Ultrasound can Predict Tumor Burden and Survival in Melanoma Patients, Sparing Unnecessary Surgery

Ultrasound can predict tumor burden and survival in melanoma patients. Researchers have shown for the first time that patterns of ultrasound signals can be used to identify whether or not cancer has started to spread in melanoma patients, and to what extent. The discovery enables doctors to decide on how much surgery, if any, is required and to predict the patient’s probable survival.

Dr Christiane Voit told Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany: “We have identified two ultrasound patterns of lymph node metastasis in melanoma patients which can identify correctly any amount of tumor cells in the sentinel lymph nodes in 75-90% of cases before proceeding to surgery on the sentinel lymph nodes.”

Voit, who is a dermatologist and head of the diagnostic unit at the Skin Cancer Centre at Charité – Universitätsmedizin Berlin, the Medical University of Berlin, said that although her research needs to be confirmed in multi-centre, randomized clinical trials, it had the potential to spare patients unnecessary surgery, especially if it was combined with ultrasound-guided fine needle biopsy of lymph nodes rather than conventional surgery.

Since 2001 Dr Voit and her colleagues in Germany and The Netherlands have included 850 melanoma patients in a prospective study to investigate the use of ultrasound in diagnosis and treatment planning. They have already demonstrated that ultrasound-guided fine needle biopsy of sentinel nodes before conventional sentinel node surgery can identify up to 65% of patients in whom the cancer has started to spread. The study presented today shows how far ultrasound patterns correlate with disease progression, tumor burden, survival and prognosis in the first 400 of these patients with stage I/II melanoma and with the longest follow-up.

Before having sentinel node surgery the patients were investigated using ultrasound, and these results were checked against the results of the subsequent surgery. The researchers found that two ultrasound patterns together could correctly identify the amount of cancer cells in the lymph nodes in 80% of cases.

A balloon shape ultrasound pattern with or without loss of central echoes (where the lymph node has lost central echoes or still has some residual central echoes, but these are wandering toward the rim, giving an asymmetrical shape to the centre) was an indicator in up to 83% of cases of a large amount of cancer cells in the sentinel node. “This ultrasound pattern was a late sign, only occurring in cases of advanced metastasis,” said Voit.

A pattern of peripheral perfusion (where small blood vessels start to surround the lymph node) was an early sign of a small number of cancer cells present. “The early signs are signs of first disruption of the normal lymph node architecture by an early stage metastasis. The most important one is peripheral perfusion, which shows angiogenesis (the formation of new blood vessels) is occurring,” she explained.

The researchers found that these two ultrasound patterns could predict overall survival. Estimates for overall survival after five years for patients with stage I/II is between 50-90% depending on the state of the tumour. Dr Voit found that 93% of patients with neither of these ultrasound patterns, 87% of patients with peripheral perfusion, and 56% of patients with balloon shapes with or without loss of central echoes, survived for at least five years; survival without cancer spreading to other parts of the body was 74%, 60% and 26% respectively.

Dr Voit said: “For the first time we have established that ultrasound patterns can be used as criteria for diagnosing disease progression and tumor burden. Balloon shaped lymph nodes with or without loss of central echoes and peripheral perfusion are independent prognostic factors for survival.”

Discovering if cancer has spread to the lymph nodes is the most important factor influencing the prognosis and treatment of melanoma patients. Doctors usually cut out one or two key lymph nodes, called sentinel nodes, and use these as an indicator of whether or not the cancer has spread to the other lymph nodes. If the sentinel node is free of cancer, patients don’t need to have more extensive lymph node removal.

However, only 20% of patients who have a sentinel node biopsy have cancer that has spread there, and so the operation, which can be accompanied by side effects such as chronic swelling and seroma, is unnecessary for 80% of patients. Using ultrasound first to detect the presence or not of sentinel node metastases could be a non-invasive way of limiting the numbers of patients who require subsequent surgery or simply watchful follow-up care.

For more information:

• Abstract no: 9303. Melanoma session, Wednesday 14.45-17.00 hrs CEST (Hall 7)

Also read these PubMed abstracts:

• Voit C, Kron M, Schäfer G, Schoengen A, Audring H, Lukowsky A, Schwürzer-Voit M, Sterry W, Winter H, Rademaker J. Ultrasound-guided fine needle aspiration cytology prior to sentinel lymph node biopsy in melanoma patients. Ann Surg Oncol. 2006 Dec;13(12):1682-9.
• Voit CA, Schäfer-Hesterberg G, Kron M, van Akkooi AC, Rademaker J, Lukowsky A, Schoengen A, Schwürzer-Voit M, Sterry W, Krause M, Röwert-Huber J, Eggermont AM.
  Impact of molecular staging methods in primary melanoma: reverse-transcriptase polymerase chain reaction (RT-PCR) of ultrasound-guided aspirate of the sentinel node does not improve diagnostic accuracy, but RT-PCR of peripheral blood does predict survival. J Clin Oncol. 2008 Dec 10;26(35):5742-7. Epub 2008 Nov 3.

Images courtesy American Society of Clinical oncology (ASCO).

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).

An Unusual Request: Help the Melanoma Research Foundation

The Melanoma Research Foundation (MRF) is working with a U.S. women's health magazine that’s writing an article highlighting that melanomas can appear in areas that don't get a lot of UV exposure. For this article they are looking looking for a young woman who has (or had) melanoma to profile in the story.

Specifically, the magazine is looking for a woman meeting the following caracteristics:

• In her 20’s, 30’s or 40's
• Lives in the United States
• Recently diagnosis with stage III or IV melanoma (within the past few years)
• The melanoma was found in an area that doesn’t get sun exposure or very surprising place such as the groin, fingers, toes, nail beds, palms, the soles of feet or eyes.
• Did not tan
• Did not have any other health issue when she was diagnosed (otherwise healthy and in shape)
• Is available for a phone interview this week.

If this describes you or one of your patients or someone you know, please contact the Melanoma Research Foundation. The link takes give access to a form you or your patient should complete. The Melanoma Research Foundation will contact the you or your patient and the writer to schedule phone interview.

For more information:

• Help the Melanoma Research Foundation

Melanoma Research Foundation Launches Digital Resources, leveraging online tools to reach consumers during Melanoma Awareness Month

As part of Melanoma Awareness Month this May, the Melanoma Research Foundation (MRF -) the largest independent, national organization devoted to melanoma in the United States committed to the support of medical research in finding effective treatments and eventually a cure for melanoma, is launching three new resources to reach the online community. Now digital users can learn more about melanoma and access tools to fight this deadly disease through Facebook, Twitter and the MRF Melanoma Messengers programs.

"Melanoma Awareness Month exists because this disease is not sufficiently in the public's mind. If we are going to stop melanoma, we need to extend our reach to include young people, who have the fastest rising incidence rates." said Tim Turnham, executive director of the MRF. "We are really excited about the potential of these online programs to reach Americans where they live, work and play."

Created as a grassroots, volunteer program, the MRF Melanoma Messengers toolkit will enable individuals to join a national network dedicated to supporting medical research, educating patients and physicians, and acting as an advocate for the melanoma community. The additional social networking sites, including Facebook and Twitter, will enable volunteers to stay connected, share tips and offer support to others.

"Our Facebook, Twitter and MRF Melanoma Messengers programs give people the tools and resources they need to raise awareness in their local and online communities," continued Turnham. "Whether you are a fan, a tweeter or a volunteer, it's now easier than ever before to show your support for those affected by this deadly disease."

"This month, the MRF's Messengers will be involved in nearly 30 different fundraising events and activities across the country to raise money to find a cure, including our first 'Melanoma Tweetments' fundraiser," said C. Randy Lomax, chairman of the MRF's board of directors. "Individual Twitter users can make a difference by sending tweets about melanoma to their followers and donating a few dollars to fund melanoma research."

The Most Deadly type of Skin Cancer
Melanoma, the most deadly type of skin cancer, claims the life of approximately one American every hour and is the fastest growing cancer in the United States and worldwide. It strikes men and women of all ages, all races and all skin types. In fact, with a one in 50 lifetime risk of developing melanoma, more than 62,000 Americans were expected to be diagnosed with the disease in 2008, resulting in an estimated 8,400 deaths. Melanoma is the most common form of cancer for young adults 25- to 29-years-old and the second most common cancer in adolescents and young adults 15- to 29-years-old.

In its early stages, melanoma can be successfully removed and monitored by regular skin screenings. However, the disease is deadly in its most advanced stages, as few treatment options exist. The median life expectancy for patients with advanced melanoma is less than one year and existing therapies have not improved survival in more than a decade.

Social media users can stay up-to-date on what's going on at the MRF and in the melanoma community by following @curemelanoma on Twitter and becoming a fan of the Melanoma Research Foundation and inviting friends to support the cause on Facebook

• MRF's Twitter Page
• MRF's Facebook Page
• MRF's Facebook Cause
• MRF's Melanoma Messengers Group on Facebook

Modifications in Assay Design Increase Detectable Frequency of Tumorigenic Cells

How common is the tumorigenic potential or tumor promoting property in human cancers? For many years, cancer researchers have tried to answer the fundamental question whether all tumor cells are equally likely to cause new cancers.

A generally supported idea is that only a tiny subset of highly prolific cancer cells, dubbed cancer stem cells and estimated to be as few as one in a million, are capable in promoting tumors growth. The fact that these cells are distinguishable from other cancer cells is an important property that scientists would theoretically be able to exploit in designing new, targeted, therapies. Research on diverse cancers, including melanoma, seems to support the hypnotists that only rare human cancer cells form tumors when transplanted into non-obese diabetic/severe combined immunodeficiency mice.

But when a team of researchers from the Howard Hughes Medical Institute, Life Science Institute, Department of Internal Medicine, and the Center for Stem Cell Biology, at the University of Michigan, Ann Arbor, MI, looked at 50 different molecular markers found on the surface of the melanoma cells, they could not find differences between the tumor-causing cells and those that did not spawn tumors. Therefore, they concluded that scientists may have underestimated the frequency of tumorigenic human cancer cells, the extent of which is so far uncertain.

In the 4 December 2008 issue of Nature, the international weekly science journal, the researchers show that by modifying the design of an assay (including the use of more highly immunocompromised non-obese diabetic/severe combined immunodeficiency interleukin-2 receptor gamma-chain-null mice), as many as 25%, or one in four, of the melanoma cells were able to reproduce. Furthermore, in single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumors. The authors therefore concluded that modifications to xenotransplantation assays increase the detectable frequency of tumorigenic cells and that they are common in some human cancers.

The researchers acknowledge that it is possible that cancer stem cells are simply more common in certain cancers. They expect that in some cancers, a cancer stem cell model will be more prevalent that in other cancers. The evidence for cancer stem cells in certain cancers is particularly convincing. But, as was reported in the same issue of Nature, researchers who report cancer stem cells in solid tumors should be wary about these results, and should repeat their experiments using techniques that could help transplanted human cells survive in mice. Otherwise, the reserachers conclude, it’s unclear whether they have detected a rare subset of cells that can propagate tumors – or simply a rare subset of human cells that can establish themselves in mice.

Click here for the PubMed abstract. Elsa Quintana, Mark Shackleton, Michael S. Sabel, et al., Efficient tumour formation by single human melanoma cells. Nature 2008 Dec 4;456(7222):593-8.