Checkpoint inhibitors whiff in head and neck cancer trials

Source: www.medpagetoday.com
Author: Charles Bankhead

Three different checkpoint inhibitors missed the primary endpoints in separate randomized trials of head and neck cancer.

In one trial, adding avelumab (Bavencio) to standard treatment did not significantly improve progression-free survival (PFS) in cisplatin-eligible or ineligible patients with locally advanced head and neck squamous cell carcinoma (HNSCC). In another trial, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) did not improve overall survival (OS) as first-line treatment for recurrent/metastatic HNSCC.

Both trials were reported during the European Society for Medical Oncology (ESMO) virtual meeting. Although subgroup analyses suggested benefits for certain patients, neither study should influence clinical practice at this point, said ESMO invited discussant Amanda Psyrri, MD, of the University of Athens in Greece.

In the avelumab study, known as GORTEC-REACH, results in cisplatin-eligible patients were consistent with those of the previously reported JAVELIN trial with avelumab, said Psyrri. A signal of benefit was evident in cisplatin-ineligible patients but did not achieve statistical significance.

With regard to the CheckMate 651 trial of nivolumab and ipilimumab, Psyrri said, “Combined PD-1 and CTLA-4 inhibition does not appear to be an effective strategy in recurrent/metastatic HNSCC. Future research efforts may identify predictive biomarkers for response to anti-PD-1 and anti-CTLA-4 combinations in HNSCC.”

Additionally, a smaller trial of pembrolizumab (Keytruda) showed no significant improvement in OS versus chemotherapy for platinum-treated relapsed/metastatic nasopharyngeal carcinoma.

GORTEC-REACH
This trial evolved from evidence of potential synergy with PD-1/L1 inhibition, cetuximab (Erbitux), and radiotherapy, said Jean Bourhis, MD, of University Hospital Center Vaudois in Lausanne, Switzerland. The trial included a total of 707 patients with stage III/IV HNSCC, divided into cohorts by eligibility to receive cisplatin. The cisplatin-ineligible cohort comprised 277 patients, and the cisplatin-eligible group included 430 patients.

Cisplatin-ineligible patients all received radiotherapy and cetuximab and were randomized to avelumab or no additional treatment. Cisplatin-eligible patients received cisplatin-based chemoradiation with or without avelumab. The primary endpoint for both cohorts was PFS.

After a median follow-up of 21.3 months in the cisplatin-ineligible cohort, the 2-year PFS rate favored the avelumab arm (44% vs 31%), but the difference did not achieve statistical significance (HR 0.84, 95% CI 0.61-1.15, P=0.14). The difference in the secondary endpoint of metastatic progression did reach statistical significance (14.3% with cetuximab vs 5.4% with avelumab-cetuximab, HR 0.31, P=0.007).

In the cisplatin-eligible group, a planned interim analysis showed a 1-year PFS rate of 73% without avelumab and 64% with the PD-L1 inhibitor, which translated into a hazard ratio of 1.27, crossing the boundary for futility and favoring standard of care, said Bourhis. The key secondary endpoint of OS showed a numerical advantage for the avelumab arm at 2 years (58% vs 54%), but the difference did not achieve statistical significance (P=0.69).

CheckMate 651
This trial followed the progression of treatment standards for relapsed/metastatic HNSCC from chemotherapy, to cetuximab plus chemotherapy, to a migration toward immunotherapy with recent approvals for pembrolizumab with or without chemotherapy, said Athanassios Argiris, MD, of Hygeia Hospital in Marousi, Greece. The combination of nivolumab and ipilimumab has produced durable responses and a survival benefit in several types of advanced solid tumors.

The trial involved 947 patients with untreated platinum-eligible recurrent/metastatic HNSCC. They were randomized to nivolumab-ipilimumab or to the combination of cetuximab, platinum, and 5-fluorouracil. The primary endpoints were OS in all patients and in the patients with a combined positive score (CPS) ≥20 for PD-L1 expression, who accounted for about 38% of the total population.

The primary analysis in all patients showed a median OS of 13.9 months with nivolumab-ipilimumab versus 13.5 months with standard treatment, a nonsignificant difference (P=0.4951). In the CPS ≥20 subgroup, median OS was 17.6 months with nivolumab-ipilimumab and 14.6 months with standard care, representing a 22% reduction in the hazard ratio but did not meet prespecified criteria for statistical significance. The survival benefit in the CPS ≥20 subgroup increased over time, from 63% versus 58% at 1 year to 41% versus 33% at 2 years.

Argiris noted that OS in the control group exceeded expectations based on historical data with standard therapy. Nivolumab-ipilimumab delayed symptom deterioration, was associated with improved overall health status, and had a favorable safety profile versus the control group.

KEYNOTE-122
This pembrolizumab study followed favorable results from a phase I trial of patients with heavily treated recurrent/metastatic PD-L1-positive nasopharyngeal carcinoma (NPC). Moreover, NPC has a strong association with Epstein-Barr virus (EBV) infection, which in turn is associated with PD-L1 expression, said Anthony Chan, MD, of the Chinese University of Hong Kong.

The phase III KEYNOTE-122 trial included 233 patients with recurrent/metastatic EBV-positive NPC previously treated with platinum-based chemotherapy. They were randomized to pembrolizumab or investigator’s choice of chemotherapy, which continued until disease progression or intolerable toxicity. The primary endpoint was OS.

About 85% of the patients were Asian, about 40% had CPS ≥10 PD-L1 expression (47% in the pembrolizumab arm), and about 60% of the patients had recurrent metastatic disease.

The primary analysis showed a median OS of 17.2 months with pembrolizumab and 15.3 months with chemotherapy, a nonsignificant difference (HR 0.90, 95% CI 0.67-1.19). The 2-year OS rate favored the pembrolizumab arm (40.2% vs 32.2%). Subgroup analysis showed no consistent pattern of benefit with pembrolizumab, including PD-L1 status. A majority of patients in both arms received one or more subsequent therapies, said Chan.

PFS, objective response rate, disease control rate, and duration of response all did not differ significantly between treatment groups, but trended in favor of the chemotherapy arm.

EBV-positive NPC is a chemosensitive disease; as a result, the chemotherapy control arm was expected to be difficult to top, said ESMO invited discussant Lisa Licitra, MD, of the Istituto Nazionale dei Tumori and University of Milan.

“Immuno-oncology is not lost; anti-PD-1 therapy remains the standard in first line,” she said.

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

2021-09-24T06:54:20-07:00September, 2021|Oral Cancer News|

Chemotherapy and radiation therapy issues: What audiologists need to know

Source: journals.lww.com
Author: A. Croutch, Carl AuD

With hearing loss, tinnitus, and imbalance as among the numerous side-effects of cancer treatment,1 audiologists play a critical role in monitoring patients receiving chemotherapy and radiation therapy. Sensorineural hearing loss (SNHL) attributed to chemotherapy and radiation therapy is usually permanent, making audiometric monitoring essential to detect its early occurrence.2

Cisplatin, carboplatin & radiation therapy
Chemotherapy is used to treat cancer, control the growth and spread of cancer cells, and ease cancer symptoms. Cisplatin and carboplatin are two common antineoplastic agents used to treat testicular, ovarian, breast, esophageal, lung, and head and neck cancers among others. Besides hearing loss, these can cause other side effects including kidney, gastrointestinal disorders, allergic reactions, decreased immunity to infections, and hemorrhaging. Cisplatin was first found to have cytotoxic properties in the 1960s, and in 1978 was the first platinum compound approved by the FDA for cancer treatment.3 On the other hand, carboplatin is less potent than cisplatin and does have fewer side effects, especially on kidney problems.3

Both drugs work by interfering with DNA repair mechanisms causing DNA damage and inducing apoptosis in cancer cells. Cancerous cells cannot limit cell division as do normal cells. Normal cells cease dividing when they encounter similar cells whereas cancerous cells do not. The effectiveness of chemotherapy is determined by its ability to damage the RNA or DNA that gives the cell instructions to copy itself. The cells will die if they are unable to divide. The more quickly they are dividing, the more effective is the chemotherapy.4

The incidence of hearing loss in post-chemotherapy patients is highly variable, ranging from 17% to 80% depending on the age, baseline hearing levels, and cisplatin dosage.5 Generally, those receiving a higher dose of cisplatin showed more hearing loss than those receiving a smaller dose.6,7

In addition to chemotherapy, a cancer patient may also be treated with radiation therapy (RT), which is the use of high-energy X-rays or other types of energy such as protons to kill cancer cells. RT also works by destroying the genetic material that regulates cell growth and division. The objective of RT is to kill fewer normal cells since it can damage both cancerous and normal cells. The incidence of SNHL ranges from 0-43% depending on the radiation dosage to the cochlea as well as age and baseline hearing levels.5 Radiation dosage reaching the cochlea may be higher when treating cancer of the nasopharynx, parotid salivary gland, and paranasal sinuses compared to other sites.7

RT can cause both SNHL and conductive hearing loss (CHL). SNHL may occur if the RT is directed near the cochlea, and CHL if it is near the Eustachian tube. Factors that may influence whether a hearing loss occurs include the strength and direction of the beam, location, size of the tumor, patient age, and pre-treatment hearing levels. The frequency of otitis media with effusion in head and neck cancer patients undergoing RT was found to be 39.3% with retracted tympanic membrane and 7.1% with air-fluid levels seen.8 Treatment of head and neck squamous cell carcinoma (HNSCC) patients using radiation can result in mixed (SNHL and CHL) hearing loss, which can be more severe in those with tumors near the ear as well as those treated with cisplatin.7

Stages & grades of cancer
Cancer has four stages: Stage 0 is when the cancer has not spread from its original location (in situ), Stage 1 is when a small cancer has not spread, Stage 2 is when it has grown but not spread, Stage 3 is when it may have spread to near-by tissues possibly the lymph nodes, and Stage 4 is when it has metastasized and spread to at least another body organ. Cancer is also divided into three grades, with the lower grades indicating a slower-growing malignancy and a high grade, a faster-growing one.9

Nasopharyngeal cancer (NPC) is frequently seen in head and neck clinics and offices. Tumors originating in the nasopharynx may be benign or malignant. The majority of nasopharyngeal cancers are nasopharyngeal carcinoma. A carcinoma is a cancer that originates in the epithelial cells, which line the internal and external surfaces of the body. A patient about to undergo chemotherapy and radiation therapy should be seen for a baseline audiogram prior to the initiation of any treatment. An in-depth history of any occupational or recreational noise exposure is essential.

Audiometric test battery
Both chemotherapy and noise exposure can result in high-frequency SNHL. Distinguishing between the two can be difficult, which is why obtaining a baseline audiogram and careful case history is essential. One tip-off may be the high-frequency notch seen between 3000 and 6000 Hz often present in cases of noise trauma.

Speech-in-noise testing should be done since understanding speech in background noise is a common complaint from most adults. Using the Quick Speech-in-Noise (Q-Sin) test may aid in the treatment of these patients.1 Extended high-frequency pure-tone audiometry (EHF-PT) and distortion-product otoacoustic emissions (DP-OAEs) are useful tests in monitoring these patients. Ototoxic effects frequently occur initially at frequencies above 8 kHz. EHF-PT are tested from 8-20 kHz and can often detect hearing loss in these ranges before it affects the speech frequencies. This will enable the oncologist to monitor the treatment and if possible, conserve the patient’s hearing. DP-OAEs are measured from 0.5-8 kHz. They can determine if the outer hair cells are intact since they are usually damaged prior to inner hair cells (IHC) and can result in a more severe hearing loss compared with outer hair cell damage. This may provide useful information to the oncologist. It is also an objective test and can be used regardless of the patient’s age or state of health.2

Criteria for change
In addition to baseline testing, follow-up testing should occur after each treatment, when the course of treatment is completed, and on an annual basis or sooner if indicated. A significant change is considered per the ASHA 1994 guidelines13:

>= 20 dB change at one frequency
>= 10 dB change at two consecutive frequencies
No response at three consecutive frequencies where responses were previously obtained

Ototoxicity can be grouped by using at least 13 different classification systems based on changes from a baseline audiogram to those that focus on the functional impact of the hearing loss. These scales do not consider high-frequency audiometry.13

Despite these grading scales, most clinicians do not use them on a routine basis. How ototoxicity is defined is a significant part of the inconsistencies between pre- and post-clinical data across patient groups.13

Two commonly used ototoxic grading systems in use are the Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) and the American Speech-Language-Hearing Association (ASHA) system. Each of these systems has certain shortcomings.13

To devise a more comprehensive system, Theunissen et al., purposed the TUNE grading system, which details the shortcomings of both the CTCAEv4 and the ASHA systems14 and propose seven different grade levels:

  • Grade 0: No hearing loss
  • Grade 1a: Threshold shift >= 10 dB at 8, 10, and 12.5 kHz OR subjective complaints in the absence of a threshold shift
  • Grade 1b: Threshold shift >= 10 dB at 1, 2, and 4 kHz
  • Grade 2a: Threshold shift >= 20 dB at 8, 10, and 12.5 kHz
  • Grade 2b: Threshold shift >= 20 dB at 1, 2, and 4 kHz
  • Grade 3: Hearing level >= 35 dB at 1, 2, and 4 kHz
  • Grade 4: Hearing level >= 70 dB at 1, 2, and 4 kHz

They feel this system can better assess the effects of hearing loss in daily life and can distinguish between mild, moderate, and severe degrees of ototoxicity compared to the current systems in use.14

Significant changes in DP-OAE findings were a reduction in the signal-to-noise ratio at f2 frequencies below 1 kHz of > 14 dB and a reduction of 7 dB of f2 frequencies above 1 kHz. These criteria were used by Yu, et.al.,2 but no standard criteria are available for defining changes in the DP-OAEs.15

The potential for hearing loss from chemotherapy and radiation therapy is dependent upon the patient’s baseline hearing levels and the strength and frequency of the treatments. Dosage is often determined by the patient’s body surface area indicated by m2. It is calculated by taking the square root of the product of the weight in kilograms times the height in centimeters divided by 3600. The average body surface area for adult men is 1.9 m2 and for women is 1.6 m2.16 Typical doses vary from 25-100 mg/m2. The frequency of treatments is also patient-specific. Chemotherapy is given in cycles—-typically one week of chemotherapy followed by three weeks of rest.

Treatment Options
SNHL may be treated with hearing aids, and CHL by medicine, myringotomy, or PE tube placement. If any hearing loss is found, treatment options should be discussed with the patient. In cases of SNHL that will benefit from amplification, the patient may wish to postpone it until after the cancer treatment has been completed. Some may wish to obtain hearing aids right away to better participate and understand their treatment options. In patients with CHL, a referral to HNS is usually indicated. At Kaiser Permanente, for example, patients with a unilateral CHL without an NPC diagnosis are referred to HNS as that may be an indication of NPC.

Overall, audiologists need to monitor hearing loss in cancer patients undergoing chemotherapy and radiation therapy and provide treatment and counseling when hearing loss has become inevitable.

References:
1. Baguley D, Prayuenyong P. Looking beyond the audiogram in ototoxicity associated with platinum-based chemotherapy. Cancer Chemother Pharmacol. 2020; 82(2): 245-250.

2. Yu K, Choi, C. et.al. Comparison of the effectiveness of monitoring cisplatin-induced ototoxicity with extended high-frequency pure-tone audiometry or distortion-product otoacoustic emission. Korean J of Audiology. 2014;18(2):58-68.

Source:
The Hearing Journal: September 2021 – Volume 74 – Issue 9 – p 44-45

2021-09-09T06:48:49-07:00September, 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

‘On the rise:’ Immunotherapy options for head and neck cancer

Source: www.curetoday.com
Author: Kristie L. Kahl

On behalf of the Head and Neck Cancer Alliance, Dr. Michael Moore spoke with CURE® about emerging therapies that potentially offer exciting new options for the future.

Although rates of head and neck cancer have risen, in part because of the human papillomavirus (HPV), emerging therapies such as targeted agents and immunotherapies are paving the way for future treatment of the disease, according to Dr. Michael Moore.

“I would say (immunotherapy) is probably one of the more exciting parts of what we’ve learned about head and neck cancer in recent years,” he told CURE® as a part of its “Speaking Out” video series.

On behalf of the Head and Neck Cancer Alliance, CURE® spoke with Moore, associate professor of otolaryngology-head and neck surgery and chief of head and neck surgery at Indiana University School of Medicine in Indianapolis, about targeted therapies, immunotherapy and how clinical trials are leading the way for future treatments.

How have genomics and targeted therapies played a role in head and neck cancer treatment?

Well, I would say it’s an emerging role. And it’s not used as commonly in head-neck cancer as it is in some other areas. So molecular testing or targeted therapies essentially are looking at a very specific part of the tumor to see if we can develop a specific drug that will target just that; (the goal is to) weaken the cancer’s defense — that is one way to say it — and try to very specifically treat that cancer in a way that will give us the best chance of getting rid of it and potentially try to limit the side effects related to the treatments. This has become a little bit more common now that the ability to analyze these tumors has become more widely available across the country. But still, the majority of these types of treatment approaches will be in the context of a clinical trial.

Do we have any currently approved targeted therapies for head and neck cancer?

That’s a great question. I think these are kind of different and are emerging all the time. There are ones that are focused on very specific mutations, such as what’s called the BRAF mutation, which is one that can be present in melanoma or certain aggressive cancers, such as thyroid cancer. And other ones will target things like tyrosine kinase inhibitors that have a more focused route to try to combat these tumors. And then there are ones that will be discussed a little later, such as immuno-oncology drugs that focus on the program cell death ligand and the receptor to try to turn the body’s immune system back on. Another example is what’s called Erbitux (cetuximab), which is focusing on a specific receptor on cancer cells, really trying to exploit this particular difference in cancer cells compared with normal tissue to try to give the best chance of getting rid of the tumor, but minimizing the side effects of the treatment.
What role has immunotherapy had in head and neck cancer treatment?

Cancer has a way of almost turning off the local immune system. It blocks many of the local immune responses to it. Normally, the body would say, “Yeah, that’s not part of our normal tissue, we want to get rid of it.” And some cancers have a way of blocking that. These immunotherapies have a way of almost inhibiting that blockage, if you will, or turning the immune system back on and allowing your own body’s immune system to fight these tumors. These can be incredibly effective. The challenge is if they’re only effective in a small minority of cancers. And so, when they do work, they can work extremely well and can give really good and long-lasting results. But in a high percentage of patients, the responses are much more modest or (patients) may not even respond at all.

Can you discuss the currently available immunotherapies for head and neck cancer?

There are two. Opdivo (nivolumab) is one that can be used in patients who have not responded or progressed despite standard therapy, including recent treatment with chemotherapy, including cisplatin. And then Keytruda (pembrolizumab) is another similar amino therapy that can be used and has actually achieved approval for use in the primary setting. When cancer comes back in an area that can’t be treated with either definitive surgery or definitive radiation therapy, you can use that as a next avenue for treatment. These are the two (Food and Drug Administration)-approved drugs that are out there. They also have ongoing studies where they’re being combined with other standard-of- care, primary treatments for head and neck cancer. I think in the next five to 10 years, they’ll likely be integrated much more on the front end of cancer therapy, rather than just offering them to those who don’t have other treatment options.

How do clinical trials help to advance these therapies, and why should patients consider joining one?

These are really what allows us to make our cancer treatment better. We constantly are. It’s not just going out and experimenting on people but, rather, we’re comparing these treatments to see how we can improve on the current standard approach to therapy. If you were to look back 50 to 60 years ago, all we had were big, morbid surgeries that people were put through and possibly adding radiation therapy. And then we added cisplatin, which is a drug that can be effective in enhancing the effects of radiation therapy. Now, as we add these other treatments, such as immunotherapy and other targeted therapies, the only way we know if they have any advantage over what we have to offer, currently, is to compare them in a clinical trial.

And with these clinical trials, those who have designed them have been very thoughtful in trying to do so in a way that compares them and then looks to see: Does that give us a benefit in getting rid of the cancer or curing the cancer, or at a minimum, slowing it down or giving a longer life? And/or does it give better quality of life or reduce the level of side effects? That’s what many of these clinical trials are. Some are adding new agents to see if those work better than other ones. For example, in the HPV-related cancer, some of the clinical trials are saying these respond fairly well to treatment. Can we actually back off on the severity of treatment, give them just as good of a cancer cure but (with) fewer long-term side effects? I think they’re critical as the only way we’re going to figure out how best to manage these types of cancers.

On treating advanced head and neck cancer without cisplatin – an oncology grand rounds discussion

Source: www.medpagetoday.com
Author: Mark L. Fuerst

An oncology grand rounds discussion with Sachin Jhawar, MD.

Head and neck squamous cell carcinoma (HNSCC) represents a heterogeneous set of diseases with different features and treatment recommendations. Physicians face challenges in initial treatment decision-making and response assessments, including the changing role of surgery, the incorporation of human papilloma and Epstein Barr virus status, as well as the potential for treatment de-escalation using patient-related and tumor-related factors.

A recent “Oncology Grand Rounds” article in the Journal of Clinical Oncology provides an overview of treating advanced HNSCC when cisplatin is not an option, including concurrent chemotherapy, cetuximab, targeted therapy, and immunotherapy.

In the following interview, the paper’s lead author, Sachin Jhawar, MD, of Ohio State University Comprehensive Cancer Center in Columbus, reviews the main issues.

What is the focus of the article?
Jhawar:
We focused on patients with locally advanced disease who would be receiving definitive non-surgical treatment when possible treatment with concurrent cisplatin, delivered either every 3 weeks or weekly, is always the preferred treatment.

We specifically wanted to delve into the subset of patients who we would not recommend to receive cisplatin because of age or comorbidities. This could be concurrent chemotherapy (carboplatin/paclitaxel), concurrent cetuximab, and altered or standard fractionation radiation schedules without systemic therapy, as well as when to consider immunotherapy and palliative radiation for those with recurrent or metastatic disease.

There is also a great deal of institutional preference involved. At our institution, we prefer concurrent carboplatin/paclitaxel in patients who cannot receive cisplatin. Generally, we reserve definitive radiation alone options for patients who are completely ineligible for any systemic therapy.

If definitive therapy would be considered too difficult, or for those who have metastatic disease, still other palliative regimens are available.

When should clinicians consider nivolumab or pembrolizumab?
Jhawar:
At this time, immuno-oncology agents such as nivolumab or pembrolizumab are approved and used regularly only in the recurrent or metastatic setting. Even in the recurrent setting, they are generally considered only if surgery or re-irradiation therapy is not an option.

These novel agents should only be considered earlier in a patient’s treatment course in place of more traditional systemic options via a clinical trial.

What are the potential benefits of the combined use of immunotherapy, chemotherapy, and vaccines?
Jhawar:
The potential benefits of combination strategies using checkpoint inhibitors and other immuno-oncology treatments, including vaccines, in combination with more traditional therapies including surgery, radiation, and chemotherapy are still being worked out. It is likely that we will first see applications of these newer therapies in the recurrent and metastatic setting, but they may be incorporated earlier into patient care as more data about safety and efficacy emerges.

We have seen regular use of immuno-oncology treatments in other disease sites, and these therapies are being introduced earlier in the treatment course for patients. I would expect a similar pattern to emerge for HNSCC, although we will need to wait for phase III randomized controlled trial data for these immunotherapies to be ready for prime time.

It should be noted, however, that given the heterogeneity of HNSCC, there are certain scenarios in which we are working towards de-escalation of therapy, and addition of more therapies may not be needed.

In the patients with HPV-positive oropharyngeal squamous cell carcinoma and less than 10 pack-year smoking histories, the cure rates are more than 90% with current standard-of-care treatment. We are now working towards de-escalating therapy. It is not clear what role, if any, immuno-oncology will play in these already favorable situations.

What about the potential synergy of molecular targeted agents with radiation?
Jhawar:
There are multiple potential targets that could lead to synergy with radiation. Cetuximab actually acts on one of these targets, the epidermal growth factor receptor. Other potential targets that are being studied for combinations with radiation include cell signaling pathways (mTOR, AKT), cancer metabolism, tumor hypoxia, and DNA repair pathways (PARP, ATR).

There are other studies that have been completed or are ongoing that use agents to improve radioprotection of normal tissues. To date, none of these targeted agents are being regularly used on their own or in combination in the care of patients outside of clinical trials.

What improvements with new targeted therapies and immunotherapies do you foresee?
Jhawar:
As our understanding of the molecular mechanisms of carcinogenesis, aberrant cancer signaling pathways, and the tumor microenvironment improves, I expect that the number of targets and, therefore, the number of molecular targeted agents will grow. This will lead to a large increase in the number of clinical trials and expansion of our armamentarium against HNSCC.

Similarly, as our understanding of the interplay between cancer and the immune system and mechanism of immune escape improves, I suspect we will be able to improve response rates from immuno-oncology drugs. Currently, only 10% to 20% of patients respond to immuno-oncology treatments, leaving a great deal of room for improvement.

Taken together, this will allow for more individualized, patient-specific care and afford the ability to test novel combinations to improve cure rates. Simultaneously, this will decrease toxicity by choosing the right treatment for the right patient, rather than having a one-size-fits-all approach to therapy.

What’s the take-home message for practicing oncologists?
Jhawar:
There is a great deal of change forthcoming in the treatment of HNSCC, but at this time standard-of-care therapy still consists of some combination of traditional cancer therapies, including radiation, surgery, and chemotherapy.

Read the study here and expert commentary about the clinical implications here.

Experts release new guidelines for studies into most effective treatments for HPV-positive throat cancer

Source: en.brinkwire.com
Author: provided by University of Birmingham, United Kingdom

Heightened caution is needed when considering de-escalation trials for patients with Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC), to ensure minimal harm to patients, new guidelines from a group of international head and neck cancer experts have suggested.

HPV-positive oropharyngeal cancer is a cancer of the throat caused by the human papillomavirus—a common, but symptomless group of sexually transmitted viruses. Instances of many throat and neck cancers have declined as smoking rates have fallen, whereas HPV-positive OPC has increased, largely affecting younger patients.

The standard course of treatment for this disease is a combination of cisplatin (a common chemotherapy drug) and radiotherapy. The younger age of the patient population, significantly improved prognosis, and relatively minimal morbidities caused by the standard treatment pathway have led to the popularisation of the concept of treatment de-escalation as a way to improve the quality of life of patients by reducing dosage or frequency of treatment.

These new recommendations, published today in the Journal of Clinical Oncology have been created by the Head and Neck Cancer International Group, a group of experts from nineteen countries, led by the University of Birmingham, UK. The guidelines have been prompted by the recent results of the first three randomised de-escalation trials which suggested a clear detriment in survival when cisplatin is omitted or substituted to minimise side effects.

After a review of available HPV-positive OPC literature, the guidelines recommend an overall need for caution when considering de-escalation options, even in instances where there appears to be possible favourable disease outcomes. Experts also recommend a revised approach to how findings are evaluated during phase II studies to ensure that any potential risks to survival are identified and only if none are present should phase III trials follow.

The guidelines also recommend that de-escalation trials should only be considered for well-defined, very low risk groups and only when there is a strong rationale for investigating a particular treatment strategy. Additionally harm-minimisation techniques should be considered as an alternative. Importantly, treatments should not be implemented into clinical practice before high level evidence is available.

Corresponding author Professor Hisham Mehanna, Director, Institute of Head and Neck Studies and Education (InHANSE) at the University of Birmingham said: “Clinicians and researchers have to be careful when planning and undertaking de-escalation studies, as trials to date have that harm can befall patient. Very controlled and small strides need to be taken when evaluating a possible de-escalation strategy, especially one that removes cisplatin.”

FDA grants fast track designation to NBTXR3 in locally advanced head and neck cancers

Source: www.targetedonc.com
Author: Nichole Tucker

An FDA Fast Track Designation was granted to the first-in-class radioenhancer NBTXR3 with or without cetuximab (Erbitux) for the treatment of patients with locally advanced head and neck squamous cell cancer who are not eligible for platinum-based chemotherapy, according to a press release from Nanobiotix.1

NBTXR3 showed preliminary signals of antitumor activity in this patient population in a phase I study of 12 patients with advanced-stage head and neck squamous cell carcinoma (HNSCC). Specifically, 10 of the 11 evaluable patients had a complete response (CR) or a partial response to treatment, which included 2 CRs at dose levels ≤10% and 5 CRs at dose levels >10%.2

Treatment with NBTXR3 was also found to be safe and tolerable in patients with HNSCC. There were no serious adverse events or dose-limiting toxicities (DLTs) observed, which allowed patients to continue with their treatment as planned. The adverse events found to be related to injection with NBTXR3 included grade 1/2 injection pain and tumor hemorrhage.

Patients in the study received either a single intratumor injection or single-arterial injection of NBTXR3 on day 1 followed by intensity-modulated radiation therapy 2 hours later, which lasted for up to 7 weeks. Radiotherapy was continued in all patients unless their tumor did not shrink by 50% of the baseline size. Those patients who did achieve the tumor shrinkage goals then received salvage tumor surgery.

The primary end point of the study was the determination of the recommended dose of the drug and early dose-limiting toxicities. Secondarily, the investigators evaluated safety and tolerability, objective response rate, local progression-free survival, progression-free survival, kinetics profile, and the feasibility of local administration of NBTXR3.

Patients aged 70 years or older who were intolerant to cisplatin or cetuximab or that could not receive the combination of chemoradiation were eligible for treatment in the study. Patients were required to have histologically or cytologically confirmed squamous cell carcinoma of the oral cavity or oropharynx; have a T3 or T4 primary tumor or stage III or IVA disease; be clinically eligible for intra-arterial or intratumor implantation by injection; have a Karnofsky performance status ≥70; and have adequate bone marrow, kidney, and liver function.

The study excluded patients who had prior radiotherapy; tumor-related dyspnea; prior or concurrent non-head and neck malignancies, excluding adequately treated basal or squamous cell cancer of the skin, and in situ cervical cancer; concurrent treatment with any other anticancer therapy; tumor-related dyspnea; tumor ulceration which implies vascular risk; non-measurable disease; and those with infections and illnesses that may have interfered with treatment.

The data from this trial are part of a proof-of-concept for launching a phase III study in which NBTXR3 will undergo further assessment for the treatment of head and neck cancers.3

References
1. Nanobiotix announces fast track designation granted by US FDA for investigation of first-in-class nbtxr3 in head and neck cancer [news release]. Cambridge, Massachusetts: Nanobiotix; February 10, 2020. https://bit.ly/2vpwDQU. Accessed February 10, 2020.
2. Le Tourneau C, Calugaru V, Jouffroy T, et al. A phase 1 trial of NBTXR3 nanoparticles activated by intensity-modulated radiation therapy (IMRT) in the treatment of advanced-stage head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2017;35(suppl 5;abstr 6080). doi: 10.1200/JCO.2017.35.15_suppl.6080.
3. Nanobiotix announces plan for global phase III head and neck cancer registration trial along with overall development update [news release]. Cambridge, Massachusetts: Nanobiotix; January 7, 2020. https://bwnews.pr/2Hczpfc. Accessed February 10, 2020.

2020-02-11T08:31:16-07:00February, 2020|Oral Cancer News|

Standard chemotherapy treatment for HPV-positive throat cancer remains the most effective, study finds

Source: www.eurekalert.org
Author: press release, University of Birmingham

A new study funded by Cancer Research UK and led by the University of Birmingham has found that the standard chemotherapy used to treat a specific type of throat cancer remains the most effective.

The findings of the trial, which aimed to compare for the first time the outcomes of using two different kinds of treatment for patients with Human papillomavirus (HPV)-positive throat cancer, are published today (November 15th) in The Lancet.

Throat cancer is one of the fastest rising cancers in Western countries. In the UK, incidence was unchanged between 1970 and 1995, then doubled between 1996 and 2006, and doubled again between 2006 and 2010. The rise has been attributed to HPV, which is often a sexually transmitted infection. Most throat cancers were previously caused by smoking and alcohol and affected 65 to 70 year old working class men. Today, HPV is the main cause of throat cancer and patients are middle class, working, have young children and are aged around 55.

HPV-positive throat cancer responds well to a combination of cisplatin chemotherapy and radiotherapy, and patients can survive for 30 to 40 years, but the treatment causes lifelong side effects including dry mouth, difficulty swallowing, and loss of taste.

The De-ESCALaTE HPV study, which was sponsored by the University of Warwick, compared the side effects and survival of 164 patients who were treated with radiotherapy and cisplatin, and 162 who were given radiotherapy and cetuximab. The patients were enrolled between 2012 and 2016 at 32 centres in the UK, Ireland, and the Netherlands. Patients were randomly allocated to be treated with radiotherapy and either cisplatin or cetuximab. Eight in ten patients were male and the average age was 57 years.

Importantly, the results found that there was very little difference between the two drugs in terms of toxicity in patients and side effects such as dry mouth, however, there was a significant difference in the survival rates and recurrences of cancer in patients taking part in the trial.

They found that the patients who received the current standard chemotherapy cisplatin had a significantly higher two-year overall survival rate (97.5%) than those on cetuximab (89.4%). During the six-year study, there were 29 recurrences and 20 deaths with cetuximab, compared to 10 recurrences of cancer and six deaths in patients who were treated with the current standard chemotherapy cisplatin.

And cancer was three times more likely to recur in two years following treatment with cetuximab compared to cisplatin, with recurrence rates of 16.1 per cent versus six per cent, respectively.

Study lead Professor Hisham Mehanna, Director of the University of Birmingham’s Institute of Head and Neck Studies and Education, said: “Many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as cisplatin chemotherapy with radiotherapy and caused fewer side effects but there has been no head-to-head comparison of the two treatments.

“Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin.

“This was a surprise – we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV positive should be given cisplatin, and not cetuximab, where possible.”

Dr Emma King, Cancer Research UK Associate Professor in head and neck surgery at the University of Southampton, said: “Studies like this are essential for us to optimise treatments for patients. We now know that for HPV-positive throat cancer, the standard chemotherapy treatment remains the most effective option.

“However, we must keep testing new alternatives to ensure patients always have access to cutting-edge and kinder treatments. Chemotherapy and radiotherapy can leave head and neck cancer patients with long term pain and difficulties swallowing, so we should always strive to minimise side effects.”

Professor Janet Dunn from the University of Warwick, whose team ran the De-ESCALaTE HPV trial, said: “In the current trend for de-escalation of treatment, the results of the De-ESCALaTE HPV trial are very important as they were not as we expected. They do highlight the need for academic clinical trials and are an acknowledgement of the key role played by Warwick Clinical Trials Unit at the University of Warwick as the co-ordination and analysis centre for this important international trial.”

The patients on the De-ESCALaTE trial Steering Committee endorsed the importance of research findings.

Malcom Babb, who is also President of the National Association of Laryngectomee Clubs, said: “From a patient perspective, De-ESCALaTE has been a success by providing definitive information about the comparative effectiveness of treatment choices.”

2018-11-16T09:36:03-07:00November, 2018|Oral Cancer News|

No De-escalation of Therapy for HPV+ Throat Cancer

Source: www.medscape.com
Author: Alexander M. Castellino, PhD

Another trial has shown that de-escalating therapy does not work in patients with good prognosis human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma or throat cancers.

Results from the De-ESCALaTE HPV study show that using the targeted drug cetuximab with radiotherapy does not improve side effects and, more importantly, has worse survival compared with the standard of care — chemotherapy with cisplatin and radiotherapy.

The finding echoes the results from the US National Cancer Institute’s Radiation Therapy Oncology Group (RTOG) 1016 trial, the top-line results of which were released earlier this year, and details of which were presented this week at the American Society of Radiation Oncology (ASTRO) 2018 meeting.

“Do not change your clinical practice of using cisplatin with radiotherapy in these patients,” cautioned Hisham Mehanna, MBChB, PhD, chair of head and neck surgery at the University of Birmingham, United Kingdom, and lead investigator of the De-ESCALaTe study. He presented the results during a presidential session here at the European Society for Medical Oncology (ESMO) 2018 Congress (abstract LBA9).

“Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin. This was a surprise — we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV+ should be given cisplatin, and not cetuximab, where possible,” Mehanna said in a statement.

Hope for Fewer Side Effects
Cetuximab with radiation is already approved by the US Food and Drug Administration for use in head and neck cancer, including oropharyngeal cancer, and is an accepted standard of care, especially for patients who cannot tolerate cisplatin.

The hope behind de-escalation of therapy was that this regimen would offer similar efficacy but have fewer side effects than the standard regimen of cisplatin plus radiation.

“The side effects of treatment for patients with head and neck cancers are devastating. They experience loss of speech, loss of taste, and have trouble swallowing,” explained ESMO expert Jean-Pascal Machiels, MD, PhD, head of the department of medical oncology at the Cliniques Universitaires Saint-Luc, Brussels, Belgium.

“With HPV increasing rapidly in the Western world, HPV+ head and neck cancers are typically seen in younger patients who respond well to treatment and live for three to four decades. These patients would like to live without the toxicities associated with treatment,” he added.

“Based on a large study in 2006, many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as chemotherapy with radiotherapy and caused fewer side effects,” Mehanna commented. That study showed that for patients with squamous cell carcinoma of the head and neck, treatment with cetuximab and high-dose radiotherapy improved locoregional control and reduced mortality. At the same time, side effects were no worse (N Engl J Med. 2006;354:567-578).

 

OCF NOTE: The foundation’s donors were funders of the RTOG 1016 clinical trial over several years.

Patients with HPV-positive oropharynx cancer should receive chemoradiation

Source: medicalxpress.com
Author: provided by European Society for Medical Oncology

Patients with human papilloma virus (HPV)-positive throat cancer should receive chemoradiotherapy rather than cetuximab with radiotherapy, according to late-breaking research reported at the ESMO 2018 Congress in Munich.

“Many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as chemotherapy with radiotherapy and caused less side effects but there has been no head-to-head comparison of the two treatments,” said study author Prof Hisham Mehanna, Chair, Head and Neck Surgery, Institute of Cancer and Genomic Sciences, University of Birmingham, UK.

Throat cancer is rapidly becoming more common in Western countries. For example in the UK, incidence was unchanged in 1970 to 1995, then doubled in 1996 to 2006, and doubled again in 2006 to 2010.The rise has been attributed to HPV, a sexually transmitted infection. Most throat cancer was previously caused by smoking and alcohol and affected 65-70 year-old working class men. Today HPV is the main cause and patients are around 55, middle class, working, and have young children.

HPV-positive throat cancer responds well to a combination of cisplatin chemotherapy and radiotherapy, and patients can survive for 30-40 years, but the treatment causes lifelong side effects including dry mouth, difficulty swallowing, and loss of taste. Patients deemed unable to tolerate chemotherapy, for example because of poor kidney function or older age, receive cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, and radiotherapy.

This study compared side effects and survival with the two treatments in 334 patients with HPV-positive throat cancer enrolled from 32 centres in the UK, Ireland, and the Netherlands. Patients were randomly allocated to radiotherapy and either cisplatin or cetuximab. Eight in ten patients were male and the average age was 57 years.

During the two-year study there were ten recurrences and six deaths with cisplatin compared to 29 recurrences and 20 deaths with cetuximab. Patients on cisplatin had a significantly higher two-year overall survival rate (97.5%) than those on cetuximab (89.4%; p=0.001, hazard ratio [HR] 4.99, 95% confidence interval [CI] 1.70-14.67). Cancer was over three times more likely to recur in two years with cetuximab compared to cisplatin, with recurrence rates of 16.1% versus 6.0%, respectively (p=0.0007, HR 3.39, 95% CI 1.61-7.19).

There were no differences between groups in the overall number of side effects, or of acute or late severe (grade 3-5) toxic events including dry mouth and difficulty swallowing. There were significantly more serious adverse events such as renal and haematological problems with cisplatin than with cetuximab.

Mehanna said: “Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin. This was a surprise—we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV positive should be given cisplatin, and not cetuximab, where possible.”

Commenting on the study for ESMO, Dr. Branislav Bystricky, Head, Medical and Radiation Oncology Department, University Hospital Trencin, Slovakia, said: “It was believed that cetuximab causes less side effects and was therefore a good option for HPV-positive throat cancer patients who are young and expected to survive for several decades, as well as those less able to tolerate chemotherapy. This study shows that the best treatment choice for patients with HPV-positive throat cancer is cisplatin and radiotherapy. This combination gives ‘double’ the benefit since it is more effective in terms of survival and does not worsen all grade toxicity compared to cetuximab with radiotherapy.”

Bystricky noted that the results were in agreement with interim findings of the US National Cancer Institute’s RTOG 1016 trial, which is scheduled to report this month. He said: “We now have two studies showing that these patients should not be given cetuximab. Future research should examine whether genotyping for the KRAS-variant can select a group of patients that will benefit from cetuximab treatment with radiotherapy.”

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