Brachytherapy Used for the First Time in United States to Treat Lung Cancer

A 58-year-old man who lives in Corona, Queens came to the emergency room of New York Hospital Queens (NYHQ) with extreme pain and tingling in his left arm. Although he did not realize it at the time, he had lung cancer. Recently, he made medical history as the first patient in the United States to be treated for lung cancer through the use of radioactive pellets placed directly in the tumor, and today his recovery is going well. Known as brachytherapy, this treatment approach is commonly used to treat prostate cancer.

"Although the patient came in because of pain in his arm, it was not due to an injury. It was discovered that the cause was a Pancoast tumor, a tumor in the lungs that affects the arms and shoulders but rarely causes symptoms, such as cough or shortness of breath, typically associated with the lungs," according to Dattatreyudu Nori, M.D., chairman, Radiation Oncology and one of the world's leading authorities in the subspecialty of brachytherapy.

Pancoast tumors form at the extreme pulmonary apex of either the right or left lung in the superior sulcus. The initial symptom is severe and constant pain in the shoulder, inner part of the scapula, or both.

In addition to general cancer symptoms such as malaise, fever, weight loss and fatigue, pancoast tumor may include a complete Horner’s syndrome caused by damage to the sympathetic nervous system, and in severe and progressive cases, miosis, anhidrosis, ptosis, and brachial plexus.

Dr Nori was the first physician in the United States to work with a computerized brachytherapy treatment system and was instrumental in the development and successful application of it to combat cancer.

The patient was treated with high dose chemotherapy and then underwent treatment with external beam radiation. Although he did have some positive response, the tumor was still present. Because of the location of the tumor, the NYHQ physicians knew that additional conventional treatment could endanger surrounding critical structures including nerves and vessels, and could affect the other organs of his body.

With the options becoming limited, Dr. Nori, along with colleague Paul C. Lee, M.D., the hospital's vice chairman of cardiothoracic surgery, decided to perform a surgical resection of the tumor and then implanted the tumor bed with radioactive Cesium 131 pellets - in a new type of brachytherapy procedure. Brachytherapy involves the implantation of radioactive seeds into the tumor site to kill the remaining cancer cells after surgical resection, while limiting the damage to healthy tissue. Brachytherapy has been successful in treating prostate cancer, but had never been used to treat this form of aggressive lung cancer.

"The tumor was very aggressive. We decided to use radioactive Cesium-131 pellets due to their high success rate in treating prostate cancer. This patient has responded well to the treatment, with an outcome that would not have been possible with traditional treatment," reports Dr. Nori.

According to Dr. Nori, Cesium-131 pellets have several advantages over the older radioactive isotopes including a shorter half-life, which means faster delivery of a radiation dose that allows less time and opportunity for the cancer cells to repopulate.

Dr. Nori has trained several hundred physicians in the U.S. on the use of brachytherapy procedures in the treatment of cancer, and more recently on the use of Cesium-131 in lung cancer treatment. He is renowned in the field of radiation oncology and for pioneering the use of use of radioactive isotopes to treat prostate cancer. He was one of the first to use the radioactive isotopes Iodine-125 and Palladium-103 in 1975 and 1985 as well as Cesium-131, which was approved by the U.S. Food and Drug Administration (FDA) in 2003 for treating prostate and other cancers.

New York Hospital Queens is a member of the New York-Presbyterian Healthcare System and an affiliate of the Weill Medical College of Cornell University.

For more information:

• Ziyade S, Soysal O, Ugurlucan M, Yediyildiz S. Pancoast hydatid cyst leading to horner syndrome: thoracic hydatidosis. Heart Lung Circ. 2009 Oct;18(5):363-4. Epub 2008 Jul 26.
• Fontinele e Silva J, Barbosa Mde P, Viegas CL. Small cell carcinoma in Pancoast syndrome J Bras Pneumol. 2009 Feb;35(2):190-3.
• Nag S, Kelly JF, Horton JL, Komaki R, Nori D. Brachytherapy for carcinoma of the lung. Oncology (Williston Park). 2001 Mar;15(3):371-81.
• Hilaris BS, Martini N, Wong GY, Nori D. Treatment of superior sulcus tumor (Pancoast tumor). Surg Clin North Am. 1987 Oct;67(5):965-77.

Also:

• Onco’Zine – The International Cancer Blog

Denosumab Superior to Zoledronic Acid in Reducing Incidence of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases

Data Presented at earlier this month at the San Antonio Breast Cancer Symposium demonstrates that treatment with denosumab, a new drug in late stage clinical development, is superior to the standard of care in advanced breast cancer patients. Among patients with bone metastasis from breast cancer, denosumab was superior to zoledronic acid in reducing the incidence of complications from bone metastases.

"Denosumab prevented more events, was better tolerated and is more convenient for patients," said Alison Stopeck, M.D., associate professor of medicine at the University of Arizona Cancer Center who presented the results of this phase III, double blind study at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium.

Stopeck and colleagues enrolled 2,048 patients with bone metastasis who had never received treatment with intravenous bisphosphonates. They randomly assigned patients to treatment with 120 mg subcutaneous denosumab (Amgen) or 4 mg intravenous zoledronic acid (Zometa, Novartis) every four weeks.

Denosumab, is an investigational first fully human monoclonal antibody developed by Amgen. It works differently from existing bone treatments by specifically targeting a protein called RANK Ligand (RANKL), which plays an important role in regulating osteoclast activity and function and has been linked with increased bone loss and complications from bone metastases.

Stopeck presented data confirming that denosumab significantly delayed time to first on-study skeletal-related event compared with zoledronic acid (HR=0.82; 95% CI, 0.71-0.95), as well as time to first, and subsequent, on-study skeletal-related event (rate ratio=0.77; 95% CI, 0.66-0.89). In this study, patients assigned to denosumab had 491 skeletal-related events compared with 623 for patients assigned to zoledronic acid.

"In clinical trials testing new medications for bone metastases, treatment success is measured by whether the bone complications, or skeletal related events, caused by the tumor are reduced or delayed," Stopeck explained. "Skeletal complications from bone metastases are a critical and painful health concern for patients with advanced breast cancer, and can increase the risk of mortality. Patients who have a first skeletal related event are twice as likely to experience a subsequent SRE, so it is imperative to treat these advanced breast cancer patients."

“Denosumab resulted in a considerable delay in the development of moderate-to-severe pain compared to zoledronic acid,” Stopeck said.

Additional data from this study showed that denosumab significantly reduced the mean annual skeletal morbidity rate (SMR) (the ratio of the number of skeletal complications to the time on trial) compared with Zometa (0.45 vs. 0.58, respectively; p=0.004).

Overall, the incidence of adverse events (96% denosumab, 97% zoledronic acid) and serious adverse events (44% denosumab, 46% zoledronic acid) was consistent with what has previously been reported for these two agents. Adverse events potentially associated with acute phase reactions during the first three days of the study were reported in 10.4 percent of the denosumab arm and 27.3% of the zoledronic acid arm. Adverse events potentially associated with renal toxicity occurred in 4.9% of patients treated with denosumab compared to 8.5% in patients treated with zoledronic acid.

Osteonecrosis of the jaw (ONJ) was seen infrequently in both treatment groups (20 patients receiving denosumab [2.0%] as compared with 14 patients [1.4%t] receiving Zometa). Rates of new primary malignancies were similar between treatment arms (5 patients receiving denosumab [0.5%] and 5 receiving zoledronic acid [0.5%]). Time to disease progression or overall survival was balanced between the study arms.

At 34 months, 30.7% of patients treated with denosumab arm experienced at least one skeletal-related event (95% CI, 33.5%-39.4%) compared with 36.5% of those treated with zoledronic acid. Denosumab also reduced mean skeletal morbidity rate (0.45 vs. 0.58; P=.004).

Clinical relevance
Bone metastases, cancer cells that separate from tumors and migrate to bone tissue where they settle and grow, occur in more than 1.5 million people worldwide. With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates, the number of patients developing metastatic disease secondary to a primary cancer is increasing. Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100 percent in myeloma patients and as high as 75 percent in breast and prostate cancer patients.

With bone metastases the growing cancer cells weaken and destroy the bone around the tumor. The damage the tumor has caused to the bone can result in a number of serious complications, collectively called SREs. These include fracture of a bone, the need for radiation to bone, the need for bone surgery, or spinal cord compression. All are serious complications for advanced cancer patients.

The economic burden of United States (U.S.) patients with bone metastases is significant and was estimated to be $12.6 billion last year. Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.

The results of this study are therefore clinically relevant. Before the availability of bisphosphonates 64% patients with breast cancer with bone metastases generally developed a skeletal-related event, including fracture or pain. With the introduction of Bisphosphonates, this was reduced this to 43%. Today, with more potent agents such as zoledronic acid, the development of skeletal-related event are less than 34%. The results of this trial comparing denosumab vs zoledronic acid shows further improvement with a 27% reduction of incidence rate.

This oral presentation of the denosumab 136 data by Dr. Alison Stopeck was presented at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium. on Thursday, December 10 at 3:15 PM (CT) in Exhibit Hall D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

For more information

• Downey L, Livingstone R, Stopeck A. Diagnosing and treating breast cancer in elderly women: a call for improved understanding. J Am Geriatr Soc 2007 Oct;55(10):1636-44. Epub 2007 Aug 28.
• Coleman R. Potential use of bisphosphonates in the prevention of metastases in early-stage breast cancer. Clin Breast Cancer 2007 Jul;7 Suppl 1:S29-35
• Coleman R. On the horizon: can bisphosphonates prevent bone metastases? Breast. 2007 Dec;16 Suppl 3:S21-7. Epub 2007 Nov 7. Review.
• Coleman RE. The benefits and costs of bisphosphonates. J Support Oncol 2007 Nov-Dec;5(10):483-4.
• Brown JE, Coleman RE. The present and future role of bisphosphonates in the management of patients with breast cancer. Breast Cancer Res. 2002;4(1):24-9. Epub 2001 Nov 26. Review.
• Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001 Sep-Oct;7(5):377-87.
• Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001 Jun;27(3):165-76. Review.
• Capanna R, Coia LR, Coleman R. et al. eds. Textbook of Bone Metastases Hoboken, NJ: Edition: John Wiley and Sons; 2005:105.
• Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002 Aug;2(8):584-93. Review
• Schulman KL, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007 Jun 1;109(11):2334-42.
• Mortimer JE, Schulman K, Kohles JD. Patterns of bisphosphonate use in the United States in the treatment of metastatic bone disease. Clin Breast Cancer. 2007 Aug;7(9):682-9.

Also follow

• Onco'Zine - The International Cancer Network

Oral Bisphosphonates May Significantly Reduce Breast Cancer

Results of a new analysis of data from the Women's Health Initiative (WHI) observational study showed that women who used bisphosphonates, which are commonly prescribed bone-strengthening pills, had significantly fewer invasive breast cancers than women who did not use bisphosphonates. These findings were presented at the CRTC-AACR San Antonio Breast Cancer Symposium.

In the 150,000-plus cohort of generally healthy postmenopausal women, the researchers found that women who used bisphosphonates, mostly alendronate, which is sold as Fosamax (alendronate sodium) by Merck, had 32% fewer cases of invasive breast cancer compared to women who did not use such drugs.

"The idea that bisphosphonates could reduce breast cancer incidence is very exciting because there are about 30 million prescriptions for these agents written annually in the United States targeting bone health, and more could easily be used to counteract both osteoporosis and breast cancer," said the study's lead investigator, Rowan Chlebowski, M.D., Ph.D., medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center.

The concept arose from findings in a report on an adjuvant breast cancer trial where use of the bisphosphonate zoledronic acid given intravenously every six months resulted in fewer contralateral breast cancers.

"It appeared to make bone less hospitable to breast cancer," Chlebowski said.

However, since bisphosphonates are prescribed for women with low bone mineral density and low bone mineral density has been associated with lower breast cancer incidence, a means to control for potential differences between women prescribed bisphosphonate and those not prescribed bisphosphonate in the cohort was needed.

Given that, Chlebowski and colleagues devised a way to control for use of bisphosphonates in the WHI. About 10,000 of the participants had bone mineral density analysis as part of the study, and for the rest they used a 10-item hip fracture predictive score to measure bone density. The researchers were able to correlate the findings from the women who had bone mineral density tests to findings from the predictive score in order to correct for any potential difference in bone density in women using bisphosphonates compared to non-users.

Studying 2,216 WHI participants who were using bisphosphonates when they entered the study, the researchers found that only 64 women developed breast cancer, and most of those cases (50) were estrogen receptor positive. Overall, there was a mean 32 percent fewer breast cancers in women using bisphosphonates compared to women who did not. There were 30 percent fewer estrogen receptor-positive cancers and 34 percent fewer entry receptor-negative cancers in bisphosphonate users. The latter finding was not statistically significant as there were very few receptor-negative cases.

"Bisphosphonates reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators," Chlebowski said. "This association needs to be studied further. While we currently have several options for reducing receptor-positive breast cancers, none are available for receptor-negative cancers."

Several ongoing adjuvant breast cancer trials evaluating oral and intravenous bisphosphonate will be available in the near future to provide randomized clinical trial evidence regarding their influence on new contralateral breast cancer risk, Chlebowski said.

For more information:

•  Onco'Zine - The International Cancer Network

Bisphosphonates and the Risk of Postmenopausal Breast Cancer

Bisphosphonates are routinely given to women with postmenopausal breast cancer, but new data suggest that these agents may play an important role in reducing recurrent breast cancer as well. Results of a new trial demonstrated that the use of bisphosphonates was associated with a 29% reduction in the risk of postmenopausal breast cancer. The results were presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

Link between Bisphosphonates and Breast Cancer
When breast cancer metastasizes, it often spreads first to the bones. Bone metastases can lead to complications such as pain, fractures, spinal cord compression, bone marrow suppression, and hypercalcemia. The primary reason for this link is that breast cancer cells stimulate bone cells called osteoclasts, and these osteoclasts in turn stimulate the growth of breast cancer cells.

Bisphosphonates have emerged as a highly effective therapeutic option for the prevention of skeletal complications secondary to bone metastases. They interrupt the relationship between osteoclasts and breast cancer cells in early stage breast cancer, slowing the progression of bone metastases while, at the same time, reducing the skeletal complications in women with metastatic breast cancer. Research has also demonstrated that bisphosphonates may prevent the development of bone metastases in newly diagnosed patients with no evidence of metastasis.

A number of agents are now approved in both Europe and the US. They included Clodronate, Pamidronate, Ibandronate, Zoledronic acid.

New and ongoing research
Lead researcher Gad Rennert, M.D., Ph.D., chairman of the Department of Community Medicine and Epidemiology at the Carmel Medical Center of Clalit Health Services and a faculty member at the Technion-Israel Institute of Technology in Israel, said these data help shed light on a possible new pathway for breast cancer prevention.

"We have identified a new class of drugs that is associated with a reduced risk of breast cancer, and if proven in randomized trials, we may be able to recommend it to postmenopausal women for this purpose," said Rennert.

Rennert and colleagues extracted data from the Breast Cancer in Northern Israel Study, which is a population-based, case-control study. They evaluated the use of bisphosphonates for at least five years in 4,575 postmenopausal study participants using a structured interview. The self-reported, long-term use of bisphosphonates prior to diagnosis was associated with a significant reduced relative risk for breast cancer by approximately 34%.

This reduction remained significant, at 29%, even after adjusting for a large variety of risk factors for breast cancer such as age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, calcium supplement and hormone replacement therapy use, number of pregnancies, months of breastfeeding and age at first pregnancy.

Moreover, the breast tumors identified among patients who used bisphosphonates were more often estrogen receptor positive and less often poorly differentiated.

"These tumors are the type that are associated with a better prognosis," said Rennert.

While most experts are cautiously optimistic about the results of this study, several of them said that more information is necessary, and as of now, they would not suggest the use of bisphosphonates for women who do not have osteoporosis.

For more information:

• Coleman RE. Bisphosphonates in breast cancer. Ann Oncol 2005 May;16(5):687-95. Epub 2005 Mar 31.
• Logman JF, Heeg BM, Botteman MF, Kaura S, van Hout BA. Economic evaluation of zoledronic acid for the prevention of osteoporotic fractures in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors in the UK. Ann Oncol. 2009 Dec 2. [Epub ahead of print]
• Ghazi M, Roux C. Hormonal deprivation therapy-induced osteoporosis in postmenopausal women with breast cancer. Best Pract Res Clin Rheumatol. 2009 Dec;23(6):805-11.
• Theriault RL. Bisphosphonates: ready for use as adjuvant therapy of breast cancer? Curr Opin Obstet Gynecol. 2009 Nov 19. [Epub ahead of print]

Also see:

• Onco'Zine - The International cancer Blog

New Drug Targeting Advanced Thymic Cancer May Bring Hope to Patients

The Translational Genomics Research Institute (TGen), a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking medical research in oncology, neurological disorders and diabetes, and Scottsdale Healthcare are testing a new drug specifically for thymic cancer. The new drug candidate is designed to stop abnormal cell division and duplication, a common feature of cancer.


The thymus, a small organ that lies in the upper chest under the breastbone or sternum. As a part of the lymph system, the thymus makes lymphocytes that protect the body against infections.
There are different types of tumors of the thymus. Both thymomas (or Thymic epithelial tumors) with clearcut cytologic features of malignancy and thymic carcinomas are rare tumors of the cells that are on the outside surface of the thymus. The tumor cells in a thymoma look similar to the normal cells of the thymus, grow slowly, and rarely spread beyond the thymus. On the other hand, the tumor cells in a thymic carcinoma look very different from the normal cells of the thymus, grow more quickly, and have usually spread to other parts of the body when the cancer is found. Thymic carcinoma is more difficult to treat than thymoma.

At the time of diagnosis, thymic carcinoma has usually metastasized. This can make formulating a treatment plan more challenging. Surgical removal of the tumor is usually the first line of therapy. Depending on the stage of the cancer at diagnosis, chemotherapy, hormone therapy, and radiation may also be prescribed. The 10-year survival rate for patients diagnosed with thymic carcinoma is approximately 28%.

Thymic carcinoma often goes unnoticed until the tumor begins to press on the patient's windpipe. It can also produce hormones that frequently cause symptoms. These may include a persistent cough, asthma, swelling of the face, diarrhea, red and warm skin, and chest pain. Some patients may have no symptoms of the cancer at all. In these cases, the tumor may have been an incidental finding on a routine chest x-ray.

Preliminary results of PHA-848125AC, a TRK A antagonist pro, is uced by Nerviano Medical Sciences of Milan, Italy’s largest pharmaceutical research and development facility, showed favorable results in treating the disease.

“From the initial trial in patients with advanced cancers, this drug is well tolerated. We are now focusing on thymic cancer based on our initial results, to hopefully find a treatment that is successful for this rare cancer - where there is no standard approved treatment,” said Dr. Glen J. Weiss, principal investigator for this trial and Director of Thoracic Oncology at TGen Clinical Research Services (TCRS) at Scottsdale Healthcare.

TCRS is a partnership between TGen and Scottsdale Healthcare that enables laboratory discoveries to be quickly turned into targeted therapies that can be tested with patients at the Virginia G. Piper Cancer Center in Scottsdale.

This Phase II clinical trial of as many as 60 adults with advanced thymic cancer will help determine if PHA-848125AC is an active drug for this disease. The thymus is a small organ near the lungs and heart that is a key part of the body’s immune system during fetal and childhood development.

Dr. Jeffrey Isaacs of Southwest Hematology Oncology in Phoenix, has seen first-hand how this agent made a difference for patients with thymic cancer. He said he is enthusiastic about a drug specifically targeting this rare cancer population to hopefully improve their outcomes.

PHA-848125AC will be administered orally. The study will be open at Scottsdale Healthcare, the Institute Gustave Roussy and the Hopital Larrey in France and at the University of Turin, San Luigi Hospital in Italy.

The intent of the study is to assess the antitumor activity of PHA-848125AC as second-line treatment in patients with recurrent or metastatic, unresectable thymic carcinoma previously treated with chemotherapy. Patients will receive 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle until disease progression or unacceptable toxicity will develop.

For more information about current clinical trials:

• Phase II Study Of Oral PHA-848125AC In Patients With Thymic Carcinoma

Also read

• Johnson S B et al. Thymoma: Update for the new millennium. The Oncologist. Vol. 6, No 3, 239- 246, June 2001.
• Lara, Jr P N (2000) Malignant thymoma: current status and future directions. Cancer Treatment Reviews April 2000; 26: 2 127-131.
• Detterbeck FC, Parsons A M Thymic Tumours. The Annals of Thoracic Surgery 2004; 77:1860- 9.
• Eng T et al (2003) Thymic carcinoma: state of the art review. International Journal of Radiation Oncology Biology Physics. Vol 59 No 3.
• Giaccone G Treatment of malignant thymoma. Current Opinion in Oncology 2005 17: 140- 146.
• World Health Organisation classification of tumours. Pathology and genetics. Tumours of the lung, pleura, thymus and heart. World Health Organisation Classification of Tumours Vol.10 Eds. Travis WD et al. WHO Press, 2004.
• Textbook of Uncommon Cancer (3rd edition) Eds. Raghavan et al. Wiley, 2006.

See PubMed abstracts:

• Nakagawara A Trk receptor tyrosine kinases: a bridge between cancer and neural development Cancer Lett.2001 Aug 28;169(2):107-14.
• Mitsutake N, Yamashita S The role of cancer genes in thyroid cancer and molecular targeted therapy Nippon Naika Gakkai Zasshi. 2009 Aug 10;98(8):1999-2005.

Final Follow-Up of Z-FAST Study Shows Zoledronic Acid May Benefit Postmenopausal Woman with Aromatase Inhibitor-Associated Bone Loss

Zoledronic acid is both safe and effective in preventing bone loss in postmenopausal women with breast cancer who are treated with aromatase inhibitors, according to data presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

 "Women who take aromatase inhibitors need some sort of bone protection, and this five-year data show that zoledronic acid is a viable option," said Adam Brufsky, M.D., Ph.D., associate professor of medicine, associate chief of hematolgy-oncology, and associate director for clinical investigation, University of Pittsburgh Cancer Institute.

Brufsky estimates that between 20,000 to 30,000 women a year will benefit from this therapy and that number is growing. Anastrozole, currently sold as Arimidex by AstraZeneca, is scheduled to go off patent within the next few years.

"Women who are on Medicare tend to go with tamoxifen because the cost of anastrozole puts them squarely in the donut hole of Medicare Part D, but once the cost barrier is removed there will likely be a mass switch to the aromatase inhibitor, which will necessitate the need for bone protection," said Brufsky.

Beyond the aging population, use of zoledronic acid could increase even further if the signs that it prevents breast cancer recurrence continue in larger studies.

Brufsky's study, Z-FAST (Zometa-Femara Adjuvant Synergy Trial), focused on 602 postmenopausal women with stage I to IIIa estrogen or progesterone receptor-positive breast cancer. The researchers randomized patients to immediate zoledronic acid or delayed zoledronic acid. The delayed group received it only if the T-score dropped below two or a clinical fracture occurred.

After five years, patients in the immediate treatment arm had a bone mineral density increase of 6.2% in their lumbar spine area, while those in the delayed arm had a decrease of 2.4%. In the hip area, the increase was 2.6% with immediate treatment compared with a 4.1% decrease with delayed treatment.

Fractures occurred in 10.7% of the patients treated immediately and 12.4% of the patients who received delayed treatment. There were no serious renal events and no osteonecrosis of the jaw, which confirmed that the drug was safe and well tolerated.

For more information:

• Onco'Zine - The International Cancer Network
  

DM1, an Investigational Antibody-Drug Conjugate, Shows Encouraging Results in Women With Highly Advanced HER2-positive Breast Cancer

Results of a Phase II study of trastuzumab (Herceptin®, Genentech) in combination with DM1 (T-DM1), an investigational HER2 antibody-drug conjugate being developed by Genentech, in collaboration with Roche and Immunogen, Inc., shows encouraging results in women with highly advanced HER2-positive breast cancer.

Positive Phase I and Phase II findings were first reported at the 2007 [1] and 2008 [2], respectively, annual meetings of the American Society of Clinical Oncology (ASCO) with T-DM1 in patients with HER2-positive (HER2+) metastatic breast cancer (MBC) that progressed on treatment with trastuzumab. In the Phase II study, 60% of patients also had been treated with lapatinib (Tykerb®, GlaxoSmithKline).

As assessed by independent review, the T-DM1 combination shrank the tumors (also known as objective response) in 33% of women with advanced (metastatic) HER2-positive breast cancer that had worsened following previous treatment.

Women in this study had already received an average of seven drugs for metastatic disease, including chemotherapy, trastuzumab and lapatinib, prior to receiving T-DM1. No new or unexpected safety signals were observed. The results were presented today at the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) from 9 to 13 December 2009 (Abstract #710). [3]

Antibody-drug conjugates or ADCs [4] are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic. They have broad utility in basic, preclinical, and clinical applications. [5] T-DM1 combines two approaches in one medicine: the anti-cancer activity of the trastuzumab antibody, which blocks signals that make the cancer more aggressive and signals the body’s immune system to destroy the cancerous cells, and the targeted delivery of the potent cytotoxic DM1.

“Breast cancer is the most common cancer among women worldwide with more than one million new cases diagnosed every year and nearly 400,000 deaths, so it is vital that we continue to provide more treatment options” said William M. Burns, CEO of Roche Pharma.

According to the American Cancer Society [6], breast cancer is the second leading cause of cancer death in the United States. Women diagnosed with advanced (metastatic) disease have a poor prognosis and only 27% survive five years.

Approximately 15 to 30% of breast cancers are HER2-positive. [7] When HER2-positive breast cancer is advanced, the disease has spread to other parts of the body, most commonly to the lungs, bones, liver and brain. At this stage of the disease, the current goals of existing treatments include symptom relief, tumor shrinkage, improved quality of life and increasing the amount of time women with advanced breast cancer live without the cancer worsening. There are no treatment guidelines or FDA-approved treatment options for women with advanced HER2-positive breast cancer if the disease progresses following treatment with trastuzumab and lapatinib.

“The much anticipated data on the investigational drug T-DM1 will be welcomed by physicians treating women with early and very advanced stages of breast cancer as it will offer them more choices for fighting this devastating disease,” Burns noted.

"Despite major advances in HER2-positive breast cancer, the disease may still progress after multiple treatments, to the point where there are no approved HER2-targeted medicines," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. "Results from this study are promising for women who need new treatment options, and we will discuss next steps of the T-DM1 development program with the FDA."

"These results are significant because they demonstrate that T-DM1 was effective at shrinking tumors in women whose cancer had progressed following prior treatment with standard therapies for HER2-positive breast cancer," said Ian Krop, M.D., Ph.D., a medical oncologist at Dana-Farber Cancer Institute, and lead investigator on the study.

In this single-arm study, 45% of women experienced a clinical benefit (defined as a complete or partial tumor response, or stable disease, maintained for at least six months), as assessed by independent review. Adverse events were similar to those observed in previous clinical trials of T-DM1. The most common severe adverse events included thrombocytopenia (a low level of platelets in the blood, 5.5%) and back pain (3.6%), and the most common adverse events were fatigue (59.1%) and nausea (37.3%). No severe (Grade 3 or higher) cardiac-specific side effects were observed. One patient with pre-existing, non-alcoholic fatty liver disease died with hepatic failure.

Ongoing clinical trials
The new treatment options is currently in trial in a Phase II study, known as TDM4374g, a single-arm, multi-center trial designed to assess T-DM1 as a single agent in 110 women with HER2-positive advanced breast cancer whose disease had progressed after receiving at least two prior HER2-targeted treatments (trastuzumab and lapatinib) in the metastatic setting, as well as an anthracycline, a taxane, and capecitabine. [8]

The primary endpoint of this study is objective response rate (a complete or partial tumor shrinkage of at least 30%, determined by two tumor assessments at least 28 days apart), as measured by an independent review facility. Secondary endpoints include safety, clinical benefit rate, duration of response and progression-free survival (PFS). Duration of response and PFS data are not yet mature and will be presented at a future meeting.

The results of the data presented during the SABCS follow on from results from another phase II study (TDM4258) presented at ASCO 2009 which also showed encouraging results in women with advanced HER2-positive breast cancer [9, 10].

For more information:
[1] Beeram M, Krop I, Modi S, Tolcher A, Rabbee N, et al A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 1042.
[2] Beeram M, Burris III, HA, Modi S, Birkner M, Girish S, et al. A phase I study of trastuzumab-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with advanced HER2+ breast cancer (BC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 1028).
[3] Krop I, LoRusso P, Miller KD, Modi S, Yardley D, et al. A Phase II Study of Trastuzumab-DM1 (T-DM1), a Novel HER2 Antibody-Drug Conjugate, in Patients Previously Treated with Lapatinib, Trastuzumab, and Chemotherapy. SABCS Poster Session 5: Treatment: Her2-Targeted Therapy (Date/Time: Saturday, December 12, 2009; 5:30 PM-7:30 PM)
[4] Teicher BA. Antibody-drug conjugate targets. Curr Cancer Drug Targets. 2009 Dec;9(8):982-1004
[5] Hofer T, Skeffington LR, Chapman CM, Rader C. Molecularly defined antibody conjugation through a selenocysteine interface. Biochemistry. 2009 Dec 22;48(50):12047-57.
[6] American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta: American Cancer Society, Inc.
[7] Murphy CG, Modi S. HER2 breast cancer therapies: a review. Biologics. 2009;3:289-301. Epub 2009 Jul 13.
[8] A Study of of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer.
[9] A Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer.
[10] Vogel CL, Burris HA, Limentani S, Borson R, O'Shaughnessy J, et al. A phase II study of trastuzumab-DM1 (T-DM1), a HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (MBC): Final results. J Clin Oncol 27:15s, 2009 (suppl; abstr 1017).

Also:
Onco’Zine – The International Cancer Network

Small, HER2-Positive, Tumors Linked with Poor Prognosis

Patients with breast cancer whose tumors were HER2-positive and one centimeter or smaller had a significant risk of relapse compared with other tumor types, according to a new study presented at the CRTC-AACR San Antonio Breast Cancer Symposium.

“The current guidelines call for no further therapy if the tumors are less than five millimeters or consider therapy if the tumors are from six to 10 millimeters, but this data challenges that thinking and shows this group of women may benefit from additional therapy,” said Ana M. Gonzalez-Angulo, M.D., assistant professor in the Departments of Breast Medical Oncology and Systems Biology at the University of Texas M. D. Anderson Cancer Center (MDACC).

Gonzalez-Angulo and Ronjay Rakkhit, chief fellow of Hematology-Oncology at M. D. Anderson, and colleagues retrospectively studied 965 patients from MDACC and validated their findings with 350 patients from two European institutions. Patients with a lack of receptor information, and/or who had received adjuvant chemotherapy or trastuzumab at any time were excluded.

“This is the largest study of its kind in a patient population, and as our ability to detect tumors improves, this patient population will only continue to increase. Further, it answers a common question oncologist have in daily practice – which early stage patients may be in need of additional therapy,” said AMG. Patients were diagnosed between 1990 and 2003. Median age of the patients at diagnosis was 57 years. All tumors were one centimeter or smaller. Most of the tumors (68%) were hormone receptor-positive, while 10 percent were HER2-positive and 23% were triple receptor-negative.

Five-year, recurrence-free survival was 77.1% 93.7% in patients with HER2-positive and HER2-negative tumors, respectively, and five-year distant recurrence-free survival was 86.4% and 97.2%, in patients with HER2-positive and HER2-negative tumors, respectively. Patients with HER2-positive tumors had 2.68 times greater risk of recurrence and 5.3 times higher the risk of distant recurrence than those with HER2-negative tumors.

Patients with HER2-positive tumors had 5.09 times the risk of recurrence and 7.81 times the risk of distant recurrence compared to patients with hormone receptor-positive tumors.

Data on 350 additional patients treated at two other institutions showed reproducibility, said Gonzalez. “This paper shows that patients with HER2-positive tumors one centimeter or less have a significant risk of relapse and should be considered for clinical trials of systemic anti-HER2 adjuvant therapy, or if a clinical trial is not available, adjuvant therapy should be discussed with them”, said Gonzalez-Angulo.

Eating Pistachios Increases Serum Levels of Gamma-tocopherol, May Help in Reducing Lung Cancer Risk

A diet that incorporates a daily dose of pistachios may help reduce the risk of lung and other cancers, according to data presented at the American Association for Cancer Research Frontiers in Cancer Prevention Research Conference, held Dec. 6-9.

"It is known that vitamin E provides a degree of protection against certain forms of cancer. Higher intakes of gamma-tocopherol, which is a form of vitamin E, may reduce the risk of lung cancer," said Ladia M. Hernandez, M.S., R.D., L.D., senior research dietitian in the Department of Epidemiology at the University of Texas M. D. Anderson Cancer Center, and doctoral candidate at Texas Woman's University - Houston Center.

"Pistachios are a good source of gamma-tocopherol. Eating them increases intake of gamma-tocopherol so pistachios may help to decrease lung cancer risk," she said.

Pistachios are known to provide a heart-healthy benefit by producing a cholesterol-lowering effect and providing the antioxidants that are typically found in food products of plant origin. Hernandez and colleagues conducted a six-week, controlled clinical trial to evaluate if the consumption of pistachios would increase dietary intake and serum levels of gamma-tocopherol. A pistachio-rich diet could potentially help reduce the risk of other cancers from developing as well, according to Hernandez.
"Because epidemiologic studies suggest gamma-tocopherol is protective against prostate cancer, pistachio intake may help," she said. "Other food sources that are a rich source of gamma-tocopherol include nuts such as peanuts, pecans, walnuts, soybean and corn oils."

The study, conducted at Texas Woman's University - Houston Center, included 36 healthy participants who were randomized into either a control group or the intervention group consisting of a pistachio diet. There were 18 participants in the control group and 18 in the intervention group.
There was a two-week baseline period, followed by a four-week intervention period in which the intervention group was provided with 68 grams (about 2 ounces or 117 kernels) of pistachios per day; the control group continued with their normal diet.

The effect on the intake and serum cholesterol-adjusted gamma-tocopherol was investigated. Intake was calculated using the Nutrition Data System for Research Version 2007, and consumption was monitored using diet diaries and by measuring the weights of the returned pistachios.
Hernandez and colleagues found a significant increase in energy-adjusted dietary intake of gamma-tocopherol at weeks three and four in those on the pistachio diet compared with those on the control diet. The similar effect was seen at weeks five and six among those on the pistachio diet compared with those on the control diet. For those on the pistachio diet, cholesterol-adjusted serum gamma-tocopherol was significantly higher at the end of the intervention period compared to baseline.

"Pistachios are one of those ‘good-for-you' nuts, and 2 ounces per day could be incorporated into dietary strategies designed to reduce the risk of lung cancer without significant changes in body mass index," said Hernandez.

Targeted Breast Ultrasound Can Reduce Biopsies for Women under Forty

Targeted breast ultrasound of suspicious areas of the breast, including lumps, is a safe, reliable and cost-effective alternative to invasive biopsies for women under age 40, according to the findings of two studies presented at the 95th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA).

"By performing high-quality breast ultrasound, we can reduce the number of expensive and avoidable invasive diagnostic procedures in young women," said senior author Constance D. Lehman, M.D., Ph.D., professor and vice chair of radiology at the University of Washington and director of imaging at the Seattle Cancer Care Alliance. "We don’t want to be overly aggressive with this population."

The researchers conducted two studies in which targeted ultrasound was used to distinguish between potentially cancerous masses and benign findings in young women who had detected breast lumps or other focal (specific) areas of concern in their breasts. The first study included 1,123 ultrasound examinations of women under age 30, while the second included 1,577 ultrasound examinations of women ages 30 to 39.

Across both studies, all instances of cancer at the site of the clinical concern were positively identified through targeted ultrasound. In addition, all negative ultrasound findings correctly identified benign changes in the breast. The only malignant mass not identified by ultrasound was an unsuspected lesion outside of the targeted examination area. That cancer was identified by a full breast mammogram.

The incidence of malignancy among women in their 30s was 2%. The incidence of malignancy among women younger than 30 was 0.4 percent.

Fig 1. A breast ultrasound image showing a benign mass.

"Surgical excision or needle biopsy of tissue can be painful, expensive and frequently unnecessary in these age groups, which have very low rates of malignancies," Dr. Lehman said. "In most cases, monitoring with targeted ultrasound is a very safe alternative."

She added that ultrasound should be the diagnostic tool of choice for young women seeking care for breast lumps and other suspicious focal signs and symptoms. "It is time we used ultrasound to reduce unnecessary morbidity and costs associated with more aggressive invasive approaches," Dr. Lehman said.

Also see Abstracts:
- Outcomes of Targeted Ultrasound Evaluation in Women Under 30 Years of Age with Focal Breast Signs or Symptoms. Presented by Dr. Vilert Loving, MD
- Contribution of Mammography to Ultrasound Evaluation of Women 30 to 39 Years of Age with Focal Breast Signs or Symptoms . Presented by Michael Portillo, MD

For more information:
- Onco'Zine - The International Cancer Network

Ultrasound with Elastography May Improve Skin Cancer Detection

High-frequency ultrasound with elastography can help differentiate between cancerous and benign skin conditions, according to a study presented at the 95th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA).

"High-frequency ultrasound with elastography has the potential to improve the efficiency of skin cancer diagnosis," said lead author Eliot L. Siegel, M.D., vice chairman of the Department of Radiology at the University of Maryland School of Medicine (UMSM) in Baltimore. "It successfully delineated the extent of lesions and was able to provide measurable differentiation among a variety of benign and malignant lesions."

There are more than one million cases of skin cancer diagnosed in the U.S. every year, according to the American Cancer Society. Melanoma, the most serious type of skin cancer, will account for about 68,720 cases of skin cancer and 11,590 deaths in 2009, despite the fact that with early detection it is highly curable.

Suspicious skin lesions are typically diagnosed by dermatologists and biopsied based on their surface appearance and characteristics. Unfortunately, even to experienced dermatologists, benign and malignant lesions often appear similar visually and on physical examination, and some malignant lesions may have a benign appearance, especially in their early stages. It is not uncommon for patients to have one or more lesions that appear concerning.

"Dermatologists tend to biopsy any lesions that seem visually suspicious for disease," said coauthor Bahar Dasgeb, M.D., from the Department of Dermatology at Wayne State University in Detroit and Pinkus Dermatopathology Lab in Monroe, Michigan. "Consequently, many benign lesions are needlessly biopsied in order to avoid the risk of missing a potentially deadly melanoma."

Elastography was found to distinguish between benign and malignant lesions not by their visible appearance but by measuring their elasticity or stiffness. Since malignancies are stiffer than benign growths, elastography, when added to high-frequency ultrasound imaging of the skin, has potential to improve the accuracy of traditional clinical diagnosis of skin cancers and, in some cases, eliminate unnecessary biopsies of benign skin lesions. The procedure is noninvasive, convenient and inexpensive.

For the study, researchers used an ultra high-frequency ultrasound system to image 40 patients with a variety of malignant and nonmalignant, or benign, skin lesions. Malignant tumors included squamous cell carcinoma, basal cell carcinoma and melanoma. Benign lesions included dermatofibroma, a noncancerous growth containing scar tissue, and lipoma, a noncancerous tumor composed of fatty tissue.

Fig 1. An elastogram (left) and ultrasound (right) showing squamous cell carcinoma of the skin.


The researchers calculated the ratio of elasticity between normal skin and the adjacent skin lesion, and used laboratory analysis to confirm their diagnoses. Cystic lesions, which are not malignant, demonstrated high levels of elasticity, while malignant lesions were significantly less elastic. The elasticity ratio of normal skin to the various skin lesions ranged from 0.04 to 0.3 for cystic skin lesions to above 10.0 for malignant lesions.

In addition, high-frequency ultrasound with elastography allows for accurate characterization of the extent and depth of the lesion below the surface, which can aid physicians in treatment.

"The visualized portion of a skin lesion can be just the tip of the iceberg, and most dermatologists operate 'blindly' beyond what they can see on the surface," Dr. Siegel said. "High-frequency ultrasound provides almost microscopic resolution and enables us to get size, shape and extent of the lesion prior to biopsy."


Fig 2. An elastogram (left) and ultrasound image (right) showing a premalignant lesion


For more information, also see:
Elastographic Ultrasound Quantitative Analysis Combined with High Frequency Imaging for Characterization of Benign and Malignant Skin Lesions Presented by Dr. Bahar Dasgeb, MD.

Also see:
Ultrasound with Elastography May Improve Skin Cancer Detection

Annual Screening with Breast Ultrasound or MRI Could Benefit Some Women

Results of a large-scale clinical trial presented presented at the 95th Scientific Assembly and Annual Meeting of the Radiological Society of North America (RSNA) provide the first strong evidence of the benefit of annual screening ultrasound for women with dense breasts who are at elevated risk for breast cancer. In addition, the study confirmed that MRI is highly sensitive in depicting early breast cancer.

"We found that annual screening with ultrasound in addition to mammography significantly improves the detection of early breast cancer," said lead researcher Wendie A. Berg, M.D., Ph.D., breast imaging specialist at American Radiology Services, Johns Hopkins — Green Spring Station in Lutherville, Md., "and that significantly more early breast cancer can be found when MRI is performed, even after combined screening with both ultrasound and mammography. However, both ultrasound and MRI increase the risk of false-positive findings."

Women who are at high risk for breast cancer need to begin screening at a younger age, because they often develop cancer earlier than women at average risk. However, women below age 50 are more likely to have dense breast tissue, which can limit the effectiveness of mammography as a screening tool.

Multicenter trials have shown that MRI enables radiologists to accurately identify tumors missed by mammography and ultrasound. The American Cancer Society recommends that some groups of women with a high risk of developing breast cancer should be screened with MRI in addition to their yearly mammogram beginning at age 30. However, MRI is not for everyone.

"Because MRI is a very expensive test and requires intravenous contrast, it is something we only recommend for screening the approximately 2% of women who are known or likely carriers of BRCA1 or BRCA2 gene mutations or have other unusual circumstances that put them at very high risk for breast cancer," Dr. Berg said.

"There are another 10 to 15% of women who are at some increased risk because of personal history of breast cancer, family history of breast cancer and/or dense breast tissue," she added. "For many of these women, MRI is not currently justified, but annual ultrasound would be appropriate in addition to mammography."

Fig 1. This breast MRI showing focus of enhancement in left breast, negative on mammography and screening ultrasound. Pathology proven infiltrating ductal carcinoma

The researchers studied 612 women, mean age 55 years, at elevated risk of breast cancer enrolled at 14 sites in the American College of Radiology Imaging Network (ACRIN) 6666 trial funded by the Avon Foundation and the National Cancer Institute. Women underwent baseline screening mammography and ultrasound with follow-up exams at 12 and 24 months and then a single, contrast-enhanced MRI at 24 months.

Sixteen women were diagnosed with breast cancer. Twelve of the cancers were invasive, and four were ductal carcinoma in situ (DCIS). Over the course of the study, 50 to 56 percent of cancers were shown on mammography. Adding ultrasound allowed detection of 70 to 94% of cancers. Adding MRI allowed for detection of additional cancers at their earliest stage.

Fig 2. Ultrasound showing 9-mm benign mass (arrows) in upper inner quadrant

The study also found that supplemental screening with ultrasound or MRI significantly increased the risk of false-positive findings, leading to unnecessary biopsies in some women.

"It is important that women are advised of the increased potential of undergoing an unnecessary biopsy as a result of screening with ultrasound or MRI," Dr. Berg said, "but we hope this study motivates women and their doctors to learn more about their risk factors and to consider supplemental screening in addition to mammography where indicated."

Also see Abstracts:
Supplemental Yield and Performance Characteristics of Screening MRI after Combined Ultrasound and Mammography: ACRIN* 6666 *American College of Radiology Imaging Network.

Bisplatinates, a New Class of Platinum-Based Anti-Tumor Drugs, Demonstrates Potent Anti-Tumor Activity and Ability to Overcome Resistance to Currently Available Platinum-Based Agents

Seattle-based Cell Therapeutics, Inc, a biopharmaceutical company committed to developing an integrated portfolio of oncology products, today announced that its new class of platinum-based anti-tumor compounds, termed bis-platinates, demonstrated a stronger anti-tumor potency and activity compared to currently available platinum-based compounds as well as the ability to overcome cisplatin-resistance in cancer cell lines.

The results were presented in a paper titled "Novel Bis-platinum Complexes Endowed with an Improved Pharmacological Profile," by Laura Gatti et al. that was published in the online edition of the journal Molecular Pharmaceutics. Platinum-based compounds, such as cisplatin and oxaliplatin, are the cornerstone in the treatment of testicular, ovarian, colorectal, lung and other cancers but their effectiveness is limited by the relatively low therapeutic ratio, the ratio of the maximally tolerated dose of the drug to the effective dose, and the frequent occurrence of drug resistance leading to cancer recurrence. The novel bis-platinum compounds represent a completely new class of platinum-based drugs called bisplatinates.

The bis-platinum based compounds, unlike the currently approved platinum-based compounds, contain two platinum atoms and work by binding to and damaging both strands of DNA making it much more difficult for cancer cells to repair the damage. The research demonstrated through cancer cell assays and animal tumor models that the bis-platinum complexes exhibited greater cytotoxic potency and anti-tumor effect compared to cisplatin and oxaliplatin.

There was more than a 200-fold increase in percent accumulation in tumor cells of the bisplatinum compounds compared to cisplatin and oxaliplatin. The bisplatinates were substantially more active against human tumors grown in an immunodeficient preclinical model than the standard palatinate compounds, oxaliplatin, carboplatin and cisplatin. Furthermore, the bis-platinum compounds demonstrated the ability to overcome tumor resistance to cisplatin mediated by DNA mismatch repair defects. The complexes showed marked anti-tumor efficacy in platinum refractory tumors, with significant activity in terms of tumor growth inhibition and tumor growth delay.

"Platinum-based compounds are cornerstone agents in the treatment of very common cancers such as cancers of the lung, colon, and ovary and are also widely used in other gynecological-tumors, testicular cancers, and cancers of the esophagus, head and neck. They are increasingly being used for salvage therapy in lymphoma. However, resistance to palatinate compounds is common. The current results are encouraging as they demonstrate that the bisplatinates are not only more effective in human tumor models than the current agents, but also capable of overcoming some forms of palatinate resistance," said Jack Singer, M.D., Chief Medical Officer of CTI.

For more information:
Gatti L, Perego P, Leone R, Apostoli P, Carenini N, et al. Novel Bis-platinum Complexes Endowed with an Improved Pharmacological Profile. Mol Pharm. 2009 Nov 17. [Epub ahead of print]

Also see:
Bisplatinates, a New Class of Platinum-Based Anti-Tumor Drugs, Demonstrates Potent Anti-Tumor Activity