It has been little more than a decade since the recognition of the epidemiology, distinct molecular biology, and profile of risk factors, patient demographics, and tumor characteristics of human papillomavirus (HPV) –associated oropharyngeal squamous cell carcinoma (OPSCC). From prospective and retrospective studies, we know that patients with locally advanced, stage III/IV, HPV-associated OPSCC who are treated with standard cisplatin-based concurrent chemoradiotherapy have significantly better overall survival and reduced risk of recurrence compared with patients with HPV-negative OPSCC. More than 80% will likely be cured of their cancer. That said, it is also evident that a subset of patients demonstrate an aggressive phenotype with the development of distant spread and death as a result of their cancer.
Given that the typical patient with HPV-associated OPSCC is younger (age 40 to 60 years) and without major comorbidities, increasing discussion has been focused on deintensification of treatment in the hopes of minimizing treatment-related morbidity without compromising the current cure rates. In particular, attention has been focused on reducing the morbidity of severe late swallowing complications that result in the need for enteral nutritional support, because this has been shown to substantially affect patient quality of life.
Historically, typical rates of long-term gastrostomy-tube dependence were reported to be 15% to 20%. However, with advances in radiation technology (such as intensity-modulated radiation therapy), target delineation has become more complex, with steeper dose gradients and shifting of dose away from organs at risk, such that the current frequency of severe swallowing dysfunction needs to be reestablished. Nonetheless, maximizing quality of life by not overtreating patients is a uniformly supported goal.
Deintensification strategies have to date been based on an understanding of the treatment-related risk factors that are independently associated with late and severe swallowing complications, for example, radiotherapy dose, the volume of the pharynx irradiated, and use of concurrent chemotherapy.With the focus largely on ways to modify treatment components, it has been hypothesized that radiotherapy dose reduction and/or alterations in concurrent chemotherapy may result in the same locoregional control rates with reduced late toxicities. The ability to identify patients with HPV-associated OPSCC who are appropriate for participation in the investigation of less intense therapies is now coming into play with risk stratification modeling. It is within this context that O’Sullivan et al, in the article that accompanies this editorial, report predictors of low risk of distant metastases for potentially safe deintensification of chemotherapy.
Recent studies have explored the significance of tobacco exposure history as a variable, along with tumor (T) and regional node (N) stage as predictors of risk of recurrence and death in the patient with HPV-associated OPSCC who is treated with radiation therapy. O’Sullivan et al report the results of a large, retrospective, institutional review of 505 patients treated uniformly by stage with radiotherapy alone or concurrent cisplatin and radiotherapy, and demonstrate with recursive partitioning analysis that advanced T and N stage can significantly influence the risk of distant relapse in both HPV-positive and HPV-negative OPSCC. The HPV-positive cohort could be segregated into low-risk (T1-3, N0-2C, 7%) and high-risk (T4, N3, 24%) groups for distant metastases. O’Sullivan et al also demonstrate that the proportion of relapses is predominantly distant (given the high locoregional control rates achieved), with T4 and/or N3 stages associated with an increased risk of distant relapse. Among the low-risk HPV-positive cohort, subgroups of patients with N2b (particularly those with > 10-pack-year tobacco exposure) and N2c were found to have a higher rate of distant relapse when treated with radiotherapy alone (the majority with accelerated radiotherapy schedules) compared with patients treated with concurrent chemoradiotherapy. Thus, modifying or eliminating chemotherapy as a deintensification strategy may be most reasonably tested in patients with HPV-positive T1-3 and N0-2a stage disease, which would encompass all stage III cancers and most stage IV cancers with low-volume regional nodes. By implication, it could be that today’s treatment paradigms result in the overtreatment of many patients (and the consequent late effects on swallowing function) and undertreatment of a smaller subset. Rigorous prospective study is needed.
These findings provocatively suggest that there is a limit to the favorable biology of HPV-associated OPSCC. Advanced tumor progression resulting in T4 and N2b-N3 disease and possibly enhanced by tobacco exposure may lead to sufficient tumor heterogeneity, increasing the risk of distant relapse, although still sufficiently sensitive to concurrent chemoradiotherapy. In patients with more advanced nodal presentations and/or heavy tobacco exposure history (≥ 10 pack-years), omitting concurrent chemotherapy may increase the risk of distant relapse. In multivariable analysis, heavy tobacco exposure was a strong negative predictor for overall survival but did not predict for relapse-free survival (in both the HPV-positive and -negative cohorts), which supports the known increased risk of noncancer-related deaths from tobacco-related comorbidities. Conflicting data regarding the relationship between tobacco exposure and locoregional control has been reported.
These findings may also help to define a beneficial role for induction chemotherapy on the basis of risk of distant metastases. It is noteworthy that although phase III, controlled trials have not shown benefit for induction chemotherapy added to concurrent chemoradiotherapy, induction is frequently administered outside of a clinical trial to patients considered to have stage III/IV disease.
O’Sullivan et al appropriately highlight the limitations of their observations and recommend further validation in prospective clinical trials. Given our current knowledge, treatment of HPV-associated, locoregionally advanced cancers with anything less than the standard full doses of radiotherapy and concurrent cisplatin should only occur in the context of a clinical trial. To modify treatment components at this juncture may jeopardize a high probability of cure. The recently closed phase II Eastern Cooperative Oncology Group (ECOG) trial E1308 for stage III/IV HPV-associated OPSCC tested whether induction chemotherapy (combination paclitaxel, cisplatin, and cetuximab followed by concurrent cetuximab and radiotherapy) may allow for safe reduction in radiotherapy dose to the primary site and involved neck nodes. Those patients with complete response to induction had modification of the prescribed radiation therapy dose from 69.3 Gy (given for incomplete response) to 54 Gy, which represents a substantial reduction in dose delivered to the pharyngeal constrictor muscles, with the expectation of reducing late swallowing complications. Outcome data on toxicity, quality of life, and disease control are awaited. The Radiation Therapy Oncology Group (RTOG) is actively accruing patients to a phase III noninferiority trial, R1016, that randomly assigns patients with stage III/IV HPV-associated OPSCC to standard-dose radiotherapy and either concurrent cisplatin or concurrent cetuximab. This study is powered to demonstrate a comparable 5-year overall survival rate, with secondary objectives to demonstrate differences in acute and late treatment toxicities. The question of whether radiotherapy alone is sufficient for patients with low-volume nodal disease remains on the table. Other institutional studies are in progress.
It is interesting to note several surgical series reporting similar correlations between advanced nodal features and a higher proportion of distant relapses than expected in the patient with HPV-associated OPSCC. Advanced T stage, N stage, and the presence of extracapsular extension (ECE), including the pathologic extent of any ECE (soft tissue infiltration), have been observed to be associated with an increased distant relapse pattern. Whether or not the association between advanced clinical N stage and distant relapse is solely a result of the presence of ECE or its extent is not clear at this time. However, the observations by O’Sullivan et al should draw caution to the omission of concurrent adjuvant chemotherapy with postoperative radiation for the HPV-associated OPSCC that demonstrates microscopic ECE, despite the favorable prognosis that has been reported. Transoral surgery in appropriately selected patients may serve as a platform for deintensification in the patient with HPV-associated disease, although three treatment modalities may be indicated. This is based on the fact that the range of postoperative doses of radiotherapy (60-66 Gy) is closer to the threshold of injury for the pharyngeal constrictors, and the lower risk of late swallowing complications at these doses may allow for a larger volume of the pharyngeal constrictor muscles to be safely irradiated. Studies of transoral surgery are being planned to test this hypothesis.
Lastly, O’Sullivan et al also observed a difference in the temporal pattern of distant relapse on the basis of HPV status. Their observations suggest that patients with HPV-positive disease may be at risk of distant relapses for up to 5 years of follow-up. In contrast, the rate of distant relapses in patients with HPV-negative disease remained relatively stable beyond 2 years. These observations suggest not only a difference in the tumor biology, but may have implications regarding surveillance imaging and long-term follow-up.
In summary, ongoing research efforts to better define the patient with high-risk HPV-associated OPSCC have broad implications. Clinical, pathologic, and molecular definitions are needed. Future deintensification protocols should consider not only the risk level but the pattern of relapse for the HPV-associated OPSCC, as well as how deintensification is achieved. Future longitudinal studies to further characterize the natural history of this high-risk cohort are needed to define a more strategic and cost-effective long-term surveillance plan.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
* This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.
Leave A Comment
You must be logged in to post a comment.