cisplatin

Personalised cancer treatment

Source: medicalxpress.com
Author: University of Oslo

In Norway, more and more people are being affected by cancer of the mouth and throat. In recent years, the incidence has increased but the mortality has remained the same. Cisplatin is one of the most commonly administered cytostatics for this patient group. At the start of treatment, the drug works well. Gradually, though, most patients experience that the tumour develops resistance against this drug and the prognosis for survival then becomes very poor.

In her PhD thesis, Jian Gao wanted to find out how the cancer cells could protect themselves against this cytostatic i.e. what is the underlying mechanism of resistance.

She therefore cultured various cancer cell lines derived from oral cavity which were given differing doses of the cytostatic cisplatin. A cancer cell line is cultured from patients’ cancerous tumours and can live indefinitely in the laboratory. These types of cell lines are used to examine the biology and the changes that have resulted in the development of cancer. Because the cancer cell lines divide in the laboratory, they can also adapt to new growth conditions, for example by becoming resistant to the cytostatic cisplatin in the same way as the cancer tissue in the patients.

“First, I had to find those cancer cells that were sensitive to the cytostatic,” explains Jian Gao. By identifying the sensitive cancer cell lines that I could make resistant in the laboratory, I could then study which changes took place in the cells as they changed from being sensitive to being resistant,” clarifies Gao.

Cytostatic for cancer cell lines

“During this process I found two different cancer cell lines. At the beginning, I gave them a dose of cytostatic that was strong enough to kill half of the cancer cells. This dose was increased each week, and after eight months both types of cancer cells were resistant to the cytostatic, cisplatin,” explains Gao.

Next, these cells had a resting period from any type of treatment. Gao wanted to see whether this resistance could be reversed by the pause in cytostatic treatment. However, it became apparent that the pause did not have any effect and the cells were permanently resistant to cisplatin. The resistant cell lines had changed permanently.

“Since I have two cell types that I knew were resistant, and I could now compare these cell lines with the original sensitive cancer cell lines,” comments Gao.

To compare gene expression in the cells, Gao used a technique that studies the expression of about 21,000 genes, a so-called mRNA microarray. This technique was used to look at changes in gene expression in the resistant cancer cell lines and then compare them with the gene expression in the original sensitive cancer cell lines.

Up-regulated genes

Only three genes were found to be up-regulated in both of the resistant cell lines. Of these genes, Gao decided to look at a cytokin, interleukin 6 (IL-6), which is a signal molecule that is often up-regulated in cancer, and which is associated with a poor prognosis and cisplatin resistance in several types of cancer.

By investigating expression of the IL-6 gene in head and throat cancers in 399 patients and then comparing this with survival, Gao and her co-workers found that, after treatment with the cytostatic cisplatin, the patients with cancer tumours with the up-regulated interleukin 6 gene did not have a better prognosis for survival.

Apparently, such cancer tumours were resistant to cisplatin. However, detailed mapping of the resistant cancer cell lines revealed that IL-6 in itself did not make the cancer cisplatin resistant. The effect had to be exerted via currently unknown mechanisms, possibly in the interaction between the cancer and IL-6 stimulation in the surrounding connective tissue.

Growth factors

Connective tissue can produce growth factors which cause the cancer to grow. There are a number of different growth factors and, of the eight known epithelial growth factors, Gao and her co-workers could demonstrate a relationship between the tumour’s gene expression in four of these epithelial growth factors and survival. The four growth factors were: Amphiregulin, epidermal, heparin-binding EGF-like growth factor and betacellulin. Could increased production of these growth factors explain cisplatin resistance?

Jian Gao’s research showed that if these growth factors were up-regulated, there was a high probability that the patient would not survive. At the same time, no relationship was found between cisplatin resistance in the cancer cell lines and the production of these growth factors.

However, the researchers could demonstrate that the more of these four growth factors a tumour expressed, the poorer the prognosis for the patient. By quantifying the amount of mRNA in the tumour tissue, Gao and co-workers could predict the patient’s prognosis considerably more accurately than the TNM system, which is the traditional method used to determine the stage of a cancer. The level of these four growth factors could predict how long even the most ill patients with distant metastases would live.

These growth factors have a common receptor in the so-called EGF receptor family. Currently, there are a number of drugs in use in patient treatment that can block this receptor. For patients whose cancers demonstrate high expression of these growth factors, it could potentially be particularly appropriate to use these medicines to reduce the growth of the cancer and increase the patient’s chances of survival.

In the last part of her PhD thesis, Gao tried to find the various “inhibitors” that could affect cisplatin resistance. After several trials with various signal and receptor inhibitors, she finally found that a drug called AG825, which inhibits the activity of an EGF receptor family member (HER 2), could reduce cisplatin resistance in four different cancer cell lines. This occurred by increasing the ability of cisplatin to trigger the cells’ self-destruct programme (apoptosis).

These drugs are already in use to treat patients with other types of cancer and, even though the details of the mechanism must be investigated in more detail, Gao and co-workers have demonstrated the probability that treatment with a cytostatic combined with “inhibitors” of the cancer cells’ protective mechanism will be advantageous. This could considerably improve the effect of the cytostatic cisplatin and thereby improve the prognosis for survival for patients with cancer of the head or throat.

But a lot of work still remains, and the journey from cell line reactions in the laboratory to how cancer cells in patients react to the same type of combined therapy is often long. Only more research can provide the answer to whether this is a navigable route to a more effective, personalised treatment of cancer of the head and throat.

September, 2017|Oral Cancer News|

Beating HPV-positive throat cancer

Source: www.huffingtonpost.com
Author: Pamela Tom, Contributor

National Oral, Head, and Neck Cancer Awareness Week is April 12-18, 2017

For at least two years, 47 year-old Rob Clinton of Rochester, NY, would choke on post nasal drip in the shower. He knew something was wrong in his throat but he didn’t feel any pain.

Did he have cancer? Clinton smoked cigarettes for 30 years and worked in an auto body shop where he was regularly exposed to carcinogens, but he wasn’t experiencing the typical symptoms of throat cancer. These include hoarseness or a change in the voice, difficulty swallowing, a persistent sore throat, ear pain, a lump in the neck, cough, breathing problems, and unexplained weight loss.

In November 2015, Clinton went to the dentist to have his teeth cleaned. His dentist felt Clinton’s swollen neck and recommended that he visit a medical doctor. Clinton heeded the advice and sought the opinion of an ear, nose, and throat specialist at Strong Memorial Hospital in Rochester, NY.

The ENT doctor sent Clinton to have a CAT scan and when he scoped Clinton’s throat, the doctor said, “I see something in there.”

What he saw was a tumor and there were a few other things going on too.

The Diagnosis
The biopsy showed that Clinton had Stage IVa oral squamous cell carcinoma (OSCC) at the base of his tongue—and the cancer was HPV positive. HPV stands for the human papillomavirus and a recent survey found that more than 42% of Americans are infected with HPV. While most people’s bodies naturally clear HPV after two years, some people’s immune systems do not recognize the virus and consequently, HPV can harbor in the body for decades. HPV-related throat cancer has been linked to oral sex.

The Treatment
On December 4, 2015, Clinton underwent neck dissection surgery at Roswell Park Cancer Institute in Buffalo, NY. Dr. Hassan Arshad, a head and neck cancer surgeon, removed 30 lymph nodes; two had cancer and one tumor was the size of a golf ball. One lymph node on the other side of neck and a tongue tumor would be treated with radiation.

The first of 35 radiation treatments began one month later in conjunction with Cisplatin chemotherapy infusions. That’s seven weeks of simultaneous radiation and chemo.

“I drove myself to treatment for the first five weeks. Up until the last week of treatment, it wasn’t too terrible,” Clinton says. “But then I started getting tired and my mother took me to the cancer center.”

Clinton had decided not to get a feeding tube prior to or during treatment and as the radiation and chemo attacked his cancer, he began to lose weight. The treatment reduced Clinton’s appetite because foods began to taste different. For two weeks, he also felt a burning sensation in his mouth and says his saliva tasted like hot sauce.

“It was excruciating and the worst thing I dealt with during treatment.”

Furthermore when radiation makes the throat feel tender and raw, it becomes nearly impossible to eat normally through the mouth.

Clinton was 215 pounds before treatment. After treatment, he weighed in at a mere 165 pounds. A loss of 50 pounds. In hindsight, Clinton wishes he had the feeding tube inserted while he was still strong.

“Don’t be afraid of the treatment. It’s manageable and you can get through it. I recommend a feeding tube because it’s a comfort knowing you have an option,” says Clinton.

The Recovery
While it took a month for Clinton to recover from the initial surgery, doctors say it takes at least a year for HPV+ throat cancer patients to find their “new normal”—regaining strength, adapting to lingering side effects.

Following chemo, Clinton experienced “chemo brain” or “chemo fog,” known as a cognitive impairment that can occur after chemotherapy. The patient may experience memory loss or dysfunction, and have difficulty concentrating or multi-tasking.

The radiation also took its toll on Clinton. He researched and found a salve made of calendula flowers, olive oil, beeswax, and Vitamin E oil to soothe his parched skin. Trying to gain weight was a bigger challenge. First, his taste went “totally upside down” and spicy foods were intolerable.

“A vanilla cookie tasted like black pepper,” Clinton says. “Only frozen peas and parsley tasted normal.”

And dry mouth is a common result of the radiation treatment. While both sides of Clinton’s neck received radiation, he had less saliva production on his left side. At night he would have to wake up every 40 minutes to drink water. Clinton must make certain not to become dehydrated because it causes the dry mouth to worsen. Now he chews gum almost non-stop.

In his search to combat dry mouth, Clinton says he researched solutions online and found ALTENS, or acupuncture-like transcutaneous electrical nerve stimulation. A study led by Dr. Raimond Wong, an associate professor of oncology at McMaster University in Ontario, Canada, found evidence that ALTENS may reduce patient-reported xerostomia, the medical term for dry mouth.

Clinton joined Dr. Wong’s clinical trial to determine whether ALTENS for six weeks/four days a week would be as effective as treatment for 12 weeks/two times a week.

“Four days a week, the researchers put pads on the inside of my ankles, the outside of my knee, back of my hands, between my thumb and forefingers, and between my chin and bottom lip,” says Clinton.

Clinton says ALTENS felt like little shocks and the acupuncture-like stimulation improved his saliva production by 80 percent. “Even after I stopped ALTENS, my saliva kept improving,” says Clinton.

The Survivor
Two years after cancer treatment, regular PET scans show that Rob Clinton has no evidence of cancer. In fact, the prognosis for HPV-related throat cancer is 85 to 90 percent positive if caught early. In contrast, patients who battle advanced throat cancer caused by excessive smoking and alcohol have a five-year survival rate of 25 to 40 percent.

Dr. Arshad, Clinton’s surgeon at the Roswell Park Cancer Institute, explained why.

“The majority of tonsil and tongue base (“throat”) cancers are HPV-positive, but smoking is still a major risk factor. Typically, non-smoking patients with HPV-positive tonsil/tongue base cancers present with a lump in the neck, implying that the cancer has already spread to lymph nodes. This used to mean that the patient would have a reduced chance of long-term survival,” Arshad says. “We now know that for nonsmokers who have HPV-positive cancers, metastasis to lymph nodes doesn’t carry the same poor prognosis. The newest staging system reflects that change, i.e. Some of those patients who were previously classified as stage IV are now at stage II if the cancer is HPV-positive.”

Clinton is not only faring well physically, surviving cancer changed his outlook and lifestyle.

“My life is pretty much back to normal. I get a little nervous each time I get a PET scan but so far, it shows I am free of cancer,” Clinton says. “I have a better appreciation of things. I live healthy in terms of diet and recreation. I don’t smoke or drink heavily.”

The Future of HPV+ Oropharyngeal Cancer
De-stigmatizing HPV is a key component to building public awareness and acceptance of HPV infection, and the ability to recognize the early symptoms of HPV-related throat cancer. As more and more people are diagnosed with HPV-related throat cancer, the social stigma surrounding the virus is a disturbing deterrent because HPV cancer patients are often reticent to disclose the HPV connection.

In a 2015 public service announcement, actor Michael Douglas who was treated HPV+ base of tongue cancer called for oral screenings but never said “HPV” by name. “A very common virus, one responsible for the vast majority of cervical cancers is now identified as the cause of this rapid rise in oral cancers,” said Douglas.

In the early years of the AIDS crisis, people associated infection with illness, fear, and death. It took a decade to generate a movement and begin to change the public sentiment. Now after continual education, AIDS is accepted and the focus centers on hope instead of ostracization.

Clinton hopes more people will accept that HPV infection is common—the most common sexually-transmitted infection in the U.S., according to the CDC. The American Society of Clinical Oncologists also found that by 2020, the annual number of HPV-related oropharyngeal in nonsmoking, middle-aged men will surpass the number of cervical cancer cases.

“HPV is not a shameful thing. It’s very common. It’s just that some people can’t clear the virus from their bodies,” Clinton says. “This type of cancer is the next epidemic. I feel fortunate every day that I came through it as well as I did.”

April, 2017|Oral Cancer News|

Type 2 diabetes drug could be beneficial for head and neck cancer patients

Source: www.eurekalert.org
Author: press release

Researchers at the University of Cincinnati (UC) College of Medicine have found that adding increasing doses of an approved Type 2 diabetes drug, metformin, to a chemotherapy and radiation treatment regimen in head and neck cancer patients is not well tolerated if escalated too quickly, but allowing slower escalation could be beneficial.

These findings are being presented via poster June 4 at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting: Collective Wisdom, being held June 3-7 in Chicago.

Trisha Wise-Draper, MD, PhD, assistant professor in the Division of Hematology Oncology at the UC College of Medicine, a member of both the Cincinnati Cancer Center and UC Cancer Institute and principal investigator on this study, says retrospective studies have shown improved outcomes in tumors treated with chemotherapy and radiation if they were also on metformin for diabetes.

“In head and neck squamous cell carcinoma, which develops in the mucous membranes of the mouth, nose and throat, diabetic patients taking a medication called metformin had better overall survival compared to those not on metformin when also treated with chemotherapy and radiation,” she says. “Additionally, pancreatic cancer patients treated with chemotherapy and metformin required higher doses of metformin–1,000 milligrams twice a day–to experience positive results.

“In basic science studies, metformin has been shown to stop mTOR, a molecular pathway present and active in this type of head and neck cancer, and pretreatment with metformin resulted in a decrease in the occurrence of oral cavity tumors in animal models. In this study, we wanted to see if the combination of escalating doses of metformin with the chemotherapy agent cisplatin and radiation for head and neck cancer tumors in non-diabetic patients would be effective.”

Wise-Draper says that metformin, which is an approved Type 2 diabetes medication, was provided by their investigational pharmacy. Metformin was administered orally in escalating doses for 7 to 14 days prior to starting the cisplatin and radiation and continued throughout standard treatment. Blood samples were collected before and after metformin treatment as well as during chemotherapy. Flow cytometry, a technique used to count cells, was used to detect the percent of circulating immune activated cells, and clinical laboratory tests including glucose, B12 and C-peptide (an amino acid that is important for controlling insulin) were performed.

“This is part of an ongoing clinical trial,” says Wise-Draper. “We found that eight patients with advanced head and neck cancer have been enrolled so far; we plan to have 30 total. Due to the relatively quick escalation of metformin, the patients’ tolerance was poor with higher doses of metformin when initiated 7 days prior to their chemotherapy and radiation therapy regimen.

“Therefore, the protocol was modified to allow slower escalation over 14 days. The most common toxicities observed included nausea (71 percent of patients) and vomiting (43 percent of patients), increase in creatinine (57 percent of patients), decreased white blood cell count (43 percent of patients) and pain when swallowing (43 percent of patients) with only nausea being directly attributed to metformin and the rest attributed to cisplatin and radiation.”

She adds that there wasn’t a substantial change in T cell or glucose levels with administration of metformin in the small sample of patients but that there were increased C-peptide levels in response to metformin administration.

“These results show that the combination of metformin and cisplatin and radiation was poorly tolerated when metformin was escalated quickly. However, there has been no significant increase in side effects thus far with the addition of metformin,” Wise-Draper says. “The trial is continuing with escalation of metformin over a longer period of time to provide more data; we will also try to increase our sample size.”

Note:
This research is being funded by the UC Cancer Institute. Wise-Draper cites no conflict of interest.

Cetuximab plus RT linked with high toxicity in head and neck cancer

Source: www.cancernetwork.com
Author: Anna Azvolinsky, PhD

The combination of radiation therapy plus the EGFR inhibitor cetuximab had higher rates of acute toxicity among patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) compared with radiation therapy plus the chemotherapy cisplatin, according to results of a phase II trial based in Italy. Efficacy was similar with both combination therapies.

According to Stefano Maria Magrini, MD, professor of radiotherapy at the Università degli Studi di Brescia in Italy, and colleagues, this is the first clinical trial to directly compare radiation therapy plus cetuximab to a chemoradiation regimen for SCCHN.

The results of the randomized trial are published in the Journal of Clinical Oncology.

Cetuximab was approved in combination with radiation therapy by the US Food and Drug Administration in 2006 for the treatment of unresectable SCCHN.

Despite a goal of recruiting 130 patients, only 70 patients were recruited between 2011 and 2014.

The 1- and 2-year overall survival rates were 75% and 68% in the cetuximab arm compared with 78% in the cisplatin arm. The 1- and 2-year local control rates were 64% and 53% in the cetuximab arm and 84% and 80% in the cisplatin arm, yet the differences between arms were not statistically significant (P = .073), reflecting the inadequate statistical power of the relatively small trial.

Compliance in both treatment arms was relatively low. Only 28% of patients in the cetuximab arm and 20% of patients in the cisplatin arm received at least 7 cycles of therapy.

Patients in the radiation therapy plus cetuximab arm experienced more serious adverse events including severe cutaneous toxicity of grade 3 or higher. Four patients in the cetuximab arm developed infectious complications that led to septic shock and three of the patients died after the end of treatment. An additional patient died from respiratory failure caused by aspiration pneumonia.

Patients in the cisplatin arm had more frequent hematologic toxicities compared to patients in the cetuximab arm and one patient died from adverse events possibly related to treatment.

“The incidence of both the infusion reactions and of the other severe adverse events does not allow to consider cetuximab a safer and easy-to-use alternative to standard chemotherapy regimens,” wrote the study authors.

Based on the study results, larger prospective trials are needed to understand which SCCNH patients would best benefit from radiation therapy plus cetuximab regimen.

In an accompanying editorial, Roy H. Decker, MD, PhD, associate professor of therapeutic radiology at the Yale School of Medicine in New Haven, Connecticut, and colleagues highlighted the limitations of the current trial but look forward to results from ongoing studies to clarify the role of cetuximab in the treatment of SCCHN.

“We continue to selectively consider the use of cetuximab-based radiation therapy in patients with otherwise-favorable, low-risk disease—p16-positive, T1–T3 N0–N2b with a smoking history of less than 10 pack-years,” wrote the editorial authors.

December, 2015|Oral Cancer News|

Follow-up by advance practice nurses improves care for patients with head, neck cancer

Source: www.healio.com
Author: Anthony SanFilippo

The launch of an advance practice nurse outpatient follow-up clinic improved symptom management for high-risk patients with head and neck cancer following radiation therapy, according to findings from a study conducted at Cleveland Clinic. This initiative led to fewer ED visits and hospital admissions, results showed.

“These results are significant as they suggest more intensive follow up in high-risk head and neck patients can improve patient outcomes,” Bridgett Harr, CNP, of the department of radiation oncology at Cleveland Clinic, told HemOnc Today. “This intensive symptom management is an important role [advance practice nurses (APNs)] can fill in this and other patient groups by providing consistent, proactive management of symptoms during recovery from treatment. Our study suggests this will lead to improved patient experience, in addition to a reduction in cost to both the patient and health care system as a whole.”

Patients with head and neck cancer often undergo radiotherapy or chemoradiotherapy, and many experience debilitating side effects that require ED management or admission to the hospital. In 2014, an APN-led clinic was launched to focus on the acute rehabilitation of patients with head and neck cancer undergoing these therapies.

Harr and colleagues sought to evaluate the outcomes and incidence of adverse events among patients treated at an APN clinic compared with historical outcomes.

The analysis included data from 25 high-risk patients with head and neck cancer who received care post-treatment at an APN clinic and 24 patients who received standard follow-up care identified using a database. Clinic patients were seen 2 to 4 weeks after treatment and then every 2 to 4 weeks thereafter until their symptoms stabilized. Standard follow-up patients were seen on average between 4 to 6 weeks after treatment and then not again until 3 months post-treatment.

Patients were considered high risk if they had limited social support (35%), resided in a nursing home (16%), required multiple hydrations during treatment (18%), underwent stereotactic body re-irradiation (15%) and/or required a feeding tube (16%).

Ninety percent of patients had stage IV or recurrent cancer. Primary tumor sites included oropharynx (47%), oral cavity (16%), larynx/hypopharynx (12%) and other (25%).

All patients underwent stereotactic body radiation therapy or intensity-modulated radiation therapy. Fifty-five percent of the patients received chemoradiotherapy with either a cisplatin-based regimen (81%) or cetuximab (19%), and 45% of the patients received radiation therapy alone.

Patients in the APN clinic were seen almost twice as often as those in the standard follow-up group (median, 2 vs. 1.2 visits).

Eighteen patients experienced 26 adverse events that required either a visit to the ED or hospital admission. Six of those patients (33%) were seen in the APN clinic, whereas 12 patients (67%) were from the standard follow-up cohort.

“Not only is there greater patient satisfaction when being managed in an outpatient setting, it is more cost-effective to avoid emergency room or hospital admissions,” Harr said in a press release.

The benefits of the APN clinic appeared more substantial among patients who received radiation alone. Significantly fewer patients treated only with radiation who received their follow-up care at the APN clinic experienced an adverse event in the 90 days immediately after radiation compared with patients who received standard follow-up (60% vs. 16.7%; P = .01).

Researchers observed no difference between the arms for patients who underwent chemoradiotherapy because standard follow-up is also intensive, according to the researchers.

“This study illustrates an important role for APNs in radiation oncology,” Harr said. “APNs are in a unique position to provide more intensive follow-up care, allowing them to better manage the post-treatment symptoms of high-risk head and neck cancer patients.”

November, 2015|Oral Cancer News|

Less Is More for HPV Oropharyngeal Cancer Reduced-intensity regimen clears disease in 86% of cases

Source: www.medpagetoday.com
Author: Charles Bankhead
 

SAN ANTONIO — Less intense treatment of low-risk human papillomavirus (HPV)-related oropharyngeal cancer achieved a high rate of pathologic complete response (pCR) and favorable patient-reported outcomes, a preliminary trial showed.

Overall, 37 of 43 (86%) patients achieved pCR with deintensified chemoradiation, including all but one evaluable primary tumor. The pCR rate was virtually identical to historical rates achieved with standard regimens, according to Bhishamjit Chera, MD, of the University of North Carolina (UNC) at Chapel Hill, and colleagues.

Selected patient-reported adverse events peaked during the first 6 to 8 weeks and then declined thereafter. About 40% of patients required feeding tubes for a median duration of 15 weeks, but no patients required permanent feeding tubes, they reported here at the American Society for Radiation Oncology meeting.

The regimen consists of lower doses of radiotherapy and concurrent cisplatin, administered over 6 weeks. With high-dose therapy, the radiation protocol requires an additional week.

“Though we have limited follow-up, the pathological complete response rate with this reduced-intensity chemoradiotherapy regimen is very high in patients with favorable-risk oropharyngeal squamous-cell carcinoma,” Chera said. “The early quality-of-life measurements are encouraging, particularly the data on swallowing. We are optimistic that these results with reduced-intensity treatment will translate into good long-term disease control with less toxicity.”

The study reflects the current trend and momentum in the management of HPV-positive oropharyngeal cancer, said Zain Husain, MD, of Yale Cancer Center in New Haven, Conn.

“This is the second study to show that de-escalation of therapy might work, and so far, the results really look good,” Husain told MedPage Today. “This is a really important issue, and all of our trials are moving in that direction.”

NRG Oncology (formerly RTOG) has already launched a trial using the UNC regimen, “which gives us a lot of confidence that this is a good regimen,” Husain added. Nonetheless, reduced-intensity treatment remains investigational and should not be used in clinical practice. Randomized clinical trials with adequate follow-up will be required to determine the ultimate role of less intense therapy for HPV-positive oropharyngeal cancer, he said.

Background

HPV-positive oropharyngeal cancer accounts for 60% to 70% of new cases of oropharyngeal cancer in the U.S., and the incidence has continued to rise. In general, HPV-positive disease has a more favorable prognosis as compared with HPV-negative oropharyngeal cancer.

At many institutions, standard therapy for newly diagnosed HPV-positive oropharyngeal cancer consists of total-dose radiotherapy of 70 Gy administered over 7 weeks, and concurrent cisplatin 100 mg/m2 for 3 weeks. The regimen achieves a high rate of pCR but causes substantial toxicity. Given the overall favorable prognosis of HPV-positive oropharyngeal cancer, many specialists have begun to ask whether reduced-intensity treatment might be just as effective with less toxicity.

Chera reported findings from a prospective phase II trial of reduced-intensity chemoradiation for low-risk HPV-positive oropharyngeal cancer. Eligible patients had diagnoses of T0-3, N0-2c, M0 disease associated with minimal or negative smoking history. Treatment consisted of a total radiation dose of 60 Gy administered in 2-Gy fractions daily for 6 weeks, plus concurrent weekly cisplatin 30 mg/m2. The regimen represented a 10-Gy reduction in the usual radiation dose and a 40% reduction in the usual chemotherapy dose, Chera said.

The primary outcome was pCR and was based on experience with usual high-dose therapy, which has been associated with a pCR rate of 87%. Patients undergo biopsy of the primary site 6 to 14 weeks after completing chemoradiation, as well as resection of any initially-positive lymph nodes. Secondary endpoints included toxicity, quality of life (QOL), and clinical outcomes of treatment.

Key Findings

The 86% pCR rate compared favorably with the 87% rate demonstrated by historical data. The overall results included pCR in 40 of 41 evaluable primary tumors (two of which were stage T0 at baseline) and pCR in the neck in 33 of 39 patients (four of whom had N0 status at baseline).

After a median follow-up of 21 months, all 43 patients remain alive and without evidence of disease, including 38 patients who have at least 1 year of follow-up.

Investigators evaluated QOL by means of an instrument developed by the European Organization for Research and Treatment of Cancer (EORTC QLQ H&N-35). Focusing on common adverse effects of chemoradiation for head and neck cancer, Chera noted that the severity score for dry mouth, sticky saliva, and swallowing all increased during the first 6 to 8 weeks, particularly dry mouth and sticky saliva.

The score for dry mouth peaked at about 70 on the 100-point scale and the score for sticky saliva rose to a maximum of about 60. Score for dry mouth remained at about 60 at 12 months, whereas the saliva score declined to about 40. The effect on swallowing was less severe, reaching a maximum of about 20 and then declining to less than 10 at 12 months.

Patient-reported symptoms exhibited a similar pattern as the dry mouth score averaged less than 0.5 (0 to 4 scale) at baseline, increasing to almost 2.5 at 6 to 8 weeks, and then declining to less than 2.0 by 1 year. Patient-rated swallowing difficulty was less than 0.5 at baseline, about 1.0 at 6 to 8 weeks, and slightly less than 1.0 at 1 year.

Physician-rated grade 3/4 toxicity and patient-rated severe/very severe toxicity included mucositis (34%/45%), pain (5%/48%), nausea (18%/52%), vomiting (5%/34%), dysphagia (39%/55%), and xerostomia (2%/75%).

Chera and colleagues have already closed enrollment for another phase II trial that will evaluate a reduced-intensity regimen that makes surgery optional, omits chemotherapy for patients with T1-2 N0-1 disease, and includes patients with as much as a 30 pack-year smoking history but who have a 5-year period of abstinence.

A planned “third-generation” phase II trial will evaluate the feasibility of cancer genetics risk-based stratification of patients and examine more specifically the question of whether reduced-intensity treatment is possible for patients with a >10 pack-year smoking history.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

October, 2015|Oral Cancer News|

Critical Outcome Technologies and MD Anderson Cancer Center to evaluate COTI-2 in treating head and neck cancers

Source: www.marketwatch.com
Author: press release

Critical Outcome Technologies Inc. (“COTI”), the bioinformatics and accelerated drug discovery company, announced today that it recently executed a material transfer agreement (“MTA”) with Dr. Jeffery Myers, MD, PhD, FACS of The University of Texas MD Anderson Cancer Center for the continued evaluation of COTI-2 in the potential treatment of patients with head and neck squamous cell cancer (“HNSCC”).

There are approximately 500,000 new cases worldwide of HNSCC a year, making it the sixth leading cancer in terms of new cases. In the United States, HNSCC is considered to be a rare disease and therefore represents a second “Orphan Disease” opportunity for COTI-2.

If HNSCC is caught at an early stage, current therapies, which include surgery and radiation followed by chemotherapy, can be effective. Unfortunately, HNSCC tumors with p53 mutations tend to be more difficult to treat with such mutations occurring in 30-70% of HNSCC tumors. These mutations are associated with poorer patient outcomes as traditional chemotherapy, using the current first line chemotherapy, cisplatin, is often ineffective. The overall five-year survival rate of patients with HNSCC is 40-50%.

As a small molecule activator of misfolded mutant p53 protein, COTI-2 has demonstrated in preclinical studies its ability to restore p53 function and thus induce cancer cell death for many common p53 mutations. As previously announced, the Company is planning a Phase 1 study in gynecological cancers (ovarian, cervical and endometrial) at MD Anderson with Dr. Gordon Mills and his team and these studies in HNSCC with Dr. Myers will seek to extend the understanding of COTI-2’s ability to treat p53 mutations across multiple cancer types.

Dr. Jeffrey Myers, leader of MD Anderson’s Multi-Disciplinary Head and Neck Cancer Research Program, has been studying the impact of p53 mutation, a common event in HNSCC, on tumor progression and response to therapy. His group has evaluated a number of single agent and combination treatments for p53 mutant tumors, and his preliminary findings with single agent COTI-2 in HNSCC in vitro tumor models show tremendous promise. In addition to seeing sensitivity of HNSCC cells to COTI-2, his group has found that this drug sensitivity is associated with activation of p21, an important mediator of p53’s response to cellular DNA damage. This response is consistent with the p53-dependent mechanism of action studied by Dr. Mills in ovarian cancer. Dr. Myers and his colleagues are planning more extensive studies of COTI-2 and its dependence on p53 re-activation for its effects in both in vitro and in vivo HNSCC tumor models.

“We look forward to further exploring COTI-2’s impact on HNSCC tumors,” said Dr. Wayne Danter, President and CEO. “We continue to believe that COTI-2 represents a potential breakthrough treatment given the central importance of p53 gene mutations in many cancers, including HNSCC. This second indication would broaden the treatment opportunities for our lead oncology asset, which has already been granted the Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of ovarian cancer.”

October, 2014|Oral Cancer News|

Low-dose IMRT may be safe for patients with HPV-positive head and neck cancer

Source: www.oncologypractice.com
Author: Laura Nikolaides

Lower-dose radiation therapy may be safe for some patients with human papillomavirus (HPV)-positive oropharyngeal cancer, decreasing the risk of often long-term side effects, such as trouble swallowing, dry mouth, loss of taste, neck stiffness, and thyroid problems, investigators reported at the annual meeting of the American Society of Clinical Oncology.

Two-year overall survival and progression-free survival were 93% and 80%, respectively, among 62 patients with operable stage III/IVA HPV-positive oropharyngeal squamous carcinoma who received lower-dose intensity-modulated radiation therapy (IMRT) after clinical complete response to induction chemotherapy, reported Dr. Anthony Cmelak, professor of radiation oncology at Vanderbilt University, Nashville, Tenn., and medical director of the Vanderbilt-Ingram Cancer Center at Franklin.

Overall, the phase II study enrolled 90 patients, median age 57 years, who all received induction chemotherapy with paclitaxel, cisplatin, and cetuximab. The response to induction chemotherapy determined IMRT dose. The 62 patients who had a complete clinical response received a reduced dose (54 Gy) of IMRT, and the rest of the patients received standard dose IMRT (70 Gy). All patients received standard cetuximab along with radiation.

Two-year overall survival and progression-free survival for the higher-risk patients who received the standard dose of IMRT were 87% and 65% respectively. Among those patients receiving low-dose IMRT, survival was slightly higher for those with less than 10 pack-years of smoking and earlier-stage disease; in those patients 2-year progression-free and overall survival were 92% and 97%, respectively.

However, Dr. Cmelak does not yet recommend modifying regimens for patients with HPV-positive disease. “I don’t recommend using lower doses now, off study. Ultimately, we will need a large randomized trial,” he said. “This study represents one more piece of evidence that we need to look at the optimal regimen for both chemotherapy and radiation technique and dosage to minimize toxicities,” he added.

“We are not at the point where we know exactly how to treat patients with HPV-positive cancers. What we do know now is that there is a different biology to their tumors,” commented Dr. Gregory A. Masters, of the Helen F. Graham Cancer Center, Newark, Del., who attended the briefing but was not involved with the study. However, the study represents progress toward precision medicine, he said. “Most of what we have been doing over the last 49 years in oncology is escalating dosages. This is not necessarily always the right answer,” he added.

Aspirin may stop deafness caused by chemotherapy

Source:  www.bbc.com
Author: staff

Aspirin could save the hearing of cancer patients receiving chemotherapy, scientists in Cardiff hope.

A trial will be launched at the city’s Velindre Hospital to see if high doses of the drug can prevent permanent loss.

Conditions ranging from tinnitus to deafness are a common side effect for patients given the chemotherapy drug cisplatin.

The trial, called Coast, has recruited 88 adults prescribed cisplatin in Cardiff and other UK hospitals.

It is used to treat testicular cancer, germ cell cancer, head and neck cancer, bladder cancer, cervical cancer, non-small cell lung cancer and some types of children’s cancer.

‘Shock it was cancer’
Father-of-four Andrew Millington, 66, was given cisplatin after a tumour was found at the base of his tongue.

“I had a persistent sore throat and earache, and I went to see my GP last spring,” he said.

“I was referred to a consultant and had an MRI scan. It was a shock to be told it was cancer but… it was generally curable, which was such a relief to hear. I was offered cisplatin and, after hearing about the possible side effects, I was more than happy to take part in the Coast trial.”

Around 18,500 cancer patients receive cisplatin every year and around half suffer some form of permanent hearing loss.

Ahead of the trial’s launch on Thursday, professor Emma King, chief investigator and Cancer Research UK surgeon at the University of Southampton, said: “Aspirin can have serious side effects, including internal bleeding, so it’s important to stress that aspirin is not suitable for all cancer patients.

“To help prevent these problems we’ll be giving patients specially coated aspirin tablets, that only release the drug once it reaches the small intestine, and also using another drug that reduces digestive juices, to prevent bleeding in the stomach.

“If this trial is successful, then a larger trial will follow within two years that could potentially see aspirin become a routine part of cisplatin treatment for many thousands of cancer patients.”

Experimental EGFR inhibitor added nothing but rash

Source: www.oncologypractice.com
Author: Neil Osterweil, Oncology Report Digital Network

The addition of the experimental targeted agent zalutumumab to primary curative chemoradiation for head and neck cancers did not improve locoregional control, disease-specific survival, or overall survival at 3 years of follow-up.

The only thing that zalutumumab added to therapy was a skin rash in the large majority of patients who received it, reported Dr. Jens Overgaard, of the department of experimental clinical oncology at Aarhus University, Denmark.

Response to zalutumumab, a monoclonal antibody targeted to the epidermal growth factor receptor (EGFR), was not related to tumor human papillomavirus 16 (HPV/p16) status or to chemoradiotherapy, Dr. Overgaard reported at the Multidisciplinary Head and Neck Cancer Symposium.

The results of the DAHANCA 19 trial echo those of the RTOG (Radiation Oncology Therapy Group) trial 0522, which found no benefit from the addition of the EGFR inhibitor cetuximab (Erbitux) to accelerated cisplatin-based chemoradiotherapy, said Dr. Paul Harari, an invited discussant from the University of Wisconsin, Madison.

“Where I think we have a lot of unanswered questions is acknowledging how little we actually understand about EGFR biology, despite now 40 years of progressive knowledge,” Dr. Harari said.

“We’re now seeing very clearly in molecular and clinical correlate studies that the more we suppress the EGFR, the more we see collateral overexpression of additional RTKs [receptor tyrosine kinases], including members of the HER family, such as HER-3, that enable an escape mechanism for tumors that become resistant to EGFR inhibition,” he said.

Dr. Overgaard and his colleagues in the Danish Head and Neck Cancer Group conducted an open-label, phase III trial in which 619 patients with nonmetastatic squamous cell carcinomas of the larynx, oropharynx, hypopharynx, or oral cavity were randomly assigned to received 66-68 Gy of accelerated radiotherapy with or without zalutumumab 8 mg/kg weekly, with the first dose given a week before the start of radiation. The radiation was given concomitantly with the radiosensitizer nimorazole and, in patients with involved lymph nodes, cisplatin.

A total of 301 patients who received zalutumumab and 307 controls were included in the final intention-to-treat analysis.

At 3-year follow-up, there were no significant differences in either the primary endpoint of locoregional control (76% in zalutumumab-treated patients and 77% of controls) or in the secondary endpoints of disease-specific survival (82% and 85%, respectively) or overall survival (72% and 79%), Dr. Overgaard reported at the symposium, cosponsored by the American Society for Radiation Oncology and the American Society of Clinical Oncology.

Overall, patients who were positive for the HPV/p16 biomarker fared better than p16-negative patients, with an odds ratio for the probability of local control in negative patients of 0.52 (95% confidence interval, 0.36-0.73; P value not reported).

However, regardless of HPV 16 status, the addition of zalutumumab made no difference in the primary endpoint.

In a proportional hazard analysis, factors significantly associated with worse outcomes included worse World Health Organization performance status, higher disease stage, nodal involvement, and HPV/p16 negative status.

Although zalutumumab was generally well tolerated, 94% of patients who received it developed a rash, and of this group, 29% had grade 3 or 4 rash. In all, 11% of patients assigned to zalutumumab had to stop the drug because of rash.

Note:
The trial was sponsored by the Danish Head and Neck Cancer Group. Dr. Overgaard reported having no financial disclosures. Dr. Harari has received research funding from Amgen.

March, 2014|Oral Cancer News|