New Findings Could Be Practice-changing for the Treatment of Locally Advanced 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 tumours were heated at the time they received chemotherapy, according to new research. The finding bolsters the case for intensifying exploration of the strategy in other types of cancer.

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 in Berlin, Germany, at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24), meeting in Berlin, Germany.

“But the implications of these findings are more far-reaching,” 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.”

Soft tissue sarcomas involve cancer that starts in the soft, supporting tissues of the body, such as muscle, fat, blood vessels, nerves, tendons, tissue around the joints and deep layers of the skin. They are relatively rare, accounting for about three percent of all cancers, but are more common in children and young adults. Surgery is the primary treatment, but sometimes these tumors are difficult to remove completely, so they are often also treated with radiotherapy and sometimes chemotherapy. However, in cases where the disease is localized, the benefits of chemotherapy have been shown to be limited. In high-risk patients, any relapse usually occurs within two or three years. Survival varies widely depending on the location and severity of the tumor, with abdominal sarcomas being the most deadly.

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,” Issels noted. “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,” explained Issels. “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," Issels said, adding that "studies of heat shock protein therapy indicate that they may activate the immune system against the disease."

The study was funded by the German Cancer Foundation, Deutsche Krebshilfe and the Helmholtz Assocation, Germany’s largest scientific organization.

For more information:

• Abstract no: 1 LBA. Presidential session II, Tuesday 12.15-14.15 hrs CEST (Hall 1)

Study of New Treatment for Advanced Melanoma Shows Rapid Shrinking of Tumors

Researchers have made significant advances in the treatment of metastatic malignant melanoma – one of the most difficult cancers to treat successfully once it has started to spread – according to a study presented at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology, in Berlin, Germany.

In the phase I extension study, researchers have seen rapid and dramatic shrinking of metastatic tumors in patients treated with a new compound that blocks the activity of the cancer-causing mutation of the BRAF gene, which is implicated in about 50% melanomas and 5% of colorectal cancers. In new results from 31 melanoma patients with the BRAF mutation who were treated with 960mg of PLX4032, twice a day, 64% (14) of the 22 patients who could be evaluated so far met the official criteria for partial response (this involves the diameter of tumors shrinking by at least 30% for at least a month). A further six of the 22 patients also showed a response, but, at the time of the congress presentation, it was too early to say whether the tumors’ would shrink far enough to meet these criteria.

Dr Paul Chapman, an attending physician on the Melanoma/Sarcoma service at Memorial Sloan-Kettering Cancer Center (New York, USA) and who was one of the leaders of the trial, told a news briefing: “We are very excited about these results. Of the 22 patients we have been able to evaluate so far, 20 have had some objective tumor shrinkage. This is impressive as they all had metastatic disease and most of them had failed several prior therapies. A lot of these patients were pretty sick but many of them had a significant and rapid improvement in the way they function. We’ve had patients come off oxygen and we’ve got several patients who have been able to come off narcotic pain medication soon after starting treatment.”

The trial is investigating PLX4032, a novel, oral small molecule for the treatment of melanoma and other cancers harboring the V600E mutation of the BRAF kinase gene, in patients with the BRAF mutation, and results from the first 55 patients were reported at a cancer meeting earlier this year (ASCO 2009). These data had been aimed at finding the best dose of PLX4032 to give to patients. However, the phase I extension data reported at ECCO 15 – ESMO 34 focuses on a subsequent group of an additional 31 patients who were all treated at the maximum tolerated dose of the drug (a 960 mg pill twice a day). All the patients had the BRAF mutation.

Dr Chapman said: “What makes this treatment different from standard chemotherapy is that standard chemotherapy attacks the machinery involved in cell division; so to stop the cancer cells dividing uncontrollably, most standard chemotherapy aims to block the mechanism of division by interfering directly with DNA replication or with microtubules in the dividing cells. PLX4302 is different because it attacks the genetic program that is causing the cells to divide uncontrollably, and we think the BRAF mutation is driving that program. The drug is blocking the genetics of the tumor, rather than trying to interfere with the proliferation of the cells and, as a result, there are fewer side effects, although there are some. We are seeing some pretty dramatic and rapid responses, and they are occurring in sites where we rarely see responses to chemotherapy, such as in the bone.

“There are some important caveats. All these patients had failed previous therapies, either chemotherapy or treatment with Interleukin 2, as well as surgery. However, we know that only 10-30% of patients will respond to standard chemotherapy, so it’s not surprising that our patients had not responded, or have responded and then the cancer has recurred. In our study 64% of patients have had a partial response, but because we are only treating patients with the BRAF mutation, we are cutting out about 40% of melanoma patients who do not have this mutation and whom we know will not respond to this treatment. That is one reason why we are seeing a much higher response than with conventional treatments.

“Also, we don’t know yet how long these responses will last, and we have had patients whose cancer has progressed after initially responding; so we are putting a lot of effort in to studying the patients who do relapse, trying to understand how their tumors have become resistant.

“In addition, one of the main side effects we’ve seen is that some patients develop early, non-melanoma skin cancers such as squamous cell skin cancer. We are very vigilant about this and although they are very easy to cut out, it’s something we are keeping a close eye on.”

Dr Chapman and his colleagues are planning a phase II trial of 90 patients starting at the end of this year. In addition, a large phase III randomized controlled trial involving several hundred patients is planned to start either at the end of this year or beginning of next year involving centers in North America, Europe and Australia.

Dr Chapman said it was too early to be talking about a cure for advanced melanoma, but that this drug had potential. “Most of us think that a drug like this would ultimately be part of the regimen, but that we might need additional drugs with it to complete the cure. Right now we are seeing dramatic responses but it’s too early to say whether we’ve actually cured people because most patients still have evidence of some level of tumor on their skin. I think this is a huge step forward; whether or not it will be sufficient by itself really remains to be seen.”

Clinical trials to support a registration program for product approval are targeted to start shortly. Plexxikon Inc and Roche are co-developing PLX4032 under their 2006 license and collaboration agreement.

For more information:

• Abstract no: 6 BA. Presidential session IV, Thursday, 9.30-11.15 hrs CEST (Hall)
• Plexxikon, Inc. Berkeley, CA, USA)
• Onco'Zine - The International Cancer Network

Also read these PubMed abstracts:

• Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res. 2008 May;6(5):751-9. Epub 2008 May 5.
• Hersey P, Bastholt L, Chiarion-Sileni V, Cinat G, Dummer R, et al. Small molecules and targeted therapies in distant metastatic disease. Ann Oncol. 2009 Aug;20 Suppl 6:vi35-40.

Images courtesy American Society of Clinical oncology (ASCO).

BSI-201, an Investigational Drug, plus Chemotherapy May Offer New Treatment Option for Triple-Negative Breast Cancer

A randomized Phase II study, featured during the plenary session of the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) , shows that women with metastatic triple-negative breast cancer who received the investigational PARP inhibitor BSI-201, in combination with conventional chemotherapy, lived significantly longer and experienced significantly better progression-free survival than women who received standard chemotherapy alone.

“The results of this study provide early evidence that BSI-201, a potent inhibitor of PARP1, or poly (ADP-ribose) polymerase-1, is a promising treatment for women with triple-negative breast cancer, an aggressive form of the disease for which we need new, more effective therapies,” said Joyce O’Shaughnessy, MD, co-director of the Breast Cancer Research Program at Baylor-Charles A. Sammons Cancer Center in Dallas, Texas.

Triple-negative breast cancers (TNBC) are particularly hard to treat since they lack receptors for estrogen, progesterone and HER2, which are targeted by widely available and effective drugs. African American women are 3 times more likely than white or Hispanic women to be diagnosed with triple-negative breast cancer.

In this study, clinical benefit rate (defined by complete and partial responses and stable disease of at least 6 months), response rate, progression-free survival (the time it takes for cancer to progress), and overall survival were compared among 116 women with metastatic triple-negative breast cancer who were randomly assigned to receive a standard chemotherapy treatment (gemcitabine and carboplatin) plus BSI-201, or standard treatment alone.

Approximately 62 percent of patients receiving BSI-201 showed clinical benefit, compared with 21 percent in the chemotherapy only group. The overall response rate to treatment with the drug combination containing BSI-201 was significantly greater (48 percent) than in the group receiving only standard chemotherapy (16 percent). Women who received BSI-201 had a median survival of 9.2 months and median progression-free survival of 6.9 months compared with 5.7 months and 3.3 months, respectively, in women who received standard treatment alone.

Efficacy and Safety
BiPar Sciences Inc, a California-based subsidiary of French drug maker Sanofi–Aventis involved in the development of novel cancer therapies, reported interim safety data from this trial during the annual San Antonio Breast Cancer Symposium (SABCS) in December 2008, showing that the drug was well tolerated with no added toxicities compared with chemotherapy alone.

While inhibition of PARP has demonstrated significant anti-tumor effects in several cancers, its activity does not appear to be critical for normal, non-cancerous cells. Thus, PARP inhibition has the potential to impair a fundamental mechanism of tumor growth without rendering damage to normal cells, implying a lower risk for side effects in patients who receive PARP-inhibitor-based therapies

In general, BSI-201 has shown a strong safety profile and no significant toxicities attributable to drug in studies of more than 200 patients treated to date with monotherapy, as well as in combination with chemotherapeutic regimens.

In the trial, the incidence of side effects was similar between the two groups. BSI-201 itself was well-tolerated and did not contribute any new side effects nor add to the known side effects of gemcitabine and carboplatin.

Future research
The researchers believe that BSI-201 has first-in-class and best-in-class potential as targeted therapy for several types of cancer. The trial drug is a leading candidate in the field of PARP inhibitors and is the furthest along in clinical development of this novel therapeutic approach.

Based on the results of the Phase II trial, California based BiPar Sciences Inc will be initiating a Phase III clinical trial in triple negative metastatic breast cancer in the second half of 2009. This Phase III program has been guided by preliminary safety and efficacy data from a Phase II study in the same patient population.

ASCO 2009 abstract:

• O'Shaughnessy J, Osborne C, Pippen J, Yoffe M, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol 27:18s, 2009 (suppl; abstr 3).

For more information (posters):

• Preclinical Activity of BSI-201 + Chemotherapy in Triple Negative Breast Cancer, American Association for Cancer Research, April 2009
• O’Shaughnessy J, Osborne C, Blum J, Pippen J, Yoffe M, et al. Triple Negative Metastatic Breast Cancer: A Phase 2, Multi-Center, Open-Label, Randomized Trial of Gemcitabine/Carboplatin (G/C) With or Without BSI-201, a PARP Inhibitor. SABCS Poster 2120, December 2008.

Also read these Pubmed abstracts:

• Stead LA, Lash TL, Sobieraj JE, Chi DD, Westrup JL, et al. Triple-negative breast cancers are increased in black women regardless of age or body mass index. Breast Cancer Res. 2009;11(2):R18. Epub 2009 Mar 25.

Help your Patient to better understand:

• Triple Negative Breast Cancer Foundation

Photo courtesy of the American Society of Clinical Oncology.

Bevacizumab study does not meet primary endpoint, but results suggest future trials may hold promise for early-stage colon cancer treatment

Adding bevacizumab to standard adjuvant chemotherapy does not improve disease-free survival for early-stage colon cancer. This is the primary conclusion from the complete results from the first, randomized phase III trial of bevacizumab (Avastin, Roche) in early-stage colon cancer, known as NSABP C-08, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between Genentech and NCI, and will be presented on Sunday, May 31, during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held from May 27 – June 2, 2009 in Orlando, Florida.

NSABP C-08 was the first study to report results on the use of bevacizumab as an adjuvant treatment. Bevacizumab targets the vascular endothelial growth factor (VEGF) receptor, a key driver of tumor angiogenesis – an essential process in the development and maintenance of blood vessels which is required for a tumor to grow and to spread (metastasize) to other parts of the body.

The results of the NSABP C-08 trial have found that adding bevacizumab to standard adjuvant chemotherapy did not improve disease-free survival (the time that patients are free of tumor recurrence) in early-stage colon cancer

The current study enrolled 2,710 patients who were randomized to receive six months of standard adjuvant chemotherapy or six months of adjuvant chemotherapy combined with bevacizumab plus an additional six months of bevacizumab after the chemotherapy had ended.

All patients in the study had stage II or stage III disease and first had surgery to remove their tumors. After a median follow-up of three years, the investigators found that 77.4 percent of patients in the experimental group (bevacizumab) were alive and free of disease, compared with 75.5 percent of patients in the control group, a difference that was not statistically significant. There were no unexpected side effects in either arm and the toxicities from bevacizumab were well tolerated.

“One interesting effect was that during the year that patients were receiving bevacizumab we saw a benefit in disease-free survival (DFS) that subsequently diminished when follow-up was completed,” said Norman Wolmark, MD, chairman of the Department of Human Oncology at Allegheny General Hospital and the study’s lead author. Patients receiving bevacizumab treatment had a 40 percent lower risk of cancer returning, however, this initial improvement over chemotherapy alone gradually diminished over time.

Commenting on the trial, Walmark continued “Our overall conclusion is that bevacizumab was not effective as an adjuvant treatment for early-stage colon cancer, but the transient benefit we saw in patients who received bevacizumab illustrates that we have more to learn about how this reagent works, and we need to design more clinical trials to determine how it can be used most effectively.”

No new safety signals for bevacizumab were observed in the study and careful review of the data did not provide evidence that cancer returns faster or more aggressively after bevacizumab therapy was stopped.

“These results are encouraging and suggest that Avastin may have an important role in early cancer treatment. We are committed to the ongoing program of Avastin in early-stage cancers and believe that these results could help us optimize the use of Avastin for the benefit of patients,’’ noted William M. Burns, CEO of the pharmaceutical division of Roche, a leader in research-focused healthcare.

Study Results
The NSABP C-08, a two-arm randomized prospective multi-center Phase III study evaluated the use of bevacizumab plus chemotherapy (mFolfox6 + bevacizumab/mFF6+B) for the treatment of Stage II or III adenocarcinoma immediately following surgery (adjuvant therapy) compared to chemotherapy alone (mFolfox6/mFF6). The study showed the addition of one year of bevacizumab to chemotherapy did not result in a statistically significant improvement in overall disease-free survival (DFS). However, during the year of bevacizumab treatment there was an early and significant improvement in disease-free survival that diminished over the course of the study.

Disease-Free Survival was measured from the date of randomization to the date of any type of cancer recurrence or death from any cause. Patients enrolled in the study were randomized after surgery to receive either FOLFOX chemotherapy alone for six months or FOLFOX in combination with bevacizumab (intravenously every two weeks) for six months, followed by an additional six months of bevacizumab monotherapy. Patients continue to be followed for overall survival, a secondary endpoint of the study.

Overall in the study, there was 12 percent improvement in DFS that was not statistically significant (hazard ratio=0.89, p=0.15; risk reduction 11 percent). In the first year of the study, while patients received bevacizumab in addition to a standard six-months of adjuvant chemotherapy, disease-free survival improved by 67 percent compared to chemotherapy alone (hazard ratio=0.60; risk reduction of 40 percent). However, this early improvement in DFS began to diminish after the first year, and overall DFS was not improved.

NSABP C-08 included a comprehensive safety analysis that showed no new or unexpected safety events related to bevacizumab in the study. Specific severe (Grade 3 or greater) adverse events (AEs) that occurred with increased frequency in patients who received bevacizumab versus chemotherapy alone were: hypertension (12 percent vs. 1.8 percent), pain (11.1 percent vs. 6.3 percent), proteinuria (2.7 percent vs. 0.8 percent) and wound-healing complications (1.7 percent vs. 0.3 percent).

Other trials and standard of care
Bevacizumab is currently approved for metastatic colorectal, breast, and lung cancers and other trials are ongoing to evaluate it as an adjuvant treatment for a variety of solid tumors. Therapy with bevacizumab is the standard of care in advanced colon cancer treatment which will be further confirmed throughout the ASCO meeting with 53 efficacy and safety data presentations including more than 6,000 patients.

In addition to early-stage colon cancer, bevacizumab is being studied as an adjuvant treatment in other early-stage diseases: HER2-negative breast cancer, HER2-positive breast cancer, and non-squamous, non-small cell lung cancer. Approximately 26,000 people are expected to participate in bevacizumab based adjuvant studies, making the bevacizumab development program one of the most comprehensive undertakings in cancer research since chemotherapy. The Avastin (bevacizumab) development program includes more than 450 clinical trials worldwide in approximately 30 different tumor types.

More than 500,000 patients have been treated with bevacizumab so far. A comprehensive clinical program with more than 450 clinical trials is investigating the use of bevacizumab in various tumor types (including colorectal, breast, lung, brain, gastric, ovarian, prostate and others) and different settings (advanced or early stage disease).

Mode of Action
The precise mode of action of bevacizumab helps control tumor growth and metastases with only a limited impact on side effects of chemotherapy.

The drug has proven survival benefits across multiple tumor types and is approved in Europe for the treatment of the advanced stages of four common types of cancer, including colorectal cancer, breast cancer, lung cancer and kidney cancer. These types of cancer collectively cause nearly 3 million deaths each year in the US alone.

In the US, bevacizumab was the first anti-angiogenesis therapy approved by the FDA and is now approved for the treatment of four tumor types: breast, colorectal, glioblastoma, and non-small cell lung cancer (NSCLC).

For further information:

• American Society for Clinical Oncology
• Wolmark, G. Yothers, M. J. O’Connell, S. Sharif, J. N. et al. A phase III trial comparing mFolfox6 to mFolfox6 + bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08 N. Plenary presentation, Sunday, May 31, 3:15 PM EDT, Level 2, West Hall D2. Plenary Session, Lead Author: Norman Wolmark, MD, Allegheny General Hospital Pittsburgh, Pa. Abstract No# LBA4

Other, related, abstracts

• A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4000 First Author: D. KerrCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial).
  Meeting:2009 ASCO Annual Meeting Abstract No: 4001 First Author: S. TejparCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4002 First Author: A. D. RothCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)

Folfox Background information:

• Wikipedia (Definition)
• Cancer Research UK
• NCI – National cancer Institute

Colorectal Cancer:

• Medical Oncology (at Boomja.com)
• Goldberg RM, Therapy for Metastatic Colorectal Cancer The Oncologist Vol. 11, No. 9, 981-987, October 2006

Pharmaceutical information:

• EMEA - European Public Assessment Report (bevacizumab)
• Highlights of Prescribing Information USA (bevacizumab)