In an effort to determine whether I want to receive chemotherapy concurrent with radiation therapy, I am finding sources of information relevant to this question. The following are links to relevant studies/articles, or quotes from cited papers.
How can chemo be applied?
Update July 17, 2019
Chemo may be used in several different situations: (American Cancer Society)
- Chemo (typically combined with radiation therapy) may be used instead of surgery as the main treatment for some cancers. (This is called chemoradiation.)
- Chemo (combined with radiation therapy) may be given after surgery to try to kill any small deposits of cancer cells that may have been left behind. This is known as adjuvant chemotherapy.
- Chemo (sometimes with radiation therapy) may be used to try to shrink some larger cancers before surgery. This is called neoadjuvant or induction chemotherapy. In some cases this makes it possible to use less radical surgery and remove less tissue. This can lead to fewer serious side effects from surgery.
- Chemo (with or without radiation therapy) can be used to treat cancers that are too large or have spread too far to be removed by surgery. The goal is to slow the growth of the cancer for as long as possible and to help relieve any symptoms the cancer is causing.
History of treatment options
The following is an excellent editorial article from Annals of Translational Medicine. It provides a very clear description of chemo treatments for OPSCC.
Current Standard Treatment
The standard treatment for HPV-positive OPSCC, as of April 2019.
The standard of care for the definitive nonoperative management of cisplatin-eligible patients with advanced disease is concurrent chemoradiation with high-dose cisplatin given every 3 weeks. For patients undergoing initial surgical resection, adjuvant chemoradiation with concurrent high-dose cisplatin given every 3 weeks is recommended for patients with positive margins and/or extranodal tumor extension.
Deintensification of treatment of patients with p16+ oropharynx cancer should only be undertaken in a clinical trial. Role of Treatment Deintensification in the Management of p16+ Oropharyngeal Cancer: ASCO Provisional Clinical Opinion April 2019
Problems with Cisplatin
Cisplatin CRT leads to higher toxicity and morbidity in short and long term, and possibly has higher non-cancer mortality.
Disturbingly, 10-year results of RTOG 91-11 demonstrated increased non-cancer mortality in the concomitant chemo-radiation arm (30.8%) when compared to the induction chemotherapy arm (20.8%) and the radiation-alone arm (16.9%), suggesting the current system of monitoring and grading late effects of treatment may be inadequate . Worth noting, however, is that larynx cancer patients have higher baseline comorbidity and thus late cisplatin-related toxicity may not be mirrored in the more medically fit HPV-positive OPSCC patient population. Treatment de-intensification strategies for head and neck cancer November 2016
Regarding long-term side effects…
Oropharyngeal cancer caused by Human Papillomavirus (HPV) infection … has a better prognosis than most other head and neck cancers. Patients cured of their disease often have to live for several decades with the side-effects of their treatment which can be permanent and have a major impact on quality of life. Cardiff University Centre for Trials Research
The mainstay of treatment is combined chemoradiotherapy, and the prognosis for survival is good, but many patients will have long-term experience with the debilitating side effects of treatment. Human papillomavirus–associated oropharyngeal cancer: review of current evidence and management 2019
Regarding high vs low Cisplatin dosage schedules. Note that this study did not differentiate HPV-positive from HPV-negative.
Given concurrently with conventional radiotherapy in locally advanced head and neck cancer, high-dose three-weekly cisplatin has often been replaced with weekly low-dose infusions to increase compliance and decrease toxicity. The present meta-analysis suggests that both approaches might be equal in efficacy, both in the definitive and postoperative settings, but differ in toxicity. However, some toxicity data can be influenced by unbalanced representation, and the conclusions are not based on adequately sized prospective randomized studies. Therefore, low-dose weekly cisplatin should not be used outside clinical trials but first prospectively studied in adequately sized phase III trials versus the high-dose three-weekly approach The Oncologist May 2017
Chemo-brain really does exist
Problems with Cetuximab
At least three trials are investigating the pros and cons of using Cetuximab rather than Cisplatin in combination with IMRT.
- 5 years results: RTOG 1016: Cetuximab versus high-dose cisplatin concurrent with accelerated IMRT (70 Gy in 6 weeks)
- 2 years results: De-ESCALaTE HPV: Cetuximab versus high-dose cisplatin concurrent with RT (70 Gy)
- No results yet: TROG 12.01: Cetuximab versus weekly cisplatin concurrent with RT (70 Gy) once per week
However, Cetuximab appears not to have suitable overall survival outcomes.
For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial November 2018
Results of our study show that, in the setting of low-risk oropharyngeal squamous cell carcinoma, the use of cetuximab bioradiotherapy instead of cisplatin-based chemoradiotherapy resulted in no overall benefit in terms of toxicity but showed significant detriment in tumour control. Our trial also highlights that the good survival outcomes of HPV-positive low-risk oropharyngeal squamous cell carcinoma are in part a function of the type of treatment received, and not merely a reflection of favourable intrinsic tumour biology. Therefore, cisplatin-based chemoradiotherapy should continue to be considered the standard of care in this setting. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial November 2018
Cisplatin vs Cisplatin & 5-FU
In the following, Regimen A was Cisplatin CRT (IMRT) with 6 weekly cycles, and Regimen B was Cisplatin and 5-FU CRT in 2 weekly cycles.
Patients on regimen A were more likely than patients on regimen B to experience thrombocytopenia (odds ratio 2.41, 95% confidence interval 1.14–5.14, P = 0.02); 46% (22 of 48) of patients on regimen A experienced acute thrombocytopenia compared to 26% (21 of 81) of patients on regimen B (Table 2). However, the majority of thrombocytopenia experienced (90.0%) was less than grade 2 in severity and therefore not limiting (Table 3) Comparison of Acute Toxicities in Two Primary Chemoradiation Regimens in the Treatment of Advanced Head and Neck Squamous Cell Carcinoma June 2012
De-escalated treatments have good results
The following study reports that de-escalation of both RT and CRT is very possible.
As of July 11, 2019, it appears that the survival rates for HPV-positive OPSCC patients receiving radiation only (i.e. no chemo) are very high, in fact much higher than for many other cancers.
Several studies have demonstrated that amongst HPV-positive patients some have an extremely low oncologic failure risk (especially non-smokers with less than T4 or N2c-N3 disease) , . For these patients the addition of chemotherapy to radiotherapy does not seem to significantly increase overall survival benefit, suggesting that chemotherapy may be omitted completely. Chen et al.  have reported very good outcomes in a series of 19 HPV-positive OPSCCs treated exclusively by radiation, including 17 (74%) patients with stage III/IV and 18 (79%) non-smokers (<100 cigarettes in a lifetime). The 3-years overall survival and locoregional control rates for patients with stage III/IV disease were 81% and 88%, respectively. Among the 18 HPV-positive patients who were never-smokers, the 3-years rates of overall survival and locoregional control were 100% for both. Treatment de-escalation for HPV-driven oropharyngeal cancer: Where do we stand? January 2018
Can chemotherapy be completely removed, leaving only IMRT treatment?
An alternative de-intensification approach is the omission of chemotherapy. The ongoing HN-002 trial (NCT02254278) is a large randomised phase II study of nearly 300 patients assessing two different de-escalation strategies. Eligible patients are those with HPV-associated T1–T3 tumours with N0–N2b nodal status and ≤ 10 pack-years smoking history, falling under the low-risk classification put forth by Ang et al. . Patients are randomised to receive accelerated radiotherapy alone to 60 Gy given six fractions a week over 5 weeks versus 60 Gy using standard fractionation over 6 weeks with dose-reduced weekly cisplatin (40 mg/m2 weekly, total 240 mg/m ). Retrospective data suggest that the weekly chemotherapy schedule results in significantly reduced severity of mucositis compared to the traditional schedule of delivery every 3 weeks . Notably, both arms represent a 10 Gy reduction in total radiotherapy dose. The primary end-point of the study is 2-year progression-free survival of at least 85% as well acceptable swallowing function based on the MD Anderson Dysphagia Inventory. This combination efficacy and toxicity end-point is novel, and demonstrates the emphasis of selecting therapies in which patients are likely to be cured, but also have minimal long-term morbidity. Treatment de-intensification strategies for head and neck cancer November 2016
Studies of radiation therapy (RT) vs chemoradiation (CRT) therapy showed RT alone to have very good results.
RESULTS: In all, 23 patients with HPV-positive cancers were identified. With a median follow-up of 28 months (range, 6-85 months), the 3-year actuarial rates of overall survival, locoregional control, and distant metastasis-free survival were 83%, 90%, and 88%, respectively.
CONCLUSION: These findings attest to the exquisite radiosensitivity of HPV-positive head and neck cancer. The clinical outcomes observed from this selected series compare favorably with historical controls treated by more intensive chemoradiotherapy strategies. Definitive radiation therapy without chemotherapy for human papillomavirus-positive head and neck cancer November 2013
Apparent improvements from CRT may be false.
In this study of real-world patients what appeared to be improvement in OS with the addition of concurrent chemotherapy to conventional radiotherapy was confounded by HPV status. Did the addition of chemotherapy to conventional radiotherapy improve outcomes in treatment of oropharynx cancer in Ontario, Canada? A marker-treatment interaction study 2016
As of July 11, 2019, I am leaning towards not having any chemotherapy, but I’m still in my information-gathering phase.
I will be meeting with my radiation oncologist tomorrow to get answers to some questions, and I’ll try to get his opinion about this. I’ll also set up another meeting with my medical oncologist, and I’ll be attending an information session all about chemotherapy at the Victoria Cancer Clinic next Tuesday July 16 where nurses and pharmacists will be able to answer questions.
Updates, July 15, 2019
I found another article that indicates CRT is not recommended for Stage II (that’s me) HPV-positive oropharyngeal cancer.
Stage I-II: Concurrent systemic therapy is not recommended for patients with stage I-II OPSCC receiving definitive RT, due to a lack of evidence supporting its use for early-stage disease. New ASTRO guideline establishes standard of care for curative treatment of oropharyngeal cancer with radiation therapy April 16, 2017
The American Cancer Society makes it clear that CRT is really tough.
Side effects tend to be worse if chemotherapy is given at the same time as radiation (chemoradiation). Both the radiation and the chemotherapy side effects are worse, which can make this treatment hard to tolerate. For this reason, it’s important that anyone getting chemoradiation be in relatively good health before starting treatment, that they understand the possibility of serious side effects, and that they’re treated at a medical center with a lot of experience with this approach. Radiation Therapy for Oral Cavity and Oropharyngeal Cancer March 2018
Update, July 17, 2019
In the context of HPV-positive head & neck SCC, high-dose Cisplatin treatments significantly increase short-term side effects.
… higher incidences in severe (grade 3 or higher) adverse effects in functional mucosal, muscular fibrosis, as well as cytopenia and nausea/vomiting in the combined group … the addition of chemotherapy to radiotherapy increased the incidence of severe adverse effects (grade 3 and higher) from 34% to 77% … Optimal regimen of cisplatin in squamous cell carcinoma of head and neck yet to be determined June 2018
Update, July 22, 2019
The following article lists the pros and cons of de-escalation, including the option of removing systemic therapy entirely in favour of using RT only.
Point/Counterpoint: Do We De-escalate Treatment of HPV-Associated Oropharynx Cancer Now? And How? May 2018 ASCO Educational Book
The following article indicates that smoking status is a very high determinate of recurrence, leading me to think that, because neither RTOG 1016 or De-ESCALaTE had results based on smoking status, that the chance of recurrence, under Cisplatin CRT, for me is lower than those studies indicate. These were, however, mostly Stage IV patients.
One hundred and two patients (82.3%) had HPV-positive tumors. Over two thirds (68%) of patients with HPV-positive tumors were tobacco users. Among HPV-positive patients, current tobacco users were at significantly higher risk of disease recurrence than never-tobacco users (hazard ratio, 5.2). Thirty-five percent of HPV-positive ever tobacco users recurred compared with only 6% of HPV-positive never users and 50% of HPV-negative patients. All HPV-negative patients were tobacco users and had significantly shorter times to recurrence, and had reduced disease-specific survival and overall survival compared with HPV-positive patients. Compared with HPV-positive never-tobacco users, those with a tobacco history showed a trend for reduced disease-specific survival but not overall survival. Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence February 2010 PubMed
The following article indicates that for patients with low risk of metastasis, there was no significant difference in controlling distant metastasis between RT and CRT.
The [distant control] rates for HPV-positive, low-risk [of distant metastasis] N0-2a or less than 10 pack-year N2b patients were similar for RT alone and CRT… Deintensification Candidate Subgroups in Human Papillomavirus–Related Oropharyngeal Cancer According to Minimal Risk of Distant Metastasis
February 2013 Journal of Clinical Oncology
The following article implies that some recurrences are due to inadequate volume delineation.
A significant proportion of local–regional recurrences from HPV-positive oropharyngeal cancer represented geographical misses which possibly could have been prevented with more meticulous attention to IMRT planning. Inadequate target volume delineation and local–regional recurrence after intensity-modulated radiotherapy for human papillomavirus-positive oropharynx cancer June 2017 Radiotherapy and Oncology