How treatment paradigms regarding HPV-positive squamous cell carcinoma will evolve, particularly in the era of precision medicine, is a provocative question and is the subject of this review.
Human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma (SCC), which accounts for an increasing proportion of all head and neck cancers, represents a specific entity with distinct clinical and molecular characteristics. It is now firmly established that patients with HPV-positive oropharyngeal SCC have a significantly improved prognosis because this variant has exquisite radiosensitivity compared with HPV-negative oropharyngeal SCC; thus, it can be targeted with de-escalated approaches using reduced doses of radiation and/or chemotherapy. The overriding goal of de-escalation is to maintain the high cure and survival rates associated with traditional approaches while reducing the incidence of both short- and long-term toxicity. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, prospective studies have now been published demonstrating that de-escalated radiation can successfully maintain high rates of cure and preserve the quality of life for appropriately selected patients with this disease. However, these studies have been complicated by such factors as the relatively limited sample sizes, as well as the variability in treatment, inclusion criteria, and follow-up. How treatment paradigms will evolve, particularly in the era of precision medicine, is a provocative question and is the subject of this review.
Oncology (Williston Park). 2023;37(7):281-287.
Data have accumulated to demonstrate that patients with human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma (SCC) have a significantly improved prognosis because this variant has exquisite radiosensitivity compared with HPV-negative oropharyngeal SCC.1-4 These tumors have been shown to shrink briskly and robustly in both preclinical laboratory models and in actual patients. Table 1 illustrates data from prospective trials that have shown the favorable prognostic significance of HPV status. The recognition that HPV-positive oropharyngeal SCC responds favorably to radiation has prompted investigators to suggest that patients with these tumors might be overtreated and unnecessarily subjected to the toxicity of intensive chemoradiotherapy with excessively high radiation doses. Indeed, data from axial imaging studies obtained serially during the course of radiation to observe in vivo patterns of tumor response showed that HPV-positive oropharyngeal SCC tends to regress early during treatment, reaching a plateau by week 5 to 6, providing illustrative evidence that the intensity of treatment can possibly be reduced (Figure 1).5,11 As a result, prospective trials have been conducted investigating the role of treatment de-escalation with the goal of reducing adverse effects (AEs), particularly those related to swallowing and salivary function, while maintaining the high rates of cure historically observed.6-11
Multiple theories have been proposed as to how HPV mediates an enhanced radiation response of oropharyngeal SCC.12-20 The most direct explanation is that HPV infection and the subsequent downstream pathways initiated by the degradation of the p53 and pRb proteins through the viral products E6 and E7 lead to the deregulation of cell cycle checkpoints, downregulation of cell cycle regulatory proteins, and increased genomic instability, somehow rendering the host tumor cell more susceptible to radiation-induced apoptosis. Other studies have suggested that radiation enhances the host’s immune response to the viral antigens that are expressed in the cancer.14,15 For instance, it has been demonstrated that the degree of tumor-infiltrating lymphocytes was associated with outcomes among patients treated with radiation for HPV-positive oropharyngeal SCC.16 Researchers have also demonstrated that the presence of regulatory T lymphocytes and PD-1–positive T lymphocytes, and the levels of PD-1–positive cells, were positively correlated with a favorable clinical outcome in HPV-positive compared with HPV-negative head and neck cancers.17-19 These studies suggest that the tumor microenvironment plays a large role in mediating the differential effects of radiation between HPV-positive and HPV-negative oropharyngeal SCC. Alternatively, Vlashi et al showed that the improved radiosensitivity of HPV-positive (vs HPV-negative) head and neck cancer might be due to the lower frequency of cancer stem cells and their decreased capacity to engage in radiation-induced dedifferentiation.20
Patients with newly diagnosed HPV-positive SCC localized to the head and neck and originating from the oropharynx (ie, the tonsils, base of tongue, or uvula) are potential candidates for de-escalation. The exact type of de-escalation treatment may vary depending on the extent and location of the disease. However, given the strong link between HPV and radiation response, the American Joint Committee on Cancer (AJCC) created a new staging system in 2016 (Figure 2)21 specifically for patients diagnosed with HPV-positive oropharyngeal SCC to reflect its favorable prognosis vs HPV-negative disease.21 Notably, many HPV-positive tumors that had been previously categorized as stage IV were significantly “downstaged” to stage II or even stage I cancers. This new staging system has prompted many investigators to question historical treatment paradigms.22 Published data have also suggested that the favorable impact of HPV positivity on prognosis is particularly strong for those deemed “never smokers” or even those with a minimal smoking history, thereby suggesting that these patients might benefit the most from de-escalation.23
Lastly, it is important to recognize that the AJCC staging system, similar to most clinical trials, has considered p16 positivity to be equivalent to HPV positivity. However, the possibility of discordance needs to be considered since p16 positivity can occur in the absence of HPV and is better suited as a screening tool due to its high sensitivity. This is relevant because it is likely that p16-positive/HPV-negative SCCs do not have the same favorable prognosis as p16-positive/HPV-SCCs.
The incidence of HPV-positive oropharyngeal SCC has increased dramatically in recent years, reaching epidemic-like proportions. For many patients, radiation therapy is recommended as initial treatment, because of the excellent cure rates generally observed. Historically, this regimen has consisted of 7 weeks of daily radiation utilizing relatively high doses, often combined with cisplatin chemotherapy. However, this treatment can be difficult to tolerate and also incurs significant posttreatment sequelae: A significant proportion of patients develop long-term toxicity, including swallowing dysfunction, dry mouth, and/or neck stiffness.24 Unfortunately, these AEs can be severe, life altering, and permanent. Indeed, the detrimental effect of treatment on quality of life (QOL), psychosocial health, and overall functional capacity has been well established.25 Because patients with HPV-positive oropharyngeal SCC most often present at a relatively young age and can potentially survive for decades after treatment, the focus on decreasing long-term complications and optimizing QOL is particularly germane. In short, de-escalation is about trying to maximize the potential for a cure while also focusing on preserving QOL. Given the plethora of data that now exist showing that patients with HPV-positive oropharyngeal SCC respond robustly to treatment and have tumors that are extremely sensitive to radiation, the concept of de-escalation makes the most sense in this population.
The major AEs of standard treatment with high-dose radiation (often combined with concurrent chemotherapy) in both the short and long term pertain to difficulty with swallowing and are directly related to incidental exposure of normal tissue to radiation. Indeed, the reported rates of feeding tube dependence, aspiration pneumonia, severe dehydration, and malnutrition are not insignificant among patients completing treatment.26-29 The disruption of salivary production, which can often be permanent, also leads to challenges with chewing and speaking. Because studies have shown that the likelihood and severity of AEs increase with radiation dose, it has been hypothesized that by effectively reducing radiation to the normal structures of the head and neck, there will be a consequent decrease in AEs—particularly related to swallowing and salivation—resulting in improved QOL.30-33 Additionally, biological models have shown that reducing radiation should also decrease the incidence of radiation injuries, some of which can be debilitating, to the bone, nerves, and soft tissue.34 From a practical standpoint, reducing the intensity of treatment has the potential to eliminate or ameliorate many commonly observed AEs.
Given that the probability of developing most radiation-induced complications can be decreased by reducing the radiation dose exposure to healthy tissue, the potential of de-escalation to improve the QOL for patients undergoing treatment for head and neck cancer is profound. By potentially decreasing toxicity without lowering cure rates, de-escalation of radiation dose for HPV-positive tumors has the potential to improve QOL for survivors and to allow them to live more functional and productive lives. Since basic functions such as speaking, eating, chewing, and tasting are recognized as critical to maintaining a social life, any disruption of these abilities can dramatically affect one’s sense of well-being.
The potential of de-escalation to reduce psychosocial distress, such as symptoms of depression and anxiety, has also begun to be recognized.35 In fact, one recent study showed that de-escalation significantly reduced the proportion of survivors who are dependent on pain medications and opioids after treatment for HPV-positive oropharyngeal SCC.36
Over the past decade, several prominently published prospective trials (Table 2) have demonstrated promising outcomes with de-escalated radiation regimens using doses that are lower than those conventionally accepted.5-10 Although the trial designs have varied, the results have consistently shown that de-escalated radiation for HPV-positive oropharyngeal SCC can maintain the historically high rates of cure while significantly decreasing toxicity and improving QOL, thus largely validating the premise for which de-escalation was proposed.
Our group from the University of California performed a multicenter, phase 2 trial, treating 45 patients with locally advanced, HPV-positive oropharyngeal SCC. They received 2 cycles of induction chemotherapy given 21 days apart, followed by de-escalated radiation. At 2 years, the reported rates of disease control and overall survival were 92% and 98%, respectively, which compared favorably with historical controls treated without de-escalation.5 Just as important, at 6 months post radiation, the incidence of both gastrostomy-tube dependence and severe swallowing dysfunction was zero. A prospective analysis of end points related to the QOL and pre- and posttherapy swallow studies that de-escalation dramatically improved function with respect to every variable analyzed—including weight loss, depression, and opioid usage—compared with contemporary control participants who opted not to be treated with de-escalation.35,36 A survey of perspectives and attitudes of the patients treated on the University of California de-escalation trial showed that nearly all individuals were satisfied with their decision and had virtually no regrets about their treatment choice.37
While some research teams have helped validate the paradigm of induction chemotherapy prior to de-escalated radiation for HPV-positive oropharyngeal SCC, others have investigated different approaches. For instance, the use of up-front concurrent chemoradiation using de-escalated radiation with weekly cisplatin has also been shown to lead to excellent outcomes.6 As a result, when de-escalated radiation is considered in the setting of chemoradiation, 2 different strategies have generally been proposed: One utilizes concurrent chemotherapy, and the other utilizes induction chemotherapy.38
The purpose of chemotherapy, when given together with radiation, is widely accepted as a means to make radiation more effective. In the setting of head and neck cancer, it is considered a “radiosensitizer.” Given the exquisite sensitivity of HPV-positive oropharyngeal SCC to radiation, a logical question is whether chemotherapy is needed. Because biological models have suggested that the addition of chemotherapy is equivalent to approximately 3 to 5 extra radiation sessions, a strategy of intensifying treatments seems to be paradoxical to the premise of de-escalation.39 One way to approach this dilemma is to change the way that chemotherapy is delivered. For instance, studies have now shown that weekly delivery of attenuated doses of cisplatin might be just as effective and better tolerated as administering the chemotherapy every 3 weeks using larger doses, as is traditionally done.40 Although attempts have been made to replace cisplatin with a targeted systemic agent, cetuximab, the results of prospective trials have suggested that this may lead to inferior outcomes.41-43 Studies analyzing whether immunotherapy can be utilized as an alternative are also ongoing.44
The evidence in favor of radiation alone for appropriately selected patients with HPV-positive oropharyngeal SCC is provocative. Based on historic data from the University of California – Davis and Princess Margaret Hospital in Toronto, Ontario, Canada, showing that radiation alone can be curative for many patients with HPV-positive oropharyngeal SCC, investigators from Japan recently published findings from a phase 2 trial showing positive outcomes and a 2-year overall survival rate of 100%.45-47 For another phase 2 study, University of North Carolina investigators further reported on patients with lower tumor volumes who were treated with de-escalated radiation alone.5 Although the phase 2 NRG HN02 study (NCT02254278) results showed that the addition of concurrent cisplatin to de-escalated radiation reduced the 2-year local failure rate from 9% to 3%, it was unclear which patients benefited the most.10 When the 2-year disease control and overall survival rates were analyzed, no differences were observed between patients treated with de-escalated radiation with or without chemotherapy. These studies suggest that some patients with HPV-positive oropharyngeal SCC can be treated with de-escalation and achieve excellent outcomes. The explanation for the lack of benefit associated with cetuximab might be because HPV-related tumors are less driven by underlying alterations in cell signaling pathways due to the oncogenic properties of HPV-oncoproteins E6 and E7. In other words, compared with HPV-negative carcinoma, HPV-positive oropharyngeal SCC harbors mutational landscapes that are more devoid of driver mutations or alterations such as EGFR overexpression. Although the eligibility criteria varied between studies, both studies have suggested that cisplatin should continue to be the standard when chemotherapy is utilized with radiation in the definitive treatment of HPV-positive oropharyngeal cancer. Although the results do not truly address the question of which patients require chemotherapy for this disease, they nonetheless demonstrate the need for caution with ongoing attempts to pursue de-escalation. It must also be recognized that HPV confirmation with in situ hybridization was not standardly performed, which raises the possibility that some patients with p16-positive disease actually did not have HPV-related disease. Given the historically high rates of toxicity associated with chemotherapy, the use of radiation alone can be considered an attractive option for appropriate patients.
Minimally invasive operative techniques using transoral robotic surgery (TORS) have also been proposed as a means of de-escalating treatment for HPV-positive oropharyngeal SCC.48,49 However, the treatment by itself is not considered de-escalation because it is a type of surgery. In select patients with low-volume disease, TORS, combined with a surgical neck dissection, may actually serve as a replacement for radiation, eliminating its necessity entirely. However, although TORS has been shown to be a reasonable initial option for select patients with HPV-positive oropharyngeal SCC, it must be recognized that a substantial proportion of patients will ultimately require postoperative radiation.50 Although published studies have investigated whether lower radiation doses or smaller target volumes can be delivered after TORS, these strategies are still not considered standard.51-53 Enthusiasm for the use of TORS also may have been dampened by the results of the phase 2 ORATOR trial (NCT01590355), which randomly assigned patients with newly diagnosed HPV-positive oropharyngeal SCC to either initial TORS or to primary radiation.54 Although survival and cure rates were the same in the 2 arms, patients randomized to TORS had significantly decreased swallowing function at 1 year.54
De-escalation for HPV-positive oropharyngeal SCC is a form of precision medicine: using the biological characteristics of a tumor to drive treatment decision-making. Given that HPV-positive tumors have been shown to be innately sensitive to radiation, investigators have proposed that a “one size fits all” approach to treating oropharyngeal SCC no longer makes sense. The popularity of this de-escalation approach has been driven by both the increasing recognition that HPV-positive oropharyngeal SCC is exquisitely sensitive to radiation and the desire of patients to avoid short- and long-term AEs. Now that prospective trials have been published demonstrating its feasibility, de-escalation continues to be investigated as a curative treatment for patients with HPV-positive oropharyngeal SCC.
Given the preponderance of evidence attesting to the sensitivity of HPV-positive oropharyngeal SCC to radiation, a tremendous amount of attention has focused on investigating whether patients with locally advanced HPV-positive oropharyngeal SCC should be treated differently than those with HPV-negative tumors. The concept of de-escalation encompasses a variety of different strategies intended to make treatment gentler, such as reductions in radiation, alterations in chemotherapy regimens, and/or full elimination of either modality. However, how to best offer this approach to patients is uncertain, and the question of whether de-escalation is even ready for use outside a clinical trial is hotly debated.
The overriding goal of de-escalation is to maintain the high survival rates associated with traditional approaches while reducing the incidence of both short- and long-term toxicity by lessening the intensity of treatment. Even so, it is still not considered a standard of care, because the published data are still relatively preliminary and they are complicated by such factors as variability in treatment, inclusion criteria, and follow-up. However, the reality of clinical decision-making for HPV-positive oropharyngeal SCC has evolved to the point where patients are now routinely demanding de-escalated radiation, and it has become increasingly offered to patients with HPV-positive oropharyngeal SCC as standard treatment, a testament to the concept’s popularity.55 Although the strategy is seemingly well supported by the depth and breadth of data that have been published, we nonetheless believe that at this time, attempts to offer de-escalation outside a clinical trial should be avoided.
Continued efforts to better refine selection criteria and to dynamically monitor treatment response will define the evolution of de-escalation for HPV-positive oropharyngeal SCC. At present, the only factor (other than AJCC cancer stage) used for risk stratification is smoking history. Future advances in de-escalation will need to incorporate a combination of clinical, radiological, and biological data—helping to apply principles of precision medicine to this approach. For instance, considerable interest has arisen in using HPV DNA levels from the blood—obtained before, during, and after treatment—to monitor de-escalation.56-58 Another approach involves using special imaging techniques, often combined with machine learning and/or artificial intelligence algorithms, to predict response to de-escalation.59-63 The explosion of radiomic information also has the potential to identify who may or may not be eligible for de-escalation, both at diagnosis and midway through radiation. For instance, investigators recently used a radiomics signature of intratumoral and peritumoral regions to predict which patients might benefit from the addition of chemotherapy to radiation for HPV-positive oropharyngeal SCC.59 Although these approaches hold promise for the future, exactly how to utilize such strategies remains uncertain and the subject of ongoing research.
Given its demonstrated ability to dramatically preserve QOL and functioning while maintaining high rates of cure, de-escalation has come to light as an attractive option in the management of HPV-positive oropharyngeal SCC. Although data continue to emerge suggesting that treatment should be individualized for the subgroup of patients with HPV-positive oropharyngeal SCC, exactly how to do so remains uncertain. Some patients can likely be effectively treated with de-escalated radiation alone, but it is possible that others with higher-risk disease might benefit from the addition of chemotherapy to de-escalated radiation. However, these paradigms continue to evolve as studies contribute to an improved understanding of HPV-positive oropharyngeal SCC. While proponents argue that the data robustly support the integration of de-escalation into contemporary practice, skeptics note that the published data are still relatively preliminary, making definitive recommendations difficult. Based on the emerging evidence, as well as on the explosion in interest from patients and physicians alike, well-designed clinical trials are urgently needed to better refine selection criteria for de-escalation and to stratify patients with newly diagnosed oropharyngeal SCC into the appropriate means of treatment.
DISCLOSURE: The author has no financial disclosures or conflicts of interest to report.
Address for correspondence:
Allen M. Chen, MD
Department of Radiation Oncology
School of Medicine, University of California – Irvine
Orange, CA 92868
Ph: (714) 456-8074
Fax: (714) 456-7170