cisplatin

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|

Chemoradiation offered better survival than accelerated radiation in head and neck squamous cell carcinomas

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

Concurrent chemoradiation offered better overall survival and disease-free survival than accelerated radiotherapy in patients with moderately advanced squamous cell carcinomas of the head and neck, investigators reported at the Multidisciplinary Head and Neck Symposium.

Actuarial rates of 2-year overall survival and disease-free survival in patients treated with concurrent chemoradiation (CCR) were significantly better than for patients treated with accelerated radiotherapy alone, reported Dr. Krzysztof Skladowski of the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Gliwice, Poland.

“CCR with conventional 7 weeks of fractionation and at least two courses of high-dose cisplatin is more effective than 6 weeks of accelerated radiotherapy alone,” he said.

Even if patients can tolerate only a single course of cisplatin, CCR is still superior to accelerated radiation, he added.

The findings suggest that accelerated radiation protocols should be reserved for patients with more favorable prognosis, such as those with stage T2 disease with limited nodal involvement, and those who are positive for the human papillomavirus (HPV) p16 protein, Dr. Skladowski said at the symposium cosponsored by the American Society for Radiation Oncology and the American Society of Clinical Oncology.

The findings are “concordant with data that has been emerging now over approximately 10-14 years of the value of concurrent chemoradiation in head and neck cancer for a substantial cohort of patients over radiation alone,” said Dr. Paul Harari of the University of Wisconsin, Madison, and the invited discussant.

Although a previous meta-analysis (Lancet 2006; 368:843-54) suggested that accelerated or hyperfractionated radiotherapy was associated with a 3.4% advantage in overall survival, compared with conventional radiotherapy over 5 years, there have been no randomized studies comparing accelerated radiotherapy protocols with concurrent chemoradiation in this population, Dr. Skladowski said.

He and colleagues compared the two modalities in 101 patients with moderately advanced cancers of the oropharynx (46 patients), hypopharynx (19), and larynx (36).

They defined moderately advanced cancers as stage T2N1-2, T3N0-2, or T4AN0-2 if the involved nodes are not larger than 3 cm in diameter. Patients with oropharyngeal cancers were tested for expression of the human papillomavirus (HPV) p16 protein.

Patients were randomly assigned to receive either concurrent chemoradiation with intensity-modulated radiation therapy–delivered doses of 66-70 Gy divided into 33-35 daily fractions over 45-49 days plus cisplatin 100 mg/m2, delivered on days 1, 2 and 43, or to accelerated radiotherapy delivered via intensity-modulated radiation therapy in 1.8 Gy fractions 7 days/week to a total dose of 66.2-72 Gy.

Five patients in the CCR arm received only one dose of cisplatin, 30 received two doses, and 13 received the planned three doses.

At a median follow-up of 30 months, actuarial rates of 2-year overall survival of patients treated with CCR were 81%, compared with 62% for patients treated with accelerated radiation (P = .02). Disease-free survival rates were 75% and 60%, respectively (P = .05).

Acute adverse events were similar, with approximately 80% of patients in each treatment arm experiencing confluent mucositis, and about 10% having grade 3 dysphagia. There were no grade 4 toxicities.

The majority of treatment failures in each group were local, occurring in 21 of 52 patients treated with radiation alone, and in 11 of 49 patients treated with CCR (P = .03).

Significantly more deaths occurred in the radiation alone arm: 20 vs. 9 (P =.02).

The 2-year disease-free survival rate among patients in the CCR arm was dose dependent, at 60% of patients who received one course of cisplatin, 77% of those who received two courses, and 79% for those who received all three.

At the time of the analysis, all patients with oropharyngeal cancer who were positive for HPV p16 (five treated with accelerated radiation and six with CCR) were alive with no treatment failure. The overall survival rate for HPV-positive patients was 60% in the radiation only arm, and 80% in the CCR arm.

Note:
The study was supported by the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology. Dr. Skladowski reported having no financial disclosures. Dr. Harari has received research funding from Amgen.

March, 2014|Oral Cancer News|

PTEN loss, PIK3CA mutation predicted resistance to cetuximab in HNSCC

June 2, 2013
Source: Helio.com

 

CHICAGO — PTEN loss or PIK3CA mutation predicted resistance to treatment with cisplatin plus cetuximab in a cohort of patients with head and neck squamous cell carcinoma, according to phase 3 study results presented at the ASCO Annual Meeting.

“Cetuximab is the only targeted therapy in use in head and neck cancer, and although it prolongs survival, the effects are modest. For patients who receive [cetuximab] in the setting of metastatic or recurrent disease, median survival remains less than 1 year,” Barbara Burtness, MD, a medical oncologist at Fox Chase Cancer Center who specializes in head and neck cancers and a HemOnc Today Editorial Board member, said in an interview. “In colon cancer, patients are tested for KRAS mutations to detect patients with upfront resistance to cetuximab, but KRAS mutation is rare in head and neck cancer, and we haven’t had a biomarker to separate the sensitive from resistant patients.”

Burtness and colleagues compared cisplatin plus placebo vs. cisplatin plus cetuximab (Erbitux, Eli Lilly) in 117 patients. The researchers also assessed PIK3CA mutations and loss of PTEN expression in the cohort.

Results indicated that 34% of tumors studied had a loss of PTEN expression and 4% had PIK3CA mutations in the three hotspots studied.

Researchers did not observe any statistically significant differences in OS, PFS or overall response rates.

However, among patients with PIK3CA and PTEN expression, median PFS was 4.2 months for those assigned to cetuximab vs. 2.9 months for those assigned to placebo (adjusted P value=.07). Among patients with PIK3CA mutations but without PTEN expression, median survival was 4.6 months for those assigned to cetuximab and 3.5 months for those assigned to placebo.

“This study was limited by the small size of the original clinical trial, as well as by the fact that specimens were not available for all the patients, so the results are of borderline statistical significance,” Burtness said. “But if these data are corroborated in larger cohorts of cetuximab-treated patients, they would suggest that PTEN loss together with PIK3CA mutation could serve as a signature to identify patients who will not benefit from cetuximab therapy as it is currently given. The advent of PIK3 inhibitors could give us a new treatment strategy for these patients, potentially in combination with cetuximab.”

 

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

 

June, 2013|Oral Cancer News|

Are combination therapies effective for advanced SCCHN?

Source:
Author: DrBicuspid Staff

In a recent study, researchers from the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center examined whether the addition of multiple drugs to radiation therapy is superior to the current standard of care therapy with one drug and radiation for locally advanced squamous cell carcinoma of the head and neck (SCCHN).

Their data, published in the Journal of Clinical Oncology, suggests that it does not (March 4, 2013). Standard therapy for SCCHN is a combination of the drug cisplatin and radiotherapy.

This clinical trial compared this combination to the combination with the addition of a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) erlotinib. For the study, 204 patients with locally advanced SCCHN were recruited between December 2006 and October 2011. Participants were assigned to receive either cisplatin and radiotherapy or the same chemoradiotherapy with erlotinab.

EGFR is a therapeutic target for this type of cancer, and at least one other EGFR is approved for multiple uses in treating head and neck cancer, including in combination with radiation. To date, no data have been published on the use of EGFR inhibitors in combination with chemotherapy and radiation.

The goal of the current study was to determine if adding EGRF inhibition improved efficacy when combined with standard of care radiation. Unfortunately, the researchers found that the addition of EGRF did not improve clinical response rate or progression-free survival.

“There has been great enthusiasm and some confusion about the combinations of chemotherapy and biologic therapy such as EGFR inhibitors in conjunction with radiation in the treatment of squamous cell carcinomas of the head and neck,” stated lead author Neil Hayes, MD, MPH, from UNC Lineberger Comprehensive Cancer Center, in a press release. “For the moment, the data are clearly showing no added benefit.”

Future investigations will rely more on patients selected by the molecular tumor characteristics, he added.

Other institutions participating in the study were the University of Washington, Fred Hutchinson Cancer Research Center, Multicare Health Systems, University of New Mexico, Medical University of South Carolina, University of Miami, Coastal Carolina Radiation Oncology, and the University of Tennessee. Funding for the study was provided to the University of Washington by Genentech and Astellas Pharma Global Development.

March, 2013|Oral Cancer News|

Targeted Drugs No Help in Head and Neck Cancer

Source: medpagetoday.com
Author: Charles Bankhead, Staff Writer, MedPage Today
Date: March 05, 2013
 

The addition of targeted agents to standard chemotherapy failed to improve efficacy in two different trials of advanced head and neck cancer.

In one trial, patients given gefitinib (Iressa) in addition to docetaxel lived about a month longer than those who received docetaxel plus placebo. In the other trial, adding erlotinib (Tarceva) to cisplatin-based chemoradiation did not improve response rate or progression-free survival.

However, neither regimen was associated with increased toxicity compared with standard chemotherapy, investigators reported online in the Journal of Clinical Oncology.

Noting the lack of useful biomarkers to guide the use of targeted agents, the authors of an accompanying editorial said that experience to date suggests current strategies amount to “skimming the surface of a problem that is exceedingly complex.”

“It is unlikely that genomic sequencing alone will represent a panacea to the therapeutic challenges in squamous cell carcinoma of the head and neck,” said Aaron R. Hansen, MBBS, and Lillian L. Siu, MD, of Princess Margaret Cancer Center in Toronto. “Comprehensive characterization that encompasses a broader omics-based molecular evaluation, as well as immune function assessments, is urgently needed.”

The rationale for the gefitinib and erlotinib trials came from evidence that the drugs targeting epidermal growth factor receptors (EGFR) have synergism with conventional chemotherapeutic agents, have radiosensitizing properties, and have demonstrated modest activity as monotherapy in some clinical studies.

Cetuximab (Erbitux), another EGFR inhibitor, has been approved for use with radiation therapy or as monotherapy in selected patients with head and neck cancer.

Gefitinib-Docetaxel

Preliminary studies of the docetaxel-erlotinib combination showed considerable toxicity that required dose reductions. As a result, the investigators chose to evaluate gefitinib in combination with docetaxel.

“Our hypothesis was that the addition of gefitinib to docetaxel will be synergistic and improve outcomes of previously treated and/or compromised performance status patients with recurrent or metastatic squamous cell carcinoma of the head and neck,” Athanassios Argiris, MD, of the University of Texas Health Science Center at San Antonio, and co-authors wrote.

Eligible patients had recurrent or metastatic disease and Eastern Cooperative Oncology Group (ECOG) performance status 2 or ECOG 0 to 2 and previous exposure to chemotherapy. All patients received weekly docetaxel and were randomized to gefitinib or placebo.

Treatment continued until disease progression, and the primary endpoint was overall survival.

The phase III trial had a patient-accrual goal of 330, but enrollment ended after 270 patients when an interim analysis suggested efforts to demonstrate improvement in the primary endpoint would prove futile.

The results showed a median overall survival of 6 months in the docetaxel-placebo arm and 7.3 months with the docetaxel-gefitinib regimen. An unplanned analysis suggested that patients younger than 65 benefited from gefitinib (7.6 versus 5.2 months median overall survival, P=0.04).

Grade 3/4 toxicity occurred in a similar proportion of patients in both treatment arms, with the exception of diarrhea, which was more common with gefitinib.

Erlotinib-Cisplatin

The erlotinib trial involved 204 patients with locally advanced squamous cell carcinoma of the head and neck. All patients received cisplatin-based chemoradiation and were randomized to the EGFR inhibitor or no further therapy.

The primary endpoint was complete response rate, and progression-free survival (PFS) was the secondary endpoint, as reported by Renato G. Martins, MD, of the University of Washington in Seattle, and colleagues.

The results showed a complete response rate of 40% without chemoradiation and 52% with chemoradiation plus erlotinib, a difference that did not achieve statistical significance (P=0.08). After a median follow-up of 26 months, PFS also did not differ significantly between the two treatment arms (HR 0.9, P=0.71).

Investigators prospectively evaluated p16 status in 90 patients. A positive result was defined as “strong, diffuse nuclear and cytoplasmic staining in ≥70% of tumor cells.” Patients with p16-positive tumors had significant improvement in the hazard for progression when they received erlotinib (HR 0.39, P=0.04).

Martins and colleagues also evaluated the relationship between development of rash and PFS in patients who received erlotinib. The analysis revealed rash as a significant predictor of improved PFS (HR 0.41 versus erlotinib-treated patients without rash, P=0.03).

“Despite preclinical data suggesting that erlotinib could be synergistic with both chemotherapy and radiotherapy, erlotinib previously failed to improve outcome in metastatic non-small cell lung cancer,” Martins and colleagues noted in their discussion. “Here, erlotinib failed to improve the outcome of locally advanced squamous cell carcinoma of the head and neck when combined with cisplatin-radiotherapy.”

Although disappointing, the results do not represent the end of the line for investigation of targeted agents in head and neck cancer, Ellie Maghami, MD, of City of Hope in Duarte, Calif., told MedPage Today. Echoing the sentiments of Hansen and Liu, Maghami said the true potential of targeted agents in head and neck cancer will not be determined in the absence of accurate biomarkers to guide patient selection.

The gefitinib study was supported by AstraZeneca. The erlotinib study was supported by Genentech.

Argiris disclosed a relationship with AstraZeneca. Co-authors disclosed relationships with AstraZeneca, Boehringer Ingelheim, Genentech, and sanofi-aventis.

Martins disclosed relationships with Genentech and OSI Pharmaceuticals. Co-authors disclosed relationships with XCENDA Amerisource Bergen Consulting Services, Genentech, Intuitive Surgical, and OSI Pharmaceuticals.

Siu disclosed relatinships with Roche, Pfizer, Bristol-Myers Squibb, and Boehringer Ingelheim.

Primary source: Journal of Clinical Oncology
Source reference:
Argiris A, et al “Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: An Eastern Cooperative Oncology Group trial” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.45.4272.

Additional source: Journal of Clinical Oncology
Source reference:
Martins RG, et al “Cisplatin and radiotherapy with or withoout erlotinib in locally advanced squamous cell carcinoma of the head and neck: A randomized phase II trial” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.46.3299.

Additional source: Journal of Clinical Oncology
Source reference:
Hansen AR, Siu LL “Epidermal growth factor receptor targeting in head and neck cancer: Have we been just skimming the surface?” J Clin Oncol 2013; DOI: 10.1200/JCO.2012.47.9220.

 

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

March, 2013|Oral Cancer News|

Erbitux add-on falls short in esophageal cancer

Source: www.medpagetoday.com
Author: Charles Bankhead, Staff Writer, MedPage Today

The addition of a targeted agent to definitive chemoradiation failed to improve survival in an unselected population with esophageal cancer, a randomized trial showed. In fact, patients who received cetuximab (Erbitux) with chemoradiation had significantly worse overall survival (OS) reflected in a 50% increase in the hazard versus chemoradiation alone, reported Thomas Crosby, MD, of Velindre Hospital in Cardiff, Wales, and colleagues.

Investigators could not find any subgroup of patients who benefited from cetuximab, they said in a presentation at the Gastrointestinal Cancers Symposium.

“The addition of cetuximab cannot be recommended to standard definitive chemoradiotherapy in the treatment of unselected patients with esophageal cancer,” Crosby said.

“The use of high-quality definitive chemoradiotherapy in the treatment of localized, poor-prognosis esophageal cancer was associated with excellent survival compared with previous radiotherapy and surgical series,” he added.

Randomized trials have shown that definitive (or primary) chemoradiation improves survival in localized esophageal cancer compared with a single treatment modality. In England, definitive chemoradiation has been used primarily for patients with localized disease that is unsuitable for surgery, Crosby said.

Add-on therapy with cetuximab has improved outcomes in other cancers, notably head and neck cancer and colorectal cancer. The findings provided a rationale for evaluating the addition of cetuximab to primary radiation therapy for localized esophageal cancer.

Crosby presented results of a randomized trial wherein patients with localized (stage I-III) esophageal cancer (less than 10 cm). Patients were excluded if they had celiac lymph-node involvement.

The patients received cisplatin-capecitabine (Xeloda) chemotherapy with or without cetuximab. After 6 weeks of chemotherapy, patients underwent definitive conformal radiation therapy at a total dose of 50 Gy in 25 fractions.

The trial had two stages. The first stage had a primary endpoint of treatment failure-free survival (TFFS), defined as alive at 6 months with no residual cancer in biopsy specimens and no evidence of disease progression outside the radiation therapy field. Secondary endpoints were toxicity, quality of life, overall survival (OS), and feasibility of recruitment. The first stage of the trial had an accrual target of 180 patients.

The trial’s second stage had a primary endpoint of OS and accrual to 420 patients.

However, the trial never reached second stage, but ended after a planned stage one analysis convinced the independent review committee that continued accrual to meet the primary endpoint would be futile.

Treatment and follow-up continued with enrolled patients, and the final analysis included 258 patients who had completed the 6-month assessment of disease status.

Crosby reported that patients randomized to conventional chemoradiation without cetuximab had a TFFS of 77% whereas the cetuximab group had a TFFS of 66%. All survival outcomes favored omission of cetuximab:

Median OS: 25.4 months versus 22.1 months
2-year survival: 56% versus 43.1%
Median progression-free survival: 19.4 months versus 15.9 months
The analysis showed a marked difference in median OS between patients who met the TFFS goal at 6 months and those who did not: 26.7 months versus 8.3 months.

Comparison of OS in the two arms yielded hazard ratio of 1.53 for the cetuximab arm versus chemoradiation only (P=0.035).

In addition to the inferior outcomes with cetuximab, addition of the targeted agent added to the toxicity burden. The cetuximab arm had an 81.4% incidence of grade 3 to 5 toxicity compared with 72.9% without cetuximab.

Patients who received cetuximab in addition to chemoradiation had significantly more grade 3 to 5 dermatologic toxicity (21.7% versus 3.9%, P<0.001) and metabolic/biochemical toxicity (24.0% versus 10.9%, P=0.005).

Additionally, the analysis revealed a trend toward more cardiac adverse events in the cetuximab arm (6.2% versus 1.6%, P=0.053).

The addition of cetuximab also adversely affected adherence to the treatment protocol. Patients in the cetuximab arm were significantly less likely to receive full doses of cisplatin (76.7% versus 89.9%, P=0.005), capecitabine (69.0% versus 85.3%, P=0.002), and radiation therapy (75.2% versus 86.0%, P=0.027).

Additionally, almost a third of patients did not receive the prescribed dose of cetuximab.

“Future strategies to improve the outcome of definitive chemoradiotherapy in esophageal cancer must focus on developing evidence-based biomarkers to select treatments and incorporating newer radiotherapy technologies and targeted systemic treatment to safely intensify treatment, including a higher radiotherapy dose,” Crosby said.

January, 2013|Oral Cancer News|