Liquid biopsy provides accurate, fast Dx of HPV-associated head and neck cancer

Source: www.medpagetoday.com
Author: Mike Bassett, Staff Writer, MedPage Today

The use of liquid biopsy for the diagnosis of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) was more accurate, faster, and less expensive than standard tissue-based biopsies, according to a prospective observational study.

The sensitivity and specificity of this circulating tumor HPV DNA-based approach were 98.4% and 98.6%, respectively, with positive and negative predictive values of 98.4% and 98.6%, reported Daniel L. Faden, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues.

The diagnostic accuracy of this non-invasive approach was significantly higher than standard of care (Youden index 0.968 vs 0.707, P<0.0001), they noted in Clinical Cancer Research.

In addition, liquid biopsy reduced the time to diagnosis from a median of 41 days to 15 days, and estimated costs associated with this method were about 36% to 38% less than the traditional biopsy approach.

“Currently the way we diagnose HPV-associated cancer is either with a needle biopsy of a neck lymph node or a tissue biopsy from the oropharynx — and these approaches have a couple of different limitations,” Faden told MedPage Today. Not only are they invasive and painful for patients, but needle biopsy of a neck lymph node has high failure rates due to a lack of adequate cellular material.

“So, patients might have to undergo a repeat biopsy to get the diagnosis we are waiting for,” he noted. “That adds time to diagnosis, and we know that time from presentation to when patients start treatment impacts outcomes, so we want to start that as soon as possible.”

Considering these challenges, Faden and colleagues assessed a circulating tumor HPV DNA-based diagnostic approach compared with standard clinical workup.

They prospectively enrolled 70 patients presenting with a new or suspected diagnosis of HPV-associated oropharyngeal squamous cell carcinoma, nasopharyngeal carcinoma, or sinonasal squamous cell carcinoma, all of whom underwent standard-of-care diagnostic workup, as well as 70 control patients who were subsequently diagnosed with HPV-negative HNSCC.

Blood samples were collected and processed for circulating tumor HPV DNA, and analyzed with custom droplet digital PCR assays for HPV genotypes 16, 18, 33, 35, and 45.

Of the 70 patients in the HPV-positive group, 61 were available for analysis. Fine-needle aspiration was the first diagnostic approach in 37 patients, while primary tissue biopsy was the first for 24 patients. The overall diagnostic success rate on the first attempt was 72%, meaning that 17 patients (28%) had to undergo a repeat biopsy to achieve diagnosis.

Faden and colleagues also evaluated the diagnostic accuracy of liquid biopsy in combination with cross-sectional imaging and physical examination.

“We realized that people may be skeptical about making a diagnosis of cancer just off a blood test, and not having a traditional tissue biopsy,” Faden said. “In order to build confidence in having this non-invasive diagnosis, we took our liquid biopsy and combined it with routine things patients receive when they first present — a physical exam and cross-sectional imaging with either a CT or MRI scan.”

The researchers found that this approach yielded a specificity of 98.6%, but a sensitivity that was slightly lower (95.1%). “But this was because some patients lack classic imaging or physical exam findings, such as a mass you can see in the throat or enlarged lymph nodes in the neck,” he explained.

Faden and colleagues are preparing to open a trial designed to validate the findings from this study next year, and plan to use liquid biopsy to make real-time decisions for patients during treatment to personalize their care.

2021-12-03T05:54:26-07:00December, 2021|Oral Cancer News|

Treatment paradigms are shifting for locally advanced HPV-positive head and neck cancers

Source: www.onclive.com
Authors: Kaveh Zakeri, MD, MAS, Nancy Y. Lee, MD

The standard of care for patients with locally advanced head and neck squamous cell carcinomas does not substantially differ according to human papillomavirus (HPV) status in the National Comprehensive Cancer Network guidelines.1 Resectable tumors can be treated with surgery followed by adjuvant therapy. Alternatively, definitive chemoradiation therapy with cisplatin is the other dominant treatment paradigm. Incidence of HPV-associated oropharyngeal squamous cell carcinoma has increased rapidly and is associated with higher overall survival (OS) compared with cancers caused by smoking and alcohol.2,3 Given the unique biology of HPV-associated oropharyngeal disease, a separate staging system was developed for these tumors.4

HPV-associated oropharyngeal cancers are more radiosensitive and chemosensitive than cancers caused by smoking and alcohol, yet the traditional treatment paradigms—including high doses of radiation and chemotherapy—were developed prior to the epidemic of HPV-associated disease. De-escalation of therapy has been proposed for HPV-associated oropharyngeal cancer based on data demonstrating high OS and progression-free survival (PFS).5 De-escalation of therapy has been investigated for both definitive surgical and chemoradiation therapy paradigms. Most de-escalated approaches focus on selecting patients according to clinical features, such as disease stage and smoking status, whereas personalized de-escalation reduces treatment intensity for patients according to treatment response.

Transoral Robotic Surgery Followed by Adjuvant Radiotherapy
Transoral robotic surgery (TORS) is a minimally invasive approach that reduces morbidity compared with traditional, open surgery for patients with oropharyngeal cancers. TORS is a standard of care option for patients with resectable tonsil or base of tongue tumors when adequate functional outcome can be preserved. For patients with HPV-associated oropharyngeal disease, postoperative radiation is typically recommended for those with high-risk features including close or positive margins, lymphovascular invasion, perineural invasion, and involved lymph nodes. Adjuvant chemotherapy is recommended for patients with positive margins or lymph nodes with extracapsular extension. Standard doses of radiation consist of 50 to 60 Gy; standard adjuvant chemotherapy typically includes either high-dose or weekly cisplatin.

De-escalated postoperative treatment has been investigated, including reduced intensity of radiation and/or chemotherapy. De-escalation of adjuvant radiation therapy has involved both reduced dose and target volumes. ECOG-ACRIN 3311 (NCT01898494) was a randomized clinical trial in which investigators evaluated reduced dose adjuvant radiation therapy for patients with intermediate postoperative risk factors.6 Patients with low-risk pT1-T2, N0-1 disease with negative margins were observed. Patients with intermediate risk disease (close margins, < 1 mm of extranodal extension, 2 to 4 involved lymph nodes, perineural invasion, or lymphovascular invasion) were randomized to postoperative radiation of either 50 or 60 Gy. High-risk patients with positive margins, greater than 1 mm of extranodal extension, or more than 5 involved nodes received radiation with cisplatin. At a median follow-up of 35.1 months, the 3-year PFS rates were 96.9%, 94.9%, 93.5%, and 90.7% for the low-risk, 50 Gy, 60 Gy, and high-risk arms, respectively.6 Reduced doses of postoperative radiation and chemotherapy were also investigated in the single-arm MC1273 clinical trial (NCT01932697).7 Following surgery, patients received 30 to 36 Gy in 1.5-Gy twice-daily fractions with weekly docetaxel chemotherapy. The rates of 2-year locoregional control, PFS, and OS were 96.2%, 91.1%, and 98.7%, respectively, with 3 years of follow-up. The intensity of 30 to 36 Gy given twice daily compared with the standard 50 to 60 Gy given once daily is unclear.8 Randomized clinical trials are needed to determine whether the MC1273 treatment regimen results in noninferior cure rates with reduced toxicity compared with standard therapy. The PATHOS trial (NCT02215265) is an ongoing randomized clinical trial investigating a reduction in adjuvant radiation and chemotherapy.9 Patients with low-risk disease are observed postoperatively, patients with intermediate risk factors are randomized to 50 Gy vs 60 Gy, and patients with high-risk features are randomized to 60 Gy alone or 60 Gy with cisplatin. An additional postoperative de-escalation strategy involves omission of the primary site (tonsil or base of tongue) for patients without primary site risk factors for recurrence (perineural invasion, lymphovascular invasion, or close surgical margins).10 The AVOID trial (NCT02159703) was a single-arm study of adjuvant radiotherapy to the neck alone in patients without primary site risk factors. In total, 60 patients were enrolled and at 2.4 years of median follow-up, only 1 patient had a primary site recurrence. Although this strategy appears promising, more work is necessary to validate these findings and determine the long-term risks and benefits of this approach. Collectively, these clinical trials demonstrate that TORS followed by adjuvant radiation with or without chemotherapy results in high rates of tumor control. Reduced doses of postoperative radiation and chemotherapy appear promising as a strategy to reduce toxicity while maintaining high rates of cure, and clinical trials investigating these approaches are ongoing. Two randomized clinical trials have compared TORS plus adjuvant therapy with definitive chemoradiation—the ORATOR trial (NCT01590355) and the ORATOR2 trial (NCT03210103).11,12 The phase 2 ORATOR trial was designed to determine whether TORS would improve 1-year swallowing quality of life. After 25 months of follow-up, patients treated with radiation had a statistically significant improvement in swallowing quality of life, but the difference did not meet the prespecified threshold of clinical significance. There was no difference in PFS or OS between the groups. The follow-up ORATOR2 study randomized patients to de-escalated radiation-based treatment vs surgery with de-escalated adjuvant therapy.12 The results are pending release. Additional studies are needed to determine the differences between surgery and radiation-based paradigms for treatment of HPV-associated oropharyngeal disease.

Definitive Radiotherapy With Chemotherapy Cetuximab and/or Immunotherapy
Definitive radiotherapy with high-dose cisplatin is the alternative to TORS-based approaches and is standard for unresectable HPV-associated oropharyngeal tumors. In an attempt to reduce the toxicity of treatment, cetuximab (Erbitux) was proposed as an alternative to cisplatin chemotherapy. Three randomized phase 3 trials compared cisplatin/radiotherapy with cetuximab/radiotherapy: RTOG 1016 (NCT01302834), De-ESCALaTE HPV (NCT01874171), and TROG 12.01 (NCT01855451). Investigators of all 3 trials observed a statistically significant detriment in either PFS or OS for patients treated with cetuximab/radiation (Table).13-15 Additionally, toxicity was not reduced with cetuximab compared with cisplatin.

Omission of systemic therapy with radiation was studied in the randomized phase 2 NRG-HN002 trial (NCT02254278). Patients with p16-positive, nonmetastatic, T1-T2 N1-N2b or T3 N0-N2b (7th edition staging) oropharynx cancer with 10 or fewer pack-years of smoking were randomized to 60 Gy of radiation in 6 weeks with cisplatin vs 60 Gy of radiation in 5 weeks without any systemic therapy. The 2-year PFS rate was 90.5% for cisplatin/radiation vs 87.6% for radiation alone. The radiation alone arm did not meet the prespecified threshold for PFS superiority to 85%. There was no difference in swallowing quality of life between the 2 arms.16

Several randomized trials have investigated the role of immune checkpoint inhibitors (ICIs) in combination with definitive radiation therapy for HPV-associated oropharyngeal cancer. Immunotherapy has been proposed as an alternative to cisplatin for patients with favorable-risk disease and as an additive treatment to cisplatin/radiation for patients with high-risk disease. In patients with favorable-risk disease, the goal of replacing cisplatin with immunotherapy is to reduce the toxicity of treatment while maintaining high cure rates. Investigators are testing this strategy (NRG-HN005, CCTG HN.9 [NCT03410615], and KEYCHAIN [NCT03383094]) and have incorporated ICIs such as nivolumab (Opdivo), durvalumab (Imfinzi), tremelimumab, and pembrolizumab (Keytruda) into the radiation-based treatment paradigm.17-19

For patients with high-risk disease, ICIs have been added to the cisplatin/radiation backbone. Investigators of the randomized phase 3 JAVELIN HEAD AND NECK 100 trial (NCT02952586) evaluated the addition of avelumab (Bavencio) to cisplatin/radiotherapy and included patients with high-risk HPV-associated oropharynx cancer. There was no improvement in PFS with the addition of avelumab to cisplatin/radiotherapy.20 Additionally, investigators of the randomized phase 3 Groupe Oncologie Radiotherapie Tete et Cou REACH trial (NCT02999087) did not observe a benefit with radiation/avelumab/ cetuximab vs cisplatin/radiation.21

These randomized clinical trials highlight the importance of radiosensitizing cisplatin in combination with radiation therapy. Replacement of cisplatin with cetuximab and omission of cisplatin led to inferior tumor control without improvements in toxicity. For patients with high-risk disease, immunotherapy has not demonstrated a benefit when added to cisplatin/radiation or radiation/cetuximab. For patients with favorable-risk disease, ongoing clinical trials will determine whether there is a role for radiation/ immunotherapy.

Personalized Chemoradiation Therapy Based on Hypoxia Imaging
Personalized treatment strategies involve tailoring the intensity of radiation and chemotherapy to individual patient biology and tumor response. Among patients with HPV-associated oropharyngeal cancer, there is heterogeneity in tumor biology and resistance to treatment.22-24 Nonpersonalized treatment paradigms including omission of systemic therapy and replacement of cisplatin with cetuximab were unsuccessful, potentially because differences in tumor biology were not accounted for. Personalized treatment according to tumor biology may facilitate successful tailoring of treatment intensity. Tumor hypoxia is associated with radioresistance and inferior locoregional control and OS in head and neck cancer.25,26

18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET) is a novel method of measuring tumor hypoxia in vivo and can predict treatment outcomes in patients with head and neck cancer.27 De-escalation of radiation and chemotherapy based on tumor hypoxia using 18F-FMISO PET is a promising treatment strategy for HPV-associated oropharynx cancer. An initial pilot study at Memorial Sloan Kettering Cancer Center in New York, New York, demonstrated successful de-escalation to 60 Gy of radiation with cisplatin for patients with resolution of hypoxia according to 18F-FMISO PET imaging.28 Among the 33 enrolled patients, the 2-year locoregional control and OS rates were 100%.

The subsequent 30 ROC trial (NCT03323463) also conducted by investigators at Memorial Sloan Kettering Cancer Center investigated whether a dramatic reduction in radiation dose to 30 Gy with high-dose cisplatin or carboplatin with 5-fluorouracil could result in successful de-escalation. Patients had resection of the primary tumor prior to chemoradiation and planned neck dissection at 4 months post chemoradiation to measure pathologic response. Patients with resolution of hypoxia on 18F-FMISO PET imaging were treated to 30 Gy with 2 cycles of chemotherapy. Among the 19 enrolled patients, the 2-year rates of locoregional control and OS were 94.4% and 94.7%, respectively.29

Phase 2 of the 30 ROC trial examined the same strategy of resection of the primary tumor followed by 30 Gy of radiation and 2 cycles of chemotherapy with omission of planned neck dissections. The rates of 1-year locoregional control, distant metastasis-free survival, and OS were 94%, 100%, and 100%, respectively, at median follow-up of 1 year.30 All 8 reported local recurrences were in the neck and successfully salvaged with surgery. A subsequent phase of the 30 ROC trial is ongoing with omission of both resection of the primary tumor and planned neck dissection.

Next Steps in the Field
The standard-of-care treatment paradigms for patients with locally advanced HPV-associated head and neck cancer include up-front surgery followed by adjuvant radiation with or without chemotherapy and definitive radiation with cisplatin. De-escalation of postoperative adjuvant therapy is the subject of investigation. Replacement of cisplatin with cetuximab or omission of cisplatin with definitive radiotherapy have not been successful. The addition of immunotherapy to definitive radiation-based treatment has not demonstrated a benefit thus far. A personalized treatment paradigm based on hypoxia imaging is promising and may yield a successful, personalized de-escalation strategy for patients with HPV-associated oropharynx cancer.

Authors:
Kaveh Zakeri, MD, MAS, is a radiation oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.

Nancy Y. Lee, MD, is vice chair of the Department of Radiation Oncology, service chief of head and neck radiation oncology, and service chief of proton therapy at Memorial Sloan Kettering Cancer Center in New York, New York.

References
1. NCCN. Clinical Practice Guidelines in Oncology. Head and neck cancers, version 3.2021. Accessed October 29, 2021. https://www.nccn.org/professionals/physician_gls/ pdf/head-and-neck.pdf
2. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35. doi:10.1056/NEJMoa0912217
3. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294- 4301. doi:10.1200/JCO.2011.36.4596
4. O’Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 2016;17(4):440-451. doi:10.1016/S1470-2045(15)00560-4
5. Adelstein DJ, Ismaila N, Ku JA, et al. Role of treatment deintensification in the management of p16+ oropharyngeal cancer: ASCO provisional clinical opinion. J Clin Oncol. 2019;37(18):1578-1589. doi:10.1200/JCO.19.00441
6. Ferris RL, Flamand Y, Weinstein GS, et al. Updated report of a phase II randomized trial of transoral surgical resection followed by low-dose or standard postoperative therapy in resectable p16+ locally advanced oropharynx cancer: a trial of the ECOG-ACRIN cancer research group (E3311). J Clin Oncol. 2021;39(suppl 15):6010. doi:10.1200/ JCO.2021.39.15_suppl.6010
7. Ma DJ, Price KA, Moore EJ, et al. Phase II evaluation of aggressive dose de-escalation for adjuvant chemoradiotherapy in human papillomavirus-associated oropharynx squamous cell carcinoma. J Clin Oncol. 2019;37(22):1909-1918. doi:10.1200/ JCO.19.00463
8. Garden AS. Not all 30-Gy regimens are equal. J Clin Oncol. 2019;37(36):3558-3559. doi:10.1200/JCO.19.01666
9. Owadally W, Hurt C, Timmins H, et al. PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for human papillomavirus (HPV) positive oropharyngeal cancer. BMC Cancer. 2015;15:602. doi:10.1186/s12885-015-1598-x
10. Swisher-McClure S, Lukens JN, Aggarwal C, et al. A phase 2 trial of alternative volumes of oropharyngeal irradiation for de-intensification (AVOID): omission of the resected primary tumor bed after transoral robotic surgery for human papilloma virus–related squamous cell carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys. 2020;106(4):725-732. doi:10.1016/j.ijrobp.2019.11.021
11. Nichols AC, Theurer J, Prisman E, et al. Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial. Lancet Oncol. 2019;20(10):1349-1359. Published correction appears in Lancet Oncol. 2019;20(12):e663.
12. Nichols AC, Lang P, Prisman E, et al. Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial. BMC Cancer. 2020;20(1):125. doi:10.1186/s12885-020-6607-z
13. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393(10166):40-50. Published correction appears in Lancet. 2020;395(10226):784.
14. Mehanna H, Robinson M, Hartley A, et al; De-ESCALaTE HPV Trial Group. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019;393(10166):51-60. doi:10.1016/S0140-6736(18)32752-1
15. Rischin D, King M, Kenny L, et al. Randomized trial of radiotherapy with weekly cisplatin or cetuximab in low-risk HPV-associated oropharyngeal cancer (TROG 12.01) – a Trans-Tasman Radiation Oncology Group study. Int J Radiat Oncol Biol Phys. 2021;111(4):876-886. doi:10.1016/j.ijrobp.2021.04.015
16. Yom SS, Torres-Saavedra P, Caudell JJ, et al. Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002). J Clin Oncol. 2021;39(9):956-965. doi:10.1200/JCO.20.03128
17. Spreafico A, Sultanem K, Chen B, et al. A randomized phase II study of cisplatin plus radiotherapy versus durvalumab plus radiotherapy followed by adjuvant durvalumab versus durvalumab plus radiotherapy followed by adjuvant tremelimumab and durvalumab in intermediate risk, HPV-positive, locoregionally advanced oropharyngeal squamous cell cancer (LA-OSCC) (Canadian Cancer Trials Group HN.9). Ann Oncol. 2018;29(suppl_8):VIII399. doi:10.1093/annonc/mdy287.080
18. De-intensified radiation therapy with chemotherapy (cisplatin) or immunotherapy (nivolumab) in treating patients with early-stage, HPV-positive, non-smoking associated oropharyngeal cancer. ClinicalTrials.gov. Updated October 26, 2021. Accessed October 29, 2021. https://clinicaltrials.gov/ct2/show/NCT03952585
19. Chemoradiation vs immunotherapy and radiation for head and neck cancer. ClinicalTrials.gov. Updated October 8, 2021. Accessed October 29, 2021. https://clinicaltrials. gov/ct2/show/NCT03383094
20. Lee NY, Ferris RL, Psyrri A, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021;22(4):450-462. doi:10.1016/S1470- 2045(20)30737-3
21. Bourhis J, Tao Y, Sun X, et al. Avelumab-cetuximab-radiotherapy versus standards of care in patients with locally advanced squamous cell carcinoma of head and neck (LA-SCCHN): randomized phase III GORTEC-REACH trial. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
22. Kimple RJ, Smith MA, Blitzer GC, et al. Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res. 2013;73(15):4791-4800. doi:10.1158/0008-5472.CAN-13-0587
23. Vainshtein J, McHugh JB, Spector ME, et al. Human papillomavirus-related oropharyngeal cancer: HPV and p16 status in the recurrent versus parent tumor. Head Neck. 2015;37(1):8-11. doi:10.1002/hed.23548
24. Rieckmann T, Tribius S, Grob TJ, et al. HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol. 2013;107(2):242-246. doi:10.1016/j.radonc.2013.03.013
25. Terris DJ. Head and neck cancer: the importance of oxygen. Laryngoscope. 2000;110(5 Pt 1):697-707. doi:10.1097/00005537-200005000-00001
26. Brizel DM, Dodge RK, Clough RW, Dewhirst MW. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol. 1999;53(2):113-117. doi:10.1016/s0167-8140(99)00102-4
27. Rasey JS, Koh WJ, Evans ML, et al. Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int J Radiat Oncol Biol Phys. 1996;36(2):417-428. doi:10.1016/s0360-3016(96)00325-2
28. Lee N, Schoder H, Beattie B, et al. Strategy of using intratreatment hypoxia imaging to selectively and safely guide radiation dose de-escalation concurrent with chemotherapy for locoregionally advanced human papillomavirus-related oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2016;96(1):9-17. doi:10.1016/j.ijrobp.2016.04.027
29. Riaz N, Sherman E, Pei X, et al. Precision radiotherapy: reduction in radiation for oropharyngeal cancer in the 30 ROC trial. J Natl Cancer Inst. 2021;113(6):742-751. doi:10.1093/jnci/djaa184
30. Lee NY, Sherman EJ, Schöder H, et al. The 30 ROC trial: precision intra-treatment imaging guiding major radiation reduction in human papillomavirus related oropharyngeal cancer. J Clin Oncol. 2021;39(suppl 15):6019. doi:10.1200/JCO.2021.39.15_suppl.6019

2021-11-23T08:16:08-07:00November, 2021|Oral Cancer News|

Most men benefit from initial and catch-up cancer prevention vaccination

Source: www.precisionvaccinations.com
Author: Don Ward Hackett

The Lancet Infectious Disease published the results from an extensive cancer prevention phase 3 study on November 12, 2021, supporting quadrivalent HPV vaccination in men, including catch-up vaccinations.

The Gardasil quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in men aged 16–26 years.

The researchers assessed the incidences of external genital warts related to HPV6 or 11 and external genital lesions and anal dysplasia associated with HPV6, 11, 16, or 18, over ten years of follow-up.

The 3-year Base Study was an international, double-blind, randomized, placebo-controlled trial done at 71 sites in 18 countries.

The Vaccination Period for the Base Study encompassed Day 1 through Month 7, during which time participants received qHPV vaccination at Day 1, Month 2, and Month 6. Follow-up for the Base Study encompassed Month 7 through Month 36.

And the 7-year, open-label, long-term follow-up extension study was done at 46 centers in 16 countries.

Between August 2010 and April 2017, 1,803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group.

In early vaccine group participants during long-term follow-up compared with the placebo group in the Base Study, the incidence per 10 000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0–8·7) versus 137·3 (83·9–212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0–7·7) versus 140·4 (89·0–210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5–114·4) versus 906·2 (553·5–1399·5).

Compared with during the Base Study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 vs. 0 cases per 10 000 person-years or external genital lesions associated with HPV6, 11, 16, or 18 vs. 0 cases per 10 000 person-years, and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 vs. 101·3 cases per 10 000 person-years.

Furthermore, there were no vaccine-related serious adverse events reported.

Gardasil is endorsed by the WHO, which says HPV vaccination prevents certain cancers by preventing infection by various HPV types.

This study was funded by Merck Sharp & Dohme, the producer of the Gardasil HPV vaccine.

In the U.S., the American Cancer Society’s updated recommendations are for healthcare providers to routinely offer the HPV vaccine series to boys and girls between ages 9 and 12.

Furthermore, the Gardasil 9 vaccine is offered in the U.S. It consists of HPV proteins, Types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

HPV infections can lead to certain cervical cancers. Many females with cervical cancer were probably exposed to cancer-causing HPV types in their teens and early 20s. Additionally, males can get HPV, causing anal and throat cancers and genital warts.

2021-11-16T08:57:09-07:00November, 2021|Oral Cancer News|

New treatment for HPV-associated oropharynx cancer leads to excellent disease control, less side effects

Source: www.news-medical.net
Author: Emily Henderson, B.Sc., Mayo Clinic

Mayo Clinic researchers have found that a new, shorter treatment for patients with HPV-associated oropharynx cancer leads to excellent disease control and fewer side effects, compared to standard treatment.

The new treatment employs minimally invasive surgery and half the standard dose of radiation therapy, compared to current treatments. The new treatment also lasts for two weeks, rather than the standard six weeks.

Results of a study of the new treatment were presented Tuesday, Oct. 20, at the American Society for Radiation Oncology’s Annual Meeting.

Dr. Ma says that while the standard treatment for this type of cancer leads to high cure rates, it may also result in many short-term and long-term treatment toxicities, including dry mouth, problems swallowing, neck stiffness and jawbone problems.

“Many of these side effects are directly linked to the amount of radiation used for treatment,” says Dr. Ma.

Dr. Ma and his colleagues developed an initial clinical trial looking at a new treatment using minimally invasive surgery and half the standard dose of radiation. The initial clinical trial demonstrated that well-selected patients could have excellent disease control with much lower toxicity using the new treatment.

“Our findings suggest that in select patients with HPV-associated oropharynx a shorter course treatment, compared to the standard of care, yields a similar result,” says Dr. Ma. Based on these phase 3 results, Mayo Clinic has adopted this shorter course treatment as its standard of care for well-selected patients.

Dr. Ma and his colleagues are now developing future clinical trials that will test whether it is possible to combine lower doses of radiation with other treatment strategies, such as proton beam therapy, to further reduce toxicity to patients.

Saliva testing may allow early detection of human papillomavirus–driven head and neck cancers

Source: medicalxpress.com
Author: Elsevier

Cancer causing high-risk human papillomaviruses (HR-HPV) are responsible for the rising incidence of HR-HPV–driven head and neck cancers (HNC), particularly oropharyngeal cancers (OPC, or throat cancers). Investigators have determined that HR-HPV DNA can be detected in saliva in most patients with HPV-driven OPC at the time of diagnosis. This work highlights a potentially life-saving screening program based on salivary HR-HPV DNA testing for early cancer detection and patient monitoring. Their findings appear in The Journal of Molecular Diagnostics.

“Despite the upsurge in HPV-driven HNC, there are no early detection methods or screening strategies for this cancer type, unlike cervical cancer, which is caused by the same virus. Biomarkers enabling early detection, monitoring and disease prognostication are warranted to combat the rising incidence of HPV-driven OPC,” observed lead investigator Chamindie Punyadeera, Ph.D., head, Saliva & Liquid Biopsy Translational Laboratory, School of Biomedical Science, Faculty of Health, Queensland University of Technology (QUT), and Translational Research Institute, Brisbane, QLD, Australia.

Dr. Punyadeera and her colleagues investigated the efficacy of salivary HPV detection as a biomarker of HPV-HNC and survival patterns in patients with OPC to evaluate the utility of salivary HR-HPV as a prognostic biomarker for OPC.

Saliva testing was performed on 491 patients at the time of first diagnosis of HNC and 10 patients with recurring HNC. Forty-three percent were positive for salivary HR-HPV DNA. HPV16, a high-risk strain of the virus, was detected in 92% of the HPV-positive saliva samples. The vast majority of HPV-HNC had arisen from the oropharynx, especially from the palatine tonsils and the base of the tongue, confirming that the oropharynx is the hotspot for these cancers. Seventy-two percent of OPC patients were positive for HR-HPV DNA in their saliva, and tumor p16 overexpression was observed in 89.3%. These findings support the utility of saliva testing as a biomarker for facilitating early detection and screening of HR-HPV DNA.

Two hundred and fifteen patients with OPC were followed for up to five years. Salivary HR-HPV–positive patients had a clear survival advantage over their salivary HR-HPV–negative counterparts. The median event-free survivals were 205 months for HR-HPV–positive patients, compared to 82 months for HR-HPV–negative patients. Although the number of patients with recurrent cancer in the study was small, findings indicate that salivary HR-HPV tends to be positive in the majority of patients at the locoregional point of occurrence.

“When the noninvasive nature and convenience of the collection are considered, salivary HR-HPV testing is an ideal mode of screening asymptomatic individuals and the long-term monitoring of HPV-driven HNC patients. Our findings indicate that in the near future, salivary HR-HPV testing will become part of routine clinical management for HPV-driven OPC patients,” noted Dr. Punyadeera.

“Liquid biopsy in HNC has the potential to be truly transformative,” explained co-investigator Sarju Vasani, MD, Royal Brisbane and Women’s Hospital; and the Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. “It has the potential to personalize treatment selection and aid in assessing disease prognosis. It can help us select patients for adjuvant treatment and will alert us to recurrence before imaging or clinical examination has detected any specific abnormality. It is only a matter of time before these biomarkers translate from research settings to clinical practice.”

In some countries, including the United States, HNC and particularly OPC, have surpassed cervical cancers as the most common HPV-driven cancer. Patients are usually diagnosed at an advanced stage. In the early stages, these cancers are difficult to locate with imaging studies or physical examination. The oropharynx is difficult to access, and detection is further complicated if these smaller lesions are hidden in the crevices of the tonsils. These cancers can metastasize at an early stage, even when the primary cancer is still undetectable in size.

2021-09-22T09:38:25-07:00September, 2021|Oral Cancer News|

Bifunctional protein shows promise in HPV-related cancers

Source: www.medpagetoday.com
Author: Charles Bankhead, Senior Editor, MedPage Today September

A bifunctional fusion protein with immunotherapeutic activity proved active in advanced, difficult-to-treat cancers associated with human papillomavirus (HPV), according to pooled data from two prospective studies.

Overall, 21 of 75 patients had confirmed responses with bintrafusp alfa, which inhibits tumor growth factor-beta (TGF-β) and PD-L1 interaction with its receptor. Responses were durable in many cases and occurred in patients with a variety of HPV-associated cancers. With a median follow-up of 33 months, the two cohorts had a median overall survival (OS) of 21.3 months, reported James Gulley, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, during the virtual European Society for Medical Oncology (ESMO) meeting.

“Overall survival appears to have a plateau of around 40-45% out to beyond 3 years,” said Gulley. “The median survival compares favorably to the reported overall survival with PD-1 inhibitors of 8 to 12 months.”

“The need for effective treatment options in patients with HPV-associated malignancies is high,” he added. “Therefore, these results showing efficacy of bintrafusp alfa across different HPV-related tumor types are of interest. Clinical trials of bintrafusp alfa in HPV-associated malignancies are ongoing.”

The frequency and durability of responses are “really remarkable in a quite difficult-to-treat patient population,” said ESMO invited discussant Sebastian Kobold, MD, of Ludwig Maximilian University in Munich.

“It’s especially stunning because we all know that cervical cancers in previous trials have shown rather disappointing results with PD-1-targeting single agents, indicating that’s [the anti-PD-1 component of the drug] probably not the explanation for the results seen here, because there were no complete responses in the previous trials,” he continued.

“Single-agent TGF-beta blockade was typically associated with overall response rates ranging from zero to 10%, indicating it’s not that single agent alone. Potentially, it’s the synergy of targeting both pathways that leads to these quite impressive results,” he added.

HPV infection causes almost 700,000 cancers worldwide each year, including about 35,000 in the U.S. Since the mid-2000s, the incidence of non-cervical HPV-related cancers has increased substantially, Gulley noted.

PD-L1 expression has an association with HPV infection in patients with HPV-related cancers, and anti-PD-1/L1 agents have demonstrated activity in patients with recurrent/metastatic HPV-related malignancies. However, the durability has been modest, associated with a median OS ≤12 months.

HPV infection also has been associated with upregulation of tumor TGF-β signaling, suggesting that simultaneous inhibition of TGF-β and PD-1/L1 might offer an effective treatment option for HPV-related malignancies.

Gulley reported combined data from a phase I and a phase II trial of bintrafusp alfa in patients with previously treated HPV-related cancers but no prior exposure to PD-1/L1 inhibitors. The phase I trial included 43 patients with cervical cancer (n=25), squamous cell carcinoma of the head and neck (SCCHN; n=14), and anal cancer (n=4). The phase II trial included 32 patients with cervical (n=14), SCCHN (n=5), anal (n=5), and other cancers (n=8).

The 75 patients had a median age of 56, and women accounted for 73% of the study population. Two-thirds of the patients had received at least two prior regimens, and 89% tested positive for HPV at enrollment.

Single-agent bintrafusp alfa led to four complete responses and 17 partial responses. Eleven other patients had stable disease, resulting in a disease control rate of 42.7%. Four patients had delayed partial response, bringing the total response rate to 32%. Responses occurred across multiple tumor types, including cervical, anal, SCCHN, rectal, penile, vaginal, and vulvar cancer.

Median duration of response was 17.3 months. Gulley said 15 of the initial 21 responses lasted for at least 6 months, and 12 lasted a year or longer.

In addition to the median OS of 21.3 months, 59.7% of patients were alive at 12 months and 51.5% at 21 months.

The most common treatment-related adverse events (AEs; all grades) were pruritus (25.3%), dermatitis acneiform (24.0%), anemia (18.7%), fatigue (17.3%), and maculopapular rash (17.3%). The most common grade 3/4 AE was anemia (6.7%).

Immune-related AEs occurred in 49.3% of patients, including hemorrhage (32.0%), anemia (18.7%), skin lesions (14.7%), and infusion-related AEs (5.3%). Most immune AEs were grade 1/2.

Author:
Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007.

Primary Source
European Society for Medical Oncology
Source Reference: Strauss J, et al “Long-term follow-up of patients with human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1” ESMO 2021; Abstract 957O.

Disclosures
The research was supported by the National Cancer Institute (NCI), Merck Healthcare KGaA, and EMD Serono.
Gulley reported a cooperative research and development agreement between EMD Serono/Merck Healthcare KGaA and NCI.
Kobold disclosed relationships with Novartis, TCR2, Celyad, Arcus Biosciences, and Bristol Myers Squibb.

2021-09-21T07:23:47-07:00September, 2021|Oral Cancer News|

Study: HPV vaccination will reduce throat and mouth cancers, but overall impact will take 25-plus years to see

Source: www.newswise.com
Author: Johns Hopkins Bloomberg School of Public Health

Vaccinations against human papillomavirus (HPV), a major cause of throat and back of mouth cancers, are expected to yield significant reductions in the rates of these cancers in the U.S., but will not do so until after 2045, according to a new modeling study from researchers at the Johns Hopkins Bloomberg School of Public Health. HPV is the most common sexually transmitted infectious virus worldwide. HPV infections are often silent, and while most infections clear, some are chronic and can trigger cancers including mouth and throat (oropharyngeal), and cervical cancer because they disrupt DNA and inhibit tumor-suppressor proteins in the cells they infect. Although there is no cure for existing HPV infections, new infections are preventable with vaccines, the first of which entered use in the U.S. in 2006.

In the new study, the Bloomberg School researchers analyzed national databases on oropharyngeal cancer cases and HPV vaccinations, and projected the impact of HPV vaccination on the rates of these cancers in different age groups. They estimated that the oropharyngeal cancer rate would nearly halve between 2018 and 2045 among people ages 36–45. However, they also projected that the rate in the overall population would stay about the same from 2018-2045, due to still-rising rates of these cancers in older people, where most of these cancers occur.

The study appears online September 2 in JAMA Oncology.

“We estimate that most of the oropharyngeal cancers from 2018 to 2045 will occur among people who are 55 years and older and have not been vaccinated,” says study lead author Yuehan Zhang, a PhD candidate in the research group of Gypsyamber D’Souza, PhD, professor in the Department of Epidemiology at the Bloomberg School.

“HPV vaccination is going to work to prevent oropharyngeal cancers, but it will take time to see that impact, because these cancers mostly occur in middle age,” D’Souza says.

Oropharyngeal cancer is the most common HPV-related cancer, and according to the Oral Cancer Foundation there are more than 50,000 new cases of it in the U.S. each year. Alcohol and tobacco use also are risk factors, but are seen as increasingly less important than HPV.

Vaccination is a powerful medical weapon against this family of viruses, but has one major shortcoming: It can prevent, but not treat. In other words, it does not work against established HPV infections or against cells that have been transformed by HPV and are on their way to forming tumors. Thus it is recommended chiefly for the young who are not yet exposed to sexually transmitted HPV. (Most people who were already adults when HPV vaccination became available have never been vaccinated, and thus remain at risk for these cancers.)

For the study, the researchers estimated current and future HPV vaccination rates using data from surveys conducted by the U.S. Centers for Disease Control and Prevention, and projected oropharyngeal cancer rates based on past and current incidence data from the National Cancer Institute.

They estimated that the rates of vaccination by 2045, for different age groups—given the emphasis on vaccinating the young—will amount to about 72 percent of people ages 36–45, 37 percent of those ages 46–55, 9 percent of those ages 56–69, and 0 percent of people ages 70–83 being vaccinated.

These projections show continuing high oropharyngeal cancer rates in older, mostly unvaccinated groups, and almost no change in the overall U.S. rate of these cancers—14.3 per 100,000 assuming no vaccination; and 13.8 per 100,000, with vaccination, in 2045.

However, they foresaw the rates of new oropharyngeal cancers would fall substantially in the relatively well vaccinated 36–45 and 46–55 age groups during the 2018–2045 period: from 1.4 to 0.8 per 100,000; and from 8.7 to 7.2 per 100,000, respectively.

The results suggest, though, that by 2045 HPV vaccination will have begun to make a significant impact. “Our projections suggest that by around 2033, nearly 100 cases of oropharyngeal cancer will be prevented each year, but by 2045 that figure will have increased by about ten times,” Zhang says.

Notes:
“Projected Impact of HPV Vaccination on Oropharynx Cancer Incidence in the United States: 2020-2045” was co-authored by Yuehan Zhang, Carole Fakhry, and Gypsyamber D’Souza.

Funding was provided by the National Institute of Dental and Craniofacial Research (R35DE026631).

2021-09-03T12:26:37-07:00September, 2021|Oral Cancer News|

Immunotherapy for HPV+ head and neck cancer: Awakening the force within

Source: medicalxpress.com
Author: Emory University

A new study from scientists at Emory Vaccine Center and Winship Cancer Institute of Emory University reports that the immune cells that are the major targets of immune checkpoint inhibitors are present in tumors from head and neck cancer patients.

The study focuses on head and neck tumors that are positive for human papillomavirus (HPV), which is becoming one of most common types of head and neck cancers treated in the Western world. The results are scheduled for publication in Nature.

It suggests checkpoint inhibitors, which have transformed the treatment of several types of cancer, could be uniquely effective against this type of head and neck cancer. The results also indicate that the experimental approach of therapeutic vaccination for HPV+ cancer could be broadened to include more elements of the virus, to potentially trigger a broader and stronger immune response.

Researchers from Rafi Ahmed’s lab at Emory Vaccine Center collaborated with the co-directors of the Winship Head and Neck Cancers working group, oncologists Nabil Saba, MD and Mihir Patel, MD, to obtain samples from patients with head and neck tumors early in the course of treatment.

“About five years ago, we began to have an influx of patients that sought out our center for surgical treatment,” Patel says. “We often heard some variation of a similar story: I was sick with cold-like symptoms and once that resolved this I noticed swelling in a lymph node on the side of my neck. Stories like this made us think about how the immune system might play a unique role, different than typical smoking-related head and neck cancers.”

The team wanted to learn more about the different kinds of CD8 or “killer” T cells present within the cancers; CD8 T cells are specialized immune cells capable of detecting and killing virus-infected or tumor cells, if they are not constrained by regulatory signals. The inhibitory receptor PD-1 is highly expressed on exhausted CD8 T cells in chronic viral infections and cancer, and stem-like PD-1+ CD8 T cells are crucial for maintaining tumor-specific CD8 T cell responses. The majority of currently available checkpoint inhibitors, such as pembrolizumab and nivolumab, block the PD-1 signaling pathway.

“Our results show that a subset of HPV-specific CD8 T cells in the tumor exhibits a striking resemblance to the stem-like CD8 T cells our lab has previously defined in mouse models as proliferating in response to PD-1 blockade,” says Andreas Wieland, Ph.D., co-lead author of the paper and an instructor in Ahmed’s lab.

“It is reasonable to assume that these cells would similarly provide a proliferative burst in response to PD-1 blockade in these patients. However, this remains to be formally tested.”

HPV-positive tumors do have a relatively good response to conventional forms of treatment such as radiation and chemotherapy, Wieland adds. The group of patients studied at Winship was treatment-naïve when tumor samples were obtained; how radiation and chemotherapy affect the number and phenotype of T cells in the tumor needs additional investigation.

“These findings greatly enhance our understanding of CD8 T cell responses in the tumor micro-environment in HPV-related oropharynx cancers, and likely other virally mediated tumors,” Saba says. “It confirms the existence of the different lineages necessary for an effective T cell specific anti-tumor response. Taking advantage of the local immune-response by avoiding its possible early elimination by traditional therapeutic modalities may pave the way to an improved clinical outcome for patients. It may have implications for how best to incorporate immunotherapy in the treatment of other virally mediated tumors.”

“We now have an inclination that incorporating immune therapy with PD-1 blockade prior to surgery or radiation may benefit patients,” Patel says. “We are actively in the process of developing ‘window of opportunity’ studies to understand this.

Looking at both primary tumors and metastatic lymph nodes, the researchers were able to detect both tumor-specific stem-like CD8 T cells, which can proliferate in response to HPV peptides, and more terminally differentiated cells that do not proliferate. In contrast to significant numbers of tumor-specific CD8 T cells in the tumors, tumor-specific cells appeared at a very low abundance in patients’ blood, suggesting that they preferentially reside in tumors. The team also found that the different CD8 T cell subsets in the tumor microenvironment differ in their localization, with stem-like cells residing in distinct niches within the stroma and away from the tumor cells themselves.

Concentrating on HPV-positive tumors in this study facilitated the study of tumor-specific T cells with defined specificities across several patients as the virus is providing a defined set of tumor-associated antigens, whereas in other types of cancer the antigens caused by mutations will vary from individual to individual.

Note:
Co-first authors of the paper are Haydn Kissick, Ph.D., assistant professor of urology and microbiology and immunology, and Christiane Eberhardt, MD, a former postdoctoral fellow in Ahmed’s lab who is now at the University of Geneva. Patel is also associate professor of otolaryngology at Emory University School of Medicine. Saba is professor and Vice Chair in the Department of Hematology and Medical Oncology.

2021-09-02T20:07:01-07:00September, 2021|Oral Cancer News|

Calls grow for treatment deintensification of HPV-positive OPC

Source: ww.pharmacytimes.com
Author: Bryan Fitzgerald, PharmD, BCOP
Health-System Edition, July 2021, Volume 10, Issue 4

Oropharyngeal cancer (OPC) is a type of head and neck cancer that affects structures in the back of the throat, including the base of the tongue, the posterior pharynx, the soft palate, and the tonsils.1 In the United States, rates of OPC are increasing each year, with an estimated 54,010 new cases in 2021.2 Well-established risk factors include alcohol abuse; exposure to tobacco, including chewing tobacco, cigarettes, and pipes; and infection with human papillomavirus (HPV).

With an estimated 43 million infections in 2018, HPV is the most common sexually transmitted infection in the United States.3 HPV infection is causally linked with cancers of the anogenital region, including anal, cervical, penile, vaginal, and vulvar cancers. When HPV is spread orally, infections can also lead to the development of OPC. In the United States, more than 70% of OPC cases are caused by HPV.4

HPV is a group of more than 100 viruses, including certain high-risk strains associated with the development of cancer. The HPV-16 strain is responsible for causing the majority of HPV-positive (HPV+) OPC cases, with HPV-18, HPV-33, and HPV-35 also contributing, albeit significantly less than HPV-16.1 In these high-risk HPV strains, the viral genome encodes several oncogenic proteins that inhibit tumor suppressor proteins, leading to chromosomal instability and malignancy in infected cells.

HPV+ OPC is considered a genetically distinct form of OPC. Compared with HPV-negative (HPC–) OPC cases, HPV+ OPC is associated with a favorable prognosis with improved rates of response prognosis with improved rates of response to treatment and overall survival. Because of the difference in tumor biology, the National Comprehensive Cancer Network (NCCN) has adopted different staging criteria for HPV+ and HPV– disease and recommends that HPV status be used to stratify patients with OPC.1

The treatment landscape for localized OPC typically involves a multidisciplinary approach consisting of chemotherapy, radiation, and/or surgery. For fit patients with locally advanced OPC who are able to tolerate intensive therapy, concurrent radiation with systemic high-dose cisplatin chemotherapy is the preferred treatment regimen.1 Unfortunately, treatment of OPC is associated with a high risk of treatment-related morbidity, which may leave patients cured of their malignancy but with lifelong complications, such as dysgeusia, dysphagia, and xerostomia, but also systemic complications from cisplatin chemotherapy, including hearing loss and neurotoxicity.

Because patients with HPV+ OPC are generally younger with more favorable prognoses, clinicians have hypothesized that less intensive treatment could result in fewer long-term complications from treatment but with continued favorable cancer-related outcomes.5 This concept, called deintensification, has become popular in recent years. Several strategies for treatment deintensification have been proposed, including reducing the dose of radiation; substituting cisplatin for an alternative agent with less toxicity, such as cetuximab; and surgical resection. Several phase 3 comparison trials have been conducted, and other trials are ongoing.

Aptly named De-ESCALaTE (NCT01874171), this phase 3 trial randomized patients with 334 HPV+ OPC to receive radiation plus cetuximab or cisplatin.6

Unfortunately, the trial results did not favor substitution of cisplatin with cetuximab. At 2 years, the incidence of severe toxicities did not significantly differ between cetuximab and cisplatin (P = .98), nor did rates of overall toxicities (P = .49). Significant differences in 2-year overall survival rates and recurrence rates were seen. However, these results favored cisplatin (HR, 5.0; P = .001 for overall survival; HR, 3.4; P = .0007 for recurrence).6

RTOG-1016 (NCT01302834) was a second phase 3 trial published comparing cetuximab with cisplatin in HPV+ OPC patients.7 This trial analyzed 805 patients who were randomized to receive radiation plus cetuximab or cisplatin. Similar to the De-ESCALaTE trial, the RTOG-1016 trial results favored cisplatin over cetuximab, with 5-year overall survival rates of 84.6% versus 77.9%.8

Because of the De-ESCALaTE and RTOG-1016 results, experts advise against the substitution of cisplatin for chemoradiation regimens for patients with localized HPV+ OPC, and cisplatin plus radiation continues to be the preferred systemic treatment option per the NCCN guidelines.1,5 Because cisplatin continues to be standard of care for the treatment of localized OPC, the role of deintensification for patients with HPV+ OPC may lie in adjustments to surgical strategies or radiation therapy. Treatment deintensification should be pursued only through clinical trials, and experts encourage clinicians to conduct and analyze phase 2 trials before moving on to phase 3 studies.1,5

CONCLUSION
The treatment landscape of cancer is ever-changing. Specifically in localized HPV+ OPC, the difference in tumor biology presents a unique clinical area where reducing the intensity of treatment may be warranted, particularly with long- and short-term toxicities associated with cisplatin. Interestingly, phase 3 data have shown evidence of harm in removing cisplatin from chemoradiation regimens for HPV+ OPC; therefore, cisplatin-based chemoradiation remains the standard of care for these patients. Future trials may support treatment deintensification in ways other than removing cisplatin.

REFERENCES
1. NCCN. Clinical Practice Guidelines in Oncology. Head and neck cancers, version 3.2021. Accessed June 16, 2021. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf

2. Cancer stat facts: oral cavity and pharynx cancer. National Cancer Institute. Accessed June 16, 2021. https://seer.cancer.gov/statfacts/html/oralcav.html

3. Genital HPV infection – fact sheet. CDC. Updated January 19, 2021. Accessed June 17, 2021. https://www.cdc.gov/std/hpv/stdfact-hpv.htm
4. HPV and oropharyngeal cancer. CDC. Updated September 3, 2020. Accessed June 17, 2021. https://www.cdc.gov/cancer/hpv/basic_info/hpv_oropharyngeal.htm

5. Mehanna H, Rischin D, Wong SJ, et al. De-escalation after DE-ESCALATE and RTOG 1016: a head and neck cancer intergroup framework for future de-escalation studies. J Clin Oncol. 2020;38(22):2552-2557. doi:10.1200/JCO.20.00056

6. Mehanna H, Robinson M, Hartley A, et al; De-ESCALaTE HPV Trial Group. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019;393(10166):51-60. doi:10.1016/S0140-6736(18)32752-1

7. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X

8. Gardasil 9. Prescribing information. Pfizer; 2017. Accessed June 23, 2021. https://www.fda.gov/fi les/vaccines,%20blood%20&%20biologics/published/Package-Insert—Gardasil.pdf

Five reasons boys and young men need the HPV vaccine, too

Source: www.mskcc.org
Author: Memorial Sloan Kettering Cancer Center, News and Information

Rich Delgrosso found the lump while shaving. It was on the left side of his neck and it seemed to grow bigger by the day. He made an appointment with his ear, nose, and throat doctor.

“He said the odds were 50/50 that it was an infection,” recalls the 56-year-old father of two from Pleasantville, New York. “I asked, ‘What’s the other 50?’”

It was a possibility no one wanted to hear: Cancer. Rich underwent a biopsy and learned he had squamous cell carcinoma that had originated on the base of his tongue. His cancer, the doctor told him, was caused by the human papillomavirus (HPV).

Rich was shocked. “I knew HPV could cause cancer,” he says, “but I thought it was only cervical cancer in women.”

It’s true that HPV, a sexually transmitted virus, does cause the majority of cervical cancer cases in women. But it can also cause a variety of cancers in men, too, some of which are on the rise.

HPV led to a five-fold increase of head and neck cancers in young men from 2001 to 2017, according to data released at the 2021 American Society for Clinical Oncology annual meeting.

Memorial Sloan Kettering’s David Pfister, a medical oncologist who cares for people with head and neck cancer, says these cancer cases are just now emerging in people infected with the virus many years ago.

“Once the association between HPV infection and throat cancers was established, we better understood the significant increase in the rate of these cancers,” he says. “There is a delay between infection and the development of cancer, so there is a big reservoir of people already potentially at risk.”

But there is a way to prevent more than 90% of cancers caused by this virus: Get the HPV vaccine. It protects against head and neck cancers as well as anal cancer in both men and women. In men, it also protects against penile cancer, and in women, cervical cancer, vaginal cancer, and vulvar cancer. The vaccine is recommended for all children and can be given as early as age 9. It’s also approved for adults up to age 45.

Amidst growing concern about falling vaccination rates, MSK joined other National Cancer Institute-designated cancer centers in a May 2021 statement urging physicians, parents, and young adults to begin or keep up with HPV vaccinations, after they were interrupted by COVID-19. Early in the pandemic, HPV vaccination rates among adolescents fell by 75%. Since March 2020, an estimated one million doses of HPV vaccine have been missed by adolescents who have public insurance. That’s a decline of 21% from pre-pandemic levels.

Moreover, parents of boys are increasingly hesitant to have their sons vaccinated, according to a study in the journal Pediatrics.

MSK’s HPV Center is working to increase vaccination rates for everyone. Here are five reasons why it’s especially important for males.

1. Men get cancers caused by HPV in large numbers, too.
From 2013 to 2017, there were approximately 25,000 cases of HPV-associated cancers in women and 19,000 in men, according to the Centers for Disease Control and Prevention. More than four out of every ten cases of cancer caused by HPV are in men.

“HPV should be of concern to all since men and women are affected virtually the same by this virus,” says Abraham Aragones, an MSK physician who also studies public health.

2. There are now more cases of head and neck cancers than cervical cancers in America; HPV causes 70% of them, according to the CDC.
“My doctor told me that tumors of the neck and throat were getting more common in men,” Rich recalls.

Head and neck cancers are four times as common in men as they are in women.

3. There is no test for HPV cancers in males.
A Pap test detects early-stage cervical cancer in women. No such test exists for penile, anal, or head and neck cancers.

“Developing something like a Pap test for throat cancer would be a game-changer,” says Dr. Pfister. “When you compare the throat to the cervix, the anatomy of sites like the tonsils and the base of the tongue have hard-to-reach crevices the virus can hide in. Until an effective and reliable screening test is developed, patients should stay up to date on their HPV vaccines, know how the disease is acquired, and take any suspicious symptoms like a lump in the neck or blood in the phlegm to their doctor or dentist.”

4. The odds of getting HPV-related cancer increases with age.
“Today’s men are living longer than ever before, and that gives cancer more time to develop,” Dr. Aragones says. “Vaccination protects men from HPV-related cancers in the short and long term.”

5. The vaccine is just as safe for boys as it is girls.
The HPV vaccine went through years of rigorous safety testing before it was approved in 2006 to prevent cervical cancer in women and in 2009 to prevent HPV-related cancers in males. Since then, more than 100 million doses of the HPV vaccine have been given in the United States. Like any vaccine, there can be side effects, but they are minor, like arm soreness and fatigue. “The benefits of vaccinating against HPV far outweigh any potential risk of side effects,” says Dr. Aragones.

Rich made sure his teenage son got the HPV vaccine and says his younger daughter will follow suit.

“I didn’t want them to go through what I went through,” he says. After radiation and chemotherapy three years ago, Rich thankfully has shown no evidence of disease.

HPV-related cancers are usually able to be treated successfully. But preventing a cancer is far better than treating it, which makes the HPV vaccine a valuable weapon against cancer.

Go to Top