Hyperfractionated radiotherapy improves survival in head and neck cancer patients

Sep. 27, 2013 — The use of an intensified form of radiotherapy in patients with locally advanced head and neck cancers can improve overall survival rates compared with standard radiation therapy, according to results from a large study to be presented at the 2013 European Cancer Congress (ECC2013) [1].

A comparison of altered fractionation radiotherapy (AFRT) with standard fractionation radiotherapy (SFRT) in a meta-analysis of more than 11,000 patients showed an eight percent reduction in the risk of death in the AFRT group, as well as a nine percent reduction in the risk of progression or death.

Dr Pierre Blanchard, a radiation oncologist from the Institut Gustave Roussy, Villejuif, France, will tell the congress that, although concomitant chemoradiation (CRT), where radiotherapy and chemotherapy are delivered together, remains the standard of care for patients with locally advanced head and neck squamous cell carcinomas, AFRT should be considered when treatment intensification is sought-after and CRT is not feasible because of other pre-existing conditions such as cardiac and renal disease.

AFRT is an intensified radiotherapy treatment that can be given in various schedules. The first is hyperfractionation, where radiotherapy is given twice daily ten times per week, resulting in a higher total dose of around 80 Grays (Gy) [2] compared with the dose of 70 Gy given using SFRT in the same overall time (around seven weeks). The second way uses an accelerated schedule, where the overall treatment time is reduced but the dose is kept at the same level or at a lower dose. AFRT is associated with increased acute side effects but not late side effects, compared to SFRT.

"After than more than seven years patient follow-up, our research has shown that the higher dose intensity of AFRT works to improve outcomes," says Dr Blanchard. "The hyperfractionated regime is the most effective in terms of overall survival. Indeed, in this group of trials the risk of death is reduced by 18% by the use of hyperfractionated RT, with 41% of patients alive at five years compared to 33% in the SFRT group. While the acute side effects of AFRT are increased compared to those experienced by patients on SFRT, the late side effects are comparable and, overall, side effects are more than compensated for by the significant increase in survival in the AFRT group."

The meta-analysis was carried out by an international collaboration known as MARCH, including many countries in Europe, the USA, Canada, and Brazil, Egypt and developing countries through the International Atomic Energy Authority. The researchers say that the survival benefits are mostly related to improvements in loco-regional control, the area located close to the primary tumour being by far the most common first site of relapse in this disease.

"These data are a major advance for the understanding of the role in AFRT in head and neck squamous cell carcinoma," says Dr Blanchard. "By carrying out a large-scale analysis such as this one, we believe that we have provided enough evidence to indicate that doctors should recommend AFRT as a validated treatment option for head and neck cancer patients."

Professor Cornelis van de Velde, President of ECCO, said: "This large-scale analysis of patients with head and neck cancer shows that hyperfractionation increases survival, and local control is also improved by the use of this technique. This is an important step forward in the treatment of this devastating disease."

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Hyperfractionated radiotherapy improves survival in head and neck cancer patients

Sep. 27, 2013 — The use of an intensified form of radiotherapy in patients with locally advanced head and neck cancers can improve overall survival rates compared with standard radiation therapy, according to results from a large study to be presented at the 2013 European Cancer Congress (ECC2013) [1].

A comparison of altered fractionation radiotherapy (AFRT) with standard fractionation radiotherapy (SFRT) in a meta-analysis of more than 11,000 patients showed an eight percent reduction in the risk of death in the AFRT group, as well as a nine percent reduction in the risk of progression or death.

Dr Pierre Blanchard, a radiation oncologist from the Institut Gustave Roussy, Villejuif, France, will tell the congress that, although concomitant chemoradiation (CRT), where radiotherapy and chemotherapy are delivered together, remains the standard of care for patients with locally advanced head and neck squamous cell carcinomas, AFRT should be considered when treatment intensification is sought-after and CRT is not feasible because of other pre-existing conditions such as cardiac and renal disease.

AFRT is an intensified radiotherapy treatment that can be given in various schedules. The first is hyperfractionation, where radiotherapy is given twice daily ten times per week, resulting in a higher total dose of around 80 Grays (Gy) [2] compared with the dose of 70 Gy given using SFRT in the same overall time (around seven weeks). The second way uses an accelerated schedule, where the overall treatment time is reduced but the dose is kept at the same level or at a lower dose. AFRT is associated with increased acute side effects but not late side effects, compared to SFRT.

"After than more than seven years patient follow-up, our research has shown that the higher dose intensity of AFRT works to improve outcomes," says Dr Blanchard. "The hyperfractionated regime is the most effective in terms of overall survival. Indeed, in this group of trials the risk of death is reduced by 18% by the use of hyperfractionated RT, with 41% of patients alive at five years compared to 33% in the SFRT group. While the acute side effects of AFRT are increased compared to those experienced by patients on SFRT, the late side effects are comparable and, overall, side effects are more than compensated for by the significant increase in survival in the AFRT group."

The meta-analysis was carried out by an international collaboration known as MARCH, including many countries in Europe, the USA, Canada, and Brazil, Egypt and developing countries through the International Atomic Energy Authority. The researchers say that the survival benefits are mostly related to improvements in loco-regional control, the area located close to the primary tumour being by far the most common first site of relapse in this disease.

"These data are a major advance for the understanding of the role in AFRT in head and neck squamous cell carcinoma," says Dr Blanchard. "By carrying out a large-scale analysis such as this one, we believe that we have provided enough evidence to indicate that doctors should recommend AFRT as a validated treatment option for head and neck cancer patients."

Professor Cornelis van de Velde, President of ECCO, said: "This large-scale analysis of patients with head and neck cancer shows that hyperfractionation increases survival, and local control is also improved by the use of this technique. This is an important step forward in the treatment of this devastating disease."

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Avoiding specific region of brain during whole-brain radiotherapy prevents memory loss

AppId is over the quota
AppId is over the quota
Limiting the amount of radiation absorbed in the hippocampal portion of the brain during whole-brain radiotherapy (WBRT) for brain metastases preserves memory function in patients for up to six months after treatment, according to research presented at the American Society for Radiation Oncology's (ASTRO's) 55th Annual Meeting by researchers from the University of Wisconsin School of Medicine and Public Health, home of the UW Paul P. Carbone Comprehensive Cancer Center.

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Breast conserving treatment with radiotherapy reduces risk of local recurrence

Sep. 18, 2013 — Results of EORTC trial 10853 appearing in the Journal of Clinical Oncology show that breast conserving treatment combined with radiotherapy reduces the risk of local recurrence in women with ductal carcinoma in situ (DCIS). The incidence of DCIS has been increasing in the past decades, and this has been attributed to increased detection through breast cancer screening using mammograms. In the EORTC study, adjuvant radiotherapy after local excision reduced the incidence of both in situ and invasive local recurrences by a factor of two and resulted in an overall lower risk of mastectomy.

Following the introduction of radiotherapy combined with breast-conserving surgery for operable invasive breast cancer in the 1980's, several trials were launched to investigate the addition of radiotherapy to local excision of DCIS. These trials showed that radiotherapy reduced both the risk of DCIS and invasive local recurrences. Now the long-term outcomes of local recurrences and survival in women receiving radiotherapy in combination with breast conserving surgery for DCIS have been investigated at a median follow-up of 15.8 years.

Dr. Mila Donker of The Netherlands Cancer Institute, Amsterdam, and lead author of this paper says, "Survival after treatment for DCIS is excellent. Therefore, the question rises whether the current treatment for DCIS (local excision and adjuvant radiotherapy of the breast) is overtreatment. To answer this question, not only long-term data about local disease recurrences and prognosis are important, but also information about the prognosis and treatment in case of recurrence."

Between 1986 and 1996, the phase III EORTC trial 10853 randomized 1010 women with complete local excision of DCIS to no further treatment (503 patients) or radiotherapy (507 patients). The risk of any local recurrence was found to be reduced by 48% (HR: 0.52, 95%CI 0.40-0.68, P<0.001) in the patients who also received radiotherapy. The 15-year local recurrence-free rate was 69% for the group of patients receiving breast conserving surgery alone, but this increased to 82% for the group of patients who also received radiotherapy, and the 15-year invasive local recurrence-free rate was 84% versus 90%, respectively (HR: 0.61, 95%CI 0.42-0.87).

The differences observed in local recurrence did not lead to differences in breast cancer specific survival or overall survival, but patients with invasive local recurrence did have a significantly worse breast cancer specific survival (HR: 17.66, 95%CI 8.86-35.18) as well as overall survival (HR: 5.17, 95%CI 3.09-8.66) than those who did not recur. Thus, an invasive recurrence resulted in a worse prognosis.

A lower overall salvage mastectomy rate after a local recurrence was also observed in the group of patients who also received radiotherapy, 13%, than in those patients who just received breast conserving surgery, 19%. Thus, radiotherapy after breast-conserving surgery for DCIS resulted in an overall lower percentage of patients who were treated with a mastectomy after a local recurrence.

This study highlights the importance of conducting long term follow-up.

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Radiotherapy in girls and the risk of breast cancer later in life

Sep. 11, 2013 — Exposing young women and girls under the age of 20 to ionizing radiation can substantially raise the risk of their developing breast cancer later in life. Scientists may now know why. A collaborative study, in which Berkeley Lab researchers played a pivotal role, points to increased stem cell self-renewal and subsequent mammary stem cell enrichment as the culprits. Breasts enriched with mammary stem cells as a result of ionizing irradiation during puberty show a later-in-life propensity for developing ER negative tumors -- cells that do not have the estrogen receptor. Estrogen receptors -- proteins activated by the estrogen hormone -- are critical to the normal development of the breast and other female sexual characteristics during puberty.

"Our results are in agreement with epidemiology studies showing that radiation-induced human breast cancers are more likely to be ER negative than are spontaneous breast cancers," says Sylvain Costes, a biophysicist with Berkeley Lab's Life Sciences Division. "This is important because ER negative breast cancers are less differentiated, more aggressive, and often have a poor prognosis compared to the other breast cancer subtypes."

Costes and Jonathan Tang, also with Berkeley Lab's Life Sciences Division, were part of a collaboration led by Mary Helen Barcellos-Hoff, formerly with Berkeley Lab and now at the New York University School of Medicine, that investigated the so-called "window of susceptibility" known to exist between radiation treatments at puberty and breast cancer risk in later adulthood. The key to their success were two mammary lineage agent-based models (ABMs) they developed in which a system is modeled as a collection of autonomous decision-making entities called agents. One ABM simulated the effects of radiation on the mammary gland during either the developmental stages or during adulthood. The other simulated the growth dynamics of human mammary epithelial cells in culture after irradiation.

"Our mammary gland ABM consisted of millions of agents, with each agent representing either a mammary stem cell, a progenitor cell or a differentiated cell in the breast," says Tang. "We ran thousands of simulations on Berkeley Lab's Lawrencium supercomputer during which each agent continually assessed its situation and made decisions on the basis of a set of rules that correspond to known or hypothesized biological properties of mammary cells. The advantage of this approach is that it allows us to view the global consequences to the system that emerge over time from our assumptions about the individual agents. To our knowledge, our mammary gland model is the first multi-scale model of the development of full glands starting from the onset of puberty all the way to adulthood."

Epidemiological studies have shown that girls under 20 given radiotherapy treatment for disorders such as Hodgkin's lymphoma run about the same risk of developing breast cancer in their 40s as women who were born with a BRCA gene mutation. From their study, Costes, Tang and their collaboration partners concluded that self-renewal of stem cells was the most likely responsible mechanism.

"Stem cell self-renewal was the only mechanism in the mammary gland model that led to predictions that were consistent with data from both our in vivo mouse work and our in vitro experiments with MCF10A, a human mammary epithelial cell line," Tang says. "Additionally, our model predicts that this mechanism would only generate more stem cells during puberty while the gland is developing and considerable cell proliferation is taking place."

Costes and Tang are now looking for genetic or phenotypic biomarkers that would identify young girls who are at the greatest breast cancer risk from radiation therapy. The results of their study with Barcellos-Hoff and her research group show that the links between ionizing radiation and breast cancer extend beyond DNA damage and mutations.

"Essentially, exposure of the breast to ionizing radiation generates an overall biochemical signal that tells the system something bad happened," Costes says. "If exposure takes place during puberty, this signal triggers a regenerative response leading to a larger pool of stem cells, thereby increasing the chance of developing aggressive ER negative breast cancers later in life."

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