Clinical prognostic factors to guide treatment strategy for HPV‑positive oropharyngeal cancer using treatment outcomes of induction chemotherapy: A real‑world experience
- Authors:
- Published online on: June 21, 2024 https://doi.org/10.3892/ol.2024.14524
- Article Number: 391
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Copyright: © Bang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
It is predicted that there will be 58,450 new patients with head and neck squamous cell carcinoma (HNSCC) diagnoses in the United States in 2024 and more than 12,000 deaths (1). A comparable incidence was noted in Korea, where it constituted ~2.1% and ranked as the 10th most prevalent cancer among male patients (2). The most common cause of HNSCC is smoking, with human papillomavirus (HPV) contributing to oropharyngeal cancer (OPC) and Epstein-Barr virus linked to nasopharyngeal cancer among other associated causative factors. Notably, HPV-positive OPC is more prevalent among younger individuals, particularly in relatively high-income countries (3). Recently, there has been a growing trend in the prevalence of HPV-positive OPC among older individuals. A previous study demonstrated an increase in the median age at diagnosis from 53 to 58 years between 1998 and 2013, aligning with the observed trend in Korea (4–6). Furthermore, the incidence of HPV-positive OPC is increasing in both younger and older patients, with a noticeable shift in the burden towards older patients. However, it is noteworthy that most cases occur in patients aged <60 years.
HPV-positive OPC exhibits distinctive histopathological characteristics that impact clinical outcomes. The expression of viral E6 and E7 oncoproteins by HPV deactivates the tumor suppressor protein p53 and the retinoblastoma protein (pRb), respectively (7). Typically, HPV-positive OPC exhibits high expression of p16 protein and a lower prevalence of genetic mutations, such as those in the TP53 (p53) gene, compared with HPV-negative OPC. These features are associated with chemo- or radiosensitivity (8). Moreover, HPV-positive OPC displays a unique immune microenvironment characterized by CD8+ T-cell activation and elevated programmed death-ligand 1 (PD-L1) expression, setting it apart from HPV-negative OPC. These cells can trigger an immune response; consequently, immunotherapy is used to treat HPV-positive OPC. The favorable clinical and biological characteristics of the HPV-positive OPC led to its downstaging in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system (9). Moreover, distinct treatment strategies have been proposed in the National Comprehensive Cancer Network (NCCN) guidelines for HPV-positive OPC compared with HPV-negative OPC (10).
Given this context, a number of clinical studies have actively investigated de-intensified treatment approaches to mitigate the toxicity in patients with HPV-positive OPC (11,12). De-intensified treatments include measures such as reducing the chemotherapy dose, omitting induction chemotherapy (IC), lowering the radiation dose, and opting for less invasive surgery.
Clinical studies on de-intensified treatment have been attempted; however, there is insufficient evidence for selecting suitable patients. As a result, this approach is not widely used in clinical practice and not endorsed by the NCCN guidelines (13). Previously, it has been reported that patients with OPC with high p53 expression had inferior survival outcomes than those with low p53 expression among patients with HPV-positive OPC (14). These results suggested that even in patients with HPV-positive OPC, treatment results may differ due to a combination of variable etiologies, and it is necessary to identify high-risk factors that can predict survival and develop treatment strategies. These disparities between the theoretically favorable prognosis and practical evidence of HPV-positive OPC may derive from tumor heterogeneity in addition to staging, biological features and patient-specific characteristics.
Hence, in the present retrospective study, the authors aimed to identify clinical high-risk factors for HPV-positive OPC and conducted a survival analysis in patients with OPC treated with IC followed by chemoradiotherapy (CRT). The outcomes of the present study can provide insights into chemoresistance.
Patients and methods
Study population
Patients who underwent treatment for OPC at Chonnam National University Hwasun Hospital between June 2004 and October 2020 were retrospectively reviewed. Inclusion criteria were as follows: i) Patients with pathologically confirmed, HNSCC (stage II–III or stage IV M0); ii) underwent at least two cycles of IC followed by CRT; and iii) older than 19 years at the time of diagnosis. Patients with an initial diagnosis of stage IV M1 disease or nasopharyngeal cancer were excluded. Briefly, 100 (95%) were male and the median age at diagnosis was 60 years (range, 40–67). To be eligible for the study, their medical records needed to include information on staging using computed tomography (CT) or magnetic resonance imaging (MRI) along with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scans as necessary. Baseline patient demographics collected encompassed sex, age, Eastern Cooperative Oncology Group (ECOG) performance status score, body mass index (BMI) (15), smoking history, pathologic differentiation, chemotherapy regimen and cumulative radiation dose. To diagnose HPV-positive OPC, p16 and HPV status were confirmed through medical records. In cases where HPV was not tested, additional PCR using My HPV Chip Kit™ (AG Bio Diagnostics Co. Ltd.) was performed with archived tissue from Biobank of Chonnam National University Hwasun Hospital, a member of the Korean Biobank Network. The HPV DNA chip contained 12 types of high-risk HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 54, 56, 58) and 8 types of low-risk HPV (HPV 6, 11, 34, 40, 42, 43, 44, 54) strains. The PCR products from all samples were subjected to electrophoresis on 2.0% agarose gels, and size of HPV DNA products was 100 base pairs. After 10 µl of the amplified HPV product was denatured at 95°C for 5 min, it was mixed with a hybridization solution and then applied to the DNA chip. Hybridization HPV DNA was visualized using a DNA chip scanner (GenePix 4000B; Molecular Devices, LLC). HPV amplicons were hybridized with the corresponding type of specific oligonucleotide probe and visualized on HPV DNA chip slides as double positive spots. Among patients diagnosed before 2017, eligible individuals were re-staged according to the AJCC 8th edition staging system based on HPV status. The protocol of the present study was approved (approval no. CNUHH-2023-232) by the Institutional Review Board of Chonnam National University Hwasun Hospital (Hwasun, Republic of Korea).
Treatment and tumor assessment
The patients received IC every 3 weeks, with a dose of 70 mg/m2 docetaxel and 75 mg/m2 cisplatin administered as a 4-h intravenous infusion on day 1. Additionally, 1,000 mg/m2 5-fluorouracil was administered as a 24-h continuous infusion for 4 days. After IC, definitive treatment, such as CRT or surgery, was conducted based on the consensus of the multidisciplinary head and neck cancer team. CRT commenced within 4 weeks of IC completion, involving concurrent administration of cisplatin at a dose of 100 mg/m2 every 3 weeks (on days 1, 22 and 43) or at a dose of 40 mg/m2 weekly for 7 days (days 1, 8, 15, 22, 29, 36 and 43). Radiotherapy (RT) was administered using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated RT (IMRT). Response was evaluated by the Response Evaluation Criteria in Solid Tumors 1.1 and involved assessing complete response (CR), partial response, stable disease and progressive disease after IC and 8 weeks post CRT completion (16). Alongside imaging studies, all patients underwent a physical examination by an otolaryngologist to validate the response evaluation. Patients who achieved a CR upon physical examination and CT or MRI scan, underwent 18F-FDG-PET scans for confirmation 1 month after CR confirmation. Most patients were evaluated for response by CT, but in cases of radiation-induced swelling on CT, it was difficult to assess the response, thus in these cases, MRI was performed. After completing treatment, patients underwent monthly follow-ups with physical examinations. CT or MRI scans were conducted every 4 months for the initial 2 years, followed by biannual scans until disease progression.
Statistical analysis
Overall survival (OS) was characterized as the time from diagnosis to death. Progression-free survival (PFS) was defined as the time from diagnosis to death or the initially documented recurrence, further categorized as locoregional recurrence (tumor at the primary site or regional nodes) or distant metastasis. Patient characteristics were compared using the Chi-square test, Fisher's exact test and unpaired Student's t-test. Continuous variables are expressed as median, and categorical variables are presented in terms of frequency and percentage values. Survival analysis utilized Kaplan-Meier survival curves, and the log-rank test was used for comparison. Univariate and multivariate survival analyses were conducted using Cox proportional hazards. The level of significance adopted in all analysis was 5% with a 95% confidence interval and P<0.05 was considered to indicate a statistically significant difference. Statistical analyses were performed using R, version 4.2.2 (R Foundation for Statistical Computing; http://www.r-project.org/).
Results
Patient characteristics
The present study included 105 patients, comprising 40 HPV-negative and 65 HPV-positive individuals (Fig. 1). Baseline patient characteristics are presented in Table I. The median follow-up period for surviving patients was 60 months, and the median age at diagnosis was 60 years (range, 40–76 years). The study population primarily comprised males (95.2%), with 74.3% having a smoking history. In comparison to patients with HPV-negative OPC, those with HPV-positive OPC were younger (P=0.046), showed a lower percentage of N2 stage (P=0.024), had a less frequent smoking history (P=0.049), and a higher incidence of poorly differentiated tumors (P=0.001). Upon restaging according to the AJCC 8th edition staging system, 51 out of 65 patients (78%) with HPV-positive OPC were down-staged from their initial diagnosis, indicating a higher proportion of patients in the early stages of disease (P<0.01) compared with HPV-negative OPC. Specifically, 3 individuals were down-staged from stage III to stage II, 10 were down-staged from stage IV to stage III and 38 were downgraded from stage IV to stage II.
Treatment delivery and outcomes
Of the total participants, 102 (97.1%) underwent three cycles of IC. At the same time, 3 patients received additional cycles beyond the initial three to elicit further responses due to a minor response after the initial treatment. There was no significant difference in the relative dose intensity between patients with HPV-negative and HPV-positive OPC (HPV-negative vs. HPV-positive; docetaxel, 92.9 vs. 91.6%; cisplatin, 92.2 vs. 89.5; and 5-FU, 92.1 vs. 91.3%). Most patients (N=99, 94.3%) who completed the planned IC cycle advanced to CRT and 18 patients (17%) underwent surgery following CRT. A total of 6 patients discontinued the scheduled cycle of CRT; 2 experienced acute kidney injury and 4 declined planned CRT due to grade 3 oral mucositis, chemotherapy-induced nausea and vomiting, and odynophagia. Among them, 5 out of 6 patients who discontinued planned CRT had HPV-positive OPC. The median cumulative radiation dose was 66 Gray (Gy) (range, 27.0–72.6 Gy) and the median cumulative dose of cisplatin was 200 mg/m2 (range, 60–300 mg/m2). There were no significant differences observed between HPV-negative OPC and HPV-positive OPC, nor between older (≥60 years) and younger patients (<60 years) with a median age of 60 years. Additionally, all but three patients received radiation with a cumulative dose exceeding 50 Gy. RT modalities comprised 3D-CRT in 52 patients (50%) and IMRT in 53 (50%).
CR to IC was observed in 29 patients (27.6%), with 68 (64.8%) showing PR. Following CRT, CR was achieved in 87 patients (82.8%), and 12 (11.4%) exhibited PR. The overall response rates after IC followed by CRT, detailed in Table I, revealed no significant difference between HPV-negative and HPV-positive OPC (92.5 vs. 95.4%).
Survival analysis and patterns of recurrence
Throughout the follow-up period, recurrence was observed in 34 patients (32.4%), with 67.6% experiencing locoregional recurrence and 32.4% developing distant metastases (lung, liver, or bone). No significant differences were noted in the patterns of locoregional recurrence and distant metastasis between HPV-positive and HPV-negative OPC. The 3-year PFS for HPV-negative OPC was 57.4% [95% confidence interval (CI): 42.11–72.69] and 69.2% (95% CI: 58.03–80.37) in HPV-positive OPC. Additionally, 5-year OS was 60.9% in HPV-negative OPC (95% CI: 45.42–76.38) and 77.8% in HPV-positive OPC (95% CI: 67.41–88.19) (data not shown). While the 3-year PFS and 5-year OS exhibited a more favorable trend in HPV-positive OPC compared with HPV-negative OPC, neither the 3-year PFS (P=0.172) nor the 5-year OS (P=0.064) exhibited a statistically significant association with HPV status (Fig. 2A and B). To assess treatment outcomes based on HPV status and stage, patients were grouped into four categories: HPV-positive/stage II, HPV-negative/stage III, HPV-positive/stage II and HPV-negative/stage IV. A decline in survival outcomes with a higher stage for HPV-positive OPC and HPV-negative OPC in the 3-year PFS (P=0.005) and the 5-year OS (P=0.006) was observed (Fig. 2C and D). Notably, the survival outcomes of HPV-positive/stage III and HPV-negative/stage IV were comparable in the 3-year PFS and 5-year OS. Furthermore, the outcomes in HPV-positive/stage II and HPV-negative/stage III were similar, with no statistically significant differences among group. However, when the groups A of HPV-negative/stage III and HPV-positive/stage II and B of HPV-negative/stage IV and HPV-positive/stage III were compared, both PFS and OS were significantly worse in group A, which had a relatively poor prognosis (P=0.001) (data not shown).
Risk factors associated with survival outcomes
To identify distinct clinical prognostic factors in HPV-positive OPC, factors related to survival outcomes based on HPV status were explored. It was found that individuals ≥60 years of age and non-CR after CRT were linked to a higher risk for PFS in all patients compared with patients <60 years of age and CR after CRT (Table II). Regarding OS, non-CR at the primary site following IC, and non-CR after CRT were identified as significant adverse factors, while being overweight emerged as a favorable factor (Table III). Although age had no statistical significance for OS in the multivariate analysis, this data revealed a close relationship between survival outcomes and age. Hence, the survival outcomes were examined based on the median age of 60 years (<60 vs. ≥60 years) to ascertain the association depending on HPV status. It was demonstrated that PFS (P=0.013) and OS (P=0.056) were poorer in patients aged ≥60 years than in those <60 years (Fig. 2E and F).
 | Table II.Uni- and multivariate analyses of survival outcomes in all patients, HPV-negative OPC and HPV-positive OPC for progression-free survival. |
| Table III.Uni- and multivariate analysis of survival outcomes in all patients, HPV-negative OPC and HPV-positive OPC for overall survival. |
In addition to the aforementioned data, Tables II and III revealed significant clinical factors in HPV-negative and HPV-positive OPC. Non-CR after CRT emerged as an adverse risk factor for survival in HPV-negative OPC. In contrast to HPV-negative OPC, age ≥60 years, T4 stage and non-CR after CRT were identified as significant risk factors for PFS, while T4 stage and non-CR at the primary site after IC were associated with significantly worse survival outcomes for OS in patients with HPV-positive OPC. Utilizing these results, patients with HPV-positive OPC were categorized into three groups based on the number of clinical risk factors at diagnosis (age and T4 stage). As depicted in Fig. 3, the PFS and OS demonstrated significant stratification across each group as the number of clinical risk factors was increased.
Discussion
Theoretically, HPV-positive OPC is expected to exhibit more favorable survival outcomes than HPV-negative OPC due to its better responsiveness to chemotherapy (7,17). Contrary to previous studies (7,17), the data of the present study revealed no significant survival difference between the two groups. This could be because the tumorigenesis of HPV-positive OPC involves multiple confounding factors, such as smoking, alcohol consumption and environmental factors, alongside viral pathogens in head and neck cancer (18,19). Consequently, using a single factor such as HPV status to predict treatment response in all cases is challenging. Furthermore, interpersonal or intrapersonal heterogeneity can lead to varied treatment outcomes depending on host factors, even if it involves a single pathogen. To identify the clinical factors in patients with HPV-positive OPC that exhibited a poor prognosis comparable with those in patients with HPV-negative OPC, each group was analyzed. Therefore, it is crucial to consider known pathogens and additional clinical indicators when evaluating prognostic factors.
As aforementioned, the routine use of IC is not recommended in current standard guidelines because OPC typically responds well to chemotherapy and radiation (20). Nevertheless, IC has advantages of reducing the rate of distant metastasis, selecting chemosensitive patients to minimize subsequent therapies, and facilitating organ preservation. In previous randomized clinical trials with subgroup analyses of patients with and without OPC, no survival benefit was observed in the OPC group (21–23). Nevertheless, these trials had several limitations, such as the absence of HPV assessment, diverse tumor stages or IC regimens and lack of standard CRT. Despite these limitations, IC remains an attractive treatment option due to its potential to reduce bulky masses, thereby increasing the possibility of de-intensifying radiotherapy or enhancing operability, ultimately improving the likelihood of achieving CR (22).
Furthermore, it is established that the response to IC is a reliable predictor of survival outcomes in head and neck cancer, a trend consistent with that of OPC (24–27). Consequently, attempts to de-escalate CRT based on the IC response have been made in most clinical studies involving HPV-positive OPC, which tends to be more sensitive to radiation. This approach aims to mitigate adverse effects associated with radiation.
The ECOG E1308 study demonstrated that reduced-dose IMRT benefited patients who achieved clinical CR at the primary site after IC with cisplatin, paclitaxel and cetuximab. However, in a subgroup analysis, T4 stage, N2c [metastasis in bilateral or contralateral lymph node(s), non-larger than 6-cm in greatest dimension and extranodal extension (ENE) negative], or a smoking history exceeding 10 years demonstrated a statistically significant decrease in PFS (11). In the OPTIMA study, patients with HPV-positive OPC were classified into low-risk [T1-3, N0-2b (N0, no regional lymph node; N1 metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE negative; N2a, metastasis in a single ipsilateral node >3 cm but not >6 cm in greatest dimension and ENE negative; N2b, metastases in multiple ipsilateral nodes, non-larger than 6 cm in greatest dimension and ENE negative), smoking history ≤10 years] and high-risk {T4 or N2c-N3 [N2c, metastasis in bilateral or contralateral lymph nodes, non-larger than 6 cm in greatest dimension and ENE negative; N3, metastasis in a lymph node larger than 6 cm in greatest dimension and ENE negative; or metastasis in any node(s) and clinically overt ENE positive], smoking history >10 years} categories. De-escalation treatment was subsequently administered with 50 Gy RT alone, 45 Gy CRT, or 75 Gy CRT based on the response to IC (12). De-escalated RT or CRT for HPV-positive OPC based on risk stratification and response to IC showed no significant difference in the 2-year PFS or OS, and toxicity could be minimized by reducing the RT dose. This study highlighted that risk-stratified patients with <50% response following IC exhibited comparable outcomes, with 28 and 27% for low- and high-risk patients, respectively.
While Ang et al (7) illustrated risk stratification based on the N stages of the AJCC 5th edition, the results of the present study indicated that the T stage remained a crucial prognostic factor for survival in HPV-positive OPC even after IC. This difference could be attributed to alterations in the AJCC staging system. In the earlier AJCC 5–7th staging systems, there was no distinction in the TNM stage system or treatment strategy for HPV-positive OPC. However, in the AJCC 8th staging system, the N stage of HPV-positive OPC has been modified and defined as multiple ipsilateral, equivalent to N1. By contrast, in the AJCC 7th staging system, this stage was identical to N2 in multiple ipsilateral regardless of HPV status. As a result, most patients in the present study were downstaged to stage II or III according to the AJCC 8th staging system. This prompts the question of whether the current staging system for HPV-positive OPC is sufficient to reflect the prognosis as depicted in Fig. 2C and D. Yoo et al (28) similarly highlighted an advanced T stage in the univariate analysis, indicating that patients may not be suitable for de-escalation treatment. T4 stage emerged as a risk factor for poor prognosis in other clinical trials that had previously attempted de-escalation treatment (11). Combining previous findings with the results of the present study, it has become evident that the T4 stage is a distinct high-risk factor in HPV-positive OPC. The N stage in HPV-positive OPC in the AJCC 8th staging system requires modification to enhance its applicability in clinical practice.
The present study revealed no differences in treatment outcomes, including overall response rate and survival between HPV-positive and HPV-negative OPCs. This is likely due to the improved treatment outcomes compared with those in previously published results for HPV-negative OPC. In a trial in the United States by Ang et al (7), the 3-year PFS and 3-year OS of HPV-negative OPC were 43.4 and 57.1%, respectively, in a retrospective analysis of the OPC patients who were treated with CRT. Compared with this report, a higher survival rate with a 3-year PFS of 57.4% and a 5-year OS of 60.9% was observed. Furthermore, after CRT, there was a high CR rate of 80% for the HPV-negative OPC in the present study. Therefore, the enhanced survival outcome in patients with HPV-negative OPC who received the IC followed by CRT may mitigate the survival gap between HPV-negative and HPV-positive OPCs. This result could explain why the two groups exhibited no significant difference in the survival rate.
To identify other clinical factors, several studies have explored smoking, a significant etiological factor for head and neck cancer, as a prognostic factor. However, the findings were inconsistent (29–31). A recent study has indicated that age-related molecular alterations and genomic, immunological and tumor differences may contribute to tumor responses in older adults (32). The present study similarly found no relationship between survival and smoking. This could be attributed to inaccuracies in medical records or individual variations in susceptibility to smoking. de la Iglesia et al (33) demonstrated that smoking status was not linked to tumor heterogeneity based on gene mutation burden. Instead, active smoking manifests an immunosuppressive effect by inhibiting the infiltration of cytotoxic T cells into the tumor. Hence, there is a need to identify a biomarker that can reflect the molecular and immunological changes induced by current smoking rather than relying solely on smoking history.
Extensive research has been conducted on genes influencing the prognosis and novel treatments for HPV-positive OPC (5). Khwaja et al demonstrated that elevated E6 expression was linked to a high risk of distant metastasis and poor survival outcomes (34). A recent study revealed that patients with HPV-positive OPC exhibiting high levels of FGF11, recognized for its oncogenic functions, had poor survival outcomes (35). TP53, identified in HPV-positive OPC in heavy smokers, has been linked to poor prognosis. However, it can function as a target for viral enzymes E6/E7, resulting in the degradation of TP53 (36,37). Hence, next-generation sequencing (NGS) enables the analysis of biomarkers related to tumor response to chemotherapy and facilitates the exploration of age-related biomarkers, aiding in the identification of patients at high risk for HPV-positive OPC and complementing traditional markers such as HPV or p16.
The present study has several limitations in terms of adopting a clinical treatment strategy based on the results. First, the present study relied on retrospective data collected from a single institution. Therefore, further validation with data from multiple centers is necessary. However, the eligible patients in the present study received a consistent IC regimen and CRT method, minimizing treatment-related bias. Second, biomarkers such as p53 expression or NGS were not assessed. Finally, recently proposed as standard treatment, immune checkpoint inhibitors were not utilized during this period. Therefore, future studies are warranted to conduct these evaluations.
In conclusion, a clinical T4 stage and age ≥60 years at diagnosis were associated with a poor prognosis in patients with HPV-positive OPC. The innovative finding in the present study is that it is not appropriate to consider a de-escalated treatment strategy for high-risk patients, even for HPV-positive patients with OPC. In addition, further clinical trials using a combined modality, such as the introduction of IC to chemoradiotherapy are needed to improve survival.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
SHC conceived and designed the study. HJB, SHL, and SHC confirm the authenticity of all the raw data. HJB, HJK, SHL, HJS, JEH, WKB, IJC and SHC performed the data analysis and interpretation of the data. HJB and SHC drafted the manuscript. HJB, HJK, SHL, HJS, JEH, WKB, IJC and SHC critically revised the manuscript. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
The study protocol was approved (approval no. CNUHH-2023-232) by the Institutional Review Board of Chonnam National University Hwasun Hospital (Hwasun, Republic of Korea).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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