Monthly Archives: June 2005

Harmonic scalpel could reduce operative time and blood loss in patients

  • 6/29/2005
  • Augusta, Georgia
  • staff report
  • News-Medical.net (www.news-medical.net)

A harmonic scalpel that uses ultrasound to coagulate as it cuts can reduce blood loss and postoperative facial paralysis in patients who need a portion of their salivary gland removed, surgeons say.
Infection of the sponge-like parotid gland is uncomfortable but temporary, says Dr. Christine G. Gourin, otolaryngologist at the Medical College of Georgia.

But when the gland develops cancerous or benign tumors or stones that interfere with saliva flow, a rather tricky surgery to remove part or all of the gland is needed.

Surgical removal is delicate because the parotid sits between the cheekbone and jawbone and the facial nerve runs right through it, Dr. Gourin says of the gland which contributes a watery fluid to the saliva mix that helps lubricate the mouth and tongue and digest food.

The standard approach is making an incision in a skin fold in front of the ear that runs back into the hairline – the same as for a facelift – then using surgical scissors to remove the gland and surgical ties or electrocautery to stop bleeding.

A small pilot study published in Otolaryngology – Head and Neck Surgery in 2004 described how the harmonic scalpel could reduce operative time and blood loss in patients who had benign disease and needed only a portion of their gland removed.

The new expanded study, published in the June issue of Laryngoscope, compared a larger mix of patients: 41 patients who underwent conventional surgery and 44 who underwent harmonic scalpel parotidectomy for benign or malignant disease and required superficial or total gland removal.

In the superficial group, the harmonic scalpel reduced blood loss during surgery, drainage afterward and facial nerve trauma, says Dr. Gourin, corresponding author on the study.

In the 13 patients who needed total parotidectomy, no significant differences were noted between the four who had conventional surgery and the nine who had harmonic scalpel parotidectomy. Researchers say their findings warrant further study of the scalpel’s potential in patients with malignancies who need their entire gland removed.

“We pooled our data and looked at patients with all kinds of tumors and more extensive surgery and found that the harmonic scalpel was just as effective when it was used for malignant disease,” says Dr. Gourin. “When malignant disease involves the deep lobe of the parotid gland underneath the facial nerve, there is more risk from the surgery but the harmonic scalpel appears to be safe for use in this area.”

While the number of patients with deep lobe disease was small, the evidence showed the harmonic scalpel worked as well as the standard approach and suggested a trend toward some of the same improvements seen with less extensive surgery, Dr. Gourin says.

The facial nerve is the main reason Dr. Gourin sought better surgery options. “Anything we use in the parotid gland to cut tissue or stop bleeding cannot harm the nerve. Standard electrocautery is not a great option because there is a rim of thermal injury around the tip of the cautery blade that can theoretically injure facial nerve branches,” Dr. Gourin says. The harmonic scalpel, which uses ultrasonic vibrations instead of electricity to coagulate tissue, doesn’t have this potential for collateral injury.

Facial nerve injury, resulting in paralysis including a droopy smile and inability to completely close the eye, is the biggest risk of parotidectomy. Another consequence can be a sunken-look where the parotid is removed. Dr. Gourin and her MCG colleagues now use fat from the abdomen to fill the deficit. “We are doing it more and more,” even with cancer because the fat will not interfere with follow-up treatment, she says.

She noted that about 80 percent of parotid tumors are benign but must be removed because they keep growing and risk becoming malignant.

The harmonic scalpel came into use in 1993 and is widely used for other head and neck surgeries, such as thyroid surgery, where it’s been shown to reduce surgery time, and tonsillectomy, where it reduces postoperative pain. Patients included in the parotid gland study were treated at MCG Medical Center and the Veterans Affairs Medical Center in Augusta from 1999-2004.

June, 2005|Archive|

Cancer treatment targets villains

  • 6/29/2005
  • Scranton, PA
  • Jeff Sonderman
  • The Times Tribune

Cancer researchers are always fighting a battle on two fronts: finding treatments that work while limiting the debilitating side effects. Doctors at the Northeast Radiation Oncology Center in Dunmore are testing a method that may do both.

The new treatment ­— radioimmunotherapy — goes by the less tongue-tying nickname “liquid radiation.” It uses the body’s immune system to fight non-Hodgkin’s lymphoma, the sixth-most-common cancer in the United States.

About a half-dozen people in Northeastern Pennsylvania have gotten this treatment in the past six months at NROC, which was created in October 2003 as a partnership between four cancer doctors and Mercy Hospital in Scranton.

Clinical trials nationwide have shown that as many as eight of every 10 lymphoma patients are responsive to the treatment.

Liquid radiation uses tiny radioactive particles attached to antibodies that target cancerous cells.

When the antibody arrives, the particle then penetrates and kills that specific cancer cell, leaving other healthy cells undamaged.

This allows effective treatment with little or no pain or side effects.

“The problem with traditional chemotherapy is it gives you a lot of side effects,” said Chi K. Tsang, M.D., one of the four oncologists at the Northeast Radiation Oncology Center. “(Liquid radiation, however,) goes after where the cancer is, and only the cancer.”

Patients get several diagnostic scans before the treatment, and report for blood tests in the weeks or months afterward. The injection itself takes only about 10 minutes from an IV needle, said Harmar Brereton, M.D., another oncologist at NROC.

The Food and Drug Administration has approved it only for patients who have already tried conventional therapy for non-Hodgkin’s lymphoma.

Eventually, however, the strategy of liquid radiation could be used to treat other types of cancer. The well-established cancer treatments, chemotherapy and radiation, also were developed first for lymphoma and then expanded to other cancers, Dr. Brereton said.

Researchers are trying to adapt liquid radiation for breast cancer and prostate cancer. “It is all experimental, but it is simply a matter of time,” Dr. Brereton said.

June, 2005|Archive|

Standard Whole Body PET/CT Misses Distant Lesions

  • 6/29/2005
  • Toronto, Ontario, Canada
  • Pippa Wysong
  • Medscape (/www.medscape.com)

The routinely used whole body (WB) positron emission tomography (PET)/computed tomography (CT) scans, also known as limited whole body (LWB), can miss more than 5% of metastatic cancer lesions, according to researchers from Saint Louis University (SLU) who presented their findings here at the Society of Nuclear Medicine 52nd Annual Meeting.

Researchers suggest true whole body (TWB) scans would provide better staging and restaging. That is, scans from head to toe, as opposed to from the base of the skull to about midthigh.

The term “whole body” is somewhat misleading, according to the poster, coauthored by Medhat Osman, MD, from SLU. These scans are done with the patients’ arms up, and the most commonly used field of view does not cover the entire body.

WB scans do not include the brain or the skull, plus it leaves out portions of the upper and lower extremities.

A study was done to see whether performing TWB scans revealed additional lesions above and beyond the traditional approach.

A total of 500 consecutive cancer patients underwent F-18 fluorodeoxyglucose-PET (FDG-PET)/CT scans that extended from the top of the skull to the bottom of their feet. Scans were done 60 minutes after patients received an injection of 0.14 mCi per kg of FDG.

Patients in whom it was already known that malignancies were present outside of the normal LWB area were excluded from the study.

The images were evaluated and newly suspected metastases outside the normal LWB areas were recorded. These newly found lesions in the brain skull and upper or lower extremities were followed up to confirm that they were indeed cancerous.

New lesions were found in 35 (7%) patients, but what the lesions were in two of patients was not confirmed because of a problem with follow-up.

In the remaining 33 patients, five of the lesions yielded false-positive results, whereas metastatic involvement was confirmed in the remaining 28 patients. This gave an overall rate of 5.6% of patients who had metastatic lesions that would have been missed with the traditional WB field of view.

“Of importance, two of the 28 patients had their only metastatic lesion outside the typical WB,” according to the poster.

Doing TWB takes a few minutes longer than the traditional field of view. The researchers are now investigating how the detection of lesions outside the LWB may affect patient treatment.

Patients in the study had a variety of cancers, including lung, melanoma, lymphoma, head and neck, hepatocellular, colon, and more.

It would have been interesting to see more details regarding which new lesions were found in which type of cancer, said Ghassan El-Haddad, MD, a senior nuclear medicine resident at the University of Pennsylvania, Philadelphia. Dr. El-Haddad was not involved in the study.

Dr. El-Haddad points out that TWB is already done in certain types of cancer such as melanoma. He said that “skin metastasis can occur anywhere.” Generally, TWB is not done for cancers such as lung or breast because it is rare that there would be metastases to the toes or hands.

“That is why people do not do it,” Dr. El-Haddad said. He agreed that further studies could elucidate whether TWB would change how physicians manage patients with specific cancers.

There was no commercial support reported for this study.

June, 2005|Archive|

Radioprotective potential of ginseng

  • 6/27/2005
  • Tung-Kwang Lee et al.
  • Mutagenesis 2005 20(4):237-243; doi:10.1093/mutage/gei041

A majority of potential radioprotective synthetic compounds have demonstrated limited clinical application owing to their inherent toxicity, and thus, the seeking of naturally occurring herbal products, such as ginseng, for their radioprotective capability has become an attractive alternative.

In general, ginseng refers to the roots of the species of the genus Panax. As a medicinal herb, ginseng has been widely used in traditional Chinese medicine for its wide spectrum of medicinal effects, such as tonic, immunomodulatory, antimutagenic, adaptogenic and antiaging activities. Many of its medicinal effects are attributed to the triterpene glycosides known as ginsenosides (saponins).

This review addresses the issue of the radioprotective effects of ginseng on mammalian cells both in vitro and in vivo. Results indicate that the water-soluble extract of whole ginseng appears to give a better protection against radiation-induced DNA damage than does the isolated ginsenoside fractions. Since free radicals play an important role in radiation-induced damage, the underlying radioprotective mechanism of ginseng could be linked, either directly or indirectly, to its antioxidative capability by the scavenging free radicals responsible for DNA damage. In addition, ginseng’s radioprotective potential may also be related to its immunomodulating capabilities.

Ginseng is a natural product with worldwide distribution, and in addition to its antitumor properties, ginseng appears to be a promising radioprotector for therapeutic or preventive protocols capable of attenuating the deleterious effects of radiation on human normal tissue, especially for cancer patients undergoing radiotherapy.

Authors:
Tung-Kwang Lee1, Roberta M. Johnke1, Ron R. Allison1, Kevin F. O’Brien2 and Larry J. Dobbs, Jr3

Authors’ affiliations:
1Department of Radiation Oncology, Leo W.Jenkins Cancer Center, Brody School of Medicine at East Carolina University, 2Department of Biostatistics, East Carolina University School of Allied Health and 3Department of Pathology and Laboratory Medicine, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA

June, 2005|Archive|

Recurrent squamous cell carcinoma in the neopharynx treated successfully with topical 5-fluorouracil

  • 6/26/2005
  • England
  • R Banga, J Ramsden, and G Cox
  • J Laryngol Otol, May 1, 2005; 119(5): 403-4

We present the first reported case of a squamous cell carcinoma recurrence on a reconstructed flap in the pharynx treated successfully with topical chemotherapy.

The patient, treated for a pharyngeal cancer with resection and reconstruction with a free radial forearm flap, and post-operative radiotherapy, developed a tumour on the flap more than two years after surgery. The recurrence was also squamous carcinoma, but there was only superficial infiltration. This was treated with 5-fluorouracil paste placed in the pharynx, with resolution of the tumour.

The patient was alive and well more than 28 months after this treatment, with no sign of disease recurrence. Topical chemotherapy for treatment of oral cancer is well described for early disease, but we show that it may be a useful treatment in recurrent disease in selected patients.

Authors’ affiliation:
Department of Otolaryngology – Head and Neck Surgery, Radcliffe Infirmary, Oxford, UK

June, 2005|Archive|

Michigan Dental Association Launches New TV Ad Campaign to Educate the Public About the Link Between Oral Health and Overall Health

  • 6/26/2005
  • Lansing, MI
  • press release
  • biz.yahoo.com

The 5,900-member Michigan Dental Association will launch a new campaign to alert the public that a healthy mouth is vital to a healthy body. The new campaign, “Want a healthy body? Start with a healthy mouth,” kicks off June 27 with two television commercials that will air statewide, and will inform the public of some startling new research, including connections between dental health and birth complications in expectant mothers.

To view the commercials and learn more about the campaign, go to http://www.smilemichigan.com and click on the public section. Each MDA member dentist will have patient education brochures and posters available in their offices.

“More and more research shows that there is an important connection between oral health and overall health,” according to Josef F. Kolling, DDS, MS, president of the MDA. “Since the condition of your mouth mirrors the condition of your body as a whole, your dentist may be the first health care provider to see signs of a health problem,” according to Kolling. “If something unusual is discovered, a follow-up with your physician may result in early detection and successful treatment of a more serious medical problem.”

Kolling says, “The dentist may see symptoms on the lips, tongue and gums that can warn of trouble in your general health. Your dentist can screen for oral cancer, and may also observe oral symptoms of conditions such as diabetes, heart disease and pregnancy complications.”

Oral Cancer

Oral cancer is the sixth most common cancer in the U.S. and about 25 percent of people diagnosed with oral cancer have none of the traditional risk factors, such as the use of tobacco products or drinking alcohol. African Americans in Detroit have one of the highest rates of oral cancer in the country and have the highest mortality rate due to oral cancer among all race and gender groups. In addition, 46 percent of all deaths related to oral cancer in Michigan are found in the Detroit/Wayne County area.

Dentists can now use a new tool to detect oral cancer in its earliest stages. The brush biopsy allows the dentist to scrape cells from the tissue and send them to the lab for analysis. According to Kolling, “This simple screening device represents a breakthrough in the fight against cancer and is expected to aid in the early diagnosis of oral cancer and improve the survival rate.”

June, 2005|Archive|

Scientists Announce World’s Most Sensitive Cancer Test

  • 6/26/2005
  • Germany
  • Josef Käs
  • Science Daily (www.sciencedaily.com)

Speaking at the Institute of Physics conference Physics 2005 in Warwick recently (Tuesday 12th April), scientists revealed a new test for cancer, more sensitive than any existing technique and capable of predicting for the first time whether a tumour has spread

Unlike existing techniques which rely on expert visual assessment or unreliable biochemical measurements, the “optical stretcher” tests the physical strength of each cell and can give a diagnosis using as few as 50 cells, allowing doctors to test for cancer where traditional biopsies are dangerous or even impossible. The ability to measure the progress of a cancer by examining only the primary tumour should reduce the number of unnecessary and traumatic mastectomies in women with breast cancer.

Professor Josef Käs and Dr Jochen Guck from the University of Leipzig have been developing the new procedure for several years and today described how the system is being tested, both to screen for oral cancers and in the “staging” of breast cancer tumours.

Professor Käs’ technique for the first time uses a physical characteristic of each cell – its stretchiness or elasticity – instead of its biological make-up, to decide whether or not it’s cancerous. Cancer cells tend to de-differentiate, losing the special characteristics of the organ where they started life. Because of this, they no longer need the rigid cytoskeleton which holds them in shape, making them stretchier than normal cells.

Käs and Guck’s machine uses a powerful beam of infrared laser light to stretch and measure cells one by one. His optical stretcher differs from an existing tool known as optical tweezers in which the light is focused to a sharp point to grab hold of a cell. In contrast, the optical stretcher doesn’t use focused light. This allows laser beams strong enough to detect stretching to be used without killing the cell.

“Of all the physical properties of a cell,” explains Professor Käs, “elasticity is the one which varies most dramatically between normal and cancerous cells.” This makes stretching the most sensitive method known for identifying cancer. Just 50 tumour cells are needed in a sample for the optical stretcher to diagnose cancer, contrasting with traditional methods which need 10,000 to 100,000 cells. With such small samples, diagnoses can be made even before solid tumours develop, or where a traditional biopsy is problematic.

More importantly, the optical stretcher can yield crucial information on the spread of cancer. The softer the cancer cells, the more likely they are to travel through the body and produce secondary tumours (known as metastases). Traditionally, doctors have had to check nearby lymph nodes for cancer cells. However, the optical stretcher can determine, just by measuring cells from the primary tumour, whether or not the cancer will spread. This is the first time that anyone has been able to diagnose metastasis without locating the secondary tumours.

Secondary tumours can be difficult to find, and women with breast cancer often undergo precautionary mastectomy or whole-body chemotherapy. The optical stretcher will allow many women to avoid the emotional and physical side-effects of such unnecessary treatment.

The optical stretcher can test as many as 3,600 cells per minute, so is already fast enough to be useful in clinical diagnosis of cancer. Professor Käs believes that this high speed and the equipment’s low cost could even herald a shift towards cancer prevention. Dentists, for example, could swab their patients for mouth cancer cells even before a solid tumour develops. Pre-clinical trials are already underway in Germany, and Professor Käs is keen for an industrial partner to see his prototype machine through to full clinical testing.

Professor Josef Käs is Director of the Institute for Soft Matter Physics at the University of Leipzig, Germany.

June, 2005|Archive|

Alteration of radiotherapy fractionation and concurrent chemotherapy: a new frontier in head and neck oncology?

  • 6/26/2005
  • Jacques Bernier
  • Nature Clinical Practice Oncology (2005) 2, 305-314

Summary
Despite recent advances in multimodality management of patients with stage III−IV head and neck squamous cell carcinoma, the prognosis in these patients remains disappointing. In an attempt to improve treatment outcome, several teams recently investigated the role of altered fractionation radiotherapy in conjunction with systemic chemotherapy. The controlled trials that investigated this combined approach indicate that, although the magnitude of its effect was less marked for survival indices than for local-regional control, the addition of chemotherapy to altered fractionation regimens results in a clear improvement for these endpoints compared with hyperfractionated or accelerated regimens alone. The key challenge now is to optimize the synergism of these regimens in order to increase their therapeutic ratio in terms of both local-regional and systemic outcomes. This review is a critical appraisal of the real opportunities offered by the application of treatments aimed at increasing the dose intensity of radiotherapy delivered concurrently with cytotoxic drugs.

Introduction
Head and neck squamous cell carcinomas (HNSCC) represent 4−5% of all solid malignancies, with almost half a million cases diagnosed annually worldwide.1 Until the late 1970s radiation therapy was the treatment of choice for locally advanced HNSCC but, despite significant technologic improvements in radiation therapy, the high incidence of local-regional recurrences continued to pose the greatest threat.2 Tumor hypoxia, repopulation of tumor cells during treatment, and intrinsic resistance to radiotherapy, have all been implicated as causes of treatment failure.3, 4 From the late 1970s, altered fractionation radiation therapy was extensively investigated in an attempt to target some of these factors.5, 6, 7

In parallel, systemic chemotherapy applied to advanced HNSCC had demonstrated good indices of antitumor activity.8 Throughout the last two decades, therefore, chemotherapy was often added to radiotherapy, with many clinicians opting for a concurrent delivery approach for these two modalities.9, 10, 11 The biological rationale for this was twofold. First, tumor-cell clonogens could be sensitized by the concurrent delivery of chemotherapy and ionizing radiation.12 Second, the irradiated tumor and micrometastases were exposed at the same time to the drugs’ cytotoxic effects. From the biological viewpoint, concurrent chemotherapy and radiotherapy is also likely to help clinicians implement more efficacious, multitargeted therapies directed towards—among others—cell killing, oxygen-factor manipulation, cell-cycle alteration and signaling pathways attack.

Many clinical trials showed that concurrent chemotherapy and radiation therapy—also referred to as chemotherapy-enhanced radiation therapy (CERT)13—could improve the prognosis of patients with locally advanced disease.14, 15 The fact that local-regional recurrences remained a major cause of failure, however, led a number of institutions to investigate the additional impact of radiotherapy dose intensification on disease control. While the first CERT trials were based on the use of conventional fractionation radiotherapy, also called CERT-conventional fractionation (CERT-CF) a variety of hyperfractionation and acceleration schedules, known collectively as CERT-altered fractionation (CERT-AF), were more recently tested in conjunction with chemotherapy.16 This review is a critical appraisal of the real opportunities offered by the application of treatments that aim to increase the dose intensity of radiotherapy delivered concurrently with cytotoxic drugs.

The road to modern CERT-AF regimens

Altered fractionation
A conventional course of radiation for HNSCC generally delivers 70−72 Gy in 7−7.5 weeks, with a once-daily dose of 1.8−2.0 Gy delivered over 36−40 fractions. In the late 1970s, to optimize treatment delivery various efforts were initiated to alter the conventional fractionation regimen and to test new schedules; this was termed altered fractionation.17 Altered fractionation regimens allow multiple fractions per day that are smaller than the standard once-daily 1.8−2 Gy dose. There are two types of altered fractionation: hyperfractionation and accelerated fractionation. Hyperfractionation relates to radiotherapy delivered for each fraction rather than the total treatment time, and in this regimen small doses per fraction are delivered—in most cases, 1.10−1.25 Gy/fraction for a total of 56 fractions, over a relatively standard period of time (usually 7 weeks). Accelerated fractionation relates to the intensity of total dose delivered over time; the fraction size is usually larger (e.g. 1.6−1.8 Gy/fraction) and delivered more than once daily, and to a dose of 10 Gy per week but treatment is delivered over a reduced total period of time (usually 6 weeks or less) compared with hyperfractionation.

Both hyperfractionation and accelerated fractionation cause increased acute morbidity relative to conventional fractionation. Hyperfractionation aims to improve efficacy by increasing the total dose while maintaining the total treatment time and risk of late morbidity relative to standard fractionation. It exploits the difference in fractionation sensitivity between tumors and normal tissues, which lead to late morbidity, and can enhance tumor-cell killing without significantly increasing late toxicity.18 In contrast, accelerated fractionation relates to the intensity of radiation therapy delivered over time; a schedule that exceeds 10 Gy per week is classified as accelerated. Total dose must be equivalent to or slightly reduced relative to standard radiotherapy regimens in order to prevent increased late morbidity. The aim of accelerated regimens is to target tumor proliferation, which is a major cause of radiotherapy failure. Treatment acceleration helps overcome this problem because it counterbalances tumor-cell repopulation, especially in fast-growing tumors such as head and neck carcinomas.18

In terms of local-regional control, small but significant gains were observed when hyperfractionation and accelerated fractionation were tested in randomized trials, which showed that altered fractionation significantly enhances local control rates with P values of less than 0.0001. Compared with conventional regimens of 2 Gy daily fractions, hyperfractionation and acceleration also yield a small but significant benefit in terms of overall survival.19, 20 In a recent meta-analysis conducted at Villejuif,20 an absolute benefit of 3% (from 36 to 39%, hazard ratio [HR] 0.92, 95% CI 0.87−0.97; P = 0.004) was observed at 5 years in favor of the altered fractionation regimens.

CERT-CF regimens
Platinum-derived compounds and 5-fluorouracil (5-FU) are the chemotherapeutic drugs that have been most widely used in prospective trials on CERT-CF.21, 22 These drugs have been shown to sensitize cells to radiation therapy. Radiation-induced free radicals, adduct formation, DNA-damage-repair inhibition and a radiation-induced increase in cellular platinum uptake were among the potential mechanisms associated with cisplatin-mediated radiation sensitization, induced by the enhanced formation of toxic platinum intermediates.12, 23 The selectivity of the platinum radiosensitization remains unclear, however.

The rationale for adding chemotherapy to radiation therapy is based on three main clinical observations. First, although 70−75% of patients with stage III−IV disease remain free of disease at 2 years, their long-term prognosis is poor: 5-year survival rates rarely exceed 30−35%. Second, despite the fairly high number of deaths linked to concomitant diseases, the incidence of metastases can reach 15−20%. Third, a variety of cytotoxic agents have demonstrated efficacy against epithelial-cell cancers. The CERT-CF approach thus represents a logical extension of the protocols based on radiotherapy alone, and was adopted as the standard of care when the results of several meta-analyses demonstrated the superiority of the combined treatments over irradiation alone.24, 25, 26, 27, 28 In a recent analysis by Bourhis et al.,29 the HR calculated for survival rates following CERT versus radiotherapy was 0.81 (P <0.0001). Nonetheless, treatment toxicity and, in particular, early reactions, are often a limiting factor when attempts are made to intensify local-regional therapy. Although cisplatin when used as single-agent chemotherapy in CERT-CF was shown to have little effect on mucous membranes,15 acute mucosal reactions are likely to reduce and delay chemotherapy delivery, and/or prolong overall treatment time.

CERT-AF regimens
Between 1998 and 2005, seven prospective trials30, 31, 32, 33, 34, 35, 36 and one influential retrospective study37 addressed the efficacy of CERT-AF. All studies compared altered fractionation with CERT-AF. Five trials compared accelerated fractionation alone versus accelerated fractionation with chemotherapy, and in two studies altered fractionation and CERT-AF were based on hyperfractionation regimens. Four of the seven trials combined a chemotherapeutic drug—cisplatin, carboplatin or mitomycin C—with 5-FU, and the other three used mono-chemotherapy (cisplatin or mitomycin C)

Treatment outcome after CERT-AF
In the controlled trials that investigated CERT-AF, the common theme was a significant enhancement of local-regional control rates.30, 31, 32, 33, 35, 36, 37 This trend was observed for the various radiotherapy and chemotherapy schedules tested. The trial by Staar and co-workers34 was the only study that did not observe any increase in local-regional control for the experimental arm, but it is not clear whether this trial had sufficient statistical power to resolve a clinically relevant difference between the altered fractionation and CERT-AF effects. Although the magnitude of the CERT-AF effect was less marked for survival indices than for local-regional control, the addition of chemotherapy to altered fractionation regimens results in a clear improvement for these endpoints.

In the absence of a direct and randomized study, any comparative analysis between fractionation schedules or chemotherapy regimens is likely to be biased by, for instance, variations in patient selection. This review nevertheless suggests that, while it is not possible to determine whether accelerated fractionation is superior to hyperfractionation or vice versa, mono-chemotherapy appears to be as affective as multi-agent chemotherapy, because patients treated with only one cytotoxic agent (cisplatin or mitomycin C) benefited to a similar extent as those receiving either cisplatin or carboplatin in combination with 5-FU.

Compliance to treatment and acute side effects
Patient compliance to different treatment protocols varied significantly across the randomized trials and data must be interpreted with caution. Compliance to radiotherapy was clearly affected by the addition of chemotherapy in only two studies.30, 31 For example, although Brizel and colleagues31 reported differences across the two arms of the study in terms of the mean radiotherapy dose (74.00 2.73 Gy in the altered fractionation arm versus 70.50 1.6 Gy in the CERT-AF arm, P <0.001) and overall treatment time (42 6 days versus 47 5 days, P <0.001), it should be noted that this trial was intentionally designed so the radiotherapy alone arm would deliver higher doses over a shorter time period compared with the CERT-AF arm. Thus, in this trial, the compliance was excellent and in concordance with the protocol design. The acute toxicity induced by CERT regimens was shown to vary considerably for different studies. For example, the incidence of grade 3 and 4 mucositis ranged from 16 to 90% in the altered fractionation group; in the CERT-AF arms, it ranged from 38 to 95%. CERT-AF significantly increased the mucosal reaction intensity compared with altered fractionation in only two of the seven trials.30, 34 Non-hematologic acute toxicity was significantly enhanced by CERT-AF for some endpoints only. As expected, hematologic toxicity was more severe in the chemotherapy-containing arm but remained acceptable in all trials.

The advantages of aggressive interventions are also offset by treatment-related toxicities, such as severe mucositis, dysphagia, and weight loss. The transient nature of these acute toxicities, however, is also dependent on the effectiveness of supportive care, such as aggressive monitoring, early hospitalization, antibiotic therapy for neutropenic fever, and prompt nutritional intervention, all of which are known to be of critical importance. Although the toxicity encountered in patients treated with CERT-AF regimens can sometimes be formidable, it appears to remain manageable if handled by teams with expertise in supportive care. The addition of 5-FU to cisplatin or carboplatin might reduce the THERAPEUTIC RATIO of CERT-AF, as demonstrated in two trials using multi-agent chemotherapy30, 34 where a significant increase in the incidence of severe mucositis was observed compared with patients treated with mono-chemotherapy.

Treatment Toxicity
In terms of acute toxicity, side effects were observed more often during CERT-AF for some endpoints only, such as confluent mucositis or severe emesis . Undoubtedly, this increase in side effects results from the significantly enhanced cytotoxicity yielded by the high dose-intensity levels of CERT-AF compared with those of altered fractionation alone, especially in normal tissues, such as mucosa, which are characterized by a fast cell repopulation.

Differences in late toxicity across the two arms are reported in three of the seven reviewed trials,30, 31, 34 in which investigators observed that, following CERT-AF, there were higher incidences of severe diffuse laryngopharyngeal edema—necessitating a feeding tube in a significant number of patients— as well as of mucosal necrosis and severe muscular fibrosis. In the remaining four trials32, 33, 35, 36 no difference in late toxicity was observed between the altered fractionation and CERT-AF groups.

Optimization of radiotherapy and concurrent chemotherapy
The management of patients with locally advanced HNSCC has undergone a major paradigm shift during the past decade. Local control is paramount in the treatment of these patients and since the 1970s intensive efforts have been made to test the efficacy of various CERT regimens, in an attempt to improve further the prognosis of stage III−IV disease.16 The literature indicates that CERT-AF significantly enhances local-regional control rates (Box 2) and, in most studies, has been shown to improve survival indices compared with those observed after altered fractionation alone.30, 31, 32, 33, 34, 35, 36 The improved survival rates seen with CERT-AF are also associated with a high toxicity, however. For most endpoints the toxicity is not significantly higher than that observed after altered fractionation. The severity of toxicity might be a function of the dose intensity of the selected CERT-AF regimen, especially if the chemotherapy combination contains 5-FU. To investigate whether radiotherapy dose intensity and 5-FU-containing chemotherapy regimens increase toxicity severity, future randomized trials would require a factorial 2 2 design to test this formally.

Key messages from trials comparing altered fractionation with chemotherapy-enhanced radiation therapy-altered fractionation
Chemotherapy-enhanced radiation therapy-altered fractionation (CERT-AF) has the most significant impact on local-regional disease control
There are improved survival indices with CERT-AF
There is increased acute toxicity with CERT-AF, but this is still manageable
There is no significant enhancement of late toxicity with CERT-AF
There is similar efficacy of hyperfractionation and accelerated fractionation schedules in CERT-AF
Mono-chemotherapy is as efficient as multidrug chemotherapy
Careful selection of regimens and patients is of critical importance

The data retrieved from these published trials clearly reveals two conclusions. First, in most studies, the enhancement in efficacy observed for altered fractionation doesn’t differ significantly between hyperfractionated and accelerated regimens. Second, in patients treated with CERT-AF, mono-chemotherapy is as effective as multidrug regimens. This finding correlates with the results of the meta-analysis conducted by Bourhis et al.,29 which did not demonstrate any significant difference in terms of efficacy between mono-chemotherapy (HR = 0.84) and multidrug chemotherapy (HR = 0.77). In this meta-analysis, the HR for overall survival gain was lower for CERT-AF (HR = 0.73) compared with CERT-CF (HR = 0.83), indicating that alteration of fractionation might even boost the effects of CERT strategies based so far on conventional radiotherapy regimens. This suggests that CERT-based policies should also be revisited by prospectively comparing the respective efficacy of CF and altered fractionation when combined with concurrent chemotherapy.

Interestingly, the incidence of severe acute and late toxicities varies considerably from one CERT-AF study to another, which might indicate that side effects have not been reported uniformly by the investigators. Also, several late endpoints are often reported for the study as a whole rather than according to treatment arm. This makes a comparison with other studies difficult. The comparative analysis of randomized trials on both altered fractionation and CERT-AF results in high levels of acute toxicity, requiring management by an experienced supportive care team. Caution is therefore needed when introducing this type of therapeutic intervention into community hospitals, because these levels of toxicity imply an intensive supportive care that not all inpatient and outpatient units are able to manage. Moreover, the use of opioids, hospitalization, feeding tube use, and in some cases topical applications, can yield higher costs associated with the treatment of complications caused by CERT-AF-related toxicity.

Two conclusions can therefore be drawn. Despite the fact that most studies document acute toxicity, which can be severe but manageable, more attention should be directed toward possible toxicity reduction, either by modifying the type of drugs combined with radiotherapy, or by adding agents that reduce the sensitivity of normal tissues to cytotoxic attack. For cisplatin-based regimens, further investigations should compare the toxicities of this high-dose “bolus” drug and fractionated (weekly) delivery. In addition, the therapeutic ratio of some CERT-AF regimens might turn out to be lower than that of most altered fractionation schedules. For instance, in the Staar’s study,34 the proportion of long-term survivors who remained dependent on a feeding tube was unacceptable (51%), and this toxicity level indicated that the investigated regimen was too toxic and should be discarded. The results of this study do not imply that CERT-AF should be abandoned, but confirm that combining chemotherapy with intensive radiotherapy warrants caution with respect to both the drug type and dose, and fractionation selection. An inadequate choice of chemotherapy and/or radiotherapy schedule might indeed lead to an undue enhancement in acute or late toxicities likely to jeopardize any increase in therapeutic ratio.

Although the exact magnitude of therapeutic gain afforded by CERT-AF is difficult to estimate from the literature, the late-morbidity results indicate that the clinician’s decision should be made by careful consideration of the benefits and harmful effects of the treatment. This implies that a careful selection of the patients able to sustain CERT-AF dose intensities should be made through an accurate assessment of their general conditions and expected compliance not only to cytotoxic drugs, but also to supra-additive treatments. Finally, although patient mortality associated with locally advanced disease can vary, systemic failures tend to become the overwhelming cause of death. Attention should, therefore, be focused on the control of micrometastases present at the time of diagnosis.

Future options
A complementary and logical approach to improving the prognosis of stage III−IV disease is the addition of more active drugs that might boost the efficiency of CERT-AF regimens; for example cytotoxic drugs such as taxanes,38 or hypoxic-cell-killing agents such as tirapazamine.39 While the concomitant use of docetaxel and irradiation is currently being investigated in phase I and II studies, a randomized phase III trial combining tirapazamine, cisplatin and a conventional regimen of radiotherapy will soon be closed and will give important indications as to the clinical relevance of novel strategies exploiting—rather than overcoming—the presence of hypoxic cells in large tumors. Overexpression of the epidermal growth factor receptor has been correlated with a more aggressive tumor behavior and poor clinical outcome. In terms of both local-regional control and overall survival, the use of epidermal growth factor receptor monoclonal antibodies was recently shown to be a superior strategy to radiotherapy alone, and can be applied, in phase I and II studies, to CERT-AF.40 With respect to radiotherapy side effects, there has been some interest in compounds that could possibly reduce treatment toxicity. One example is the drug amifostine,41 which is currently under investigation, but it is too early to draw definitive toxicity conclusions. This is partly owing to the uncertainty regarding the value of these agents in sparing the salivary gland function after treatments with high-dose intensity radiotherapy.

To intertwine more efficiently the ‘optimal’ radiation fractionation with the ‘best’ concurrent chemotherapy will actually require both the development of highly conformal irradiation techniques, and the use of novel agents to increase tumor-cell killing and ameliorate mucosal toxicity. Regarding chemotherapy, it will be important to continue to develop techniques such as MRI to allow the measurement of intracellular metabolites over time.42 Cisplatin and gemcitabine, which are active in the micromolar range, will require high-sensitivity imaging techniques such as positron-emission tomography.42 With respect to radiotherapy, the delivery of high conformality irradiation, based on techniques of intensity modulation, is bound to spare more normal tissues and therefore allow the use of more vigorous regimens of chemoradiation.

Conclusion
Based on published data, it is clear that the use of altered fractionation and CERT significantly improve efficacy. Although the advantages of improved efficacy can be jeopardized by the severity of acute reactions, long-term complications observed after altered fractionation and CERT-AF appear to be similar, except if the dose intensification of the selected regimen is too marked. Caution should be exercised in interpreting long-term results, however, because for CERT-AF the limits of acute and late toxicities in normal tissues have only been partly elucidated. The results yielded by CERT-AF are encouraging and undoubtedly help us reshape the therapeutic approaches in patients with locally advanced disease. Owing to the use of more efficacious and less toxic combinations, unprecedented opportunities are now available for clinicians in their search for improving tumor control and functional outcomes.

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18. Peters LJ et al. (1992) Altered fractionation schedules. In Principles and practice of radiation oncology, 2nd edn, 97−113 (Eds Perez CA and Brady LW) Philadelphia: J.B. Lippincott
19. Mendenhall WM et al. (2003) Altered fractionation and/or adjuvant chemotherapy in definitive irradiation of squamous cell carcinoma of the head and neck. Laryngoscope 113: 546−551
20. Bourhis et al. (2004) Meta-analysis of conventional versus altered fractionated radiotherapy: in head and neck squamous cell carcinomas (HNSCC): final analysis. 46th American Society of Therapeutic Radiology and Oncology (ASTRO) meeting, 3−7 October 2004, Atlanta. Int J Rad Oncol Biol Phys 60 (Suppl): S190−S191
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June, 2005|Archive|

ImClone Systems to File sBLA for Use of Erbitux in Head and Neck Cancer in Third Quarter 2005

  • 6/26/2005
  • New York City, NY
  • press release
  • Genetic Engineering News (www.genengnews.com)

ImClone Systems Incorporated announced today that, following discussions with the FDA, the Company intends to submit a supplemental Biologics License Application (sBLA) to seek approval for use of Erbitux(R) (Cetuximab) in combination with radiation and as a single agent in Squamous Cell Carcinoma of the Head and Neck (SCCHN) in the third quarter of 2005. The following clinical trials would serve as the basis of the sBLA, together with other supportive data:

1. a randomized, international phase III trial (IMCL-9815), conducted by ImClone Systems and Merck KGaA, presented at the 2004 American Society of Clinical Oncology (ASCO) annual meeting examining the impact of combining Erbitux with radiation on locoregional control and overall survival in 424 patients with locally advanced SCCHN.

and

2. a multicenter phase II trial (EMR-016) conducted by Merck KGaA presented at the 2004 ASCO annual meeting evaluating the response rate of Erbitux as a single agent in 103 patients with advanced recurrent and/or metastatic SCCHN not suitable for further local therapy and who have failed platinum-based chemotherapy.

About Head and Neck Cancer

According to the American Cancer Society, approximately 40,000 Americans will be diagnosed with oral, head and neck cancer this year, including cancers of the tongue, mouth, pharynx, and larynx. More than 11,000 will die from the disease in 2005.

About Erbitux (Cetuximab)

On February 12, 2004, the FDA approved Erbitux for use in the United States in combination with irinotecan in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy and for use as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy. The effectiveness of Erbitux is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux.

June, 2005|Archive|

Introgen receives another Advexin patent

  • 6/26/2005
  • Austin, TX
  • press release
  • Austin Business Journal

Austin biopharmaceutical company Introgen Therapeutics Inc. received a patent that covers many of the features of its Advexin molecular therapy for cancer patients.

The patent is one of a family of patents that cover Advexin issued to the Board of Regents of The University of Texas System and exclusively licensed to Introgen.

“This important patent further expands Introgen’s formidable adenoviral p53 patent portfolio. This particular patent was specifically crafted to directly cover many of the special features of Introgen’s ADVEXIN product candidate, as well as to the host cells that are employed to produce the product,” says David Parker, Introgen’s vice president of Intellectual Property.

To date, Introgen has 30 issued patents and a number of pending patent applications in the U.S. and in foreign countries relating to its Advexin.

In 2003, Introgen’s investigational drug, Advexin, was granted “fast track” designation by the U.S. Food and Drug Administration as a treatment for head and neck cancer.

Introgen develops biopharmaceutical products for the treatment of cancer and other diseases. The company conducts research, development, manufacturing, clinical and regulatory activities at its Austin headquarters.

June, 2005|Archive|