ASCO: Antibody improves head and neck cancer results

Author: Michael Smith, North American Correspondent, MedPage Today

A novel antibody improved outcomes for patients with advanced and inoperable squamous cell carcinoma of the head and neck, researchers reported.

Combined with radiation or chemoradiation, the substance — a fully humanized monoclonal antibody dubbed nimotuzumab — significantly outperformed either modality alone in an open-label randomized trial, according to K. Govind Babu, MD, of Kidwai Memorial Institute of Oncology in Bangalore, India, and colleagues.

At the same time, there was little serious toxicity — such as debilitating skin rash — attributed to the compound, the researchers reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology here.

It’s the first randomized study of the drug to show clinical benefit without the toxicities associated with similar antibodies, the researchers said.

In general, neither radiation nor chemotherapy provides a good outcome for patients with inoperable stage III or IVa squamous cell carcinoma of the head and neck. However, substances such as cetuximab (Erbitux) that target the epidermal growth factor receptor (EGFR) — overexpressed in such tumors — have improved outcomes.

Nimotuzumab, like cetuximab, targets EGFR, but is highly selective for tumor tissues, limiting toxicity, the researchers said.

The study enrolled 92 patients, and 76 were evaluable for efficacy. They were treated with radiation or chemoradiation (with cisplatin), with or without nimotuzumab. The substance was given by intravenous infusion of 200 milligrams over a 60-minute period, once a week for six weeks.

In group A — radiation with or without the antibody — the locoregional response rate was 37% with radiation alone, but was 76% when nimotuzumab was added, the researchers reported. In the other group, chemoradiation and nimotuzumab led to a 100% locoregional response, compared with 70% for chemo alone, they said.

At four years of follow-up, they reported:

  • The overall survival rate was 47% for patients getting the antibody and chemoradiation, compared with 21% for chemoradiation alone, a difference that was significant at P=0.01.
  • The comparable rates in the radiation group were 34% for the combination and 13% for radiation alone, which were not significantly different.
  • Median overall survival was not reached for chemoradiation and nimotuzumab, but was 21.9 months for chemoradiation alone. The comparable figures for radiation were 14.3 months versus 12.7 months.
  • Adding nimotuzumab to chemoradiation resulted in a 65% reduction in risk of death; the hazard ratio was 0.35, which was significant at P=0.01.

The study was small, but it provides a “signal of benefit” that needs to be confirmed in larger randomized trials, according to Ranee Mehra, MD, of Fox Chase Cancer Center in Philadelphia, who was not involved in the research but who discussed it in an oral session.

She noted that the arms of the trial were imbalanced in terms of the cancer site, with a higher percentage of cancer of the oropharynx in the nimotuzumab arms.

Mehra said the results in the radiation arm don’t parallel historical data with cetuximab. In trials with that substance, the median overall survival with radiation was 29 months, and when cetuximab was added it reached 49 months.

The differences have several possible explanations, she said, including varying patient characteristics, a lower radiation dose in the nimotuzumab trial, and the effect of human papillomavirus infection, which was not recorded in this study but which plays a role in outcomes.


1. Journal of Clinical Oncology
2. Babu KG et al. “An open-label, randomized, study of h-R3mAb (nimotuzumab) in patients with advanced (stage III or IVa) squamous cell carcinoma of head and neck (SCCHN): Four-year survival results from a phase IIb study.” J Clin Oncol 28:7s, 2010 (suppl; abstr 5530)

Cancer risk reduction study reports green tea extracts may protect against oral cancer

Author: staff

Over 50 per cent of participants in the University of Texas M. D. Anderson Cancer Center study experienced a clinical response to the green tea extracts, according to findings published in Cancer Prevention Research.

“While still very early, and not definitive proof that green tea is an effective preventive agent, these results certainly encourage more study for patients at highest risk for oral cancer,” explained the research team.

“The extract’s lack of toxicity is very crucial in prevention trials. It’s very important to remember that these are otherwise healthy individuals and we need to ensure that agents studied produce no harm,” they added.

Green tea contains between 30 and 40 per cent of water-extractable polyphenols, while black tea (green tea that has been oxidized by fermentation) contains between 3 and 10 per cent. Oolong tea is semi-fermented tea and is somewhere between green and black tea.

The four primary polyphenols found in fresh tealeaves are epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC).

The study followed 41 people with oral leukoplakia, a condition is a sign of oral cancer risk. The participants were assigned to receive either placebo or green tea extract at one of three doses, including 500 milligrams or 1,000 mg three times a day.

The researchers collected oral tissue biopsies, which they say was “essential in that it allowed us to learn that not only did the green tea extract appear to have benefit for some patients, but we pointed to anti-angiogenic effects as a potential mechanism of action,” they explained.

Almost 60 per cent of people taking the two highest doses of the green tea extracts had a clinical response. Just over 36 per cent of people in the lowest extract dose group had a clinical response, compared to 18 per cent in the placebo group, said the researchers.

At an extended follow-up with a mean of 27.5 months, 15 participants had developed oral cancer, with a median time to disease development of 46.4 months.

Commenting on the safety, the researchers noted that side effects such as insomnia and nervousness were mostly only recorded in the high-dose group. None of these produced no significant toxicity, they added.

“While these are encouraging findings, much more research must be done before we can conclude that green tea may prevent oral or any other type of cancer. It’s also important to remind people that this trial enrolled very few participants who, at the highest dose levels took the equivalent of eight cups of green tea three times a day,” cautioned the researchers.

“We need to further understand if green tea offers longer-term prevention effects for patients,” they added. Future studies with such high-risk people investigate the effects of longer supplementation periods, said the researchers.

According to the American Cancer Society, more than 35,720 are expected to be diagnosed with oral and/or pharynx cancer and the five year survival rate is less than 50 per cent.

Source: Cancer Prevention Research

Adverse events associated with concurrent chemoradiation therapy in patients with head and neck cancer

Source: Arch Otolaryngol Head Neck Surg. 2009;135(12):1209-1217
Authors: Daniel J. Givens, BS et al.

To assess toxicities, functional outcomes, and health-related quality of life associated with concurrent chemoradiation therapy (CRT) in patients with head and neck cancer.

Prospective and retrospective outcomes study.

Tertiary care institution.

Participants in the longitudinal Outcomes Assessment Project whose head and neck cancer was treated with CRT between February 1, 2000, and March 1, 2007 (n = 104).

Patients prospectively provided functional and health-related quality of life information, including data from the 1-year and most current follow-up visits. Medical records were reviewed to determine toxicity and survival rates.

Main Outcome Measures:
Well-defined acute and late toxicities; functional outcomes (diet, dentition, tracheostomies); head and neck cancer–specific, general health, and depression outcomes; and survival rates.

Most patients had oropharyngeal or laryngeal tumors (87.5%) and advanced-stage disease (75.0%). Approximately one-half had hematologic toxicities and toxicity-related treatment delays. Approximately one-quarter had neurotoxicities and/or ototoxicites, moist desquamation, pneumonia, nausea and vomiting requiring hospitalization or intravenous fluids, dehydration or malnutrition requiring hospitalization, and mild or moderate fever. Although patients receiving the current intensity-modulated radiation therapy (IMRT) protocol using the Pinnacle3 planning system had more toxicity-related treatment delays, they had fewer toxicities and better functional and health-related quality of life outcomes compared with those receiving conventional lateral opposing-field radiation or the initial IMRT protocol using the Best nomos PEACOCK planning system.

Patients receiving CRT experience a substantial number of treatment-related adverse events, primarily affecting oropharyngeal and laryngeal function, with improvement noted for the current IMRT protocol. Improving dental prosthetic rehabilitation and including evaluations with speech and swallowing pathologists before and during treatment may enhance patient outcomes.

Daniel J. Givens, BS; Lucy Hynds Karnell, PhD; Anjali K. Gupta, MD; Gerald H. Clamon, MD; Nitin A. Pagedar, MD; Kristi E. Chang, MD; Douglas J. Van Daele, MD; Gerry F. Funk, MD

Author Affiliations:
Departments of Otolaryngology–Head and Neck Surgery (Mr Givens and Drs Karnell, Pagedar, Chang, Van Daele, and Funk), Radiation Oncology (Dr Gupta), and Internal Medicine (Dr Clamon), University of Iowa College of Medicine, Iowa City.

December, 2009|Oral Cancer News|

Weekly radiation of more than 10 gy improves local control in head and neck cancer patients

Author: John Otrompke

Patients with head and neck squamous cell carcinoma who receive an average weekly fractionated radiation dose of more than 10 gy experience significantly better local control at 2 years, unless they are receiving chemotherapy at the same time, according to a study presented here at the American Society of Therapeutic Radiology and Oncology (ASTRO) 51st Annual Meeting.

“We’re not seeing the benefit in those who also receive chemotherapy with the radiation,” said Alek F. Dragovic, MD, Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama. If they have low-stage cancer, they may not necessarily need chemotherapy along with radiation. Also, patients are often not healthy enough to receive chemotherapy if they can’t tolerate the side effects, Dr. Dragovic explained in his presentation on November 3.

In the study, 601 patients who received definitive radiotherapy were divided retrospectively into those who received more or less than an average weekly dose of 10 gy.

Patients who received the traditional schedule of once per day made up 45.1% of the patient population, those who received concomitant boost radiation, in which patients get treated twice per day during the last 2 weeks of radiotherapy, were 17.6% of the population; while 17.5% were treated with simultaneous integrated boost, 15.1% received radiation twice daily, and other received other schedules.

Overall, patients who received on average more than 10 gy per week experienced 77.4% local regional control at 2 years, compared with 71.4% who received less than 10 gy per week. For those who received no chemotherapy, however, average weekly dose of more than 10 gy was associated with 80.9% local regional control at 2 years, compared with 60.9% for those who received less.

But for those patients who also received chemotherapy, on the other hand, the numbers were 77.3% and 75.3%, respectively, and the results were not statistically significant,

Additionally, for those treated with concurrent chemotherapy, severe late dysphagia (including difficulty swallowing, scarring of the oesophagus, and dependence on a stomach tube) was found in 38.4% of those who received more than 10 gy per week, compared with 32% of those who received less.

“Those who received the higher dose per week also had more acute toxicity, such as oral ulcers and mucositis, but long-term toxicity does not end up being increased,” concluded Dr. Dragovic.

1. presented at Presented at ASTRO
2. Presentation title: The Importance of Average Weekly Dose in Patients With Head-and-Neck Cancer Treated With Definitive Radiotherapy. Abstract 66

November, 2009|Oral Cancer News|

Does green tea prevent cancer?

Author: staff

Evidence continues to brew about the protective effects of green tea against cancer, but scientists are still not sure the tea leaves reveal the answer.

Vassiliki Papadimitrakopoulo, M.D., professor of medicine in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas M. D. Anderson Cancer Center, and colleagues tested 41 patients who took green tea extract orally for three months at three dose levels.

Nearly 60 percent of patients with oral pre-malignant lesions, who were at the highest dose levels, displayed clinical response, compared with less than 20 percent among those taking placebo. Researchers also observed a trend toward improved histology, and a trend toward improvement in a handful of biomarkers that may be important in predicting cancer development.

Patients were followed for 27.5 months, and at the end of the study period, 15 developed oral cancer. Although there was no difference in oral cancer development overall between those who took green tea extract and those who did not, patients who presented with mild to moderate dysplasia had a longer time to develop oral cancer if they took green tea extract.

Although encouraged by the results, Dr. Papadimitrakopoulo cautioned against any recommendations that green tea could definitely prevent cancer.

“This is a phase II study with a very limited number of patients who took what would be the equivalent of drinking eight to 10 cups of green tea every single day,” Dr. Papadimitrakopoulo was quoted as saying. “We cannot with certainty claim prevention benefits from a trial this size.”

Dong Shin, M.D., professor of hematology and medical oncology and Blomeyer Endowed Chair in Cancer Research at Emory School of Medicine, agreed, but indicated he thought this trial was certainly a step in the right direction.

“A clinical trial with a natural compound is no easy task, and these researchers have accomplished that,” Dr. Shin was quoted as saying. “The lack of toxicity is also important because often when you give supplements at higher doses than what would occur naturally, you induce nausea and vomiting. That did not happen in this trial.”

“The goal of this kind of research is to determine whether or not these supplements have long-term prevention effects,” Dr. Papadimitrakopoulou said. “More research including studies in which individuals at high risk are exposed to these supplements for longer time period is still needed to answer that sort of question.”

Source: Cancer Prevention Research, November, 2009

November, 2009|Oral Cancer News|

Chemoradiation confers long-term benefits in head and neck cancer

Author: Zosia Chustecka

In patients with head and neck cancer who do not undergo surgery, chemotherapy with nonplatinum agents given concurrently with radiotherapy offers clear benefits for recurrence and survival, say the authors of one of the largest and longest randomized trials carried out in this patient group.

Event-free survival in patients who received concomitant chemoradiation was double that seen in patients who received radiotherapy alone or in those who received chemotherapy after radiation (with or without concurrent chemotherapy). Overall survival was also nearly doubled, although this result was not statistically significant.

These benefits persisted for 10 years, the researchers note in their report published online October 27 in the Lancet Oncology.

The results come from the UK Head and Neck (UKHAN1) trial, headed by Jeremy Tobias, FRCP, from the Department of Clinical Oncology, University College Hospital, London, United Kingdom.

Chemoradiation as a treatment option for head and neck cancer is still rather controversial, Dr. Tobias told Medscape Oncology, and there are some physicians who would consider using radiation alone. “I think this study has gone quite a long way toward showing that chemotherapy given simultaneously with radiation is useful,” he said. The benefits were “so striking that they trump any additional toxicity,” he added.

However, chemotherapy given after radiation did not confer any benefit, and it increased toxicity. Also, there was no benefit from the addition of chemotherapy to radiation in patients with head and neck cancer who had undergone surgery.

Details of the Long-Term Results
The UKHAN1 study started 20 years ago, and involved 966 patients with locally advanced head and neck cancer; most participants were from the United Kingdom, but some were from Turkey and Malta.

The majority of these patients (n = 713) had not undergone surgery. They were randomized to receive 1 of 4 treatments: radiotherapy alone, radiotherapy with simultaneous nonplatinum chemotherapy (i.e., concurrent chemoradiation), radiotherapy followed by chemotherapy, or radiotherapy with simultaneous chemotherapy followed by chemotherapy alone.

Chemotherapy was either methotrexate alone or a combination of vincristine, bleomycin, methotrexate, and fluorouracil. Toxicity did not differ substantially between these 2 options, the researchers note.

The median survival was 4.7 years in the concurrent chemoradiation group, compared with 2.3 to 2.7 years in the other 3 groups. However, this difference in overall survival did not reach statistical significance (P = .09), probably because the numbers were too small, the researchers explain.

The corresponding median event-free survival was 2.2 years in the concurrent chemoradiation group, compared with 1 year in the other groups (P = .005). The researchers estimate that for every 100 patients treated with concurrent chemoradiation, there were 11 fewer events in the 10 years after treatment than in the other treatment groups. Events included recurrence, death, and diagnosis of a new tumor.

Dr. Tobias said that the increase in overall survival, although not statistically significant, is “clinically important,” and that the increase in time to an event such as a local recurrence, which was significant, is of “immense importance” in this group of patients. The location of these tumors means that a recurrence can necessitate radical surgery, which can then leave the patient without speech or normal swallowing function, which can be “catastrophic,” he said.

Treatment with chemotherapy at the same time as radiation increased toxicity. Significant toxicity was reported by 28% of patients in the concurrent chemoradiation group, compared with 11% in the group receiving radiotherapy alone, 12% in the group receiving radiotherapy followed by chemotherapy, and 36% in the group receiving concurrent chemoradiation followed by chemotherapy. The most common toxicity during treatment was mucositis.

The authors note that the acute toxicity rates reported for the nonplatinum chemotherapy used in this trial (28%) is much lower than that reported in other trials with platinum-containing chemotherapy (41% to 77%).

Platinum compounds, particularly cisplatin, are commonly used in these patients, but Dr. Tobias said that he is “not convinced that this is backed by evidence” and suggested that nonplatinum chemotherapy offers an alternative for patients who are unfit for cisplatin. “It appears to work as well and has substantially lower toxicity, and these drugs are inexpensive,” he noted.

No Benefits Seen After Surgery
A small subgroup of patients (n = 253) in the UKHAN1 trial had undergone radical surgery and were randomized to 1 of 2 treatment options: radiotherapy alone or concurrent chemoradiation.

In this group, there was no significant difference in outcomes between the 2 treatment groups. Overall survival was 5 years for radiotherapy alone and 4.6 years for concurrent chemoradiation, and event-free survival was 3.7 and 3 years, respectively. Significant toxicity was reported by 9% of patients receiving radiotherapy alone and by 20% of those receiving concurrent chemoradiation.

“Adding chemotherapy to radiotherapy was not effective in patients who had undergone surgery previously,” the researchers conclude. It had no significant effect on outcomes, but doubled the acute toxicity.

Recent Meta-Analysis Update
A recent update of ahuge meta-analysis of chemotherapy in head and neck cancer concluded that concurrent chemoradiation should now be the routine treatment of choice for all patients with nonsurgically treated head and neck cancer (Radiother Oncol. 2009;92:4-14). That updated analyzed data from 93 trials and 17,346 patients, including some older data from the UKHAN1 trial, and had a median follow-up of 5.6 years.

These latest results from the UKHAN1 trial (with a median follow-up of 10 years) confirm the conclusion from that updated meta-analysis, Dr. Tobias and colleagues note.

However, they also show that a long-term benefit in terms of recurrence and deaths can be achieved with nonplatinum agents that are inexpensive, relatively easy to deliver, and have lower toxicity than platinum therapies, they add.

“With this particular group of patients, characteristically with multiple comorbidity and relatively low compliance to chemotherapy, the inability to tolerate platinum-based regimens is often a serious barrier to radical chemoradiation,” they write. “Because this is a high-risk and generally unfit patient group, many of whom are excessive users of alcohol and tobacco throughout treatment, the availability of a relatively simple, inexpensive, and low toxicity chemoradiation regimen considerably improves the likelihood of completing treatment, essential for improving the chance of cure.”

1. This trial was funded by the Cancer Research UK. None of the authors have disclosed any relevant financial relationships.

Lancet Oncol. Published online October 27, 2009. Abstract

November, 2009|Oral Cancer News|

YM Biosciences reports positive nimotuzumab four-year survival data

Author: press release

YM BioSciences Inc., a life sciences product development company that identifies and advances a diverse portfolio of promising cancer-related products at various stages of development, announced that an oral presentation at the American Society for Therapeutic Radiology and Oncology (ASTRO) 2009 Annual Meeting reported positive 48-month survival data for its EGFR-targeting antibody, nimotuzumab. The “BEST” trial was a randomized four-arm study treating patients with inoperable, locoregionally-advanced, stage III/IVa head and neck cancer with radiation alone, chemoradiation alone, or radiation or chemoradiation in combination with nimotuzumab.

These data were a follow-up to 30-month survival data presented at ASCO 2009 and demonstrate that the benefit of adding nimotuzumab to radiation and chemoradiation is durable and persists for several years. “These data are convincing evidence that nimotuzumab is an efficacious and safe drug and highlight its potential in the head and neck cancer indication. In this respect we note that the National Cancer Centre of Singapore has initiated a global Phase III trial with nimotuzumab in the adjuvant setting for head and neck cancer patients,” said David Allan, Chairman and CEO of YM BioSciences. “Activity of nimotuzumab in the BEST trial was similar to that demonstrated in separate trials with cetuximab in locally advanced head and neck cancer but there was no evidence that nimotuzumab’s activity was accompanied by the advanced toxicities of the class.”

In the ASTRO presentation, Dr. Lokesh Viswanth, Kidwani Memorial Institute of Oncology, Bangalore, India described that the addition of nimotuzumab to radiotherapy (RT) and chemoradiotherapy (CRT) had an important effect on overall survival. At 48 months, 41% of the patients in the nimotuzumab+CRT arm were alive compared to 21% in CRT-alone arm, and 34.7% in the nimotuzumab+RT arm were alive compared to 13% in the RT-alone arm. The difference at 48 months between CRT and nimotuzumab+CRT arms reached statistical significance (p=0.0149). Kaplan-Meier curves for survival maintained a consistent separation at the 48-month update, demonstrating that the benefit of adding a fixed course of nimotuzumab to RT and CRT persists for an extended period. Because efficacy results in the control groups in this trial were similar to those published in contemporaneous international trials in this indication, and because imbalances between the study arms were minor, authors concluded that the benefit presented in this proof of principle trial must be attributable to the activity of nimotuzumab.

The trial contained no reports of late toxicity with nimotuzumab and its benign side-effect profile continued to be demonstrated. The combination of nimotuzumab with radiotherapy and chemoradiotherapy was safe and nimotuzumab did not potentiate radiation dermatitis. As a consequence, continuing reports concerning cetuximab and its significant potentiation of severe radiation dermatitis in the treatment of head and neck cancer with radiation continues to differentiate nimotuzumab which, as first described in a poster at AACR 2009, binds selectivity to cancer tissues thereby avoiding exacerbation of damage to healthy tissues by radiation.

“This trial adds to the body of clinical data concerning the activity of nimotuzumab in head and neck cancer, which includes a number of earlier trials. The presentation at ASTRO 2009 adds an important level of understanding for nimotuzumab’s development highlighting its prospect to be the best anti-EGFR monoclonal antibody in this patient population,” said Leonardo Viana Nicacio, M.D., Director of Clinical Affairs for YM BioSciences. “The data are now shown to be reproducible in three separate studies, all of which reported nimotuzumab’s characteristically benign toxicity profile. While the chemoradiotherapy and radiotherapy protocols in BEST differ from those commonly used in North America and Europe, treatments were consistent between the arms allowing for an appropriate assessment of nimotuzumab’s activity and efficacy. These data, which suggest activity and durability similar to other anti-EGFR antibodies in this population, support the intended initiation of Phase III trials in this patient population.”

A total of 92 patients were enrolled in the BEST trial, of which 76 were considered evaluable. The trial was sponsored by Biocon Ltd., the licensee from CIMAB S.A. for nimotuzumab in India. A poster describing 30-month data from this trial was presented at the 2009 ASCO Annual Meeting and is entitled: “A Phase IIb 4-arm open-label randomized study to assess the safety and efficacy of h-R3 monoclonal antibody against EGFR in combination with chemoradiation therapy or radiation therapy in patients with advanced (Stage III or IVa) inoperable head and neck cancer”, by Reddy BK et al. (Citation: J Clin Oncol 27:15s, 2009; Abstract No: 6041; Session: Head and Neck Cancer).

The data presented at ASCO demonstrated that the addition of nimotuzumab to both the radiation and chemoradiation regimens improved the overall response rate, survival rate at 30 months, median progression-free survival and median overall survival. An unplanned, retrospective, combined group analysis of the nimotuzumab arms vs. the non-nimotuzumab arms demonstrated a significant difference in overall survival (p=0.0018) favoring nimotuzumab. The addition of nimotuzumab did not add to the severe toxicities of either regimen, with no Grade 3-4 skin toxicities observed. The authors concluded that the efficacy of nimotuzumab compares favorably to results reported for cetuximab and that this efficacy was not accompanied by the latter’s severe toxicities. They also concluded that this trial is the first randomized study in head and neck cancer to their knowledge that challenges the adopted tenet that the efficacy of EGFR inhibitors is linked to the toxicity of the class.

November, 2009|Oral Cancer News|

Light-mediated therapy aims to overcome both tumour cell uptake barriers and toxicity problems

Author: press release

PCI Biotech Holding ASA, the Norwegian drug delivery company focusing on effective delivery of cancer therapeutics, today announced that the first patient has received treatment in the Phase I/II trial with the lead candidate Amphinex(R), which uses a new approach called photochemical internalisation. The patient was treated at the University College Hospital (UCH) in London. PCI’s proprietary photosensitiser Amphinex(R) is in this study combined with the therapeutic agent bleomycin. When activated by light, Amphinex(R) promotes effective delivery of large therapeutic molecules such as bleomycin through triggered endosomal release. The trial will investigate a broadly representative spectrum of cancers including head and neck cancer and breast cancer, to demonstrate the safety and potential of this new approach.

The primary objective of this study is to assess the maximum tolerated dose of Amphinex(R), in PCI treatment with bleomycin. Secondary objectives include determination of the antitumor activity of Amphinex(R) when used in combination with bleomycin, as well as its pharmacokinetics.

Colin Hopper, Principal Investigator at UCH, said: “At UCH we are dedicated to high quality patient care and we have extensive experience in the use of photodynamic therapy to treat cancer patients. PCI is a very exciting new approach in photodynamic medicine that has shown great promise in preclinical studies. We are very proud of being the first centre to move this new technology into the clinic.”

Per Walday CEO of PCI Biotech, said: “This first in man trial is an important step forward for the company. We are confident that our approach addresses one major challenge in oncology – how to deliver therapeutics with large enough loads to effectively destroy tumours while at the same time reducing the risk of damaging healthy cells. Bleomycin is ideal for demonstrating this – there is no doubt about its therapeutic potential, but until now delivery problems and associated toxicity have prevented the realisation of its full potential. We expect to have the first preliminary results of the trial early in 2010.”

In addition, whilst our main initial focus is cancer, we strongly believe the PCI technology also has potential to improve the effect of emerging treatments such as gene therapy and therapies based on nanotechnology or on biotechnological principles. In particular, we are looking at siRNA through projects funded by EU and by the Norwegian Research Council.”

PCI Biotech

August, 2009|Oral Cancer News|

Intensity-modulated radiotherapy reduces xerostomia in head and neck cancer

Author: staff

Intensity-modulated radiotherapy significantly reduces the risk of subjective xerostomia by about 50% in patients with pharyngeal tumors, according to the first results of the multicenter, phase III PARSPORT trial.

Cancer Research UK’s PARSPORT (Parotid-Sparing Intensity-Modulated Radiation Therapy Compared With Conventional Radiation Therapy in Treating Patients With Oropharyngeal or Hypopharyngeal Cancer Who Are at High Risk of Radiation-Induced Xerostomia) trial evenly randomized 94 patients with pharyngeal tumors to conventional radiotherapy (conventional radiotherapy ) or intensity-modulated radiotherapy (IMRT). A three-dimensional technique, IMRT produces highly conformal dose distributions that can reduce the radiation dose to the salivary glands and normal tissue.

At 12 months, the incidence of grade 2 or higher xerostomia was 74% in CRT patients vs. 39% in IMRT patients, based on the subjective portion of the LENT/SOM (Late Effects on Normal Tissue-Subjective/Objective Management) questionnaire (P = .004).

The benefit of IMRT appeared to continue over time, with an 18-month xerostomia incidence of 71% with conventional therapy vs. 29% with IMRT (P = .003), principal investigator Dr. Christopher Nutting reported in a late-breaking abstract presentation at the annual meeting of the American Society of Clinical Oncology.

A similar pattern was observed using the RTOG (Radiotherapy Oncology Group) scale. The incidence of at least grade 2 xerostomia was 64% with CRT vs. 41% with IMRT at 12 months (P = .05), and 81% vs. 20% at 18 months (P less than .001).

This is the first randomized IMRT trial in head and neck squamous cell carcinoma, although phase II data suggest that parotid gland-sparing IMRT maintains saliva production, said Dr. Nutting, head of the head and neck unit at the Royal Marsden Hospital in London.

Grade 2 or higher radiation fatigue during and up to 8 weeks post treatment was significantly higher in the IMRT arm than in the CRT arm (76% vs. 41%; P less than .01), possibly because of more irradiation of brain tissue, he said. No other significant differences in acute or late toxicities were seen between the two arms.

“These data support the adoption of IMRT as the standard of care for head and neck cancer patients,” Dr. Nutting said.

The importance of the PARSPORT trial is that it confirms findings from two prior randomized trials in nasopharyngeal carcinoma patients (who also have a high risk of xerostomia), and it “shows that an improvement in radiation technology can translate into a decrease in toxicity,” Dr. Anthony Cmelak, medical director of the Vanderbilt-Ingram Cancer Center at Franklin (Tenn.), said during a discussion of the study.

He applauded the study’s use of a centralized quality assurance program because, he said, there are no set standards of delivery or quality assurance for IMRT in the community. Radiotherapy was delivered according to protocol in 43 CRT patients and 46 IMRT patients. (The remaining five patients either refused or were ineligible for treatment, or deviated from the protocol.).

When given as primary treatment, the mean dosage in both arms was 65 Gy in 30 fractions over 6 weeks. The mean contralateral parotid dose was 60 Gy in the CRT arm, which is capable of producing long-term damage, compared with 26 Gy in the IMRT arm, Dr. Nutting said. Ipsilateral parotid mean doses were similar, at 59 Gy vs. 45 Gy.

When given postoperatively, the mean radiotherapy dose was 64 Gy in the CRT arm vs. 61 Gy in the IMRT arm, the mean contralateral parotid dose was 57 Gy vs. 27 Gy, and the mean ipsilateral parotid dose was 61 Gy vs. 50 Gy.

In all, 85% of patients had tumors arising in the oropharynx and 15% in the hypopharynx; 77% had AJCC (American Joint Committee on Cancer) stage III/IV disease, and about 40% received neoadjuvant chemotherapy. Their mean age was 58 years.

Dr. Nutting said that one of the concerns about not treating part of the anatomy of the head and neck region is that locoregional progression-free survival may be poorer with IMRT. No significant difference was observed in this outcome between the IMRT (87.3%) and CRT (88%) arms (hazard ratio, 1.59).

With a median follow-up of 32 months, 91% of CRT and 93.6% of IMRT patients were alive at 1 year, although the confidence interval of 0.38-2.90 (HR, 1.05) precludes any significant conclusions, he said.

Dr. Cmelak said outstanding questions are whether the use of concurrent chemotherapy that sensitizes tissue would influence xerostomia outcomes or the ability of IMRT to spare parotid parenchyma, and whether reduced xerostomia justifies the increased integral dose. It has been asserted that the large number of beams and monitor units used in IMRT leads to an increase in integral dose (that is, the total amount of energy absorbed by a patient during radiation).

He said that the future of radiation delivery lies in arc-modulated radiation technology, which is available on roughly 70% of machines being produced today and which can reduce the integral dose by about one-half and a 15-minute IMRT session to about 5 minutes.

Finally, Dr. Cmelak said that additional research should include a cost-benefit comparison, citing a substantial difference in Medicare global costs of $23,715 for IMRT vs. $12,850 for 3-D radiation. Quality-of-life data from PARSPORT will be forthcoming.

The investigators disclosed receiving honoraria from Elekta AB and Varian Medical Systems Inc.

From cars to cancer: UH professor employs auto industry tools for tumor therapy

Author: staff

An effort is under way at the University of Houston to use technologies with origins in the automobile industry to develop new tools that will help doctors and technicians better plan radiation therapy for patients with head and neck cancer.

Dr. Ali Kamrani, founding director of the Design and Free Form Fabrication Laboratory at UH and a former auto industry researcher, is teaming up with Dr. Lei Dong, associate professor and deputy research director of radiation physics at the University of Texas M.D. Anderson Cancer Center, to develop predictive models of tumors that hopefully will increase the accuracy of radiation therapy.

“We aim to better understand tumor deformations using geometric and statistical models rather than repetitive CT scans,” said Kamrani, an associate professor of industrial engineering at the Cullen College of Engineering. “In this case, patients will undergo a minimum number of CT scans, and the radiation plans will be developed using the predictive models.”

Traditional computed tomography sessions, also known as CT scans, require a large series of two-dimensional X-ray images that, when combined, provide detailed three-dimensional images of many types of tissue.

“A CT scan is used to collect information with respect to tumor size, location and volume,” he said. “But the CT scan itself is a source of harmful radiation to body tissues and other organs. During the treatment, patients undergo a series of CT scans, which are costly and tedious.”

Reducing the number of CT scans is a primary objective for Kamrani, because it will reduce patient’s risk to unwanted radiation.

Dong said patients receiving radiation usually have up to 40 treatment sessions, which are administered about five days a week for six to eight weeks. Thanks to computers, the treatment plans are now designed “almost perfectly,” he said, and they may be “too good to be true.”

“A tumor shrinks as it responds to the treatment,” Dong said. “Unfortunately, as they do, the beautiful plan at the beginning may not be optimal for later treatment. Essentially, the patient has changed.”

Since 2000, Dong and his colleagues at M.D. Anderson have been using computerized treatment planning systems, called “intensity-modulated radiation therapy,” to design highly precise dose distributions tailored to the specific shape of the tumor. For the past year, they have been designing new radiation plans that account for changes in the tumor volume and organ position in a selection of patients who are being rescanned daily.

“You can imagine there is lots of new information as you rescan a patient,” Dong said. “Replanning a patient can take between three and five days. It’s a big effort. Then the question becomes: Can we predict how the tumor changes based on a limited number of CT scans? Then, we can decide when to replan during the treatment course.”

Treatment for a head and neck tumor depends upon the type, size and stage of the cancer, where it is located and the patient’s general health.

“Radiation therapy is a compromise between treating the cancer cells and, at the same time, sparing normal cells,” Dong said. “It’s very easy to kill cancer by radiation, but not harming normal organs at the same time can be tricky. So, it’s a delicate, fine balance.”

Kamrani hopes that, based upon initial CT scan readings, the team will be able to classify tumors and predict through radiation models the various stages of their demise.

“The purpose is to create a model to show this trend, with some level of acceptable error, by looking at the initial tumor and classifying it based on these attributes,” Kamrani said. “If there is a correlation, we have to figure out why there is a correlation and then create classification of tumors. So if a patient comes in, and he falls into that attribute, we can say, with some degree of accuracy, the tumor will be of this size at this point.”

As a tumor changes, Dong said, radiation oncologists can reduce the radiation treatment volume.

“Say the tumor shrinks by half. Then you can reduce the target volume and spare the normal tissue,” he said. “Your side effects will be reduced because you’re adapting. The benefit is you’re not compromising the treatment and still reducing the toxicity.”

Dong emphasized the importance of high-quality visualization tools in his field.

“You need that object that 3-D representation to make your plan,” he said. “This is a real human patient. It’s not a theory. It’s both.”

Kamrani has a long history with visualization and rapid prototyping, a fabrication technique common in the auto and manufacturing industries.

“Rapid prototyping is a technology that allows the automatic construction of physical models and prototyping of parts directly from a three-dimensional computer-aided design model,” Kamrani said. “Thin, horizontal cross-sections are used to transform materials into physical prototypes layer by layer.”

Rapid prototyping, also known as solid free-form fabrication, has changed the face of manufacturing, he said.

“In traditional manufacturing, you design something, send it to a foundry, and they make it for you. Now, with rapid prototyping, you design something and send it directly to the printer,” he said.

Back in Michigan, Kamrani prototyped valves and cylinders. Today, he’s prototyping bones and organs.

“The concept is the same,” he said. “When I came here, with the Texas Medical Center, it kind of came together. The industry is different here, so I started focusing on a particular problem: trying to create a three-dimensional geometry, going from valves to skulls and things like that.”

Dong called Kamrani’s idea of applying the auto prototyping tools to tumor modeling “novel.”

“It can help us solve the problem. There’s a big workflow issue. If we do replanning every day and re-CT every day, that’s lot of effort,” he said. “We’re thinking there is a better, smarter way.”