In a nutshell, concurrent chemoradiation is what we do in advanced disease.
—Jonathan Beitler, MD
For smokers with T4, N2c, N3, and N2b disease, we agree that chemotherapy is clearly indicated. For N2b disease in nonsmokers, omitting chemotherapy is a step into the unknown.
—Nabil Saba, MD
Are there patients with locally advanced squamous cell carcinoma of the head and neck associated with human papillomavirus (HPV) for whom chemotherapy can be omitted? Experts debated this question at the 2015 Debates and Didactics in Hematology and Oncology Conference in Sea Island, Georgia, sponsored by Emory University. Jonathan Beitler, MD, Professor of Radiation Oncology, Otolaryngology, Hematology, and Oncology at Emory, and Nabil Saba, MD, Professor of Hematology and Medical Oncology and Director of Head and Neck Medical Oncology at Emory, focused on the controversies surrounding the management of HPV-related head and neck cancer, especially in nonsmokers with N2b tumors.
Prognostic Effect of HPV Positivity
Clearly, HPV status has a prognostic effect, but does it influence treatment? In their 2010 report in The New England Journal of Medicine, Ang and colleagues found that HPV-positive patients, compared with their HPV-negative counterparts, had better progression-free survival and lower locoregional failure rates as well as improved 3-year overall survival (82.4% vs 57.1%; P < .001).1 The rate of distant metastasis, however, was not significantly different between the two groups (8.7% vs 14.6%; P = .21).
Subsequent to this important study, HPV-positive diagnoses have increased. “While these patients are doing well with locoregional control,” according to Dr. Saba, “a new paradigm has emerged—more distant failures seen in patients being treated for locally advanced disease.”
Dr. Beitler added that similar findings were made in the TAX 324 trial, in which patients with HPV-16–associated tumors had far better survival outcomes than HPV-negative patients after treatment with sequential chemoradiation.2 The DAHANCA5 study also showed that HPV-associated tumors had better outcomes, this time after radiotherapy alone.3
Not only does HPV positivity confer a more favorable prognosis, it is “platform-independent,” Dr. Beitler told listeners. “These patients just do better regardless of whether they are treated with chemoradiation, radiation alone, or even surgery with or without adjuvant therapy.”
Staging Issues With HPV Positivity
A current problem for clinicians is that HPV positivity has not been incorporated into the current TNM staging system. Huang et al recently showed, among more than 600 subjects, that higher stage of disease was not associated with poor 5-year survival for patients with HPV-associated tumors, as it was for those with HPV-unrelated cancers—indicating “prognostic discordance.”4
A problem with the Huang analysis is that it included very few patients with stage I (1%) or II (4%) disease, and it did not utilize the stage IVa and IVb designations of the current AJCC (American Joint Committee on Cancer) system,5 according to Dr. Beitler. “We don’t even know if extracapsular extension makes a difference in HPV-related cancers,” he added.
The lack of an accurate staging system for these patients makes it impossible to identify those HPV-positive patients who truly need chemotherapy, Dr. Beitler said. It appears that patients most at risk for metastatic disease are those with N2c and N3 disease, a relatively infrequent subgroup.6
Benefit of Chemotherapy Still Debated
Although the use of chemotherapy is supported in N3 and T3/4 disease, “mission creep” has occurred, and “somehow chemotherapy gets added in other stages, and that may not be appropriate,” Dr. Beitler explained. In many cases, he suggested, chemotherapy adds toxicity but not benefit. As a locoregional radiation sensitizer, it “is worth” about 12 Gy7 and “isn’t worth a heck of a lot” for protection against systemic disease, at least according to the MACH-NC meta-analysis.8
Regarding chemotherapy toxicity, the GORTEC 94-01 final analysis found significantly higher rates of teeth-related problems and numerically higher rates of several other side effects.9 The percentage of patients with no evidence of disease but grade 3/4 late effects was 30% with radiotherapy alone and 56% with chemoradiation (although this was not statistically significant; P = .12). Other studies have indicated that as more chemotherapy is added, the relative risk of toxicity increases, Dr. Beitler said.
In sum, he said that surgery, radiotherapy, and chemoradiation are all effective for HPV-associated cancers, but staging is not particularly useful in selecting the best approach for a given patient.
Dr. Beitler pointed to data from the MACH-NC meta-analysis to support his opinion that concomitant chemoradiation is beneficial, but induction chemotherapy is not.8 MACH-NC, which included more than 17,000 patients from 93 randomized trials, found that concomitant chemotherapy and radiation significantly improved overall survival (hazard ratio [HR] = 0.81), but induction chemotherapy did not improve survival (HR = 0.96) and reduced distant failures by only 2% to 3%. Concomitant therapy was also superior to induction chemotherapy for event-free survival and locoregional failure.
“In a nutshell, concurrent chemoradiation is what we do in advanced disease,” Dr. Beitler said.
However, Dr. Saba had a different perspective on the study and argued that the benefit of induction chemotherapy in reducing distant metastases (HR = 0.73, P = .001) is significant in the meta-analysis. The concomitant schedules markedly improved locoregional control (HR = 0.74, P < .001), with a significant but less impressive improvement in distant control (HR = 0.88, P = .04).8
It is important to note that this meta-analysis was performed before HPV status became a factor, and therefore the distant metastatic rate by HPV status is not known, added Dr. Saba. Nevertheless, he suggested, “the findings suggest that systemic chemotherapy does help ameliorate the rate of distant metastasis.”
‘Unusual Pattern of Metastasis’
Dr. Saba emphasized the importance of this finding in the case of HPV-positive tumors, which have “an unusual pattern of metastasis.” He added, “We were the first to report on the unusual pattern of metastases in the HPV-positive oropharyngeal squamous cell carcinoma group.”10 In the large retrospective Princess Margaret Hospital data set, investigators also found a higher risk for multiple-organ failure in HPV-positive patients (not seen in HPV-negative patients).
A “fair proportion of these patients,” noted Dr. Saba, manifested a “disseminating” phenotype with spread to two or more organs that was relatively frequent (33%), although it was not seen in HPV-negative cases. Of the HPV-positive patients who had distant metastases, 20% demonstrated an “explosive” character, with numerous metastatic lesions occupying almost the entire organ and developing rapidly. “Strikingly, 72% of the HPV-positive distant metastatic cases were without locoregional failure,” Dr. Saba added.
This finding, he continued, provokes several questions: How and when does the transformed HPV-positive tumor cell clone escape from the primary site and disseminate? How can such “occult” distant metastasis be identified? “We simply don’t know. Until we are proficient at this, the only way to target these clones is with systemic therapy,” Dr. Saba said.
Is Deintensification an Acceptable Approach?
Is deintensification of chemotherapy an acceptable approach to treating HPV-related N2b cancers? Dr. Saba emphasized that deintensification is not equivalent to omitting or even reducing the dose of chemotherapy. “It can take several forms,” he explained.
One approach is to modify systemic agents to relieve toxicity (as in RTOG 1016). Risk stratification after surgery is another means (as in ECOG 3311, which introduced a lower dose of radiation in low-risk patients). “Chemo selection” is yet another approach that deintensifies treatment by reducing radiation based on response to appropriate chemotherapy agents.
Deintensification of radiotherapy was shown to be effective in the E1308 trial, which evaluated induction chemotherapy followed by cetuximab (Erbitux) with low-dose vs standard-dose radiotherapy in stage III/IV HPV-positive patients.11 Patients deemed to have the best prognosis (< T4, T1–N2b, < 10 pack-years of smoking) did very well when they received a reduced radiation dose (54 Gy). Dr. Beitler pointed out that E1308 did not quite meet its own minimal threshold for overall 2-year disease-free survival.
In 62 patients in the low-dose group, 2-year progression-free survival was 84%, and 2-year overall survival was 95%. Patients with ≤ 10 pack-years of smoking had slightly higher rates: 96% for progression-free survival and 97% for overall survival. For higher-risk patients who received full-dose intensity-modulated radiation therapy, 2-year progression-free survival was 65%, and overall survival was 87%.
“The trial showed that in the group we are discussing—the low-risk group, including nonsmokers with N2b disease—we can reduce the radiotherapy dose if we give enough systemic therapy upfront,” Dr. Saba said.
Dr. Saba did express some concerns that the increasing use of deintensification may be contributing to the distant failure rate seen with HPV-positive tumors. A combined analysis of RTOG 0129 and RTOG 0522 showed distant failure to be the predominant pattern of failure, occurring in 41% of HPV-positive patients and 38% of HPV-negative patients.12 It appeared that in HPV-negative tumors, the risk of distant metastases plateaued at about 2 years, but in HPV-positive tumors, the risk seemed to persist for a longer time. “This is a topic of concern for medical oncologists, as far as omitting systemic therapy in their treatment,” Dr. Saba said.
Radiotherapy Alone for Some Tumors
For small primary tumors (T1–2, N1–2a), outcomes with radiation alone (66 Gy in 30 fractions) can be excellent, Dr. Beitler said. MD Anderson has reported a 5-year locoregional control rate of 98%. The addition of a systemic radiosensitizer did not improve results in patients with intermediate-stage oropharyngeal disease, even without accounting for HPV status.
Similarly, data from Princess Margaret Hospital in Toronto have shown radiotherapy to be at least as effective as chemoradiation therapy, in a large series of patients. However, Dr. Saba responded that in the Princess Margaret Hospital cohort, distant and local disease control for patients with N2b disease was lower with radiotherapy alone, and some of these patients were nonsmokers, raising concerns about the control arm of NRG HN002 for patients with N2b disease.
“As medical oncologists, we have to ask, if we have patients with N2b disease who are nonsmokers, are we comfortable omitting chemotherapy? We in our group have said no. We are not comfortable giving radiation therapy only to these patients,” Dr. Saba said. “For smokers with T4, N2c, N3, and N2b disease, we agree that chemotherapy is clearly indicated. For N2b disease in nonsmokers, omitting chemotherapy is a step into the unknown.”
Clinical Trials May Offer Answers
Two important clinical trials may provide some answers to guide clinicians in treating HPV-positive locally advanced disease. ECOG 3311 has enrolled HPV-16–positive patients with stage III/IV disease (cT1–3, N1–2b [no T1N1]), stratifying them by risk. Low-risk patients will be observed; high-risk patients will be treated with radiotherapy and chemotherapy; and intermediate-risk patients will be randomized to two different radiotherapy schedules. Patients will be evaluated at 2 years.
The NRG HN002 trial has enrolled HPV-16–positive, nonsmoking patients with locoregionally advanced oropharyngeal cancer to receive radiotherapy alone (60 Gy, 6 fractions per week for 5 weeks, ie, slightly accelerated) or radiotherapy (60 Gy in 6 weeks) plus cisplatin 40 mg/m2 weekly for 6 cycles.
“Hopefully, we are embarking on randomized trials that will change preconceptions,” Dr. Beitler said. ■
Disclosure: Drs. Beitler and Saba reported no potential conflicts of interest.
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