October 2009

Odds and Ends

An ESUN Resource

Chemotherapy in adult soft tissue sarcoma

Recent results of various meta-analyses and development of newer drugs have changed the medical management of soft tissue sarcoma. This review article gives an outline of chemotherapy and the newer targeted therapies for treatment of soft tissue sarcoma.  The authors carried out an extensive search in PubMed, Medline for almost all relevant articles concerning chemotherapy of soft tissue sarcoma. The available data from the literature is mainly composed of the most recent reviews, meta-analyses, phase II, and randomized phase III trials published in various peer reviewed journals and various international conferences. The role of neoadjuvant and adjuvant chemotherapy has been found to be controversial. The recent meta-analysis for adjuvant therapy in STSs has shown an increase in the overall survival with combination of ifosfamide and adriamycin. In locally advanced and metastatic STSs, single agent adriamycin remains the basic standard of medication. The combination of ifosfamide and adriamycin may also be used for rapid symptom relief and in patients planned for curative resection for metastases. Newer combinations of docetaxel and gemcitabine appear promising in selected subgroups, especially in leiomyosarcoma and malignant fibrous histiocytoma. Some recent developments include the European Union's approval of trabectedin for advanced STSs patients who had progressed on adriamycin and ifosfamide therapy. The future of mTOR inhibitors, insulin like growth factor receptor inhibitors and anti-angiogenic drugs appear quite promising. Newer methodologies such as, Bayesian adaptive randomization and inclusion of newer end points like progression-free rate, time of progression rate, and tumor growth rate will improve the results of sarcoma trials. The authors also present recommendations from the European Society of Medical Oncology and the National Comprehensive Cancer Network guidelines v.1.2009 for better correlation with the present literature.

 
Flow Cytometric Detection of Ewing Sarcoma Cells in Peripheral Blood and Bone Marrow

How do doctors determine whether a newly diagnosed case of Ewing's sarcoma is local or metastatic?  How accurate are current methods of detecting Ewings Sarcoma cells that have spread throughout the body, but are so small they cannot be detected by current scanning technologies?   According to researchers at the University of California in San Francisco, doctors believe many patients who are found to have local sarcoma also have microscopic spread of disease that goes undetected in the assessment of disease at diagnosis.   The presence of microscopic spread of disease could account for the large numbers of patients who develop recurrence in locations distant from the site of the primary tumor.

In the introduction to this study, the researchers describe the only current technique available for discovering Ewing sarcoma cells circulating in patient blood and bone marrow.  That technique is referred to as RT-PCR (reverse transcriptase-polymerase chain reaction).   The problems with RT-PCR include the fact that the EWS fusion involved in the case under study has to be identified first.   This critical information isn’t usually available early in diagnosis of EWS and researchers point out that it "may never be determined in the clinical care of a patient with Ewing sarcoma."   Moreover, they observe that RT-PCR is "prone to contamination and false-positive results."   This study presents an alternative to RT-PCR using flow cytometry (see definition below). 

The new procedure is described in the study as follows:  "Ewing sarcoma cell line A673, peripheral blood mononuclear cells (PBMCs), and bone marrow mononuclear cells (BMMCs) were stained for CD99 and CD45 in order to detect CD99þCD45_ cells by flow cytometry.  Known quantities of A673 Ewing sarcoma cells were spiked into control PBMCs to test the accuracy of this method. Control PBMCs were evaluated to assess the level of background staining."  In addition to providing a way to identify micrometastasis for cancers that don’t express any markers, such as Ewings sarcoma, the researchers note a particular advantage of flow cytometry: the samples can be evaluated much more quickly than those using RT-PCR. 

Positive results in testing this procedure lead researchers to conclude that flow cytometry may provide a way to more accurately assess the risk associated with any given new diagnosis of Ewings Sarcoma.  The clinical treatment plan can then be developed taking into account the systemic spread of disease which might otherwise be assumed to be local.

Definitions useful in reading the study document:

 

Targeted Heat Therapy Offers New Treatment Option For Soft Tissue Sarcoma

Patients with soft-tissue sarcomas at high risk of spreading were 30% more likely to be alive and cancer free almost three years after starting treatment if their tumors were heated at the time they received chemotherapy, according to new research. The study, which found that the addition of the innovative heat technique more than doubled the proportion of patients whose tumors responded to chemotherapy without increasing toxicity, is also the first to show that any treatment other than surgery followed by radiation can prolong survival of this type of patient. "These findings provide a new standard treatment option and we believe they are likely to change the way many specialists treat these tumors," said the study's leader, Professor Rolf Issels, a professor of medical oncology at Klinikum Grosshadern Medical Center at the University of Munich in Germany, who presented the results on September 22nd in Berlin at Europe's largest cancer congress, ECCO 15 - ESMO 34 [1].

"But the implications of these findings are more far-reaching," Prof Issels said. "This is also the first clear evidence that targeted heat therapy adds to chemotherapy. We expect our findings will encourage other researchers to test the approach in other locally advanced cancers. Targeted heat therapy has already shown promise in recurrent breast and locally advanced cervical cancer in combination with radiation and studies combining it with chemotherapy in other localized tumors such as those in the pancreas and rectum are ongoing." The phase III study involved 341 patients being treated at several centers in Europe and the United States between July 1997 and November 2006 for locally advanced soft tissue sarcomas that were at high risk of recurrence and spread. More than half of the tumors were located in the abdomen, while the rest were in the arms and legs. All patients were given chemotherapy before and after surgery and radiotherapy.

Half were randomly given targeted heat treatment along with the chemotherapy. The technique, known as regional hyperthermia, uses focused electromagnetic energy to warm the tissue in and around the tumor to between 40 and 43 degrees Celsius (104 - 109.4 degrees Fahrenheit). The heat not only kills cancer cells, but it also seems to make chemotherapy work better by making cancer cells more sensitive. It also improves blood flow, which allows chemotherapy to be more effective.

After an average follow-up of 34 months, only 153 patients (44.9%) in total had died. The improvement in overall survival was not statistically meaningful when all patients were analyzed, but an analysis of the 269 who completed the full treatment of either four cycles of initial chemotherapy alone or four chemotherapy cycles and eight heat treatments found that those who got the heat therapy were 44% less likely to die during the follow-up period than those who got chemotherapy alone. "The patients receiving the targeted heat therapy fared better on all outcome measurements," Prof Issels said. "Almost three years after starting treatment, they were 42% less likely to experience a recurrence of their cancer at the same site or to die than those who were getting chemotherapy alone, surviving an estimated 120 months before local progression of their disease, compared with an estimated 75 months. Similarly, the average length of time that patients remained disease free was 32 months in the group that got both treatments, compared with 18 months in the group that got chemotherapy alone - an improvement of 30%."

At two years, 76 percent of the patients in the heat therapy group were still alive without local progression of their cancer, compared with 61 percent in the chemotherapy alone group. The proportion of patients who experienced tumor shrinkage rose from 12.7% in the chemotherapy alone group to 28.8%, while the proportion of patients who saw their tumor grow was 6.8% in the heat therapy group, compared with 20% in the chemotherapy alone group.

The most frequent side effect of the heat therapy was mild to moderate discomfort, reported in 45% of patients. The most serious side effect was severe burns, seen in one patient (0.6%). Blisters occurred in 17.8%.

"This strategy has been in development for about 20 years, with about 150 leading groups studying it, but the clear results of this trial show that the field has now matured to the point where we must step up efforts to explore its potential to offer an entirely new way of treating locally advanced disease in several major cancers," Prof Issels said. "That will take investment from public funders to underwrite trials that investigate, for instance, whether it will be possible to reduce the dose of chemotherapy drugs by boosting their effectiveness with targeted heat therapy and whether the technique can enhance the effectiveness of newer targeted drugs." Other questions remaining include whether targeted heat therapy can play a role in stimulating the immune system to more effectively attack cancer, Prof Issels said, adding that studies of heat shock protein therapy indicate that they may activate the immune system against the disease.

 

Sarcoma Derived from Cultured Mesenchymal Stem Cells

An international team of scientists set out to study a possible role of mesenchymal stem cells (MSCs) in treating side effects of radiation in patients undergoing allogenic bone marrow transplants.  In their venture to observe and document the way in which MSC’s injected into mice travel through the body, they made an unexpected discovery.  After injection with a combination of MSCs and fluorescent biological material designed to help the researcher’s observe the behavior of MSCs, the lab mice began dying.  Those that survived were found to have developed sarcomas in their lungs and/or extremities.  Further investigation revealed that the biological characteristics of the tumors are similar to those of human sarcoma.  The cells, which can be reproduced in the lab, are fast-growing and "express immature osteoblast markers consistent with the majority (75%) of human osteosarcomas [45]."  Moreover, when these cells of MSC origin are introduced into other mice, they also develop sarcoma tumors. 

Thus, research that had been intended to develop treatments for radiation-induced tissue damage resulted in the discovery of a new method to create sarcoma cells in the lab.  The new line is named "S1."   The S1 line is important not only because it was derived from MSC cultures, but also because of it’s similarity to human sarcoma and its use of light producing genes.   In discussing their results, researchers refer to the value of using light producing genes in studies of "organ homing, cellular biodistribution, and dynamics of tumor response to chemotherapy and radiation in real time in vivo."  This means that scientists can observe what is happening in the living organism (the mouse) as it occurs.

While this is good news for the future of sarcoma research, the authors conclude with a warning that clinical protocols using human MSCs need to be carefully monitored:  "We describe transformation of murine MSCs into sarcoma.  These findings underline the potential of MSCs for ectopic ossification and malignant transformation.  In this context, our study highlights the importance of quality-control measures needed for ongoing and future clinical trials using human MSCs."

Helpful definitions of terms used in this article:

 

Ariad continues enrollment in ridaforolimus sarcoma study

On September 14th, Ariad Pharmaceuticals Inc. announced that independent experts recommended continuing a Phase III study of the company's developing sarcoma treatment ridaforolimus. The late-stage study is evaluating the drug as a potential treatment for metastatic sarcoma. Ariad is testing ridaforolimus in a partnership with Merck & Co. Ariad said an independent monitoring committee recommended the company continue with full patient enrollment in the study. The committee indicated that no modifications were necessary. Full patient enrollment is expected by year end and another interim analysis will take place in the first quarter of 2010. "The recommendation by the DMC (committee) to continue the Phase III SUCCEED trial to completion represents an important step in the development of oral ridaforolimus as a potential new treatment option for patients with metastatic sarcomas," said Ariad Chairman and CEO Dr. Harvey J. Berger, in a statement.

 

Personalized Medicine and Complementary and Alternative Medicine: In Search of Common Grounds

Video: Alternative Therapies by Dr. Murray BrennanComplementary and alternative medicine (CAM) continues to assume influence in medical care delivery. At the same time, the biomedical orthodoxy has experienced landmark technoscientific advances, tempting analysts to question the relevance of CAM to 21st century medical provision. This article focuses on one representation of contemporary advances in biomedicine, namely, the phenomenon of personalized medicine (PM) and the technoscientific contexts for its evolution. It examines whether biomedicine's embrace of the PM concept widens the conceptual and philosophical gulf between it and CAM. Focusing on genomics and its translation into PM, the article finds that presently, the gene–environment dynamic is an important aspect of genomics and PM. However, there is a lopsided emphasis in the gene–environment matrix that focuses on toxicogenomics (i.e., the effect of toxins and chemicals, including drugs on genes and genetic materials). This approach to genomics ignores the role of other environmental stressors, which constitute components of an individual's health experience critical to PM. The author concludes that if this lopsided approach is addressed, in a counterintuitive way, PM has potential for engendering a confluence between biomedicine and CAM as a part of the paradox of the 21st century medical landscape.

 

An onco-informatics database for anticancer drug interactions with complementary and alternative medicines used in cancer treatment and supportive care: an overview of the OncoRx project

Cancer patients are at high risk of interactions from use of anticancer drugs (ACDs) and complementary and alternative medicines (CAMs). These interactions can result in sub-therapeutic effects or increased toxicities which may compromise the outcome of chemotherapy. It is important for practitioners to gain convenient access to ACD–CAM interaction information so as to make better-informed decisions in daily practice. This paper describes the creation of an oncology database (OncoRx) that documents ACD–CAM interactions, including traditional Chinese medicines (TCMs) that are commonly used for cancer treatment, prevention, and supportive care therapy.

Information regarding ACDs, CAMs, and drug interactions were collated from 14 sources, inclusive of hardcopy and online resources, and input into a modified web server with a database engine and a programming interface using a combination of software and programming scripts. The OncoRx database currently contains a total of 117 ACDs and 166 CAMs. Users are able to search for interactions based on various CAM uses: cancer treatment or prevention, immune-system-related, alopecia, nausea, and vomiting, peripheral neuropathy and pain, inflammation, fatigue, and non-cancer related. Pharmacokinetic data on ACDs and CAMs, characteristics of CAMs based on TCM principles, and drug interaction parameters such as effects, mechanisms, evidences, and proposed management plans, are shown in the search results. It is hoped that OncoRx will serve as a useful resource to clinicians, educators, trainers, and students working in the oncology setting.

 

V6N5 ESUN Copyright © 2009 Liddy Shriver Sarcoma Initiative.