Radiation Therapy (with or without neck surgery) for Phenotypic HPV- associated Oropharyngeal Cancer

Abstract

Background

Favorable outcomes for HPV-associated oropharyngeal cancer (OPC) has led to interest in identifying a subgroup of patients with the lowest risk of disease recurrence following therapy. De-intensification of therapy for this group may result in survival outcomes that are similar to current therapy but with less toxicity. To advance this effort, we analyzed the outcomes of OPC patients treated with and without systemic therapy.

Methods

This is a retrospective study of oropharyngeal cancer patients treated between 1985–2012. Criteria for inclusion were ≤ 10 pack-years of cigarette smoking and stage III and IVA limited to T1-3, N1-N2b and T3N0. Survival analysis was performed with the primary endpoint of progression-free survival (PFS).

Results

The cohort included 857 patients. Systemic therapy was given to 439 patients (51%). Median survival was 80 months. The 2-year PFS rates was 91%. Limiting analysis to 324 patients irradiated without systemic therapy, the 2- and 5- year PFS rates were 90% and 85%, respectively. Further, for these 324 patients the 5- year PFS rates for T1, T2, and T3 disease were 90%, 83%, and 70%, respectively. The 5-year PFS rate for patients treated with systemic therapy for T3 disease was 77% (p = .07).

Conclusions

Using the low-risk definition currently established in cooperative trials, our patients had a 2-year PFS rates approximating 90%. When evaluating patients treated with radiation alone, we did not observe a compromise in this high rate of PFS, which is higher than the 2-year PFS thresholds used in current cooperative trials.

Introduction

The management of “locally-advanced” or stage III and IV ¹, head and neck cancer has undergone many changes over the past several decades. In the 1990s and 2000s, trials evaluating treatment intensification through the addition of systemic therapy to radiation ultimately led to concurrent chemoradiation becoming a standard of care. ²

Retrospective analyses of several treatment intensification trials identified a subgroup of patients with oropharyngeal cancer that was associated with human papillomavirus (HPV). ^{3, 4} Further, this association with HPV is prognostically favorable. The Radiation Therapy Oncology Group (RTOG) reported in 2 separate chemoradiation trials 3-year overall survival rates greater than 80% for patients with oropharyngeal HPV-associated cancer. These results are in contrast to the HPV-negative group for whom the 3-year survival rate was less than 60%. ^{3, 5}

This observation that a specific cohort of patients has a very favorable prognosis has led to great interest in de-intensification of therapy for patients with HPV-associated oropharyngeal cancer. However, there is concern about modifying an effective therapy with excellent survival rates. This concern has led to an effort to identify a subgroup of patients with the lowest risk of disease recurrence within this larger group of patients with a favorable presentation; De-intensification is potentially safest in this subgroup. In their analysis of the impact of HPV on oropharyngeal cancer, the RTOG identified a lower risk group based on limited tobacco exposure, and lower tumor burden. ³ Similarly, O’Sullivan and colleagues, identified patients with T1-3, N0-2b patients as being suitable for de-intensification strategies that omit chemotherapy. ⁶

Based on the interest in de-intensification, and the works described above, the NRG Oncology Group is conducting a phase II trial for patients classified as having very low-risk HPV-associated oropharyngeal cancer. One arm combines 60 Gy of radiation delivered over 6 weeks with concurrent cisplatin, while the second experimental arm evaluates radiation alone with 60 Gy in 5 weeks. The primary objective is to select the better arm with 2-year progression-free survival of ≥85%. While several authors have suggested that radiation alone can result in good outcomes for patients with HPV-associated oropharyngeal cancer, specifics regarding outcomes for these patients treated without chemotherapy are limited. We thus conducted this retrospective analysis to demonstrate oncologic safety of radiation alone in a large series of low-risk patients with oropharyngeal cancer.

Methods

This retrospective study was conducted with Institutional Review Board approval. To identify oropharyngeal cancer patients with NRG-defined low risk of recurrence we utilized the database maintained by the Department of Radiation Oncology at University of Texas MD. Anderson was conducted to derive the population of interest. The search criteria included all patients with oropharyngeal cancer irradiated between 1985 and 2012 who met the following criteria: ≤ 10 pack-years of cigarette smoking and stage III and IVA oropharyngeal cancers limited to T1-3, N1-N2b and T3N0. We excluded patients with prior malignancies of the head and neck, previous irradiation to the head and neck and multiple primary tumors, and those who had resections of their primary tumors; those with tonsillectomies done for diagnostic purposes were included in the analysis.

Patient management evolved over this 27 year experience. During the earlier part of this study period, patients were more commonly treated without systemic therapy. Altered fractionation was used often in the 1980s and 1990s, and systemic therapy was ultimately added, including neoadjuvant chemotherapy, concurrent chemotherapy, and concurrent biologic therapy. Patients’ management was individualized by their treating physicians, though all cases were reviewed in a multidisciplinary tumor board and the specifics of their radiation were peer-reviewed by a group of dedicated head and neck radiation oncologists.

Data regarding patient demographics, tumor characteristics, and treatment details were collected through review of the patients’ medical records. Tumors were staged using the TNM classification and revised if needed based on the most recent AJCC staging manual.

Statistical methodology included frequency tabulation, and survival analysis using the Kaplan-Meier test. Comparison of survival curves was done with the log-rank test. The primary endpoint tested was progression-free survival (PFS). Patients were censored at last follow-up, and events were scored for any disease recurrence or death.

Results

Patient and tumor characteristics

We identified 857 patients who met our criteria (Table 1). The majority of patients were male (84%) with a median age of 54 years old. Six hundred seventy-three patients (78%) were never smokers, and the remainder (22%) had ≤ 10 pack-year cigarette use.

TABLE 1.

Patient Demographics, Staging, and Treatment

Sex, No.
Male	719
Female	138
Age, median (range), Yrs.	54 (19–84)
Primary site, No.
Tonsil	426
Base of tongue	404
Other	27
Tobacco exposure, No.
Yes, ≤10 pack-y	185
No	672
HPV or p16, No.
Positive	270
Negative	20
TN category, No.
T1N1	120
T1N2a	75
T1N2b	170
T2N1	75
T2N2a	58
T2N2b	194
T3N0	38
T3N1	41
T3N2a	12
T3N2b	74
Radiation technique, No.
IMRT	612
3-field	235
Other	10
Radiation fractionation, No.
Once daily	625
Concomitant boost	205
Other	27
Radiation dose, median (range), Gy	66 (20–82)
Systemic therapy, No
Yes	439
No	418
Induction	185
Concurrent	321
Concurrent biologic only	132

Abbreviation: HPV, human papillomavirus; IMRT, intensity-modulated radiation therapy.

Tumor sites were nearly evenly divided between the tonsil (50%) and base of tongue (47%). HPV or p16 status was obtained in 290 patients, (34%) and was positive in 270 (93%). T and N categorization is shown in Table 1. The majority (81%) of patients had either T1 or T2 tumors. Nearly all patients were node positive (as node negative patients were limited to those with T3), and 51% had N2b disease.

Treatment

The median dose of radiation was 66 Gy. Fractionation was conventional (2 – 2.2 Gy, once daily) in 625 patients (73%), with altered fractionation schedules used to treat 232 (27%). IMRT was used to treat 612 patients (71%).

One hundred thirty-eight patients (16%) had tonsillectomies with no evidence of primary disease at the time of their radiation. A neck dissection was performed in 43 patients (5%) prior to radiation, and 124 (15%) had nodal excisions prior to radiation. A neck dissection was performed post radiation in 170 patients (20%).

Systemic therapy was given to 439 patients (51%). Treatment was neoadjuvant in 185 (22%), and concurrent in 321 (37%), as 67 patients had both neoadjuvant and concurrent therapy. Among patients who received concurrent therapy, 132 (15%) were treated with a biologic agent exclusively, while 189 (22%) received a cytotoxin.

One hundred sixty-one patients (19%) were treated prior to the year 2000; of these, 29 (18% of subgroup, 3% of total) received systemic therapy. By comparison, of the 696 patients treated since 2000, 410 (59% of subgroup, 48% of total) received drugs in addition to radiation (P < .001).

Outcomes

The median survival for all patients was 80 months (range, 1 – 121 months). The 2- and 5- year PFS rates were 91% and 86%, respectively. There were no differences in PFS rates comparing patients with HPV-associated disease, HPV non-associated disease, and patients for whom tumor was not tested for HPV/p16 (p= .67). The 5-year PFS rates for patients without obvious primary disease (following tonsillectomy) and those with intact disease were 90% and 85%, respectively (p=.007). Limiting analysis to 324 patients treated with intact primary disease and irradiated without systemic therapy, the 2- and 5- year PFS rates were 90% and 85%, respectively. There were no differences in PFS rates between those patients who did or did not receive systemic therapy (figure 1).

Figure 1.

Progression-free survival of 857 patients treated with radiation or radiation and systemic therapy

The 2- and 5- year PFS rates for T1, T2 and T3 disease were 93% and 90%, 91% and 86%, and 84% and 75%, respectively (p < .001, figure 2a). Differences in PFS for the 3 T categorizations were maintained when patients without intact disease following tonsillectomy were excluded, and were also maintained in patients treated with and without chemotherapy. Limiting analysis to 324 patients treated with intact primary disease and without systemic therapy, the 5- year PFS rates for T1, T2, and T3 disease were 90%, 83%, and 70%, respectively (figure 2b). The comparative 5-year PFS rate for patients treated with systemic therapy for T3 disease was 77% (p = .07, figure 2c). Differences between rates of PFS among patients with differing N-categories was not significant (p= .3) overall, nor in all pairwise comparisons.

Figure 2.

a) Progression-free survival stratified by T-category, b) Progression-free survival stratified by T-category limited to 324 patients treated without systemic therapy and c) treated with systemic therapy.

Fifty-six patients had locoregional recurrence. The 2- and 5-year actuarial locoregional control rates were 96% and 94%, respectively. Sixty-three patients, 10 with locoregional recurrences developed distant metastases. The 2- and 5-year distant control and recurrence free survival rates were 96% and 93%, and 92% and 88%, respectively.

One hundred fifty-five patients have died, and the 3- and 5-year actuarial overall survival rates were 93% and 90%.

Discussion

Our goal was to determine the PFS in a cohort of patients that cooperative groups are targeting as appropriate for treatment de-intensification strategies. We found 2-year PFS rates approximating 90% in all our ‘low-risk’ patients, and further when evaluating patients treated with radiation alone, we did not observe a compromise in this high rate of PFS.

Ang and colleagues ³ utilized RTOG-0129, a phase 3 trial evaluating radiation fractionation in patients receiving concurrent cisplatin and radiation to identify a ‘low-risk’ group of patients with head and neck cancer. This group included 114 patients with HPV-positive tumors who had either < 10 pack-years of smoking or had N0-N2a nodal disease. The reported 3-year overall survival was 93% which was similar to our findings. Building on this concept, O’Sullivan et al. attempted to identify a group of patients to potentially de-intensify therapy. ⁶ Their primary goal was to identify a group who not only had high rates of local and regional control, but also low rates of distant recurrence. They found that T and N stage could distinguish low- risk patients, and the model could be improved by including patients with little or no tobacco exposure. They ultimately proposed that patients with T1-3, N0-2b, and < 10 pack years of smoking would be the safest group to de-intensify therapy.

While all our patients had stage III and IVA disease per the latest AJCC staging manual, the data for the intense treatment regimens currently recommended for this subgroup of patients with nominal locally advance disease is based on historic cohorts that are not representative of current demographics and prognosis. Numerous trials testing concurrent chemoradiation, focused more on patients with bulky disease. ^7,8,8 The MACH metanalysis of over 17000 patients had a ratio of 3:1 of patients with T3-4 tumors: T1-2 tumors. ² Radiation alone has been shown to have high rates of local control for smaller tumors, and in particular T1 tumors can be controlled with 66 Gy in 33 fractions in most situations. ^9,10,11 This dose fractionation schedule is less intense than 60 Gy in 5 weeks. Additionally, the impact of concurrent chemotherapy on distant control is controversial. While the MACH study ² did demonstrate a reduction in distant failure with concurrent therapy, but the absolute benefit was very small, namely < 3% at 5 years. However, choosing patients at the lowest risk of distant failure is prudent.

One of the limitations of this trial is our focus solely on disease outcome without the corresponding toxicity. In particular, the interest in treatment de-intensification is based on reduction of toxicity, primarily dysphagia. However, there is data to suggest that this low risk group is not only at low risk for disease recurrence, but for dysphagia. Setton et al. performed a multiinstitutional analysis of gastrostomy use in patients with oropharyngeal cancer treated with IMRT. ¹² While the incidence of 1-year gastrostomy dependence was 8.8% for stage III and IV patients treated with chemoradiation, the incidence was only 5% for patients with T1-2/N0-2 disease. Furthermore, gastrostomy tube dependence increased with smoking. In addition, as half the patients in this low-risk group have low volume tonsillar cancer, ipsilateral radiotherapy should be feasible in many, which further serves to reduce rates of chronic gastrostomy use. ¹³ Our recent work has demonstrated that the majority of patients with low volume tonsillar cancer (T1-2/N0-2b) treated with either radiation or chemoradiation have low long-term symptom burden. ¹⁴

An additional potential limitation is that HPV/p16 status was not obtained on over half the tumors. However, PFS rates were similar for those with known and unknown HPV-associated disease. Of those with the phenotype of low volume disease, and < 10 pack year smoking, 93% were HPV or p16 positive. Further, had our PFS not been high, it could be argued that some patients were potentially not suitable for inclusion, but with a 5-year PFS and OS of 86% and 90%, respectively, either the vast majority of our patients have HPV-associated disease, or our data suggests that the phenotype is as important if not more so than HPV association.

While the low-risk category excludes those with the most advanced disease (T4 or N2c-3), the majority of patient with HPV associated disease have T and N categorization that would qualify as low-risk. Hence,- the grouping assumes equipoise between patients irrespective of tumor size. This may be due to these grouping analyses being based only on modest sized cohorts, where single digit differences in PFS may not have been detected as significantly different. We did find a statistical difference in PFS based on T stage, and while our overall results exceed the 85% 2-year PFS used as the cutoff for success, the 2-year PFS rate of 84% for all T3 patients, and 5-year 70% PFS rate for T3 patients treated with radiation alone should be cautionary. While our cohort had over 100 patients with T3 disease, we could only detect a trend (p =.07) to poorer outcome when systemic therapy was not used for these patients with bulky primary disease.

An additional cautionary note regards the use of 2-year outcomes to judge the safety of de-intensification. The absolute differences in 2- and 5- year disease control measures were small. However, roughly one-third of recurrences were detected in 3–5 years post treatment. Thus while 2-year PFS may be adequate for selecting a de-intensification strategy, longer follow-up in phase 3 trials will be required to assess that these strategies result in equivalent cure rates, rather than just delaying recurrences.

In conclusion, our retrospective analysis of over 800 patients including over 300 patients with gross primary oropharyngeal cancer treated with radiation without systemic therapy who had the HPV-associated phenotype had PFS that exceeded the threshold being used in cooperative trials as the level of success for treatment de-intensification. Our results support the current de-intensification strategy and suggest that these patients will have equivalent survival outcomes when chemotherapy is omitted from their therapy potentially reducing cost and toxicity of therapy.