sanofi Pasteur; research funding from AstraZeneca, GlaxoSmithKline (Inst), MSD (Inst), Sanofi Pasteur (Inst), and Silence Therapeutics (Inst); and travel, accommodations, and expenses from Merck, MSD, and Sanofi Pasteur.

Saba reports honoraria from Aduro Biotech, Bristol-Myers Squibb, Cue Biopharma, Genentech/Roche, GSK, Kura, Lilly, Merck, and Pfizer; a consulting or advisory role with Biontech, Bluprint, Bristol-Myers Squibb, Lilly, Merck, and Pfizer; research funding from Bristol-Myers Squibb and Exelixis; travel, accommodations, and expenses from Bluprint, Bristol-Myers Squibb, Genentech/Roche, GSK, Lilly, Merck, and Pfizer.

American Society of Clinical Oncology 2020 Annual Meeting: Abstract 6502.

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SALIVARAY TEST FOR HPV+ ORAL CANCER

A saliva test for detecting oropharyngeal cancer caused by human papillomavirus-16 (HPV-16) has scored a world first: it detected such a cancer in an asymptomatic adult.

If the finding can be replicated in a larger cohort of healthy asymptomatic individuals, widespread screening for HPV-16 — the main driver behind skyrocketing rates of oropharyngeal cancer — ­­­­­could be one step closer, the researchers suggest.

"Oropharyngeal squamous cells carcinoma often presents at a late stage with patients suffering huge morbidity as a result of treatment [so] we must find strategies to detect these cancers earlier," senior author Chamindie Punyadeera, PhD, Queensland University of Technology in Brisbane, Australia, told Medscape Medical News in an email.

"This study for the first time provides a solid scientific foundation to initiate a screening trial in high-risk individuals to detect HPV-driven oropharyngeal cancer, she added. "Saliva testing could be broadly implemented and [used] in a screening trial in the future," she said.  

The case report was published online March 31 in Frontiers in Oncology.

The saliva test was developed by Punyadeera and first author Kai Dun Tang, PhD, also from Queensland University of Technology. It is administered as an oral rinse: the individual swishes a saline solution around in his or her mouth for a minute or two, and then spits the sample into a tube.

Prevalence Study

The saliva test was being scrutinized in an ongoing HPV-16 DNA prevalence study, which involved 650 healthy participants being tested for oral HPV-16 DNA.

"Of these, 3 have been identified to have persistent oral HPV-16 DNA infection," investigators report.

After having approached these three participants, one middle-aged male who had been consistently HPV-16 DNA positive for a period of 36 months — and whose HPV-16 viral load had been steadily rising over time — was invited to attend an ear, nose and throat clinic for assessment.

"Initial clinical examination of the oropharynx including palpation and white light revealed no significant abnormalities," researchers emphasize.

As Punyadeera explained, standard clinical assessment for oropharyngeal malignancy includes white light examination for masses, detection of irregularities or asymmetry of the underlying structures and palpation of the tonsil and tongue base.

Cross-sectional imaging with CT or MRI can be helpful as well, she said, but  these imaging studies are unable to detect lesions smaller than a few millimeters in size.

In the case of this individual, salivary oral rinse samples had been collected at baseline, and again at 6, 12, and 36 months after study enrollment as well as 2 weeks after the patient decided to undergo a bilateral tonsillectomy.

DNA was extracted from the salivary oral rinse samples, as well as from the tonsillar tissue obtained after resection. HPV-16 DNA genotyping and viral loads were analyzed with a PCR assay.

Results from the salivary samples indicated that the patient's HPV-16 DNA viral load had increased exponentially across the 36 months of follow-up, from 3.43 copies/50 ng at baseline to 1281.69 copies/50 ng at 36 months.

On surgery, the patient was found to have a 2 mm squamous cell carcinoma in the left tonsil, but all all other oropharyngeal tissues were normal and HPV-16 DNA negative. 

Two weeks after undergoing the tonsillectomy, the patient's HPV-16 DNA viral load in the saliva samples became undetectable.

This case report demonstrates that salivary HPV can both detect smaller lesions than either clinical examination or even radiological investigation, and that the same salivary test can likely also be used to monitor treatment response, Punyadeera commented.

Long-Term Persistence

As researchers explain in their paper, long-term persistence of HPV-16 infection is most likely a prerequisite for the development of subsequent malignancy.

Unlike cervical cancer caused by HPV-16 infection, the natural history of HPV infection in the oropharyngeal cavity is not known.

However, clinical assessment of patients with either persistent HPV infection or microscopic carcinoma has failed to detect any identifiable abnormalities.

Thus, this is the first report of a histologically confirmed diagnosis of an asymptomatic occult oropharyngeal cancer detected by a screening test through serial measurements of HPV-16 DNA, the investigators emphasize.

The report also demonstrated that very early lesions can be eradicated with minimal morbidity. Unfortunately, most oropharyngeal cancer is currently diagnosed at much later stages, and surgical removal of these is often associated with significant disabilities including difficulties with swallowing and even communicating.   

"It's amazing to think that this man was cured of his disease with a 15-minute procedure which left him with no lasting issues at all," Punyadeera commented. "We need to try and make this the norm, not the exception."

"So we must have a well-designed screening study using all the insights we have gained from this case. We owe it to patients to explore these findings to their fullest," Punyadeera emphasized.

The authors have disclosed no relevant financial relationships.

Frontiers in Oncology. Published online March 31, 2020. Full text

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ASCO 2020-SLNB FOR EARLY STAGE ORAL CANCER

In a randomized multicenter study, a strategy based on sentinel node biopsy (SNB) was equivalent to elective neck dissection (END) in the management of T1-T2N0 oral and oropharyngeal squamous cell carcinomas, with comparable 2-year neck recurrence-free survival (RFS) and lower morbidity in year 1 after surgery (Abstract 6501). Renaud Garrel, MD, of CHU Montpellier, France, presented the results during the ASCO20 Virtual Scientific Program.

This phase III trial provides a high level of evidence of similarity for SNB and END, Dr. Garrel asserted, with no significant differences in neck RFS and overall survival (OS) in comparable groups in a representative population.

Dr. Hisham Mehanna

The study was designed to demonstrate equivalence of these two approaches in the management of T1-T2N0 oral and oropharyngeal squamous cell carcinomas. The primary outcome was 2-year neck RFS, and secondary outcomes included 2- and 5-year locoregional RFS, disease-specific survival, and OS. Morbidity, as assessed by hospital stay, a neck and shoulder impairment questionnaire/objective arm abduction test, and the amount of physiotherapy prescribed during follow-up, were other secondary endpoints.

In the randomized trial, patients in the standard treatment arm underwent surgery for the primary tumor and systematic END; patients in the experimental arm underwent SNB and then had surgery only of the primary tumor if they were SNB-negative, or END if they were SNB-positive. Secondary END was performed if further tissue analysis detected a false SNB-negative. The sample size was determined on the basis of a hypothesis of equivalence of 2-year neck RFS, with an alpha-risk of 5% and a power of 90%, requiring a total of 310 patients.

Over a period of 5 years, 307 patients were randomly assigned to one of the treatment arms. After exclusions, the researchers analyzed 139 patients in the END arm and 140 in the SNB arm. Mean follow-up was 4.95 years.

In the primary outcome, neck RFS at 2 years was 89.6% in the END arm and 90.7% in the SNB arm, a difference of 1.1%, which was “far less than the 10% hypothesis, confirming the equivalence with p = 0.008,” Dr. Garrel noted. At 5 years, neck RFS was 89.6% in the END arm and 89.4% in the SNB arm. Survival curves were not statistically significantly different at 2- and 5-year analysis of locoregional RFS, disease-specific survival, nor OS, respectively.

At 2-, 4-, and 6-month postoperative morbidity evaluations, several functional outcomes assessed by the questionnaire were statistically worse in the END arm than in the SNB arm. By month 12, only being bothered by the appearance of the neck was worse in the END arm. The length of hospital stay was shorter (median 7 vs. 8 days, p = 0.001), the results of the arm abduction test were better, and the rate of physical therapy prescription was lower in the SNB arm than in the END arm.

Dr. Garrel acknowledged that the study did not meet its accrual goal, but he noted that it nonetheless achieved statistical significance in the primary endpoint. He also acknowledged that the study did not include an estimate of costs.

“This establishes SNB as the standard of care for the treatment of T1-T2N0 squamous cell carcinoma of the oral cavity and oropharynx,” Dr. Garrel said.

“This establishes SNB as the standard of care for the treatment of T1-T2N0 squamous cell carcinoma of the oral cavity and oropharynx,” Dr. Garrel said.

Discussant Hisham Mehanna, PhD, of the University of Birmingham, United Kingdom, had a slightly different assessment. “SNB should be considered astandard of care,” he said, emphasizing the indefinite article. “It should be offered as an option alongside or instead of END.”

“Make no mistake,” Dr. Mehanna said, “this is a significant achievement, to do this trial. We’ve been talking about it for a long time. … But really data on cost effectiveness would be important if this strategy is going to be adopted widely because SNB is resource intensive. If [SNB] is more expensive, this will remain an issue.”

— Tim Donald, ELS

IMMUNOTHERAPY FOR ORAL CANCER

A short course of neoadjuvant immunotherapy used for the treatment of oral cavity cancers leads to impressive tumor responses as measured by multiple metrics and does not delay definitive surgery, a multicenter, phase 2 study indicates.

"With roughly 3 weeks of treatment, we were able to trigger significant tumor regression," said Jonathan Schoenfeld, MD, MPH, Dana-Farber/Brigham and Women's Cancer Center in Boston, Massachusetts, in a statement.

"Our hope is that even a couple of doses of immunotherapy can stimulate an immune response that continues to prevent the cancer from coming back after patients have surgery and other therapy," he added.

The study was presented at the 2020 Multidisciplinary Head and Neck Cancers Symposium in Scottsdale, Arizona.

"Oral cavity cancer is a notoriously difficult cancer with high rates of disease recurrence and death, and the side effects from standard treatment tend to be particularly challenging because the treated area is essential for speaking, swallowing, and breathing," Schoenfeld said.

Two Treatment Groups

Twenty-nine evaluable patients with newly diagnosed squamous cell carcinoma of the oral cavity were randomly assigned to either two cycles of the programmed death-1 (PD-1) inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) given on weeks 1 and 3 or to the CTLA-4 immune checkpoint inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb), given with nivolumab on week 1 only.

Nivolumab was given at a dose of 3 mg/kg while ipilimumab was given at a dose of 1 mg/kg.

The most common primary tumor site was the oral tongue — 58% of patients had clinically node positive disease and 62% had stage IVA disease.

Patients underwent imaging before and after receiving immunotherapy prior to surgery. Surgery was performed 72 hours to 1 week following cycle 2 restaging scans. The median time to surgery was 19 days.

Treatment in both arms was "relatively well tolerated," Schoenfeld noted.

Immune-related toxicities included grade 3 pneumonitis in one patient and grade 3 colitis in one patient, both in patients treated with the combination of nivolumab and ipilimumab. One patient who received nivolumab monotherapy developed new-onset diabetes requiring treatment with insulin.

"Of note, all of these toxicities occurred following surgical resection, so again, there were no delays to the prespecified surgical date," Schoenfeld emphasized.

Perioperative toxicities included pulmonary embolism, postoperative hematoma, several flap failures, and one perioperative stroke resulting in death.

Volumetric responses — defined as any clinical, radiologic, or pathologic shrinkage of the tumor — were seen in 50% of patients treated with single-agent nivolumab and 53% of patients receiving nivolumab + ipilimumab.

Moreover, "we also observed significant pathologic responses in some patients," Schoenfeld said.

For example, investigators observed a complete pathologic response (greater than 90%) in one patient (8%) treated with nivolumab alone and in three patients (20%) receiving both agents.

At a median follow-up of 14 months, 85% of patients were still free of disease progression at 1 year, and 89% of them were still alive.

At baseline, researchers did not identify any differences in PD-L1 expression in tumor cells between groups.

On the other hand, CD4+ T cells correlated with pathologic response.

Interestingly, this association was only seen in patients treated with nivolumab + ipilimumab but not with nivolumab alone.

"We're excited about moving immunotherapy earlier to treat more of these curative patients and, in the future, possibly reduce how aggressive their other treatments need to be," Schoenfeld observed.

The study was funded by Bristol-Myers Squibb. Schoenfeld declares his institution received research funding from Merck, Bristol-Myers Squibb, and Regeneron. He has served as a consultant or on scientific advisory boards and/or has received travel fees from Immunitas, Debiopharm, Bristol-Myers Squibb, Nanobiotix, Tilos, AstraZeneca, LEK, Catenion, and ACI Clinical.

2020 Multidisciplinary Head and Neck Cancers Symposium: Abstract 1. Presented February 27, 2020.

ADJUVANT EVEROLIMUS FOR HEAD-NECK CANCER

The mTOR inhibitor everolimus may extend progression-free survival for patients with advanced head and neck cancer who are at high risk for recurrence after standard treatment. Patients enrolled in a randomized phase II trial who received the agent were more likely to be cancer-free 1 year after therapy than those treated with placebo, and the benefit persisted for those with TP53 genetic mutations. The findings were presented by Nathan et al at the 2020 Multidisciplinary Head and Neck Cancers Symposium“While cure rates tend to be upward of 85% for patients with head and neck cancers associated with human papillomavirus (HPV), they tend to be less than 40% for patients with disease related to smoking,” said lead author Cherie-Ann O. Nathan, MD, Professor and Chair of Otolaryngology/Head and Neck Surgery at Louisiana State University Health Shreveport and Director of Head and Neck Surgery at Feist-Weiller Cancer Center. “These patients are [having disease recurrence] most often, and their survival rates have not changed in decades, despite advances in surgery, radiation therapy, and chemotherapy.”

Study Methodology

To address this disparity, the researchers focused on patients with advanced HPV-negative head and neck squamous cell carcinoma or HPV-positive disease and smoking history of more than 10 pack-years. They enrolled 52 patients to receive up to 1 year of either everolimus or placebo. Eligible patients had to be free of disease after either definitive treatment with chemoradiation therapy or surgery followed by chemoradiation.

Results

After 1 year, 81% of patients on everolimus remained progression-free, compared to 57% of those in the placebo group (P = .039). Dr. Nathan clarified that this timepoint was not stipulated a priori and is a post hoc analysis.

Two-year progression-free survival, which was the primary endpoint, continued to favor everolimus, but was no longer significant. Subset analysis determined that for patients with TP53 mutations, the survival difference remained significant for an additional year after they stopped immunotherapy (2-year progression-free survival of 70% vs 22.5%, P = .036). The difference was not significant at 2 years for patients without the mutation.

Although TP53 mutations occur in almost 80% of HPV-negative, smoking-related cases of head and neck squamous cell carcinoma, the potential link between TP53, the mTOR pathway, and survival was a surprise to the researchers.

“There's really no drug that targets TP53, and so we've never had a targeted therapy for it or considered it an actionable mutation,” explained Dr. Nathan.

Sixteen of the 28 patients on everolimus and 7 of the 24 patients on the placebo drug experienced grade 3 or higher toxicities, including three and five serious adverse events, respectively. Dr. Nathan said everolimus’s tolerability indicates that it may have potential as longer-term maintenance therapy to delay recurrence for high-risk patients.

“Although the sample size is small, as it closed due to lack of accrual, these findings indicate that patients [with head and neck squamous cell carcinoma] at high risk for tumor relapse could be given mTOR inhibitors to stall progression and keep any residual cancer cells from growing. Our hope is that head and neck cancer can be treated as chronic disease, similar to some breast cancers,” she explained.

Additional trials are needed to confirm the link between TP53 and survival, as well as to determine the safety of keeping patients with head and neck cancer on treatment with everolimus for multiple years.

PEMBROLIZUMAB FOR HEAD-NECK CANCER

Immunotherapy with pembrolizumab (Keytruda, Merck & Co), either as monotherapy or in combination with chemotherapy, offers a new standard of care for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), say experts discussing the results from the company-sponsored KEYNOTE-48 trial.

Pembrolizumab plus chemotherapy yielded a significant survival benefit in comparison with standard therapy for both the total patient population and for patients whose tumors were positive for programmed cell death–ligand-1 (PD-L1).

Monotherapy with pembrolizumab yielded a significant overall survival benefit for patients with tumors that were PD-L1 positive; and in the total study population, overall survival was noninferior.

"Thus, pembrolizumab monotherapy is a new standard of care, first-line therapy option for patients with PD-L1-positive recurrent or metastatic HNSCC. Pembrolizumab with chemotherapy is also a new option for all patients, regardless of PD-L1 status," comment Robert L. Ferris, MD, PhD, from the University of Pittsburgh, Pennsylvania, and Lisa Licitra MD, from the University of Milan, Italy, in a commentary that accompanies article in the Lancet.

"The positive results of KEYNOTE-048 represent substantial progress for patients with recurrent or metastatic HNSCC," Ferris and Licitria add.

These comments echo the reactions from experts when the study was presented earlier this year at the annual meeting of the American Society for Clinical Oncology (ASCO), as reported by Medscape Medical News at that time.

Presenter Danny Rischin, MD, from the Peter MacCallum Cancer Center, Melbourne, Australia, said: "These data support pembrolizumab plus platinum-based CT [chemotherapy] and pembrolizumab monotherapy as new first-line standard-of-care therapies for relapsed/metastatic head and neck squamous cell carcinoma."

At the ASCO meeting, the study was highlighted as "most important" by Francis P. Worden, MD, of the University of Michigan Rogel Cancer Center, Ann Arbor. He predicted that pembrolizumab in combination with chemotherapy will replace the EXTREME regimen (cetuximab with platinum-based therapy and fluorouracil) as first-line therapy in HNSCC.

However, while agreeing that the data are practice changing, Vinita Noronha, MD, of the Tata Memorial Cancer Center in Mumbai, India, emphasized that several questions remained unansweredIn a discussion of the paper, Noronha pointed out that the findings do not provide guidance on which patients should receive pembrolizumab alone or in combination with chemotherapy, and there are also questions as to why both the response rate and progression-free survival rate failed to improve. It was also unclear whether there was a role for sequential therapy or whether all patients should receive the combination up front. Some of these questions have been addressed in the commentary to the Lancet article.

Study Details

KEYNOTE-048 was a randomized, phase 3 study that included 882 participants with untreated locally incurable recurrent or metastatic HNSCC. It was conducted at 200 sites in 37 countries.

Patients were stratified by PD-L1 expression, p16 status, and performance status and were randomly assigned in a 1:1:1 ratio to one of three groups: pembrolizumab monotherapy at 200 mg every 3 weeks for 35 cycles; pembrolizumab 200 mg every 3 weeks for six cycles combined with a platinum and 5-fluorouracil followed by maintenance pembrolizumab 200 mg every 3 weeks for an additional 29 cycles; or cetuximab plus a platinum and 5-fluorouracil (ie, the EXTREME regimen).

Most patients (85%, n = 754) had tumors that were PD-L1 positive and had a PD-L1 combined positive score (CPS) of ≥1; 381 (43%) had a CPS of ≥20.

The final results of the study showed that pembrolizumab alone improved overall survival as compared to cetuximab with chemotherapy in the CPS ≥20 cohort (median, 14.9 vs 10.7 months; hazard ratio [HR], 0.61; P = .0007) as well as in the larger group with CPS ≥1 (12.3 vs 10.3 months; HR, 0.78; P = .0086). It also proved to be noninferior within the total patient population (11.6 vs 10.7 months; HR, 0.85).

Pembrolizumab combined with chemotherapy also improved overall survival compared to cetuximab with chemotherapy in the total patient population (13.0 vs 10.7 months; HR, 0.77; P = .0034). Combination therapy was also superior to chemotherapy in patients with CPS ≥20 (14.7 vs 11.0 months; HR, 0.60; P = .0004) and in those with CPS ≥1 (13.6 vs 10.4 months; HR, 0.65; P < .0001).

However, neither pembrolizumab alone nor pembrolizumab in combination with chemotherapy improved progression-free survival or the overall objective response rate, as compared with combination cetuximab and chemotherapy. The proportion of patients for whom progressive disease was the best response was also higher in the pembrolizumab-alone group compared with cetuximab-plus-chemotherapy group.

As for toxicity, all-cause adverse events of grade 3 or greater occurred in 164 (55%) patients in the pembrolizumab-alone group, 235 (85%) in the pembrolizumab-plus-chemotherapy group, and 239 (83%) in the cetuximab-with-chemotherapy group.

Events that led to death occurred in 25 (8%) participants in the pembrolizumab-alone group, 32 (12%) in the pembrolizumab-plus-chemotherapy group, and 28 (10%) in the cetuximab-with-chemotherapy group.

Two New Standards Available

In their commentary, Ferris and Licitra point out that although the present study was not designed to compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy, "we can qualitatively evaluate the study results."

They note that median OS was similar for pembrolizumab alone and pembrolizumab with chemotherapy in the cohort with CPS ≥20 and was better for pembrolizumab with chemotherapy in the cohort with CPS ≥1 and in the total population. Objective response was higher for pembrolizumab with chemotherapy in PD-L1-positive patients and in the total population, and the duration of response was better than for pembrolizumab alone.

"In this scenario, two new standards are available for the same patients, offering the opportunity to tailor treatment for clinical and patient preferences and individual decision making," they comment. On the basis of the findings of KEYNOTE-048, the PD-L1 biomarker will now become more useful for therapy selection for patients with HNSCC

However, as with any change in standard of care, there are substantial implications for subsequent therapy, they continue. For patients who do not improve after receiving first-line pembrolizumab monotherapy, second-line standard-of-care systemic therapy options will now include platinum doublets containing cetuximab. For those who experience disease progression after receiving first-line pembrolizumab with chemotherapy, cetuximab will subsequently be offered.

The study was funded by Merck Sharp & Dohme. Several of the coauthors have disclosed multiple relationships with industry, as noted in the original article. Ferris reports multiple relationships with industry. Licitra has disclosed no relevant financial relationships.

Lancet. Published Online October 31, 2019. Abstract, Commentary

IMPROVMENT IN SURVIVAL OF ANAPLASTIC THYROID CANCER

As hope prevails for better outcomes in the management of anaplastic thyroid cancer, experts here at the 89th American Thyroid Association (ATA) Annual Meeting previewed forthcoming new guidelines for this uncommon but highly aggressive cancer.

Dr Keith Bible

"The time is past when nihilism should prevail when we see an anaplastic thyroid cancer patient," said Keith C. Bible, MD, PhD, a co-chair of the ATA Anaplastic Thyroid Cancer Task Force, noting that although there is a lack of randomized clinical trials in anaplastic thyroid cancer, there have been developments in systemic and radiotherapies.
Among key areas of progress are the development of multimodal therapies that have improved 1-year survival rates in patients with stage 4A and 4B anaplastic thyroid cancer from just 10% to 20%, and sometimes to as high as 40%.
"This represents a doubling of this endpoint compared to 10 years ago, so there has been some progress," emphasized Bible, an oncologist in the Division of Endocrine and Oncology Care at the Mayo Clinic in Rochester, Minnesota.
However, for the time being, these improvements in survival are generally confined to centers of excellence in treating anaplastic thyroid cancer, he said.
Indeed, Mark Zafereo, MD, a head and neck surgeon from one such institution, MD Anderson Cancer Center in Houston, Texas, told the meeting: "We have seen remarkable improvement in survival over the last 3 years for patients with anaplastic thyroid cancer."
"This type of dramatic improvement in survival in such a short period of time is rarely seen with any type of cancer," he added.
Still, stressed Bible, "We have much need and room for improvement in both community care and also with regard to the immediate recognition and referral to centers of excellence."

Progress in Therapy but Still Some Extreme Toxicity

One example of improvement, said Bible, is that in stage 4B patients, multimodal approaches can help reduce the significant problem of asphyxiation.
"With the availability and rapid administration of combined modality chemoradiation therapy, we're seeing patients less frequently die from asphyxiation in the presence of definitive intention treatment to the neck, so that's been a benefit," said Bible.
An important caveat, however, is the approach's extreme toxicity.
"Patients who elect this have to be willing to accept the collateral damage and very high morbidity associated with this in the hopes of improved survival, and [yet] realize they may not gain improved survival," Bible emphasized.

Progress is also being made in terms of targeted therapies, most notably in the combination treatment of dabrafenib (Tafinlar, Novartis) plus trametinin (Mekinist, Novartis) for BRAF V600E-mutant anaplastic thyroid cancer, which received received approval from the US Food and Drug Administration (FDA) in 2018.
Zafereo is principal investigator for a clinical trial funded by Merck for dabrafenib/trametinin and pembrolizumab (Keytruda, Merck) as neoadjuvant therapy followed by surgery for anaplastic thyroid cancer.
With encouraging developments in targeted therapies for other genetic mutations as well, Bible said one of the new guideline recommendations will support genetic testing.
"[These developments] account for our recommendation to do rapid BRAF assessment [with immunohistochemical, molecular testing], with parallel comprehensive genetic testing," he explained.

Change From Prior Guidelines

Key treatment algorithms are recommended to offer guidance for initial treatment of anaplastic thyroid cancer by disease stage: For stage 4A, for instance, "we recommend an aggressive approach — the encouragement is for surgery and then definitive intention systemic and intensity-modulated radiation therapy (IMRT)," Bible explained.
For stage 4B, where the survival rate is less robust, the recommended approach should be more individualized, with multimodal therapy — as long as patients are willing to accept the substantial potential toxicities and possible surgery, if the cancer is resectable.
If the tumor is unresectable in stage 4B patients, there are two possible approaches: a possible combined radiation treatment plan with surgery, or the alternative of a targeted therapeutic approach in BRAF-altered tumors, with the desired intention of downstaging the tumor so that feasibly it could be surgically resectable and subject to more definitive treatments.
"This discussion of this neoadjuvant approach, particularly in unresectable tumors, is a change from prior guidelines," Bible said.

Stage 4C Harder to Manage

For stage 4C, which Bible said makes up about half of the patients with anaplastic thyroid cancer seen at the Mayo Clinic, the treatment options are fewer.
"We have much less evidence on the impact of survival, so it's particularly important to talk with patients about the best supportive care options," he outlined.
For patients with stage 4C disease who do desire an aggressive therapy approach, evaluation of the possibility of targeted therapy is recommended.
"Cytotoxic chemotherapy may be started as a 'bridge' while awaiting genomic information or to receive targeted therapy, such as dabrafenib and trametinib," he noted.
Bible underscored that, despite progress in the field, more changes are needed.
"A 40% survival at 1 year is obviously in need of considerable improvement, but this represents a doubling of this endpoint compared to 10 years ago," he reiterated.
However, "less toxic therapies with better outcomes are needed across the board in anaplastic thyroid cancer."  Furthermore, he added, "metastatic anaplastic thyroid cancer is still a uniformly fatal disease with all therapies only transiently beneficial, [so] we need more effective therapies in this space."

MD Anderson Experience Underscores Targeted Therapy Benefits

Meanwhile, research presented in a separate session describing an anaplastic thyroid cancer intervention at MD Anderson Cancer Center underscored the benefits of many of these principles.
The study showed that the center's Facilitating Anaplastic Thyroid Cancer Specialized Treatment team (FAST) initiative was associated with an increase in survival of anaplastic thyroid cancer at 2 years from 16.5% in a 2000–2013 group of patients — prior to the program's initiation — to 36.5% in the 2017–2019 group (representing the FAST program patients).
This represented a hazard ratio for death of 0.76 (95% confidence interval, 0.66 - 0.87) for the 2017–2019 group compared to a combined 2000–2016 group (P  <  .001).
This represents a "remarkable improvement in survival over the last 3 years, with our current median survival of 16 months for all-comers far exceeding historical median survivals of 3 to 6 months, which were commonly reported only 5 years ago," study coauthor Zafereo told Medscape Medical News.
And "for patients with a BRAF mutation who receive targeted therapy, this improvement in survival is even more pronounced," noted Zafereo.
In the FAST program, patients have access to a rapid evaluation and work-up of their disease, including molecular and genetic workup of the tumor, followed by targeted mutation-based therapy, often on a clinical trial, he explained.
Zafereo said that the endorsement of some of those approaches in the upcoming ATA guidelines will represent exciting changes.
"For the first time, we expect the concept of neoadjuvant mutation-based molecular therapy [most importantly BRAF/MEK inhibition for patients with BRAF mutations] to be incorporated into the ATA anaplastic thyroid cancer guidelines," he said.

Barriers to Care at Specialty Centers a Concern

While noting that other centers of excellence in anaplastic thyroid cancer also report improvements, Bible said it is important to keep in mind that "a very real issue is that few patients can travel to centers of excellence because of increased out-of-pocket costs and other socioeconomic factors, [and/or] constrained insurance referral networks that delay or prevent referral out of networks."
He added that "the rarity of anaplastic thyroid cancer means that there is a very low level of community expertise in the optimal management of [the disease] for most patients."
Surveillance, Epidemiology, and End Results (SEER) are also not nearly as favorable as those presented from centers of anaplastic thyroid cancer excellence, Bible stressed.
"Universal outcomes are still lagging behind centers of anaplastic thyroid cancer excellence outcomes in North America," he concluded.
Bible and Zafereo have disclosed no relevant financial relationships.

GOOD PREGNANCY OUTCOMES 6 MONTHS AFTER RAIT

Receipt of radioactive-iodine treatment (RAIT) after thyroidectomy for thyroid cancer does not appear to be associated with adverse pregnancy outcomes when conception occurs six months or more after treatment, researchers from South Korea report.

"Women are concerned about the risks associated with pregnancy after radioactive iodine treatment," Dr. Hye Ok Kim from Health Insurance Review and Assessment (HIRA) Service and Ewha Womans University, in Seoul, told Reuters Health by email. "Therefore, accurate information about the recommended interval between radioactive iodine treatment and conception is critical for childbearing-age women and their treating physicians."

RAIT is commonly associated with oligomenorrhea and is a risk factor for congenital malformations. The American Thyroid Association and the European Association of Nuclear Medicine Therapy Committee recommend avoiding pregnancy for at least six months after RAIT, albeit based on relatively low quality of supporting evidence.

Dr. Kim's team used data from South Korea's HIRA database to investigate whether RAIT was associated with an increase in adverse pregnancy outcomes among more than 10,000 women who became pregnant after thyroidectomy for thyroid cancer; 55% had surgery alone, while the rest had surgery plus RAIT.

Conception rates in the RAIT group were significantly lower than in the surgery-only group in both the 0-to-5- and 6-to-11-month intervals after treatment but did not differ between the groups in the 12-to-23 months after treatment.

Overall, there were no significant differences between the surgery-only and surgery-plus-RAIT groups in rates of abortion (spontaneous and induced), preterm deliveries or congenital malformations, the researchers report in JAMA Internal Medicine, online October 21.

Among women who received RAIT, congenital malformation rates were higher, though not significantly so, for those whose interval between treatment and conception was 0 to 5 months (13.3%) versus 6 to 11 months (7.9%), 12 to 23 months (8.3%), or 24 months or more (9.6%).

After adjusting for age at conception and cumulative radioactive iodine dose, the odds of congenital malformation were 74% higher (P=0.04) for early conception (0 to 5 months after RAIT) versus late conception (12 to 23 months after RAIT).

The cumulative dose of radioactive iodine, however, was not associated with the risk of congenital malformations.

The odds of abortion were also significantly higher (OR, 4.08) among women who received RAIT less than six months before conception versus those who conceived later.

"These large-scale real-world data suggest that radioactive-iodine treatment after thyroidectomy is not associated with an increase in adverse pregnancy outcomes when conception occurs after a 6-month waiting period," Dr. Kim said.

"This study is the first large-scale, nationwide cohort study to examine the associations between radioactive-iodine treatment and pregnancy outcomes," she said. "We believe that this data would be informative to women who attempt pregnancy during the early period after radioactive iodine treatment and their treating physicians."

Dr. James Wu of UCLA Section of Endocrine Surgery, in Los Angeles, who earlier reported delayed childbearing among women treated with radioactive-iodine ablation for well-differentiated thyroid cancer, told Reuters Health by email, "These findings provide more evidence that radioactive-iodine therapy does not impact birth outcomes long-term, but prolongs the time to conception. It reassures younger women with thyroid cancer that radioactive-iodine therapy will not adversely affect their offspring."

"On the other hand, the average time from radioiodine treatment to conception was a little over two years - a significant amount of time to women diagnosed in their thirties who desire children," he said. "Women near advanced maternal age (35) who desire future pregnancy should communicate that clearly to their endocrinologists, as it may influence the decision to treat with radioactive iodine or not after thyroid surgery."

Dr. Wu added, "In general, radioactive iodine is an effective therapy for thyroid cancer with minimal side effects. However, it has only been proven to benefit high-risk cases of thyroid cancer and it is likely overused in cases in lower risk patients. All patients, especially those desiring future children, should have a thoughtful discussion with their endocrinologist about the risks and benefits of radioactive-iodine therapy."

NEOADJUVANT CHEMOTHERAPY FOR NASOPHARYNGEAL CANCER

In a Chinese phase III trial reported in The New England Journal of Medicine, Zhang et al found that the addition of gemcitabine/cisplatin induction chemotherapy to standard platinum-based chemoradiotherapy improved recurrence-free survival vs chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma.

“Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival as compared with chemoradiotherapy alone among patients with locoregionally advanced nasopharyngeal carcinoma.”

The open-label trial included 480 patients with newly diagnosed disease from 12 centers. Patients were randomly assigned between December 2013 and September 2016 to receive gemcitabine at 1 g/m² on days 1 and 8 and cisplatin at 80 mg/m² on day 1 every 3 weeks for three cycles plus standard chemoradiotherapy (n = 242) or standard chemoradiotherapy alone (n = 238). Chemoradiotherapy consisted of 100 mg/m² of cisplatin every 3 weeks on days 1, 22, and 43, plus intensity-modulated radiotherapy. Randomization was stratified by treatment center and disease stage III or IV. It was recommended that patients in the induction chemotherapy group begin chemoradiotherapy within 21 to 28 days after the first day of the last cycle of induction chemotherapy.
The primary endpoint was recurrence-free survival in the intention-to-treat population.
Recurrence-Free Survival
Median follow-up was 42.7 months. In total, 96.7% of patients in the induction chemotherapy group completed three cycles of induction chemotherapy. Recurrence-free survival at 3 years was 85.3% with induction chemotherapy vs 76.5% with standard therapy (stratified hazard ratio [HR] = 0.51, P = .001). Overall survival at 3 years was 94.6% vs 90.3% (HR = 0.43, 95% confidence interval [CI] = 0.24–0.77). The 3-year distant recurrence-free survival rates were 91.1% vs 84.4% (HR = 0.43, 95% CI = 0.25–0.73), and the 3-year locoregional recurrence-free survival rates were 91.8% vs 91.0% (HR = 0.77, 95% CI = 0.42–1.41).

• The addition of induction chemotherapy to standard chemoradiation significantly increased recurrence-free survival.
• Recurrence-free survival at 3 years was 85.3% in the induction chemotherapy group vs 76.5% in the standard therapy group.

Adverse Events
Acute grade 3 or 4 adverse events occurred in 75.7% of the induction-chemotherapy group and 55.7% of the standard-therapy group, with the induction-chemotherapy group having a higher incidence of neutropenia (28.0% vs 10.5%), thrombocytopenia (11.3% vs 1.3%), anemia (9.6% vs 0.8%), nausea (23.0% vs 13.9%), and vomiting (22.6% vs 13.9%). Grade 3 or 4 mucositis occurred in 28.9% vs 32.1% of patients. Grade 3 or 4 late toxicity occurred in 9.2% vs 11.4% of patients, with the most common being deafness/otitis (5.4% vs 6.8%).
The investigators concluded, “Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival as compared with chemoradiotherapy alone among patients with locoregionally advanced nasopharyngeal carcinoma.”
Disclosure: The study was funded by the Innovation Team Development Plan of the Ministry of Education and others. For full disclosures of the study authors, visit nejm.org.

INCREASING SURVIVAL IN NASOPHARYNGEAL CANCER

Adding induction chemotherapy to standard concurrent chemoradiotherapy boosted overall survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, but at a cost of higher rates of acute grade 3 or 4 toxicities, in a phase 3 study conducted in China.
"The increase from 90.3% to 94.6% in overall survival is a big jump. It means the new treatment lowered the risk of death by about 50% " Jun Ma, MD, of the Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Quangzhou, China, told Medscape Medical News.
As for side effects, "most acute side effects were temporary and reversible [and] would not significantly impair the patient's quality of life. The incidence of late side effects was not increased with the induction chemotherapy, with the exception of mild peripheral neuropathy," Ma said.
Approached for comment, Marcelo Bonomi, MD, of the Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital, Columbus, said the study has already changed practice at his institution, where use of induction chemotherapy is now standard in these patients.
The absolute benefit in overall survival is "huge," and acute toxicity is the "price to pay" for improved overall survival, Bonomi told Medscape Medical News.
The study was published online September 19 in the New England Journal of Medicine and was presented earlier this year at the annual meeting of the American Society of Clinical Oncology.

Clear-cut Survival Advantage

The authors explain that, at presentation, 70% of patients with nasopharyngeal carcinoma have locoregionally advanced disease and an unfavorable prognosis. Chemoradiotherapy with a platinum-based agent is the backbone of therapy in this group.
In their study, the investigators explored adding induction chemotherapy with gemcitabine and cisplatin, which had already shown promising efficacy in phase 2 trials.
Theirs was a phase 3 study, conducted in 480 patients with previously untreated, locoregionally advanced, nonmetastatic stage III–IVB nasopharyngeal carcinoma.
Roughly half of the patients were randomly allocated to receive induction chemotherapy with gemcitabine (1 g/m² on days 1 and 8) plus cisplatin (80 mg/m² on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg/m² every 3 weeks for three cycles plus intensity-modulated radiotherapy).
The patients in the other group were treated with chemoradiotherapy alone.
At a median follow-up of 42.7 months, the primary endpoint of 3-year recurrence-free survival was 85.3% with induction chemotherapy vs 76.5% with chemoradiotherapy alone (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 – 0.77; P = .001).

 

 

Adding induction chemotherapy to standard concurrent chemoradiotherapy boosted overall survival in patients with high-risk locoregionally advanced nasopharyngeal carcinoma, but at a cost of higher rates of acute grade 3 or 4 toxicities, in a phase 3 study conducted in China.
"The increase from 90.3% to 94.6% in overall survival is a big jump. It means the new treatment lowered the risk of death by about 50% " Jun Ma, MD, of the Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Quangzhou, China, told Medscape Medical News.
As for side effects, "most acute side effects were temporary and reversible [and] would not significantly impair the patient's quality of life. The incidence of late side effects was not increased with the induction chemotherapy, with the exception of mild peripheral neuropathy," Ma said.
Approached for comment, Marcelo Bonomi, MD, of the Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital, Columbus, said the study has already changed practice at his institution, where use of induction chemotherapy is now standard in these patients.
The absolute benefit in overall survival is "huge," and acute toxicity is the "price to pay" for improved overall survival, Bonomi told Medscape Medical News.
The study was published online September 19 in the New England Journal of Medicine and was presented earlier this year at the annual meeting of the American Society of Clinical Oncology.

Clear-cut Survival Advantage

The authors explain that, at presentation, 70% of patients with nasopharyngeal carcinoma have locoregionally advanced disease and an unfavorable prognosis. Chemoradiotherapy with a platinum-based agent is the backbone of therapy in this group.
In their study, the investigators explored adding induction chemotherapy with gemcitabine and cisplatin, which had already shown promising efficacy in phase 2 trials.
Theirs was a phase 3 study, conducted in 480 patients with previously untreated, locoregionally advanced, nonmetastatic stage III–IVB nasopharyngeal carcinoma.
Roughly half of the patients were randomly allocated to receive induction chemotherapy with gemcitabine (1 g/m² on days 1 and 8) plus cisplatin (80 mg/m² on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg/m² every 3 weeks for three cycles plus intensity-modulated radiotherapy).
The patients in the other group were treated with chemoradiotherapy alone.
At a median follow-up of 42.7 months, the primary endpoint of 3-year recurrence-free survival was 85.3% with induction chemotherapy vs 76.5% with chemoradiotherapy alone (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 – 0.77; P = .001).