Claim: Reducing Radiation Successfully Treats HPV-Positive Oropharynx Cancers and Minimizes Side Effects
Verdict: REFUTES

Retrieved passages:
title: HPV-positive oropharyngeal cancer
text: pathological examination, most radiation oncologists recommend radiation to the primary site, and concurrent chemotherapy. A negative margin is more likely to be treted with lower doses and a smaller treatment volume. Also the removal of a bulky tumour may allow reduced dosage to adjacent uninvolved pharyngeal structures and hence less effect on normal swallowing. The cancer outcomes (local control, regional control, and survival) for transoral resection followed by adjuvant therapy are comparable to primary chemoradiation, so that treatment decisions depend more on treatment-related morbidity, functional outcome, and quality of life. Patient factors also need to be taken into account, including

title: HPV-positive oropharyngeal cancer
text: overtreatment and unnecessary side effects. Current toxicities have been described as "not tolerable", and hence an intense interest in de-escalation. While comparison with historical controls has limited value compared to randomised clinical trials (phase III), phase II studies using reduced doses of radiation compared to the historical standard of 70 Gy have been carried out. A study using 54–60 Gy (a 15–20% reduction, stratified by response to initial induction chemotherapy) demonstrated comparable levels of disease control with much lower complication rates, when compared to similar studies, using 70 Gy, such as ECOG 2399. The percentage of patients alive after 2

title: HPV-positive oropharyngeal cancer
text: associated with traditional open surgical en-bloc resection, led to exploring alternative approaches using radiation. Intensity modulated radiation therapy (IMRT) can provide good control of primary tumours while preserving excellent control rates, with reduced toxicity to salivary and pharyngeal structures relative to earlier technology. HPV+OPC has shown increased sensitivity to radiation with more rapid regression, compared to HPV-OPC. Generally, radiation can safely be delivered to the involved side alone (ipsilateral), due to the low rate of recurrent cancer on the opposite side (contralateral), and significantly less toxicity compared to bilateral treatment. IMRT has a two-year disease free survival between 82 and

title: HPV-positive oropharyngeal cancer
text: addition of chemotherapy to radiation in either HPV+OPC or HPV-OPC, and significant concerns about added toxicity. Chemotherapy also has a role, combined with radiation, in the postoperative setting (adjuvant therapy). Generally it is used where the pathology of the resected specimen indicates features associated with high risk of locoregional recurrence (e.g. extracapsular extension through involved lymph nodes or very close margins). It has shown improved disease-free survival and locoregional control in two very similar clinical trials in such high risk patients, EORTC 22931 (1994–2000) and RTOG 9501 (1995–2000). However, for HPV+OPC patients, such extracapsular spread does not appear to be

title: HPV-positive oropharyngeal cancer
text: to minimize loss of function but maintain disease control. In the absence of specific clinical trials and guidelines, patient preferences need to be taken into consideration to minimise short and long term toxicity and functional loss and optimize quality of life, given the prolonged survival frequently seen. This may involve exploring patients' values regarding trade-offs of disease control against adverse effects of treatment. Patients who have received CRT as primary treatment for OPC place a high value on survival, and although agreeing that deintensification is desirable, were reluctant to trade off much survival advantage for lower toxicity, though would be

title: HPV-positive oropharyngeal cancer
text: MC1273 and DART-HPV have evaluated doses as low as 30–36 Gy. Lowering the radiation dose to 54 Gy was identified as one of the important Clinical Cancer Advances of 2018 by the American Society of Clinical Oncology, under the general theme of "Less Is More: Preserving Quality of Life With Less Treatment". Chemotherapy has been used concurrently with radiation in this setting, as in primary treatment with radical radiation, particularly where pathological features indicated a higher risk of cancer recurrence. A number of studies have suggested that this does not improve local control, although adding toxicity. Concerns over the morbidity

title: HPV-positive oropharyngeal cancer
text: a single modality, especially in earlier stages, e.g. T1-T2, N0-1, and its use in later stages is being explored in clinical trials such as RTOG 1333 which compares radiation alone to radiation with reduced chemotherapy, in non or light smokers. As with the radiotherapy data, most of the available knowledge on the efficacy of chemotherapy derives from the treatment of advanced head and neck cancer rather than specific studies of HPV+OPC. Since 1976, many clinical studies have compared CRT to RT alone in the primary management of locally advanced head and neck cancers and have demonstrated an advantage to CRT

title: HPV-positive oropharyngeal cancer
text: similar population in the National Cancer Database (2004–2013) of over 9,000 patients found a survival advantage but this was only in HPV-OPC, not in 410 HPV+OPC patients, and a subsequent study of 2,500 low and intermediate risk HPV+OPC patients showed similar overall survival whether PORT was given or not. While less studies have been completed examining deintensification (de-escalation) in this setting, than in primary radical radiation for this cancer (see below), it is an area of active investigation. In one single institution study, a decision was made to reduce the radiation dose in high risk patients with HPV+OPC from 66

title: HPV-positive oropharyngeal cancer
text: OPC, but was associated with increased mucositis and need for feeding by gastrostomy. Chemotherapy and radiation are associated with a risk of death of 3–4% in this context. It is unclear whether the added toxicity of adding chemotherapy to radiation is offset by significant clinical benefit in disease control and survival. It is thought that HPV+OPC patients benefit better from radiotherapy and concurrent cetuximab treatment than HPV-OPC patients receiving the same treatment, and that radiation and cisplatin induce an immune response against an antigenic tumour which enhances their effect on the cancer cells. Although the incidence of HPV positivity is

title: HPV-positive oropharyngeal cancer
text: an adverse factor and the addition of chemotherapy to radiation in this group provided no further advantage. Since the sample size to detect a survival advantage is large, given the small number of events in this group, these studies may have been underpowered and the question of the utility of adding chemotherapy is being addressed in a randomized clinical trial (ADEPT) with two year locoregional control and disease free survival as the endpoint. The addition of chemotherapy to radiation increases acute and late toxicity. In the GORTEC trial, chemotherapy with docetaxel provided improved survival and locoregional control in locally advanced

title: HPV-positive oropharyngeal cancer
text: the absence of what are considered adverse pathology (positive margins, extracapsular extension) will likely be treated by surgery alone or radiation including ipsilateral or bilateral neck radiation fields, with surgery for those instances where the likelihood of adjuvant therapy is low. But many HPV+OPC present with involvement of the lymph nodes in the neck, and hence a higher stage of disease, generally referred to as locally advanced disease. This group is mostly treated with multimodality therapy, with the exception of one of the more favourable subgroups with small primary tumours and lymph node involvement confined to a single node no

title: HPV-positive oropharyngeal cancer
text: the body (metastasis), while minimising short and long term morbidity. There is no high quality Level I evidence from prospective clinical trials in HPV+OPC, therefore treatment guidelines must rely on data from treatment of OPC in general and from some retrospective unplanned subsetting of those studies, together with data for head and neck cancer in general. Treatment for OPC has traditionally relied on radiotherapy, chemotherapy and/or other systemic treatments, and surgical resection. Depending on stage and other factors treatment may include a combination of modalities. The mainstay has been radiotherapy in most cases. a pooled analysis of published studies suggested

title: HPV-positive oropharyngeal cancer
text: primary radiation or chemoradiation. Even if recurrence or metastases occur, HPV positivity still confers an advantage. By contrast tobacco usage is an independently negative prognostic factor, with decreased response to therapy, increased disease recurrence rates and decreased survival. The negative effects of smoking, increases with amount smoked, particularly if greater than 10 pack-years. For patients such as those treated on RTOG 0129 with primary chemoradiation, detailed nomograms have been derived from that dataset combined with RTOG 0522, enabling prediction of outcome based on a large number of variables. For instance, a 71 year old married non-smoking high school graduate with

title: HPV-positive oropharyngeal cancer
text: had lower failure rates of 2% and 11% respectively. In addition, one randomised study from the 1970s (RTOG 73-03) compared preoperative radiation to PORT, and found lower failure rates with the latter. The addition of another modality of treatment is referred to as adjuvant (literally helping) therapy, compared to its use as the initial (primary) therapy, also referred to as radical therapy. Consequently, many of these patients have been treated with adjuvant radiation, with or without chemotherapy. In the above series of reports of minimally invasive surgery, many (30–80%) patients received adjuvant radiation. However, functional outcomes were worse if radiation

title: HPV-positive oropharyngeal cancer
text: efficacy of less intense treatment. A retrospective analysis of advanced (N+) HPV+OPC suggested 96% 5 year local control with deintensified radiation of 54 Gy and concurrent cisplatin based chemotherapy. The conclusions of the above pair of similar phase II trials have been supported by several other phase II trials. A prospective trial (ECOG 1308) demonstrated similar locoregional control with 54 Gy, and another study, a high pathological complete response rate at 60 Gy. The Quarterback trial showed comparable outcomes between 56 and 70 Gy. and was followed by Quarterback 2, comparing 50 to 56 Gy. Similarly, the Optima trial showed

title: HPV-positive oropharyngeal cancer
text: HPV+. Prevention of HPV+OPC involves avoiding or reducing exposure to risk factors where possible. About 90% of HPV+OPC carry HPV 16, and another 5% type 18. These two types are both targets of available vaccines. HPV vaccines given prior to exposure can prevent persistent genital infection and the consequent precancerous state. Therefore, they have a theoretical potential to prevent oral HPV infection. A 2010 review study has found that HPV16 oral infection was rare (1.3%) among the 3,977 healthy subjects analyzed. The goals of care are to optimise survival and locoregional disease control, and prevent spread to distant areas of

title: HPV-positive oropharyngeal cancer
text: low (10–20%), an advantage for HPV+OPC was seen in trials of both cetuximab and panitumumab, a similar anti-EGFR agent, but not a consistent interaction with treatment, although HPV+OPC appears not to benefit to the same extent as HPV-OPC to second line anti-EGFR therapy, possibly due to lower EGFR expression in HPV+OPC. In the absence of high quality evidence comparing a primary surgical approach to other modalities, decisions are based on consideration of factors such as adequate surgical exposure and anatomically favourable features for adequate resection, post treatment function and quality of life. Such patient selection may enable them to avoid

title: HPV-positive oropharyngeal cancer
text: factors, likely functional loss and patient preferences. Some HPV+OPC may first appear in lymph nodes in the neck, without an obvious source (cancer of unknown primary origin) but removal of tonsil tissue from the oropharynx will often show hidden disease. The presence of HPV in the tumour is associated with a better response to treatment and a better outcome, independent of the treatment methods used and a nearly 60% reduced risk of dying from the cancer. Most recurrence occurs locally and within the first year after treatment. The use of tobacco decreases the chances of survival. While most head and

title: HPV-positive oropharyngeal cancer
text: to 60 Gy, corresponding to the actual evidence, and follow up has shown no decrease in cancer control. Current trials, both in North America and Europe (such as ECOG 3311 and PATHOS) use 50 Gy as the comparison arm. The comparator of 50 Gy was chosen on the grounds of (i) the exquisite sensitivity of HPV+OPC to radiation, both "in vitro" and "in vivo"; ECOG 1308 showing excellent disease control at 54 Gy; and data suggesting that 50 Gy in 1.43 Gy (iso-effective dose 43 Gy in 2.0 Gy) was sufficient to electively treat the neck. Other studies, such as

title: HPV-positive oropharyngeal cancer
text: free survival has been reported as 75–82% and 45–57%, respectively, for HPV+ and HPV- cancer, and improving over increasing time. It is likely that HPV+OPC is inherently less malignant than HPV-OPC, since patients treated by surgery alone have a better survival after adjustment for stage. In one study, less than 50% of patients with HPV-OPC were still alive after five years, compared to more than 70% with HPV+OPC and an equivalent stage and disease burden. In RTOG clinical trial 0129, in which all patients with advanced disease received radiation and chemotherapy, a retrospective analysis (recursive-partitioning analysis, or RPA) at three