Monthly Archives: August 2006

Phase I/II Study of Docetaxel, Cisplatin, and Concomitant Boost Radiation for Locally Advanced Squamous Cell Cancer of the Head and Neck

  • 8/31/2006
  • Houston, TX
  • Anne S. Tsao et al.
  • Journal of Clinical Oncology, Vol 24, No 25 (September 1), 2006: pp. 4163-4169

Purpose:
To investigate the feasibility of combining concomitant boost accelerated radiation with docetaxel and cisplatin and assess the regimen’s toxicity, locoregional control rate, and survival in patients with locally advanced head and neck cancer (HNSCC).

Patients & Methods:
Patients with stage III-IV HNSCC were eligible. Phase I included two schedules of docetaxel and cisplatin: arm 1, once per week during weeks 1 to 4; arm 2, every 21 days for weeks 1 and 4. Radiation consisted of 72 Gy in 42 fractions over 6 weeks (concomitant boost).

Results:
Twenty patients were enrolled in phase I. The arm 1 maximum-tolerated dose (MTD) was defined at docetaxel 15 mg/m2 and cisplatin 20 mg/m2 based on prolonged mucositis in 29% of patients. The initial dose level in arm 2 was above the MTD. In total, 52 patients were treated using the arm 1 regimen in phase II. Acute toxicity included grade 3 mucositis and dermatitis in 81% and 44% of patients. The 2-year locoregional control rate was 71%. The 2-year progression-free and overall survival rates were 61% and 65%. Median survival was 37.8 months. Late effects included feeding tube dependence in 17% of patients alive and free of disease.

Conclusion:
Locoregional control, survival, and acute toxicity with this regimen were comparable with other trials utilizing taxanes and/or platins and concomitant conventional or altered fractionation radiation. Our data suggest that chemotherapy added to concomitant boost fractionation may increase rates of long-term feeding tube dependence. Phase III trials are needed to assess the contribution of concomitant boost fractionation to chemoradiotherapy.

Authors:
Anne S. Tsao, Adam S. Garden, Merrill S. Kies, William Morrison, Lei Feng, J. Jack Lee, Fadlo Khuri, Ralph Zinner, Jeffery Myers, Vassiliki Papadimitrakopoulou, Jan Lewin, Gary L. Clayman, K. Kian Ang, Bonnie S. Glisson

Authors’ affiliation:
From the Departments of Thoracic/Head and Neck Medical Oncology, Radiation Oncology, and Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, TX

August, 2006|Archive|

Smokers and cigarette sellers are going to extraordinary levels to avoid graphic new tobacco warnings.

  • 8/27/2006
  • Syndey, Australia
  • Danny Buttler
  • Herald Sun (www.news.com.au)

Smokers and cigarette sellers are going to extraordinary levels to avoid graphic new tobacco warnings.

Retailers are displaying packets upside down so the explicit health warnings are not visible to customers. And smokers are requesting specific packs, which have statistical warnings rather than gruesome images of smoking-related illnesses. Other are buying cheap plastic cigarette packet covers or transferring their smokes to “retro” glo-mesh containers.

The trend comes as new research shows more than half of Victorians want plain paper packaging on tobacco products. Shocking images of gangrenous limbs, cancerous mouths and choked arteries were introduced to Victoria in March.

Southbank Newsagency is one cigarette seller that has turned packets upside-down to keep the vivid images from the public eye.

“We do it so we or the customers who don’t smoke don’t have to see them,” Sue Lomax said.

“They make me feel ill, they turn my stomach.”

Ms Lomax said smokers had been requesting staff hunt through their favourite brand to find packets without the stomach-churning images.

“They come and ask for the ones with statistics,” she said.

“They don’t want to see the teeth or the feet.”

Quit executive director Todd Harper said the reaction of smokers showed the new packaging was making people think twice about their potentially fatal habit.

“It highlights that they are having an impact if consumers are going to such lengths that they don’t want certain images on their packets.

“My guess is that they would be avoiding the gangrene and mouth cancer images — we’ve done a lot of research and they seem to be the ones with the most impact. In those two instances they are a very visible manifestation of the illnesses associated with smoking.”

But Mr Harper suggested tobacco companies could be behind point-of-sale tricks.

“I’m sure that is part of a deliberate strategy by the tobacco companies.”

A Cancer Council of Victoria study into cigarette packaging has revealed that more than half of Victorians approve of plain packaging for cigarettes.

August, 2006|Archive|

Safety Trial of Diabetes Drug for Use in the Prevention of Oral Cancer Shows Side Effects of Edema, Effect on Lymphocytes and Calcium: Presented at AHNS

  • 8/26/2006
  • Chicago, IL
  • John Otrompke
  • www.docguide.com

Researchers who are evaluating the safety of pioglitazone in nondiabetic patients with precancerous leukoplakia say the drug can be delivered safely for 90 days to non-diabetic people with oral leukoplakia.

Nelson Rhodus, MD, professor of oral medicine, department of diagnostic and biological sciences, University of Minnesota, Minneapolis, Minnesota, and colleagues conducted a phase 2a trial to evaluate the safety of pioglitazone in nondiabetic patients with high-risk oropharyngeal leukoplagia. Their findings were presented in a poster session here at the 2006 annual meeting of the American Head and Neck Society (AHNS).

Leukoplakia is a precancerous oral condition which affects 1% of the U.S. adult population. Individuals with the condition are at relatively high-risk for conversion to malignancy, with 5% of those with leukoplakia going on to develop oral cancer. By comparison, 1% of those with colonic polyps go on to develop intestinal cancer, the poster said.

The researchers undertook this study because the thiazolidinedione class of drugs, commonly used for treatment of type 2 diabetes, bind to peroxisome proliferating-activated receptor (PPAR) gamma nuclear receptors and are therefore theorized to drive dysplastic cells to decrease proliferation and increase maturation.

The trial enrolled patients with precancerous leukoplakia but no oral cancer, diabetes, prior radiation to the oral cavity, or serious oral infections between January of 2004 and March of 2006.

All patients received 45 mg daily of pioglitazone for 12 weeks. Researchers evaluated laboratory abnormalities using paired Student’s t-test and clinical side effects using National Cancer Institute Common Toxicity Criteria version 3.

After 12 weeks of treatment, 1 patient (5.5%) experienced idiopathic peripheral edema of the lower extremity and underwent dose reduction to 30 mg daily. There were no other treatment-related side effects, according to the abstract, which is a similar rate as the 7% rate seen among diabetics reported in the literature, according to the abstract.

The researchers observed a 10% decrease in blood lymphocyte counts — 31.1% pre-treatment; 27.9% post-treatment (P < .025) — which was not significant. There was also a decrease in absolute lymphocyte counts from 2.24 to 1.96 (P = .02) which fall within the normal range, according to the researchers.

The authors theorized that the lymphocyte effects may be related to the anti-inflammatory effects of this class of drugs.

“We conclude that 45 mg daily of pioglitazone can be delivered safely for 90 days to non-diabetic people with oral leukoplakia in a phase 2 clinical trial setting,” the authors stated in their poster.

Source:
Presentation title: Safety of PPAR Gamma Activation Strategies for Precancerous Leukoplakia – AHNS

August, 2006|Archive|

Autologous Tumor Vaccine May Benefit Some Head and Neck Cancer Patients: Presented at AHNS

  • 8/26/2006
  • Chicago, Il
  • John Otrompke
  • www.docguide.com

Treatment with an intranodal vaccine prepared by feeding apoptotic autologous tumor cells to dendritic cells may benefit some patients with squamous cell head and neck cancer, but lymph node sterility may limit the viability of the treatment for certain patients.

Thirty patients with stage III/IV resectable squamous cell carcinoma of the head and neck were assessed for the experimental treatment as part of a trial reported here at the annual meeting of the American Head and Neck Society (AHNS).

Lymph nodes from the patients were processed, and sterile tumor cells were recovered from 10 of the 30 patients. Lymph nodes from five of the patients in the trial underwent leukapheresis to generate immature dendritic cells, which were then coincubated with apoptotic cells, according to the abstract by Theresa L. Whiteside, PhD, professor of pathology and otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, and colleagues.

The researchers evaluated the dendritic cell vaccines for cell recovery, viability, purity, and potency and delivered them to four of the patients.

Of the four patients who received the vaccine, none showed toxic effects, and all are alive with no evidence of cancer. The patients all generated immune responses to the vaccines.

However, the researchers noted in their abstract, autologous tumor sterility and small cell numbers limited this vaccination strategy to few enrolled subjects.

Source:
Presentation title: Dendritic Cell (DC)-Based Vaccine for Patients With SCCHN Using Autologous Tumor Cells as Immunogens. Abstract s012_AHNS

August, 2006|Archive|

Mitochondrial DNA sequencing tool updated

  • 8/26/2006
  • Bethesda, MD
  • press release
  • EurekAlert.com

High-tech laboratory tools, like computers, are often updated publicly as their analytical capabilities expand. In the September issue of the Journal of Molecular Diagnostics, NIH grantees report they have developed a second generation “lab on a silicon chip” called the MitoChip v2.0 that for the first time rapidly and reliably sequences all mitochondrial DNA. Mitochondria, the energy-producing organelles that power our cells, are unique because they are equipped with their own genetic instructions distinct from the DNA stored in the cell nucleus.

The authors say their full-sequence chip will be a key tool in accelerating research on mitochondrial DNA, a growing area of scientific interest. This interest stems from data that suggests natural sequence variations and/or mutations in each person’s mitochondrial DNA could be biologically informative in fields as diverse as cancer diagnostics, gerontology, and criminal forensics.

According to Dr. Joseph Califano, a scientist at Johns Hopkins University School of Medicine in Baltimore and senior author on the paper, the MitoChip v2.0 showed in his group’s hands better sensitivity that its predecessor to sequence variations in head and neck cancer samples. The v2.0 also detected nearly three dozen variations in the non-coding D-loop, long considered to be a sequencing no-man’s land and which the original MitoChip did not include.

“At this point, we don’t foresee a MitoChip v3.0,” said Califano, whose research was supported by the NIH’s National Institute of Dental and Craniofacial Research. “The v2.0 is a very good tool in that we’ve also arrayed 500 of the most common haplotypes – or grouped patterns of known DNA variations – banked in the mitochondrial public database.”

Mitochondria are oblong, thread-like structures dispersed throughout the cell’s cytoplasm. Hundreds to thousands of mitochondria exist in each human cell, occupying up to a quarter of their cytoplasm. Sometimes informally described as “cellular power plants,” mitochondria convert organic materials into ATP, the cell’s energy currency and without which life would cease.

As early as the 1920s, scientists uncovered clues that mitochondria might play a role in causing cancer. But like the other DNA in the cell nucleus, scientists lacked the needed research tools throughout most of the 20th century to systematically study the chemical composition of the mitochondrial genome, or complete set of genes, and its association to human disease.

In the early 1980s, scientists in England performed the then-Herculean feat of sequencing the complete human mitochondrial genome. The genome consisted of 16,568 base pair, or units, of DNA and encoded 37 contiguous genes. But because of the balky sequencing tools of the day and their high cost, much of the subsequent research progressed slowly or stalled.

By 1996, new technology brought new opportunity. Scientists with the company Affymetrix in Santa Clara, Calif. developed the first mitochondrial sequencing microarray. Roughly the size of a quarter, the silicon chip had lithographically annealed to it up to 135,000 short, arrayed bits of DNA sequence that, collectively, spanned most of a single strand of mitochondrial DNA.

The chip exploited the fact that DNA exists naturally as a double-stranded molecule. By gathering mitochondrial DNA and breaking it into short, single-stranded bits, the scientists showed that each bit would pair, or hybridize, with its complementary sequence arrayed on the chip. By crude analogy, each bit is like a unique magnet that sticks to its mirror image.

But if the extracted DNA contains mutations or other variations from the standard consensus sequence annealed to the chip, the bits with those changes would appear abnormal to the specially designed computer software programs that read the chip. The software programs will read not only the identity of the expected bases of DNA in a process called “base calling” but those of the variations.

The Affymatrix chip enabled laboratories to resequence the mitochondrial genome much faster than the traditional manual and automated strategies. Just as importantly, like an iPod to music lover, the chip served as the broad technological platform for laboratories to customize arrays more attuned to their research interests.

In 2004, Dr. Anirban Maitra and his colleagues at Johns Hopkins did exactly that with the MitoChip v1.0. In addition to nitty-gritty technical innovations that vastly improved the rate and speed of the chip, the v1.0 marked the first mitochondrial resequencing microarray designed as a potential screening tool for cancer. “With mitochondrial DNA, there is a mass advantage,” said Dr. Anirban Maitra, an author on this month’s paper whose research is supported by the NIH’s National Cancer Institute. “Whereas nuclear DNA contains just two copies of every gene, there are literally hundreds of mitochondria in most cells. If you are screening saliva or other bodily fluids with a limited number of cells to analyze, mitochondrial DNA gives you more to work with and a better chance of detecting mutations that might be associated with a developing cancer.”

Dr. Maitra said that despite the original Mitochip’s 96 percent success rate assigning base calls, there was room for improvement. Led by Drs. Shaoyu Zhou and Keyaunoosh Kassauei, the Hopkins group cobbled together the MitoChip v2.0. reported in this month’s Journal of Molecular Diagnostics. It yielded essentially the same base-call success rate as its predecessor, showed near perfect reproducibility in replicate experiments, and detected more variations than the first-generation chip.

As a proof of principle, the Mitochip v2.0 also detected 31 variations in the non-coding D-loop of 14 head and neck tumor samples. Included in this tally were several mutations that possibly are informative of the disease.

“The real interesting thing is nobody has been able to study these D-loop alterations very well,” said Califano “They clearly occur in tumor cells, and there is some type of selection process for them. But their functional significance has been hard to know. Now, you can sequence the D loop so readily and begin to look harder for associations in certain cancers.”

August, 2006|Archive|

Bacteria may be weapon in fighting some cases of throat cancer

  • 8/25/2006
  • Scotland
  • Ian Johnston
  • news.scotsman.com

PROBIOTIC bacteria might be able to prevent a deadly form of throat cancer which kills 500 people a year in Scotland, according to new research by Dundee University scientists.

They discovered that the kind of bacteria living in the throats of people with a disease called Barrett’s Oesophagus, which increases the risk of cancer by up to 125 times, was significantly different from the “flora” found in healthy people.

Those with the disease were found to have one particular kind of bacteria, an unusual form of campylobacter, which has been linked with cancer of the oesophagus in animals.

The researchers now plan to investigate whether the use of probiotics, prebiotics or a combination of the two called synbiotics can change the make-up of the bacteria and prevent the genetic damage that results in cancer.

Cancer deaths resulting from Barrett’s Oesophagus have been increasing in Europe over the last three decades and in the UK it has risen from the 20th most common type of cancer death to the seventh most common.

Dr Sandra MacFarlane, an expert in the bacteria which lives inside the human digestive tract, carried out a study which tested the microflora found in the throats of seven Barrett’s patients and seven healthy people.

“We found in the Barrett’s patients there was a greater species diversity of bacteria, but the most important thing we found was a significant difference in numbers of campylobacter,” she said.

“Fifty-seven per cent of Barrett’s patients had them in the distal oesophagus, the area where it goes down in the stomach, and there was none in the controls.

“The thing about this bacteria was they were not the normal campylobacter that causes food poisoning. They were an atypical kind that have been linked to enteritis, dental infections and biliary tract infections.

“They produce nitrosamines and these can cause DNA damage. It has been shown in animals if you give them nitrosamines they can produce cancer in the oesophagus.

Dr MacFarlane, who is working with Dr John Dillon, a consultant gastro-enterologist who treats people with Barrett’s, said they were now looking to confirm a link between the bacteria and cancer in humans.

“If we found there was something, we could then maybe treat the Barrett’s at an early stage and stop the progression to the cancer,” she said.

“Various studies would need to be done to see what probiotics or synbiotics were actually effective against them and to see if we can combat it. We could maybe change the bacteria.

“There might be some way of modulating the system, but we have no idea what probiotics would do, whether there would be any interaction.”

Barrett’s Oesophagus is a complication of gastro-oesophageal reflux disease (Gord).”About 10 per cent of those patients, who have a chronic condition – they have acid coming up all the time – will get Barrett’s,” Dr MacFarlane said.”And with Barrett’s, there is an increased risk, 30 to 125-fold, of getting cancer.”

Doctors currently try to treat Gord and prevent Barrett’s using drugs to prevent the production of as much stomach acid. Surgery can also be used to try to prevent the reflux problem.

August, 2006|Archive|

Induction Chemotherapy and Concomitant Taxotere® and Radiation Therapy Effective for Advanced Head and Neck Cancer

  • 8/25/2006
  • Iowa City, IA
  • staff
  • CancerConsultants.com

Researchers from Harvard University have reported that a regimen of induction chemotherapy followed by concomitant Taxotere (docetaxel) results in disease eradication in 70% of patients with locally advanced head and neck cancer. The details of this phase II study appeared in the July 15, 2006, issue of the International Journal of Radiation Oncology Biology Physics .

There have been several randomized and non-randomized clinical trials which suggest that the concomitant administration of platinum-based chemotherapy and radiotherapy is superior to radiotherapy alone for the treatment of patients with advanced head and neck cancer for local and regional control. Most, but not all, have also shown a survival advantage for combined treatment. More recently, Taxotere has emerged as a very effective agent for the treatment of head and neck cancer.

The current study was carried out by researchers at the Beth Israel Deaconess Medical Center, the Dana-Farber Cancer Institute, and the Brigham and Women’s Hospital in Boston.

They treated 31 patients with locally advanced head and neck cancer with induction chemotherapy, concomitant Taxotere and radiation therapy and surgery for neck dissections when indicated. The induction regimens in this trial were Platinol® (cisplatin) and 5-fluorouracil (5-FU), Paraplatin® (carboplatin) and 5-FU or Taxotere, Platinol and 5-FU. All patients received Taxotere 4 times per week while receiving radiation therapy.
The complete response rate to induction chemotherapy was 20%, the complete response rate after Taxotere and radiation therapy was 70%. Nineteen patients had a neck dissection and 7 were positive for cancer. After all planned therapy 93% were considered to be disease-free. At the time of writing this article 70% of patients were alive and disease-free. Toxicities were considered manageable.

Comments: This appears to be a very effective strategy for locally advanced head and neck cancer. These data also confirm the utility of Taxotere for treatment of head and neck cancer.

Reference:
Tishler RB, Posner MR, Norris CM, et al. Concurrent weekly docetaxel and concomitant boost radiation therapy in the treatment of locally advanced squamous cell cancer of the head and neck. International Journal of Radiation Oncology Biology Physics . 2006;65:1036-1044.

August, 2006|Archive|

Oxaliplatin Regimen Investigated in Heavily Pre-treated Patients With Head and Neck Cancer: Presented at AHNS

  • 8/24/2006
  • Chicago, IL
  • John Otrompke
  • www.docguide.com

An investigational chemotherapeutic agent under research in the treatment of gastrointestinal carcinoma may also have utility as part of a combination regimen for head and neck cancer, according to a poster presented here at the 2006 annual meeting of the American Head and Neck Society (AHNS).

“These patients are heavily pretreated, and they’re ill. Often it is not possible to give them cisplatin, because it is nephrotoxic and cardiotoxic. But we can give them oxaliplatin even if they have heart failure,” said study presenter Jan Raguse, MD, oral and maxillofacial surgeon, Charite Campus, Berlin, Germany.

Between 2002 and 2004, Dr. Raguse and colleagues enrolled 36 patients with recurrent and/or metastatic disease and treated them with the combined regimen. The overall response was 60.6% (21.2% complete responders and 39.4% partial responders), and the 1-year survival rate was 43.2%. Twenty-four percent of patients were alive after 2 years.

Of those enrolled, 14 had previously been treated with surgery and radiation, and 22 had been treated with radiation and chemotherapy, Dr. Raguse said. The median age of patients was 59 years, and overall survival was nearly 1 year in 60% of the study’s patients, he said. Median survival for those receiving conventional palliative chemotherapy is usually in the 4-to6-month range, the poster said.

Another advantage of the oxaliplatin regimen was that the treatment was administered over a 24-hour period, compared with the corresponding cisplatin regimen, which often occurs over the course of a week.

However, drawbacks of the oxaliplatin regimen included paresthesias and other adverse effects. All patients who received more than 3 cycles of oxaliplatin developed paresthesias, and dose reduction was necessary in 2 patients due to grade-3 diarrhea, according to the abstract.

Locoregional recurrence occurred in 60% of patients, with distant metastases in 25%.

“Oxaliplatin has nearly the same action as cisplatin, which has been used to treat these patients for years, but it is not nephrotoxic,” Dr. Raguse said.

Source:
Presentation title: Oxaliplatin, Folic Acid, and 5-Fluorouracil [OFF] in Recurrent Advanced Head and Neck Cancer: a Phase II Trial. Poster 016 – AHNS 2006

August, 2006|Archive|

Cancer stem cells – new and potentially important targets for the therapy of oral squamous cell carcinoma

  • 8/23/2006
  • Bergen, Norway
  • DE Costea et al.
  • Oral Dis, September 1, 2006; 12(5): 443-54

There is increasing evidence that the growth and spread of cancers is driven by a small subpopulation of cancer stem cells (CSCs) – the only cells that are capable of long-term self-renewal and generation of the phenotypically diverse tumour cell population. Current failure of cancer therapies may be due to their lesser effect on potentially quiescent CSCs which remain vital and retain their full capacity to repopulate the tumour. Treatment strategies for the elimination of cancer therefore need to consider the consequences of the presence of CSCs.

However, the development of new CSC-targeted strategies is currently hindered by the lack of reliable markers for the identification of CSCs and the poor understanding of their behaviour and fate determinants.

Recent studies of cell lines derived from oral squamous cell carcinoma (OSCC) indicate the presence of subpopulations of cells with phenotypic and behavioural characteristics corresponding to both normal epithelial stem cells and to cells capable of initiating tumours in vivo. The present review discusses the relevance to OSCC of current CSC concepts, the state of various methods for CSC identification, characterization and isolation (clonal functional assay, cell sorting based on surface markers or uptake of Hoechst dye), and possible new approaches to therapy.

Authors:
DE Costea, O Tsinkalovsky, OK Vintermyr, AC Johannessen, and IC Mackenzie

Authors’ affiliation:
Bergen Oral Cancer Group, Department of Oral Sciences, Oral Pathology and Forensic Odontology, University of Bergen, Bergen, Norway

August, 2006|Archive|

Surgical salvage for local and regional recurrence in oral cancer

  • 8/23/2006
  • Baltimore, MD
  • RA Ord
  • J Oral Maxillofac Surg, September 1, 2006; 64(9): 1409-14

Purpose:
To evaluate local and regional recurrence and the outcomes for salvage surgery in patients for oral cancer.

Patients and Methods:
This study analyzed 354 consecutive patients with oral cancer treated primarily by surgery or surgery combined with adjuvant therapy by 1 surgeon (R.A.O.) between February 1991 and September 2001.

Results:
Overall recurrence rate was 15.5%; with 5.4% local, 8.5% regional, and 1.4% locoregional. Overall salvage for local recurrence was 52.6% 3-year survival, and statistically significant favorable prognostic factors were salvaged by surgery alone and initial cancer staging of I/II. Overall salvage for regional recurrence was 50%, with recurrence in a previously untreated neck and salvage with radical neck dissection plus radiotherapy giving the best prognosis. No patients with locoregional recurrence were salvaged.

Conclusions:
Patients who were stage I/II and were treated initially by surgery alone were the best candidates for salvage if they recurred. Salvage was best achieved with surgery or surgery + adjuvant therapy, and patients recurring within 6 months had a worse survival. Patients with locoregional recurrence or treated with RT +/- chemotherapy alone have negligible survival.

Authors:
RA Ord, A Kolokythas, and MA Reynolds

Authors’ affiliation:
Department of Oral and Maxillofacial Surgery, University of Maryland, Greenbaum Cancer Center, Baltimore, MD

August, 2006|Archive|