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).

Escalated Dose-Intensified Combined Modality Treatment Shows Survival Benefit In Patients With Early Unfavourable Hodgekin Lymphoma

With more than 7,500 participants from more than 100 European and non-European countries in attendance, the 14th congress of the European Hematology Association (EHA), which was held in Berlin, Germany, from June 4 – 7, 2009, proved record-breaking. The delegates gathered in Berlin to share the most recent developments in hematological research and improvements in care.

The program included sessions on clinical and laboratory hematology and covered all the major hematological subspecialties, including hemato-oncology, red cell disorders, hemostasis, thrombosis, pediatric hematology and transfusion medicine.

The program featured a session, presented by Prof. Peter Borchmann on behalf of the German Hodgkin Study Group / GHSG (abstract number 0553) discussing an analysis of Dose-Intensified Combined Modality Treatment In Patients With Early Unfavourable Hodgekin Lymphoma (HL).

As a result of intensified medical research, Hodgkin's lymphoma has become one of the most curable tumors in adults. Today, about 80% - 90% of patients experience long-term disease free survival (DFS). This is mainly the result of numerous large clinical trials initiated by the German Hodgkin Study Group and other organizations, taking place since the late 1970's, using risk-adapted, highly effective therapy modalities. From the late '70s nearly 15,000 patients have been randomized and treated in these prospectively randomized trials.

Risk Groups
Patients with Hodgkin lymphoma are divided in three risk groups according to the initial staging and additional clinical risk factors: early favorable, early unfavorable and advanced-stage risk groups.

Abstract 0553 (Interim Analysis of the GHSG HD14 Trial for Patients With Early Unfavourable HL) compared the results of the arms of the GHSG HD14 trial. The rational of this trial was to improve the prognosis of patients with early unfavorable disease by comparing the old standard treatment, 4 courses of ABVD (adriamycin, bleomycin, vinblastine, and dacarbacine) followed by localized radiotherapy (30 Gy IF-RT), with a more intensive chemotherapy regimen consisting of 2 cycles of escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by 2 cycles of ABVD and the same radiotherapy as in the standard arm.

Treatment-associated toxicities
A previous GHSG trial (GHSG HD11) compared 4 cycles of ABVD with BEACOPP, followed by either 30 or 20 Gy IF-RT. This trial showed no difference with respect to outcomes, and despite excellent initial remission rates, approximately 15% of patients with early unfavorable-stage HL relapsed within 5 years and another 5% suffered from progressive disease. Nevertheless, these good results of the GHSG trials are threatened by treatment-associated toxicities such as infertility, cardiopulmonary toxicity and secondary malignancies.

Improving trial results
The GHSG HD14 trial showed a significantly better outcome in terms of progression-free survival in the more intensive escalated BEACOPP regimen than the standard regimen of 4 cycles of ABVD in patients with early unfavorable Hodgkin's lymphoma (HL).
The study, conducted by the German Hodgkin Study Group (GHSG), included 1645 patients in 346 centres. These patients had early unfavorable Hodgkin's lymphoma, clinical stage 1 or 2 and risk factors, including large mediastinal mass, extranodal disease, high erythrocyte sedimentation rate, and 3 or more areas affected.

Interim analysis
After the third interim analysis with 1127 patients, researchers decided to terminate the GHSD HD14 trial early because of the significantly better outcome for patients treated with BEACOPP compared to ABVD. The interim results showed that progression free survival (PFS) was significantly better for patients treated with the hybrid regimen than for patients treated with 4 courses of ABVD. After 3 years, progression-free survival was observed in 97% of patients in the escalated BEACOPP group and 91% in the ABVD group.

Furthermore, the interim analysis showed freedom from treatment failure to be 95% in the escalated BEACOPP group versus 91% in the ABVD group. Overall, there were more patients with progressive disease, relapse and a higher mortality in those receiving 4 cycles of ABVD. These results prompted the GHSG to adopt a regimen of two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy radiotherapy as the new standard treatment for patients with early unfavorable Hodgkin's lymphoma.

Escalated BEACOPP, compared to standard BEACOPP, uses a higher doses of etoposide (200 vs 100 mg/m2), doxorubicin (35 vs 25 mg/m2), cyclophosphamide (1200 vs 650 mg/m2), with added granulocyte colony-stimulating factor support. Combined with local irradiation, the escalated regimen showed superior disease control compared with ABVD. Patients experienced more hematological adverse events in the escalated BEACOPP group compared to the ABVD group. This included leukopenia (22% vs , including 81%), thrombocytopenia (<1%>

Predisposition to Myeloproliferative Neoplasms
An unrelated presentation by Prof. Nick Cross, Salisbury, United Kingdom, discussed research aimed to understand what causes a group of related conditions known collectively as myeloproliferative neoplasms (abstract number 0555).

Researchers have found a common genetic 'signature' that predisposes to these disorders. The predisposition is relatively subtle and so it cannot by itself be used to predict whether anyone will develop disease or not, but it is an important step towards understanding why some people get cancer and why others do not. In the future it is possible that the abnormality we have found might be combined with other genetic and environmental risk factors to enable much better predictions of disease susceptibility to be made.

Myeloproliferative neoplasms or MPNs are conditions of the blood that are related to leukemia but in effect they are a very mild form that resembles the first steps towards cancer. They are characterised by the overproduction of red and white blood cells, which increases the risk of strokes and heart attacks. Many cases of MPDs are caused by a mutation in a gene called JAK2. When the JAK2 gene has mutated, it sends abnormal messages to the blood stem cells to produce more and more blood cells.

Scientists have found that a particular region of chromosome 9 that carries the JAK2 gene is predisposed to acquiring mutations, but only in individuals with a particular genetic makeup. It is likely that this finding will lead to a much better understanding of how the JAK2 gene mutations happen and why they lead to an increased risk of someone developing an MPD.

The study, carried out at the Wessex Regional Genetics Laboratory in Salisbury and the University of Southampton, has proved that people carrying this mutation-prone region of DNA on chromosome 9 that includes the JAK2 gene have triple the risk of developing an MPD. The chromosome 9 variant is present in 40% of the population in the United Kingdom but only 1 in 20,000 people develop an MPD each year. Nonetheless, the new research has confirmed that the inheritance of this genetic variant can contribute to inherited susceptibility to develop an MPD.The study found that the link was especially strong in polycythaemia vera (PV), one of the main three MPDs.

Professor Nick Cross, from the University of Southampton (University RoadSouthampton SO17 1BJ, United Kingdom, Tel. +44 (0)23 8059 5000, Fax +44 (0)23 8059 3131) who led the research team, said: “This research provides strong evidence that at least half of the cases of PV diagnosed each year are linked to an inherited genetic variant on chromosome 9. Whilst this risk is still very small it nonetheless confirms that individual susceptibility to acquiring cancer-causing mutations is linked to genetic inheritance. Now that we have this evidence we can carry out studies to determine exactly how the variant contributes to this risk.”

Dr Shabih Syed, Scientific Director at UK-based Leukaemia Research who sponsored the reserach, adds: “This is a very important step forward in our knowledge of the causes of myeloproliferative disorders. It helps us to understand why some people might be predisposed to acquiring genetic mutations that lead to cancers.”

For more information:

• 14th Congress of the Europan Hematology Association (EHA): Presentations.
• Diehl V, Franklin J, Hasenclever D, Tesch H, Pfreundschuh M, et al. BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group Journal of Clinical Oncology. 1998 Vol 16, 3810-3821.
• Patrice Carde P, Cavalli F, Diehl V, Franklin J. Is escalated BEACOPP a standard therapy for advanced Hodgkin's disease? The Hematology Journal (2000) 1, 282 ± 290.
• Jones AV, Chase A, Silver RT, Oscier D, Zoi K, et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nature Genetics 41, 446 - 449 (2009) Published online: 15 March 2009

Read these PubMed abstracts:

• Federico M, Luminari S, Iannitto E, Polimeno G, Marcheselli L, et al. ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. J Clin Oncol. 2009 Feb 10;27(5):805-11. Epub 2009 Jan 5
• Bosetti C, Levi F, Ferlay J, Lucchini F, Negri E, La Vecchia C. The recent decline in mortality from Hodgkin lymphomas in central and eastern Europe. Ann Oncol. 2009 Apr;20(4):767-74. Epub 2008 Dec 16.
• Eich HT, Müller RP, Engenhart-Cabillic R, Lukas P, Schmidberger H, et al. Involved-node radiotherapy in early-stage Hodgkin's lymphoma. Definition and guidelines of the German Hodgkin Study Group (GHSG). Strahlenther Onkol. 2008 Aug;184(8):406-10.
• Ben Arush MW, Shafat I, Ben Barak A, Shalom RB, Vlodavsky E, Ilan N. Plasma heparanase as a significant marker of treatment response in children with Hodgkin lymphoma: pilot study. Pediatr Hematol Oncol. 2009 Jun;26(4):157-64.
• Gobbi PG, Valentino F, Danova M, Morabito F, Rovati B, et al. Bone marrow stem cell damage after three different chemotherapy regimens for advanced Hodgkin's lymphoma. Oncol Rep. 2009 Apr;21(4):1029-35.
• Wood AD, Chen E, Donaldson IJ, Hattangadi S, Burke KA, et al. Id1 promotes expansion and survival of primary erythroid cells and is a target of JAK2V617F-STAT5 signalling. Blood. 2009 Jul 1. [Epub ahead of print].
• Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009 May 26. [Epub ahead of print]

What to tell your patients:

• US National Cancer Institute: Definition Hodgkin Lymphoma
• Mayo Clinic: Definition Hodgkin Lymphoma
• WikiPedia: Definition Hodgkin Lymphoma
• LymphomaInfo.Net: Definition Hodgkin Lymphoma
• The Leukemia & Lymphoma Society (USA): Definition Hodgekin Lymphoma
• SteadyHealth.com: Definition of Myeloproliferative Neoplasms.
• UptoDate for Patients: Overview of Myeloproliferative Neoplasms.

Illustrations courtesy of the European Hematology Association.