Seattle Genetics, Inc., Up and Coming Research-Based Concern, Developing Focused Pipeline of Targeted Therapies

Seattle Genetics, Inc., is a clinical stage biotechnology company focused on the development and commercialization of monoclonal antibody—based therapies, primarily for the treatment of cancer but also, in select instances, autoimmune disease. The company has no products on the market as of yet. What they do have is a concentrated research and development operation that is yielding results and progress across a rich but narrowly focused pipeline of six agents (three in preclinical development, three in clinical trials, all with oncology care applications) from only two select drug classes of targeted therapies that all have the potential to become breakaway drugs.

Seattle Genetics, Inc., was founded in 1997, held its initial public offering in March of 2001, and in January of 2008, completed a $103.5 million follow-on public offering.

Seattle Genetics currently employs more than 200 people. The headquarters of the company, perhaps sending a message about the depth of their research-oriented commitment, eschews the traditional corporate atmosphere. Indeed, there are offices, but the overall feel of the high-technology campus in Bothell, Washington, the Seattle suburb where Seattle Genetics makes its home, is less buttoned down and formal, more lab coats and activity. While most company executive headquarters project an image of business being done, the resource-laden Bothell campus, with its sprawling, state-of-the-art facilities, reflects a company going about the business of drug discovery.

All of the Seattle Genetics product candidates belong to one of two monoclonal antibody classes. In addition to developing very targeted and specific forms of drugs, the company can also be said to have significantly contributed to the development and advancement of the two drug classes discussed herein. In fact, one of the classes, or sub-classes, covered in this section, antibody-drug conjugates, is a proprietary discovery and creation of Seattle Genetics. That is, the company is solely responsible for its existence and evolution. Seattle Genetics is focused on the following two key antibody-based technologies:

 Some monoclonal antibodies have intrinsic antitumor activity. Once the antibody binds to a target cell, it can result in direct cancer cell death and/or activate the body’s anticancer immune response. Seattle Genetics’ lead monoclonal antibody product candidates are SGN-40, SGN-33 and SGN-70.

 While some antibodies are capable of killing cells on their own, many are not potent enough but can effectively target cancer and deliver cell-killing payloads. Utilizing proprietary ADC technology, internalizing monoclonal antibodies are linked to cell-killing drugs, resulting in highly-potent agents. The linkers are stable in the bloodstream but release drug payloads inside target cells. The novel drug-linker systems that Seattle Genetics has developed are fully synthetic and therefore readily produced in large quantity. SGN-35, SGN-75, and anti-CD19 ADC employ this proprietary technology.

Currently, Seattle Genetics is developing the following drugs in various phases of clinical trials:

 is a humanized antibody targeted to the CD40 antigen. Seattle Genetics is developing SGN-40 under a worldwide collaboration agreement with Genentech that was established in January 2007. Ongoing clinical trials under the collaboration include a phase II single-agent clinical trial in diffuse large B-cell lymphoma (DLBCL), a phase IIb combination trial of Rituxan (rituximab) -ICE +/- SGN-40 in DLBCL, a phase Ib study of SGN-40 plus Rituxan and Gemzar (gemcitabine) in DLBCL, a phase Ib trial of SGN-40 in combination with Rituxan for indolent non-Hodgkin’s lymphoma and a phase Ib combination trial of SGN-40 plus Revlimid (lenalidomide) for multiple myeloma. Seattle Genetics and Genentech recently initiated a sixth clinical trial of SGN-40 in combination with Velcade (bortezomib) for multiple myeloma.

 (lintuzumab) is a humanized antibody targeted to the CD33 antigen, which is highly expressed in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and several myeloproliferative disorders. The company is currently conducting a phase Ib single-agent clinical trial for patients with AML or MDS, a phase IIb trial of low-dose cytarabine (Cytosar) +/- SGN-33 in AML and a phase I trial of SGN-33 plus Revlimid (lenalidomide) for patients with advanced MDS.

is an antibody-drug conjugate (ADC) composed of a monoclonal antibody linked to a derivative of the highly potent class of drugs called Auristatins using proprietary ADC technology. SGN-35 is in two phase I clinical trials for CD30-positive hematologic malignancies, including Hodgkin’s lymphoma.

Seattle Genetics recently presented promising phase I clinical data on SGN-35, during a poster discussion session at the recent American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago. At the time the abstract, entitled “Objective responses in a phase I dose-escalation study of SGN-35, a novel antibody-drug conjugate targeting CD30, in patients with relapsed or refractory Hodgkin lymphoma,” was submitted, 29 patients had been enrolled in the study, including 26 with Hodgkin’s lymphoma and three with other CD30-positive hematologic malignancies. SGN-35 dose levels ranged from 0.1 to 2.7 mg/kg. Of 28 patients evaluable for response, nine had partial remissions. Stable disease was observed in 11 patients and eight patients had progressive disease. At dose levels of greater than or equal to 1.2 mg/kg, seven of 13 patients (54%) achieved partial remissions. SGN-35 was generally well tolerated. The most common related adverse events were minor (no higher than grade two), including fatigue and cough.

In addition to the trio of agents that have moved into clinical trials, Seattle Genetics has three compounds that are in the preclinical phase of development, listed as follows:

		SGN-70, a humanized antibody targeting the CD70 antigen, which possesses potent effector function and direct cell-killing ability. The CD70 antigen is expressed on renal cancer, nasopharyngeal carcinoma and certain hematologic malignancies.

		SGN-75, an ADC comprising the SGN-70 antibody linked to an auristatin derivative using proprietary ADC technology. This product candidate may have application in solid tumors, including renal cell cancer, and CD70-positive hematologic malignancies.

		Anti-CD19 ADC, which targets the CD19 antigen, a cell marker expressed on many hematologic malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia and acute lymphoblastic leukemia. This ADC has demonstrated durable tumor regressions at low doses in multiple cancer models.

In addition to developing drugs, Seattle Genetics works through numerous partnerships and alliances to expand its potential portfolio and best leverage its existing one. The company has an exclusive worldwide collaboration agreement with Genentech to develop and commercialize SGN-40. In addition, they have licensed their ADC technology to Genentech, CuraGen, Progenics, Bayer, and MedImmune, and have an agreement with Agensys, a subsidiary of Astellas Pharma, to jointly develop up to two ADC products. Since 2001, Seattle Genetics has received more than $65 million from ADC technology collaboration activities.

Foreign Companies Accelerate Investment in American Biotech: Millennium Deal Seen as Part of Larger Trend

When Takeda, Japan’s biggest drug company, recently announced its acquisition of Cambridge, Massachusetts—based Millennium Pharmaceuticals, many industry commentators did not confine their observations to the terms and value of the deal. Instead, they were busy discussing the implications of the news as part of a larger trend toward foreign ownership of homegrown drug concerns. According to numerous experts, the transaction is broadly reflective of current economic conditions in America.

The transaction, in which Millennium was purchased for a price of $8.8 billion, or $25 per share (representing a 53% premium over Millennium’s per-share price at the time of the acquisition’s announcement), was significant in its own right. Analysts, however, are asserting that the financial context in which the agreement took place is even more notable. In a recent issue of 

, for example, financial writer Matthew Herper wrote that “the deal signals a new reality for U.S. biotech companies.”

This “new reality” largely consists of an industry-wide shift from homegrown capitalization to overseas investment. As the omnipresent specter of recession continues to linger, both large- and small-scale investors from the United States have become more risk-averse. The biotech industry, of course, while offering tremendous potential upside, is not a good place for risk-averse investors looking for safe, predictable returns. In the meantime, the slack is being taken up by foreign firms, eager to gain a foothold in the American market and able to capitalize on hugely advantageous exchange rates as a result of the weak dollar.

In a research note made available to the media, Geoff Porges, analyst, Sanford C. Bernstein, wrote, “New York’s Fifth Avenue is now awash with foreign shoppers convinced that the prices of goods in U.S. dollars are a bargain. While the situation is not identical, U.S.-based biotechs and their shareholders are benefiting from the discounted value of the U.S. dollar compared to other currencies.”

Takeda, the world’s 17th largest pharmaceutical company, said the deal could create a “powerful new drug development engine.” The acquisition gives Takeda the rights to Millennium’s fast-growing cancer drug, Velcade (which generated roughly $800 million in 2007 sales, and, owing to its attainment of expanded and/or new indications, is expected to surpass that performance in 2008), and access to a rich pipeline of oncology drugs in development. Analysts believe that if Velcade is able to attain FDA approval for all—or even most&mdash;of the cancer types it is currently undergoing clinical trials to treat, the drug has the potential to deliver billions of dollars in annual sales, making it a legitimate ‘blockbuster’ drug. Millennium shares skyrocketed 48.9% to a four-year high on the day following the acquisition announcement.

The deal, which is expected to be finalized in June, marks the second major U.S. biotech acquisition by a Japanese drug maker in the last few months. In December of 2007, Eisai Co. bought MGI Pharma for $3.9 billion.

Industry watchers expect to see more Japanese expansion into the U.S. oncology marketplace. Additionally, the global economic situation has created a similarly attractive dynamic for European companies interested in U.S. biotechs. If the recent purchase of U.S.-based companies Chiron and MedImmune by European concerns Novartis and AstraZeneca, respectively, are any indication, U.S. biotech companies can expect to be entertaining suitors from across both the Atlantic and Pacific oceans. This trend is likely to last for as long as current economic conditions persist.

In a move that will significantly boost its pipeline and strengthen its position in the oncology sector, London- based Antisoma has announced the purchase of Boston-based Xanthus Pharmaceutical in an all-share deal. With the acquisition, which bears a reported price tag of $52.2 million, Antisoma will add several promising drug candidates to its portfolio, including:

		Xanafide, a treatment indicated for secondary acute myeloid leukemia that is currently in phase III clinical trial stage of development;

		Oral fludarabine, currently awaiting FDA approval for the second-line treatment of chronic lymphocytic leukemia;

		The Flt3 program, currently in preclinical testing for a number of nononcology indications. Since that the development of Flt3 does not fit in with Antisoma’s oncology-focused market strategy, analysts expect Antisoma to out-license the drug. An Antisoma spokesperson confirmed that the out-licensing of the Flt3 program was under consideration.

Details of the transaction were disclosed in an Antisoma press release. To acquire the entire issued share capital of Xanthus, Antisoma will issue to Xanthus’s shareholders an aggregate of 97.3 million new ordinary shares in the share capital of Antisoma if the closing date is on or before June 16, 2008 or an aggregate of 99.3 million new ordinary shares in the share capital of Antisoma if the closing date is on or after June 17, 2008, representing approximately 22% of the issued share capital of Antis.

Industry watchers generally applauded the move, affirming the value of Antisoma’s purchase and pointing out that the deal will decrease Antisoma’s dependence on ASA404, a non—small cell lung cancer treatment currently in latestage development. Before the Xanthus agreement, the prospects of Antisoma were directly linked to the prospects of ASA404. With the diversification attained through the Antisoma– Xanthus merger, this is no longer the case. Although the performance of ASA404 remains vital to Antisoma’s future, the company no longer faces an ‘all-or-nothing’ scenario, in which company fortunes will be determined by the corresponding fortunes of a single product candidate.

Glyn Edwards, CEO, Antisoma, stated, “This is a transforming deal. Combining Antisoma and Xanthus produces a company with the critical mass and mature pipeline needed to become a major player in oncology.”

The Xanthus acquisition may prove to be a component of a larger spending strategy by cash-rich Antisoma as part of an effort to leverage the purchasing power of its strong Euro (especially against the weak U.S. dollar) in order to strengthen and expand its presence in the global oncology marketplace. Just a few weeks before the announcement of the Xanthus deal, Antisoma bought the rights to develop a new oncology drug from Betagenon, a Swedish biotech concern.

The company said it would make an undisclosed upfront payment to privately-owned Betagenon for the rights to develop and commercialize its AMPK activators for use in cancer treatments. As part of the agreement, Antisoma has made a commitment to fund further research into cancer treatment at Betagenon.

Commenting on the deal, Mr. Edwards said that while many companies were finding it difficult to raise funds in the global credit crisis, Antisoma was fortunate to be in a strong cash position. “We just happen by great luck to be entering this really difficult economic climate with a really strong balance sheet. Right now, the market for in-licensing is less competitive than it has been for a very long time, and although we do compete with the pharma and big biotechs... competition from smaller biotech companies has just about evaporated,” stated Mr. Edwards.

Despite its recent shopping spree, Antisoma, according to a spokesperson, still has the cash to make further acquisitions of both companies and drugs, if it so chooses. Mr. Edwards stated that Antisoma hopes to complete at least one more licensing deal this year and did not rule out the purchase of other cancer drug developers (many of whom are struggling for funding due to the ongoing current credit crisis).

Progress Toward Potential Cancer Vaccines Advance to Multiple Fronts

Imagine a world in which cancer is completely preventable. At a certain age, children enter their pediatrician’s office and are given a series of antimalignancy vaccines as part of their larger regimen of inoculation against disease. It is a scenario in which one of the most dreaded categories of illness is reduced to a historical footnote, conquered in the same manner as other once fearsome, life-shattering maladies such as polio and smallpox.

Of course, the reality of such radical scientific advancement is currently as far away as space travel to other galaxies. However, researchers are taking the first tentative steps toward the most ambitious oncology treatment goals imaginable, as pioneering vaccine-based therapies become more and more viable with each passing day.

Recently, news of significant vaccine-related progress has been emanating from several sources (Sidebar). Investors in Oxford BioMedica Plc, a biotechnology company based in the United Kingdom, saw their shares surge after the company’s TroVax vaccine was shown to be effective and well-tolerated in a trial of prostate cancer patients (who had a type of prostate cancer that had spread to other parts of their bodies).

According to a statement that Oxford BioMedica released to the media, all 24 evaluable patients had “robust” responses to the vaccine. “We continue to be encouraged by the clinical data from ongoing trials of TroVax,” stated Mike McDonald, chief medical officer, Oxford BioMedica. Results of the mid-stage study of TroVax in prostate cancer, presented at the 6th International Symposium on Targeted Anticancer Therapies in Bethesda, Maryland, demonstrated disease stabilization in 20 of the patients. The time period of the disease stabilization experienced by study subjects ranged from two months to more than 10 months.

TroVax belongs to a new class of cancer drugs—known as therapeutic vaccines&mdash;that are designed to coax the body's immune system to kill tumor cells. Although the preliminary data released by the company lacks a great deal of detail, it was sufficient to impress a cross-Channel competitor: In 2007, Paris-based pharma giant Sanofi- Aventis SA agreed to pay Oxford BioMedica as much as $807 million for the rights to the product candidate, which is also being tested in other types of cancer.

In other promising vaccine news, GlaxoSmithKline Plc disclosed that its cervical cancer vaccine Cervarix provided significant protection for women against the four most common cancer-causing human papillomavirus (HPV) types for 6.4 years, the longest duration of protection reported to date.

Articles

Physician's Financial News: June 10, 2010

Second-Line Pemetrexed Does Not Provide Survival Advantage in Malignant Pleural Mesothelioma

Pemetrexed seems to be one of the few therapies to exert positive effects in patients with malignant pleural mesothelioma (MPM). Researchers from Poland, Germany, Italy, and the United States conducted a controlled, phase III study to determine whether second-line treatment with pemetrexed in patients with advanced MPM improved their overall survival.

The study group comprised 123 patients who after first-line chemotherapy experienced relapsed MPM. They were randomly assigned to receive treatment with pemetrexed 500 mg/m² plus best supportive care (BSC) every 21 days. Their progress was compared against a control group of 120 patients who received BSC alone.

The investigators did not find any significant differences in the primary outcome measure, median overall survival, between the two treatment groups (8.4 mo for the pemetrexed + BSC group and 9.7 mo for the BSC group). However, they did reveal that the combination of pemetrexed and BSC led to significantly better progression-free survival and time-to-tumor progression. Although the overall survival did not favor the second-line pemetrexed group, those receiving the combination attained a 19% rate of partial response compared with only 2% in the BSC-only group (

 < .0001). The disease control rate (partial response and stable disease) was noted in 59% of the pemetrexed group and 19% of the BSC group (

Interestingly, the investigators found that subjects who received BSC treatment only had significantly greater use of postdiscontinuation chemotherapy than the pemetrexed group (52% vs. 28%, respectively; 

 = .0002) with 18.3% of patients in the BSC group being given pemetrexed versus 3.3% in the pemetrexed group (

 = .0001). Chemotherapy was well tolerated in both groups, with 4% to 7% grade 3 and 4 hematologic toxicities.

P = Pemetrexed; BSC = best supportive care.

An overall survival improvement rate was not found in this study, concluded the researchers, because of a difference in the use of post-discontinuation chemotherapy between the two treatment groups. Those using second-line pemetrexed and BSC had better tumor response and longer-delayed disease progression compared with only BSC use in patients with advanced MPM, the researchers commented.

Jassem J, Ramlau R, Santor A, et al: Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma.

Colon Cancer Risk Reduced Dramatically by Two-Drug Combination

The risk of colon cancer may be decreased by more than 90% in high-risk patients, according to researchers from the University of Arizona who presented their findings at the American Association for Cancer Research annual meeting in San Diego. They found that the use of a synthetic amino acid that interferes with cancer development but is highly toxic at regular doses can be given with a nonsteroidal antiinflammatory drug (NSAID) but at greatly reduced doses, reduced the risk of colorectal adenomas, without significant toxicity.

The study group comprised 375 patients with a history of colorectal polyps within the past five years. The enrollees were randomly assigned to receive either a combination of difluoromethylornithine (DFMO) 500 mg/day plus sulindac 150 mg/day or a placebo.

After a three-year follow-up period, the risk of a recurrent polyp was 41.1% in the placebo group but only 12.3% with the combination treatment, a 70% reduction. Patients with a history of advanced polyps who took the active drug combination saw their risk of recurrent polyps drop 92%.

The rate of polyp reappearance in patients with multiple previous adenomas was 13.2% in the placebo group and 0.7% in the group receiving the DFMO—sulindac combination treatment (95% reduction). The lead researcher pointed out that 17 patients in the placebo group experienced regrowth of at least one adenoma, compared with only one patient in the treatment group.

The study was halted early by the trial’s Data Safety and Monitoring Board because the rate of risk reduction was so high. No differences were noted, the clinicians added, between individuals receiving treatment and placebo in terms of gastrointestinal or cardiovascular side effects as well as temporary hearing loss or side effects that required hospitalization.

Meyskens FL: Marked efficacy of difluoromethylornithine plus sulindac in reducing recurrent colorectal adenomas in patients with prior adenomas: Results of a randomized, placebo-controlled, double-blind Phase III trial.

    Presented at the 99th annual meeting of the American Association for Cancer Research, San Diego, California, 

Perioperative Chemotherapy With FOLFOX4 Versus Surgery Alone for Patients With Metastatic Colorectal Cancer

Within two years of surgical resection of primary colorectal tumors, more than half of patients will experience metastasis to the liver. In patients with liver metastases from colorectal cancer, surgical excision of the metastases is the standard of care. However, this standard therapy does not yield good outcomes; relapse frequently occurs, leading to poor prognoses. Oncologists and surgeons from multiple European centers decided to evaluate whether the use of perioperative chemotherapy can affect the progression-free survival (PFS) and overall survival in these patients compared with surgical excision alone.

Three hundred sixty-four patients with proven colorectal cancer and up to four liver metastases (which were considered resectable) were included in the study. They were randomly assigned to standard surgery alone (N = 182) or to treatment with FOLFOX4 (oxaliplatin injection combined with 5-fluorouracil/ leucovorin) six cycles before and six cycles after surgery (N = 182). A hazard ratio (HR) of 0.71 or less would denote a 40% increased PFS in this phase III study and was denoted as the objective.

Eighty-three percent of the patients in the perioperative chemotherapy group received a median of six preoperative cycles and underwent surgical resection, with 115 (63%) receiving a median six postoperative cycles. In the surgery-only group, 152 (84%) of patients were resected. At three years, the absolute increase in the PFS rate was only 7.3 percentage points (from 28.1% to 35.4%; HR, 0.79; 

 = .06) for randomized patients (patients who were randomized to participate but were not necessarily resected). The increase in PFS rate for all patients undergoing resection was 9.2 points (from 33.2% to 42.4%; HR, 0.73; 

 = .025). The researchers noted that fewer patients in the perioperative chemotherapy group died (64) compared with the surgery-only group (75) over the three-year follow- up, and that perioperative mortality was below 1% in both groups.

Serious adverse events associated with preoperative FOLFOX4 chemotherapy included grade 3/4 neutropenia (18%), grade 3 diarrhea (8%), grade 3 stomatitis and pharyngitis (6%), and grade 3/4 leucopenia (6%). When given postoperatively, the following significant adverse events occurred: grade 3/4 neutropenia (35%), grade 3 leucopenia (12%), grade 3 miscellaneous neurologic toxicity (12%), grade 3 sensory neuropathy (10%), and grade 3 thrombocytopenia (7%).

Although the use of FOLFOX4 therapy perioperatively was not associated with the 40% PFS advantage sought by the investigators, they did find that it does improve survival. The evaluation for overall survival is ongoing and will be reported in another paper.

Nordinger B, Sorbye H, Glimelius B, et al: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): A randomised controlled trial. 

Can a COX-2 Inhibitor Inhibit Oral Cancer?

In preclinical models, inhibition of cyclooxygenase- 2 (COX-2) curbs carcinogenesis and is considered a potential approach for the prevention of oral cancer. These agents have been available in the United States for a number of years, and it has been hypothesized that celecoxib might be useful in this role. Researchers from multiple centers around the United States participated in a pilot study of the safety and efficacy of celecoxib in patients with oral premalignant lesions (OPL).

In the main portion of the study, which was randomized and controlled, 18 patients received placebo, 17 were given celecoxib 100 mg twice daily, and 15 received celecoxib 200 mg twice daily for 12 weeks. In an unblinded extension of the trial, six other patients received celecoxib 400 mg twice daily. All study participants had at least one histologically confirmed early OPL (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced OPL (moderate to severe dysplasia). Biopsies were taken at baseline and at week 12.

Efficacy analyses were available for 49 patients (46 of 50 randomized and 3 of 6 open-label). Although the therapy was well tolerated, the differences among response rates in the control and placebo groups were not statistically significant: 33.3% (6 of 18) in the placebo group, 41.2% (7 of 17) in the celecoxib 100 mg twice daily group, and 20.0% (3 of 15) in the celecoxib 200 mg twice daily group and were not considered statistically significant differences. Only two of the six patients receiving celecoxib 400 mg twice daily responded. An increased risk of disease progression within three months was seen in patients with higher baseline COX-2 messenger ribonucleic acid levels.

Oral premalignant lesions were not effectively controlled by treatment with celecoxib at either 100 or 200 mg twice daily regimens, acknowledged the clinicians. Owing to the cardiovascular toxicity found in other randomized, controlled clinical trials of the COX-2 inhibitors and the lack of efficacy demonstrated in this pilot trial, the researchers acknowledge that these agents probably do not have a role in the prevention of oral cancer.

Papadimitrakopoulou VA, William WN Jr, Dannenberg AJ, et al: Pilot randomized phase II study of celecoxib in oral premalignant lesions.

Small-Cell Lung Cancer Survival Not Improved By High-Dose Chemotherapy

The ability to attain the intended dose intensity and duration of chemotherapy is sometimes limited by the patient tolerance to treatment and the need for supportive therapy. Often, a patient’s negative response to chemotherapy is attributed to this limitation.

In patients with small-cell lung cancer (SCLC), does the ability to receive a sufficiently intense dose contribute to the response to the regimen? Researchers from multiple centers throughout Europe evaluated the use of three times the normal dose intensity of a chemotherapy regimen to see if it affects survival in patients with SCLC, which is subject to frequent recurrence and therapy resistance.

Patients with limited or extensive SCLC (≤ 2 metatastic sites) received either the standard dose of ifosfamide, carboplatin, and etoposide (ICE) or the high dose, supported with blood stem-cell transfusions (which were harvested after treatment with filgrastim). The primary outcome was survival after a three-year period.

Sixty-nine patients were randomly assigned to receive high-dose chemotherapy. Standard-dose chemotherapy with ICE was given to 71 subjects. Treatment intensity in the high-ICE group of patients was almost three times greater than in the standard- ICE group (293% median relative dose intensity for high-ICE group compared with the standard chemotherapy group; range, 174%—392%). At three years the survival rates were 18% in the high-ICE group and 19% for patients receiving standard-ICE treatment. Nor were there any differences found between the therapies for overall tumor response or complete response. Subgroup analysis did not reveal any outcome benefit from greater dose intensity. The standard-ICE group of patients experienced substantial hematologic toxicity (grade ≥3) including 49 individuals with neutropenia (70%), 17 with thrombopenia (25%), and 17 with anemia (25%) while three patients (4%) died from toxicity. Severe myelosuppression was associated with high-ICE treatment and five (8%) of those patients died from toxicity.

Increasing the dose intensity of ICE chemotherapy did not improve the long-term outcome of patients with SCLC, admitted the researchers, and the toxicities were severe. They do not recommend intense ICE therapy for the treatment of SCLC in the future.

Leyvraz S, Pampallona S, Martinelli G, et al: A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: A randomized trial. 

Gastrointestinal Cancer Treatment With Prophylactic Chlorhexidine And Cryotherapy

Oral mucositis is a common side effect of cancer chemotherapy, which can result in discontinuation of therapy, poor nutrition, and negative outcomes. Danish researchers presented results of a phase II trial evaluating possible prevention of oral mucositis (OM) using chlorhexidine or placebo and oral cooling (cryotherapy) during chemotherapy in patients with gastrointestinal (GI) cancer.

Of the 225 patients initially randomized, 206 answered a questionnaire and reported the duration and severity of oral mucositis. Seventy members of the study group, all of whom were receiving bolus 5-FU/leucovorin chemotherapy (Arm A) received chlorhexidine mouthrinse three times/ day for three weeks. Sixty-four patients were given double-blind placebo (normal saline) with the same dose and frequency (Arm B), and 63 patients received cryotherapy with crushed ice for 45 minutes during chemotherapy (Arm C).

The three study groups were similar with regard to age, sex, diagnoses, smoking habits, stage, and performance status. The clinicians reported that patients in Arm B (33%) experienced grade 3 or 4 mucositis more often than those in Arm A (13%; 

 < .005). A significantly longer duration was noted in Arm B than in both Arm A (

By utilizing prophylactic chlorhexidine or cryotherapy, the frequency and duration of OM were significantly improved, the clinicians stated, although cryotherapy has limited use, because it is drug- and schedule-dependent even though it is easy and inexpensive. In fact, many therapies are available for the prevention of OM, ranging from artificial saliva to over-thecounter medications and rinses. They suggest that the role for chlorhexidine for preventing OM should be further evaluated.

Sorensen JB, Skovsgaard T, Bork E, et al: Double-blind, placebo-controlled randomized study of chlorhexidine prophylaxis for 5-fluorouracil-based chemotherapy-induced oral mucositis with non-blinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies.

Systemic Inflammation Linked With Poor Survival in Bladder Cancer

A simple prognostic test may be useful for oncologists and patients who are deciding on late-stage therapeutic management for bladder cancer. Poor survival in various malignancies has increasingly been associated with systemic inflammatory responses, and Japanese researchers have found that response of C-reactive protein (CRP) levels in patients with muscle-invasive bladder cancer seems to predict survival following chemoradiotherapy.

The researchers reviewed the records of 88 patients with bladder cancer who had been treated with external beam radiotherapy (40 Gy) and two cycles of cisplatin (50—150 mg) at three-week intervals.

Nineteen of the 88 study participants died as a result of their cancer during the follow-up period (median, 33 mo). A 73% five-year cancerspecific survival was observed overall. Ten subjects with a high CRP level (≥ 0.5 mg/dL) before undergoing treatment had survivals that were significantly lower than patients with lower CRP levels (

 = .003). C-reactive protein level was found to be an independent prognostic indicator for cancer-specific survival.< br>

The investigators found that six of the 10 patients who had initially high CRP levels before chemoradiotherapy reverted to normal levels. Five of these six patients were still living at the end of the follow-up, without metastasis or recurrence. However, the four patients whose CRP levels remained high after treatment had died within two years.

The researchers believe that this is the first study to show high levels of CRP are associated with poor survival in patients with muscleinvasive bladder cancer. In addition, they concluded survival is extremely poor for patients whose CRP levels remain elevated after chemoradiotherapy.

Yohisda S, Saito K, Koga F, et al: C-reactive protein level predicts prognosis in patients with muscleinvasive bladder cancer treated with chemoradiotherapy.

Clinical Trial Reports: June 10, 2010

An Overview of Clinical Studies Presented at the American Society of Hematology’s 49th Annual Meeting

An estimated 19,900 new cases of multiple myeloma (MM) were diagnosed in the United States in 2007, and nearly 11,000 died from the disease during the year.

 Although five-year survival rates have increased significantly over the past 10 years (with median survival increasing from approximately 2—3 years in 1998 to approximately 5–7 years in 2005), the prognosis of the disease is generally poor.

 The availability of several promising new therapies offers clinicians treatment options to further improve response rates, especially through the development of new combination regimens.

Current treatment approaches for MM focus on improving progression-free and overall survival. Generally, treatment is selected based on whether there is a need for immediate action and whether the individual patient is an appropriate candidate for high-dose chemotherapy and stem-cell transplantation.

 Recently, studies with novel agents such as bortezomib (Velcade) or the immunomodulatory drugs thalidomide and lenalidomide have shown promise in improving overall response rates when combined with dexamethasone. The following four studies, which discuss pegylated liposomal doxorubicin (PLD) (Doxil) in combination with bortezomib, were presented at this year’s 49th ASH Annual Meeting in Atlanta in December 2007.

PLD is a unique doxorubicin formulation in which a polyethylene glycol layer surrounds a doxorubicin-containing liposome. The pegylation process protects the liposome from detection by the immune system, thereby increasing the plasma half-life relative to conventional doxorubicin. Use of the PLD formulation provides several advantages. First, the extended half-life prolongs drug exposure of tumor cells, mimicking continuous infusion. This prolonged cellular exposure with PLD (combined with the slow rate of myeloma cell division) has been suggested to overcome multidrug- resistance—gene overexpression within plasma cells, thereby increasing antitumor potential and improving clinical response. Also, the size of the doxorubicin-containing vesicles allows leakage of the drug through the abnormally permeable tumor vessels, resulting in preferential concentration of doxorubicin at the tumor sites. In addition, PLD appears to have an improved cardiac safety profile compared with that of the conventional formulation.

The landscape of MM treatment continues to evolve as research results accumulate from trials of conventional and new therapies and from studies on risk factors and side effects.

1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2007. CA 

2. Durie BG. New approaches to treatment for multiple myeloma: Durable remission and quality of life as primary goals.

3. Kyle RA, Gertz MA, Witzig TE, et al: Review of 1,027 patients with newly diagnosed multiple myeloma. 

4. NCCN practice guidelines for multiple myeloma. National Comprehensive Cancer Network. 

Pegylated Liposomal Doxorubicin in Combination With Bortezomib May Provide Therapeutic Advantage for High-Risk Multiple Myeloma Patients Relapsing Within 12 Months of Stem-Cell Transplantation

Shaji Kumar, MD, Division of Hematology, Mayo Clinic, Rochester, Minnesota, presented results of a retrospective analysis of a large, phase III study (DOXIL-MMY3001; 

), which demonstrated that the combination of pegylated liposomal doxorubicin (PLD) (Doxil) plus bortezomib (Velcade) improved time to progression (TTP), compared with B monotherapy, in patients with multiple myeloma (MM) who relapse within 12 months of autologous stem-cell transplantation (SCT).

The present analysis examined the 12-month post-randomization survival of 646 patients who had early (<12 months) vs late (≥12 months) relapse following SCT, as well as the effect of PLD plus bortezomib vs bortezomib alone in patients who had relapsed early. Patients received intravenous bortezomib, 1.3 mg/m

 on days 1, 4, 8, and 11 of every 21-day cycle with or without PLD, or the same bortezomib regimen with PLD 30 mg/m

Of the 359 patients who had previously received SCT, 114 (32%) relapsed within 12 months. The median age, gender distribution, time from diagnosis at trial enrollment, baseline measures of disease burden (M-Protein levels and B2M), and renal function were comparable between the early- and laterelapse groups. There was no difference in overall response rates (complete + partial response [CR+PR]) or very good partial response (VGPR) rates between the two groups, or between treatment arms within each group. There was no significant difference in TTP between early- vs late-relapse groups (hazard ratio = 0.94). Twelve-month survival from randomization was significantly lower in the early-relapse group compared with that in the late-relapse group (83% vs 92% respectively,

However, within the early-relapse group, the 12-month post-randomization survival rate was significantly superior following treatment with PLD plus bortezomib compared with that in the group receiving bortezomib alone (52 of 56 patients [93%] vs 43 of 58 patients [74%] respectively, 

 = 0.01). Correspondingly, TTP was better in the group treated with PLD plus bortezomib, compared with that in the group receiving bortezomib alone (276 days vs 205 days, respectively, 

 = 0.13). Overall, the toxicity profiles of the combination regimen and bortezomib monotherapy were comparable regardless of early or late relapse following SCT.

According to the conclusions of study researchers, these results demonstrate that the combination of PLD plus bortezomib may provide an important therapeutic advantage for high-risk MM patients who experience early relapse following SCT.

Orlowski RZ, Nagler A, Sonneveld P, et al: Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: Combination therapy improves time to progression. 

Pegylated Liposomal Doxorubicin Plus Bortezomib Yields Improved Time-to-Progression vs. Bortezomib Alone in Patients With Relapsed or Refractory Multiple Myeloma and High-Grade or Protracted Disease

A recently reported phase III randomized trial comparing pegylated liposomal doxorubicin (PLD) (Doxil) plus bortezomib (Velcade) with bortezomib alone in relapsed or refractory multiple myeloma (MM) demonstrated improved time to progression (TTP) with the combination regimen (

). Following-up on this report, Heather J. Sutherland, MD, Department of Medicine, University of British Columbia, Vancouver, BC, Canada, presented the results of a 

 analyses evaluating the efficacy of PLD plus bortezomib according to International Staging System (ISS) disease stage, and time since initial myeloma diagnosis (TSD).

Patients with at least one prior therapy were randomized to receive PLD at 30 mg/m

 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least two cycles beyond complete response (CR), or optimal response unless disease progression or unacceptable toxicities occurred.

The improved TTP reported previously with PLD plus bortezomib over bortezomib alone in the total study population was also observed in the higher-risk groups based on disease stage (ISS 2 and 3). TTP was also significantly longer with PLD plus bortezomib compared with bortezomib alone for TSD of >2 years despite more protracted disease. The therapeutic advantage of prolonged TTP with the PLD plus bortezomib combination was maintained consistently across subgroups (heterogeneity tests: ISS 1 vs. 2 vs. 3, 

 = 0.407; TSD ≤2 years vs. TSD >2 years, 

The incidence of grade 3/4 neuropathies was low (<10%) in the two treatment arms in all subgroups. The incidence of PLD-related hand—foot syndrome was also <10% in all PLD-plus- bortezomib subgroups.

Results of the analysis demonstrated that, despite high-grade disease or protracted disease history, the PLD-plus-bortezomib combination shows significantly improved TTP compared with bortezomib alone. In addition, the combination therapy was shown to be well tolerated.

Early Normalization of Serum Free Light Chain Is Associated With Prolonged Time to Progression Following Bortezomib With or Without Pegylated Liposomal Doxorubicin Treatment of Relapsed or Refractory Multiple Myeloma

Robert Orlowski, MD, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, presented the results of a randomized, controlled study examining the association between normalization of the κ/λ ratio after one or two 21-day cycles of treatment with bortezomib (Velcade) with or without pegylated liposomal doxorubicin (PLD) (Doxil) among patients with relapsed or refractory multiple myeloma (MM).

Multiple myeloma, like other monoclonal gammopathies, frequently causes impairment of the κ/λ serum free light chain (sFLC) ratio. Based on a short half-life of sFLC as compared with the complete immunoglobulin (hours vs. days), early normalization of κ/λ could predict treatment response.

Patients with at least one prior therapy were randomized to receive PLD 30 mg/m

 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least two cycles beyond complete response (CR) or optimal response, unless disease progression or unacceptable toxicities occurred (

). The κ/λ measurements were carried out before the start of therapy and at the end of each cycle through the entire study period using an immunoassay (Freelite, The Binding Sites, Birmingham, UK). Serial sFLC κ/λ measurements were available on sera from 487 patients with baseline values (out of a total of 646 study enrollees).

At baseline, 458 of 487 patients (94%) had an abnormal κ/λ ratio (<0.26 or >1.65). The percentage of patients with a normal κ/λ ratio increased from 6% at baseline to 12% after cycle 1, 17% after cycle 2, and 23% by the end of the study. Among patients with a normal κ/λ ratio after cycle 1 (N = 54), the median time to progression (TTP) was 345 days, compared with 225 days in patients with an abnormal ratio after cycle 1 (N = 395, 

 = 0.0005, HR=0.47). Following cycle 2, TTP was 325 days vs. 224 days (

 ≤ 0.001) in patients with normal (N = 72) vs abnormal (N = 348) ratios, respectively.

In addition, patients with normalized sFLC ratios showed significantly greater overall response rates as compared with those with persistently abnormal ratios (≥ partial response [PR], 73% vs. 47%, [

 = 0.001] following cycle 1, and 77% vs. 48%, [

 < 0.0001] following cycle 2, respectively). Similarly, CR plus very good partial response (VGPR) rates were significantly greater among patients with normalized sFLC ratios after cycles 1 and 2 (

 < 0.001, respectively). As reported previously, both treatment regimens—the combination of, PLD plus bortezomib and bortezomib alone&mdash; were well tolerated (

This study demonstrated that normalization of the sFLC ratio as early as after cycle 1 of either PLD plus bortezomib or bortezomib alone was associated with a prolonged TTP and greater response rates.

Prolonged Time to Progression with Pegylated Liposomal Doxorubicin Plus Bortezomib With Bortezomib

Alone in Relapsed or Refractory Multiple Myeloma Unaffected by Extent of Prior Therapy or Previous

Joan Blade, MD, Hospital Clinic i Provincial, Barcelona, Spain, presented alpha-prespecified analysis that assessed the efficacy of pegylated liposomal doxorubicin (PLD) (Doxil) plus bortezomib (Velcade) in relapsed or refractory multiple myeloma (MM) based on the number of prior lines of therapy and previous anthracycline exposure status.

 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least two cycles beyond complete response (CR), or optimal response unless disease progression or unacceptable toxicities occurred. The baseline beta-2 microglobulin levels were comparable between the subgroup with 2 or more prior treatments and that with 1 prior treatment (median, 3.98 vs 4.01 mg/L), as well as between anthracycline-exposed and -naïve patients (median, 3.91 vs. 4.55 mg/L).

The improved time to progression (TTP) reported previously with PLD plus bortezomib vs. bortezomib alone in the total study population of patients with relapsed or refractory MM (

) was similarly observed in all four subgroups of patients (patients with ≥2 lines of prior therapy, those with 1 line of prior therapy, anthracycline-exposed patients, and anthracycline-naïve patients), indicating a consistent therapeutic benefit favoring the PLD-plusbortezomib combination. Furthermore, TTP was comparable between the PLD-plus-bortezomib combination between the groups with ≥2 lines of prior therapy and those with 1 line of prior therapy (

 = 0.523), as well as between those who were anthracycline-exposed or -naïve (

 = 0.716). The incidence of treatment-related serious adverse events, grade 3/4 neuropathy, and symptomatic cardiac events was comparable between treatment arms in each subgroup. The incidence of PLD-related hand—foot syndrome was also <10% in all PLD-plus-bortezomib subgroups.

These results demonstrate that combination therapy with PLD plus bortezomib significantly improves TTP compared with bortezomib alone, regardless of the number of prior lines of therapy, or anthracycline exposure.

Current treatment approaches for mutiple myeloma focus on improving progression-free and overall survival. Although five-year survival rates have increased significantly over the past ten years, the prognosis of the disease is generally poor. The availability of several promising new therapies offers clinicians treatment options to further improve response rates, especially through the development of new combination regimens.

Pegylated Liposomal Doxorubicin (Doxil) and Drug Combinations in Multiple Myeloma

Did Reduced Reimbursement for Medical Castration Result in More Orchiectomies?

Most men prefer medical castration with luteinizing hormone-releasing hormone (LHRH) agonists as a treatment for prostate cancer over surgical castration, but the utilization data has bucked the expected trend. This may be the unintended result of a 2004 reduction in reimbursements by the Centers for Medicare & Medicaid Services (CMS) for LHRH agonists, according to authors from the Cleveland Clinic. However, if the reimbursement for LHRH agonist use in prostate cancer is reduced to the point that it results in financial loss for the practice, can physicians balance the ethical versus the financial implications for this change in payments?

The change from average wholesale price—based to average sales price methodology, resulting in an effective 65% reduction in reimbursements over the course of a couple of years, and a 7% increase in reimbursement for surgical orchiectomy has paralleled a change in practice, stated the authors. They evaluated Medicare part B records from 2001 to 2005 for claims regarding the use of LHRH agonists and orchiectomy.

Utilization of medical castration fell by 14%, the investigators found, while the number of orchiectomies rose by 4%. Their review of the literature since 2004 does not provide alternative explanations for these trends. Although medical castration is not superior to surgical castration in terms of efficacy and outcomes, according to previous studies, men consistently prefer the medical option. The authors conclude that the “most plausible explanation” for this trend is the reimbursement, which has implications for how physicians present options to their patients with prostate cancer.

Weight CJ, Klein EA, Jones JS: Androgen deprivation falls as orchiectomy rates rise after changes in reimbursement in the U.S. Medicare population.

Tidal Wave of Breast Cancer Cases Expected as Elderly Age

As the baby boomer “age wave” continues to leave a wake in health care service consumption, it is clear that this nation’s aging population will also create a tidal wave of patients with diseases of aging, including cancer. This will tax our health care resources, skill, and ability to pay for treatment. A task force report, announced recently at the annual meeting of the National Comprehensive Cancer Network, warns that we are woefully unprepared in the treatment realm of addressing the age wave’s effect on breast cancer cases.

By 2040, it is estimated that 80 million American women will be at least 65 years of age. Task force Chairman Robert W. Carlson, MD, worried that there are few studies of breast cancer treatment in women older than 70 years—they are poorly represented in clinical trials, and the medical community does not have sufficient published experience to make treatment recommendations. Clinical practice guidelines should have separate branches to detail preferred therapeutic options in these elderly women, stated Dr. Carlson, but data do not exist on which to form the guidelines.

The task force believes that these older women will require greater use (and more effective) supportive therapies to enable them to complete chemotherapeutic regimens. Dr. Carlson also cautioned, “The benefit of treatment has to be bigger in a relative sense to be worth it in an absolute sense in the older patient because of competing causes of death.”

The task force recommended the development of new testing methodologies that can determine a woman’s “physiologic age” and “functional reserve,” which may enable the clinician to choose more conservatively among the various chemotherapy, radiation, and surgical options. Furthermore, the task force believes more interest in a patients’ priorities will be an important focus when considering how to treat these elderly women.

Carlson RW: Report of the NCCN Task Force on Breast Cancer in the Older Adult. Presented at the 13th annual meeting of the National Comprehensive Cancer Network, Hollywood, Florida, March 27, 2008.

The Cost Effectiveness of Neutropenia Treatment

The use of granulocyte colony-stimulating factors (G-CSFs) is an important tool in fighting febrile neutropenia. Health economists from the University of Rochester School of Medicine and Dentistry, New York, sought to determine the cost effectiveness of G-CSF therapy.

The investigators used a cost-utility model to estimate the cost effectiveness of the conventional G-CSF (filgrastim), pegylated form (pegfilgrastim), and no therapy was calculated. If patients received filgrastim treatment, it was assumed that it was given daily for seven to 12 days after chemotherapy was administered. If patients received pegfilgrastim, it was assumed to be administered once per chemotherapy cycle. A societal point of view was assumed for all cost-effectiveness calculations.

The economists asserted that the use of the pegylated G-CSF was more cost effective than the other treatment options, while yielding the same clinical benefit as conventional G-CSF, across various clinical scenarios. The Table provides data on the baseline situation analysis, showing that although not using G-CSF resulted in lower costs than using filgrastim, it did not provide as great a clinical benefit.

G-CSF = Granulocyte colony-stimulating factor.

Eldar-Lissai A, Cosler LE, Culakova E, et al: Economic analysis of prophylactic pegfilgrastim in adult cancer patients receiving chemotherapy.

Does Lower Toxicity Trump Efficacy in Cost-Effectiveness Study of Two Breast Cancer Regimens?

The use of the adjuvant drug combination of docetaxel, doxorubicin, and cyclophosphamide is thought to be more toxic but also more effective than the combination regimen including fluorouracil rather than docetaxel. Health economists from Manchester, United Kingdom sought to calculate whether the increased efficacy of the more toxic docetaxel combination resulted in better cost effectiveness, even when prophylactic therapy for febrile neutropenia is factored into the equation.

Using a Markov decision-analysis model for patients with node-positive early-stage breast cancer and clinical efficacy and toxicity data from the Breast Cancer International Research Group 001 trial, the researchers calculated the incremental cost per life-year saved over a 10-year time horizon as well as the incremental cost per quality-adjusted life-year (QALY) gained.

Their analysis yielded a significant advantage to the use of the docetaxel-containing regimen, even when the increased use of granulocyte colony-stimulating factor was considered. Using the docetaxel-containing regimen rather than the fluouracil-containing combination resulted in an incremental cost per life-year saved of approximately $30,600 and an incremental cost per QALY of $36,100. With the use of neutropenia prophylaxis (given to all patients) factored in, the incremental cost per QALY was slightly higher, at $40,500. The researchers noted that the results did not change substantially across a range of quality-of-life scores.

They concluded that the docetaxel-containing regimen was more cost effective than the fluouracil combination for node-positive early-stage breast cancer, even though the regimen may require greater use of granulocyte colony-stimulating factor and be more toxic overall.

Wolowacz SE, Cameron DA, Tate HC, et al: Docetaxel in combination with doxorubicin and cyclophosphamide as adjuvant treatment for early node-positive breast cancer: A cost-effectiveness and cost-utility analysis.

How Much Does It Cost to Support Breast Cancer Survivors?

Women who survive breast cancer (and the rigors of its treatment) often benefit from psychosocial support to help them adjust to their new physiologic status (e.g., altered body image resulting from mastectomy, disability resulting from surgery). However, psychosocial support programs and educational materials are not universally used. Oncologists and psychologists from Washington, DC, and Los Angeles, California, attempted to determine in an innovative study, how much these interventions would cost society.

Utilizing women who were concurrently taking part in a clinical breast cancer study, the researchers considered that positive outcomes of an increase in energy (increased vitality) or decrease in distress (both measured using validated scales) compared with the incremental cost of delivering psychoeducational programs to help women transition to breast cancer survivor status. They evaluated costs for six months after educational intervention delivered using video only information, video-provided information with counseling, or no intervention. The direct costs of not providing educational resources were determined to be $11.30, compared with $25.85 for video education, and $134.47 for video plus counseling.

In this unique economic outcomes study, the investigators found that the cost per unit energy increased or decrease in stress varied significantly with the end result—whether the woman was more prepared for transition to survivorship status. They found that video education plus counseling was less cost effective than video alone for nearly all scenarios, except in women who were more prepared for transition before the intervention was given, where it cost $1,066 per unit decrease in distress less than video alone. In most cases, video education alone was more cost-effective than doing nothing in terms of vitality improvement for all women, at $2.22 per unit increase in energy for all women. In terms of lowering distress, however, the video-intervention only cost $7,275 more than if nothing was done in the overall group. Interestingly, in those women who needed the intervention most, who were least prepared for the transition to survivorship status, the video intervention cost $355 less than the control group.

The results of this study indicate that educational video programs may be more cost effective than when combined with counseling to improve transition to breast cancer survivorship. However, the researchers caution that standards or thresholds do not yet exist for determining the cost effectiveness in the case of psychosocial endpoints.

Mandelblatt JS, Cullen J, Lawrence WF, et al: Economic evaluation alongside a clinical trial of psychoeducational interventions to improve adjustment to survivorship among patients with breast cancer.

Do Digital Mammograms Answer or Raise More Possible Questions?

Health plans and other payers know that digital mammography costs more than conventional film mammography. However, the increased cost might be justified if they can provide clearer answers in women with dense breast tissue and prevent false positives or repeat procedures. In some radiologists’ practices, more women are in fact being called back for a second test after digital imaging than with x-ray mammography. Are they too sensitive, showing artifact that confuses the radiologist interpreting the test? This is a real issue, particularly in light of the rapid growth of digital mammography centers around the country and their increased costs.

, radiologists believe that this might simply be the result of a transition period, in which they become acclimated to seeing more calcium deposits or cysts in digital images of breast tissue. Beyond the higher costs of digital mammography (up to $120 more per screening), the serious distress of the woman who is informed that she must return to the center for another screening is a major problem.

 survey of 10 radiologists using the new systems, eight admitted that their callback rates have been more than 10%, below which was considered the standard of quality.

Thirty-two percent of mammography centers now have at least one digital mammography machine. Is this simply part of the mammography learning curve, and will actually result in lower call-back rates in the long run? At a cost of $350,000 to $600,000, around four times the cost of film mammography machines, everyone involved hopes this is the case. However, there are no studies published to indicate what the longer-term trend will be.

Grady D: In shift to digital, more repeat mammograms.

Payers are increasingly adopting average sales price (ASP) methodology to reimburse for the provision of oncologic drugs, and two-thirds of physician practices responding to a survey reported lower total revenues, according to a new managed care and oncologist survey. However, the adoption of ASP methodology has been slower than payers had expected, state the researchers.

A total of 125 oncology practices responded to the research, which was part of a study of managed care and physician attitudes towards reimbursement and management. The oncologists expect to see more assertive payer roles within the next 12—18 months, involving clinical decision making and off-label use of medication, and continued movement towards ASP-based payments (ASP + 6% was the most common method reported [over 40% of respondents], but ASP + 12% was also indicated by more than 20% of respondents).

There is a little good news for oncologists when discussing contracting leverage: Payers seemingly do not have high opinions of hospital outpatient care departments’ treatment efficacy, cost efficiency, or cost-management capabilities. Although infusion clinics do compare favorably, oncologists can effectively resist payers’ moves to hospitalbased infusion centers. According to the survey, the availability of these alternative infusion sites will force oncology practices to “refine their value propositions.”

The oncologists fear that the increasing use of prior authorization and greater cost-sharing requirements on the part of patients will lead many patients to forego certain treatments. They also fear continued erosion of practice autonomy related to managed care requirements. According to the survey, payers are more focused on the cost-control aspects in oncology care than on clinical practice decision making.

Lin C, Cabanilla A, Dautel N, et al: Monitoring the changing oncology environment: Lessons for managed care pharmacy from a national study. Presented at the 20th annual meeting of the Academy of Managed Care Pharmacy, San Francisco, CA, April 16—19, 2008.

June 2008 | Oncology & Biotech News

Physician's Financial News: June 10, 2010

Clinical Trial Reports: June 10, 2010

Pegylated Liposomal Doxorubicin (Doxil) and Drug Combinations in Multiple Myeloma

Reimbusement and Managed Care News

Clinical Abstracts From Overseas: June 10, 2010

OncLive News Briefs: June 9, 2010

ASCO Policy Change Creates Massive Avalanche of Pre-Meeting Data

The American Association for Cancer Research Annual Meeting

Practical Information for the Community-Based Oncologist