CETUXIMAB IN SALIVARY GLAND CARCINOMAS?

Oral Oncol. 2008 Sep 17. [Epub ahead of print]

Related Articles, LinkOut

Cetuximab in recurrent and/or metastatic salivary gland carcinomas: A phase II study.

Locati LD, Bossi P, Perrone F, Potepan P, Crippa F, Mariani L, Casieri P, Orsenigo M, Losa M, Bergamini C, Liberatoscioli C, Quattrone P, Calderone RG, Rinaldi G, Pilotti S, Licitra L.

Head and Neck Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS "Istituto Nazionale dei Tumori", via Venezian 1, Milan, Italy.

EGFR overexpression in salivary gland carcinomas provides the rational for the investigation of anti-EGFR treatments in recurrent and/or metastatic salivary gland cancers (RMSGCs). The activity of cetuximab in terms of clinical benefit rate (CBR) defined as the occurrence of objective response (CR or PR) or stable disease (SD) for 6months was investigated. From April to December 2005, 30 patients [23 adenoid cystic carcinoma (ACC) and 7 non-ACC] were treated with cetuximab at 400mg/m(2)/week followed by 250mg/m(2)/week until progression, major toxicity or voluntary discontinuation. EGFR expression and gene status were retrospectively analyzed by immunocytochemistry and fluorescence in situ hybridization, respectively. A median of 14 courses of cetuximab (range 5-54) were infused. Skin toxicity was the main adverse event. Cetuximab provides a CBR in 50% (95% CL, 31 to 69%) of cases. None tumor sample showed EGFR gene amplification and an increased EGFR copy number was observed in 12% of samples, all ACC. Skin rash G2, EGFR overexpression and EGFR copy number were not statistically correlated to CB. In RMSGCs further evaluations of EGFR targeting agents are advisable and should take place by appropriate tumor biological selection, differentiating ACC from non-ACC.

TARCEVA HEPATOTOXICITY

Tarceva Linked to 2 Fatal Cases of Hepatotoxicity

September 23, 2008 — Cases of fatal hepatotoxicity have been reported with use of erlotinib (Tarceva, OSI Pharmaceuticals, Inc, and Genentech, Inc), the US Food and Drug Administration (FDA) warned healthcare professionals today.

Patients with hepatic impairment should be closely monitored during erlotinib therapy, and particular caution is advised for those with total bilirubin levels greater than 3 times the upper limit of normal (ULN), according to an alert issued by MedWatch, the FDA's safety information and adverse event reporting program.

Dosing should be interrupted or discontinued for severe changes in liver function, such as doubling of total bilirubin and/or tripling of transaminases in baseline levels outside the normal range.

The warning was based on findings from a postapproval pharmacokinetic study (n = 15) of patients with solid tumors and moderate hepatic impairment (Child-Pugh class B), in which 2 of 10 deaths were attributed to hepatotoxicity. One patient died from hepatorenal syndrome, and the other from rapidly progressing liver failure.

"Six out of the 10 patients who died had baseline total bilirubin > 3 × ULN suggesting severe, rather than moderate, hepatic impairment," the company said in a communication to clinicians, highlighting the limitations of using Child-Pugh criteria in oncology patients with liver involvement.

Erlotinib is indicated as monotherapy for locally advanced or metastatic non–small cell lung cancer after failure of at least 1 prior chemotherapy regimen and in combination with gemcitabine HCl (Gemzar injection, Eli Lilly & Co) for the first-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer.

Adverse events related to use of erlotinib should be reported to the manufacturer by telephone at 1-877-TARCEVA (1-877-827-2382). Alternatively, case data may be relayed to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.

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CAMPATH BENEFICIAL FOR MS PATIENTS

Alemtuzumab Shows Remarkable Efficacy in Relapsing Remitting Multiple Sclerosis

September 24, 2008 (Montreal, Quebec) — Alemtuzumab (Campath, Genzyme/Bayer Healthcare Pharmaceuticals), currently under investigation for the treatment of relapsing and remitting multiple sclerosis (RRMS), appears to have remarkable efficacy, even compared with high-dose interferon beta-1a, a new study shows.

If these phase 2 results are confirmed in phase 3 trials that are now ongoing, "this could be a powerful drug," lead author Krzysztof W. Selmaj, MD, PhD, DSc, chair of the neurology department at the Medical University of Lodz, in Poland, told Medscape Neurology & Neurosurgery.

However, adverse effects remain a concern with this drug. In this trial, alemtuzumab therapy was associated with higher rates of immune thrombocytopenic purpura, thyroid dysfunction, infusion reactions, and predominantly mild and moderate infections than with interferon beta-1a.

The phase 2 results were presented here at the World Congress on Treatment and Research in Multiple Sclerosis: 2008 Joint Meeting of the American, European, and Latin America Committees on Treatment and Research in Multiple Sclerosis (ACTRIMS, ECTRIMS, LACTRIMS). The trial was supported by Genzyme.

Monoclonal Antibody

Alemtuzumab is a humanized monoclonal antibody that targets CD52 on the surface of both T and B cells. It is currently approved for use in B-cell chronic lymphocytic leukemia (B-CLL) and is in phase 3 trials for the treatment of RRMS.

"We need better drugs for MS patients," Dr. Selmaj told Medscape Neurology & Neurosurgery in an interview here; current drugs are "quite modest" in their effects, he said. As a monoclonal antibody, alemtuzumab influences immune and pathologic processes very specifically. "This monoclonal antibody interacts with lymphocytes, and . . . we hypothesize that lymphocytes are instrumental in multiple sclerosis."

CAMMS223 was a phase 2 study in which 334 treatment-naive patients with early active RRMS were randomized to receive alemtuzumab 24 mg, alemtuzumab 12 mg, or interferon beta-1a 44 µg. Alemtuzumab was delivered via intravenous injection in yearly cycles that included once-daily administration for 5 days at month 0 and again for 3 days at month 12. Some patients also received 3 days of therapy at month 24. Interferon was given 3 times per week via subcutaneous injection.

Dr. Selmaj presented 36-month follow-up results in which data on both alemtuzumab dosing groups were pooled. The cumulative number of relapses over time was reduced by 74%, and the time to sustained accumulation of disability (SAD) was reduced by 71% with alemtuzumab, compared with interferon (P < .0001 for both).

In addition, while the Expanded Disability Status Scale (EDSS) increased by a mean of 0.38 points among those on interferon, it actually decreased by 0.39 points for those on alemtuzumab.

The proportion of patients who remained relapse free was 50% with interferon, vs 80% with alemtuzumab (P < .0001). At 3 months, 67% of patients on interferon and 86.3% on alemtuzumab were free of SAD, while 74% on interferon vs 91% on alemtuzumab were SAD free at 6 months (P < .005 for both).

Similarly, 39% of those on interferon vs 71% of those on alemtuzumab were both relapse and SAD free for 3 months, while 43% of interferon patients vs 74% of alemtuzumab patients were relapse and SAD free for 6 months (P < .0001 for both).

"These are figures that have not been seen in any clinical trials in MS, ever,” said Dr. Selmaj.

Data "Phenomenal"

Rhonda Voskuhl, MD, professor in the department of neurology and director of the Multiple Sclerosis Research and Treatment Program at the University of California, Los Angeles, moderated the session where these results were presented. She shared Dr. Selmaj's enthusiasm about the efficacy results. "The data looked phenomenal," she told Medscape Neurology & Neurosurgery.

Although among the best and safest treatments to date for MS, interferon beta-1a still reduces relapses only by about one-third, she said. "The fact that alemtuzumab looked so much better than interferon beta is very exciting."

Adverse effects were a concern with alemtuzumab, however. Overall, 13 patients taking alemtuzumab at either dose experienced grade 3 infections, vs only 1 on interferon. There were no grade 4 or 5 infections.

More alarmingly, 23% of patients on alemtuzumab experienced autoimmune thyroid dysfunction, compared with 3% on interferon. Immune thrombocytopenic purpura (ITP) occurred in 6 of the 216 patients on alemtuzumab and only 1 on interferon. The interferon-treated patient developed intracranial hemorrhage before ITP was diagnosed and subsequently died. The other 5 cases of ITP were identified early and either reversed spontaneously or responded to treatment.

"The thrombocytopenia does not have acute symptoms," said Dr. Selmaj. "They develop over time, a couple of weeks. So, it is believed that we'll be able to detect patients who are at risk of thrombocytopenia; they can be withdrawn from the [drug], and they can be given steroids, which, under normal conditions, will bring platelet count into the normal range."

Nevertheless, Dr. Voskuhl believes the risk for such an adverse event relegates the drug primarily to second-line therapy. "MS is a disease that affects really young people who don't have that much disability at [the outset]," she said, "so, until they fail 1 of these other treatments, it doesn't want to make you use [alemtuzumab] as a first-line treatment if [it has] these significant adverse events."

Two phase 3 studies with alemtuzumab are currently under way. Platelet counts will be monitored closely.

This research was funded by Genzyme. Dr. Selmaj reports he has received funds from Genzyme.

World Congress on Treatment and Research in Multiple Sclerosis: 2008 Joint Meeting of the American, European, and Latin America Committees on Treatment and Research in Multiple Sclerosis (ACTRIMS, ECTRIMS, LACTRIMS): Abstract 55. Presented September 19, 2008.

HORMONE THERAPY NOT BENEFICIAL FOR ALL PATIENTS WITH PROSTATE CANCER

Hormone Therapy Before Brachytherapy for Prostate Cancer May Shorten Life in Men Over 70

September 24, 2008 � Men older than 70 years of age with early-stage prostate cancer have 20% higher mortality when treated with hormone therapy before brachytherapy than when treated with radiation seed implants alone, according to a new study presented at the American Society for Therapeutic Radiology and Oncology (ASTRO) 50th Annual Meeting, in Boston, Massachusetts.

"This is a potentially practice-changing finding," said Louis Harrison, MD, chair of the department of radiation oncology at Beth Israel Medical Center, in New York City, New York, and chair of the ASTRO board of directors. Speaking at the ASTRO press conference at which the study was highlighted, he said: "The results challenge the current treatment paradigm and may make clinicians think twice."

"I would have to have a very strong reason to deviate from this finding," he told Medscape Oncology. "The study results are a global warning to be careful with hormone therapy. For instance, how do you proceed with a 60 year old? Practical thinking says you must be careful," he cautioned.

The finding comes from a study of 1709 men with localized prostate cancer who were at least 70 years of age (median age, 75 years), and was presented at the meeting by Amy Dosoretz, MD, lead author of the study and a radiation oncology resident at the Harvard Radiation Oncology Program, in Boston.

Dr. Dosoretz explained that hormone therapy is used before brachytherapy to shrink the size of the prostate and make the process of implanting radiation seeds technically easier. Use of brachytherapy has significantly increased over the past few decades, especially in low-risk patients, but recent research has indicated that there are more risks involved with neoadjuvant hormone therapy "than previously realized," she commented.

Neoadjuvant Hormone Therapy: Well Intended But Risky

Previous smaller studies on the impact of neoadjuvant hormonal therapy on the risk for all-cause mortality in men undergoing prostate brachytherapy for localized prostate cancer have been contradictory. In 1 study, men with a median age of 73 years were found to have an increased risk for mortality; in the second study, men with a median age of 67 years had no increased risk.

The new study adds to that understanding of risk, and is the largest cohort study of its kind to date. Patients were treated with (n = 786) or without (n = 916) androgen-deprivation therapy and brachytherapy between 1991 and 2005 at centers within the 21st Century Oncology consortium. None of the patients received supplemental external-beam radiation therapy.

After a median follow-up of 4.8 years and adjustment for known prostate cancer prognostic factors and age, treatment with hormone therapy was found to be significantly associated with an increased risk for all-cause mortality (adjusted hazard ratio [AHR], 1.2; P = .04). Increasing age (AHR, 1.1; P < .001) and a Gleason score of 7 or higher (AHR, 1.2 [95% CI, 1.0�1.5]; P = .05) were also significantly associated with an increased risk for mortality.

Low-, intermediate-, and high-risk disease was present in 61%, 25%, and 14%, respectively, of the men. The causes of death of the men are not detailed in the study yet.

"Our message is that in older patients it's very important to weigh the risks and benefits of hormone treatment when designing a treatment program for these patients," Dr. Dosoretz commented.

Dr. Harrison added that hormone therapy is a "controversial area" and that oncologists are still learning which patients benefit and which don't. He said that use of neoadjuvant hormone therapy has been well intended. "By shrinking the prostate, you are able to give a smaller dose of radiation," he noted

When to Forgo Hormone Therapy

Another presentation at the same meeting provided evidence of when to use and when to forgo hormone therapy in men with early-stage prostate cancer treated with radiation.

In men who have already been treated with radiation therapy, hormone therapy should begin immediately if the prostate-specific antigen (PSA) rises quickly and doubles within 6 months at any time after treatment. If the PSA doesn't rise as quickly, these men should forgo hormones, according to researchers from Fox Chase Cancer Center, in Philadelphia, Pennsylvania.

"We've been using PSA doubling time to help guide our decision about when to begin hormone therapy, but this study gives us new and critical information that suggests we should start therapy sooner than previously thought for some patients and delay treatment for others," explained Eric Horwitz, MD, acting chair and clinical director of the radiation oncology department at Fox Chase Cancer Center, who led the study.

"While hormone therapy can have side effects, such as hot flashes, decreased libido, and osteoporosis, it can help prevent the cancer from spreading to the bones, causing pain and leading to an earlier death from the disease," he explained to reporters.

Previous studies have indicated that if the PSA doubling time occurs within 12 months, there is an increased likelihood that the prostate cancer will spread and that hormone therapy will provide a potential benefit if started at that point, according to the researchers.

"What we now know is that when the PSA rises and doubles within 6 months (vs 12 months), we need to act," explains Dr. Horwitz. "Our study suggests that these are the men who will benefit most from hormone therapy."

Dr. Horwitz also said that the study helps identify who is less likely to benefit from hormone therapy, which might indicate a necessary change in current practice.

"Men whose PSA rises but does so over a longer period of time, may not benefit from hormones," he said.

American Society for Therapeutic Radiology and Oncology (ASTRO) 50th Annual Meeting: Abstracts 84 and 1050. Presented September 23, 2008.

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RADIATION THERAPY FOR T3 DISEASE

Radiation Added to ADT Halves Risk of Prostate Cancer Death

September 23, 2008 — Adding radiation to androgen deprivation therapy in older men with locally advanced prostate cancer reduces the risk of dying from the disease by half. These results, from a randomized clinical trial, suggest that men should be offered this additional option, says lead researcher Anders Widmark, MD, professor in radiation oncology at Umea University in Umea, Sweden.

Dr. Widmark presented the results at a plenary session during the American Society for Therapeutic Radiology and Oncology (ASTRO) 50th Annual Meeting in Boston, Massachusetts.

"This trial will change clinical practice," predicted Anthony Zietman from Massachusetts General Hospital in Boston, who was moderating a press briefing at which the results were highlighted. Dr. Zietman is also president-elect of the ASTRO, taking on the role of president effective September 23, 2008.

"At present, there is a bit of a fatalistic attitude towards locally advanced prostate cancer, as it generally considered to have already quietly spread elsewhere," Dr. Zietman commented. "Often the only treatment often offered to older men with this stage of disease is hormonal therapy," he continued. "This attitude is maybe more common in Europe, but it's also prevalent in the United States."

"The thinking is that the cat is already out of the bag," Dr. Zietman commented, but "the results from this trial prove that this is not the case."

"This randomised trial is the first to show that men with locally advanced prostate cancer will survive substantially longer when radiation is added to their treatment plan," Dr. Widmark told journalists.

The trial involved 880 patients, median age 67 years, the majority of whom had stage T3 disease. All of the patients underwent 3 months of intense hormone therapy to achieve total androgen blockade, followed by continuous antiandrogen therapy, but 1 group also received radiotherapy.

After a median follow-up of 7.5 years, death from prostate cancer had occurred in 79 (18%) of 437 patients in the antiandrogen group vs 37 (8.5%) of 436 patients in the combined antiandrogen and radiotherapy group. "It was rather surprising that the addition of radiation cut by half the risk of death from prostate cancer," Dr. Widmark commented. The absolute difference in cumulative incidence from prostate cancer death increased from 2.9% at 7 years to 12% at 10 years, with a relative risk of 0.44 (P = .00003).

In addition, significant reductions were seen in 2 other outcome measures. Overall mortality rate was 30% in the antiandrogen group vs 21.6% in the combination antiandrogen and radiotherapy group (P = .004). Plus, recurrence of high levels of prostate-specific antigen occurred in 65% of the antiandrogen group but in only 17.5% in the combination antiandrogen and radiotherapy group (P = .00001).

Quality of life, as reported both by patients and by clinicians, was "slightly worse" in patients who received combination antiandrogen and radiotherapy vs those in the antiandrogen group but "only marginally," Dr. Widmark commented. Adverse events included moderate to severe urinary leakage (reported by 6% of patients in the combination groups vs 3% in the hormone group 4 years after treatment) and pain on urination (reported by 2% vs 4%, respectively). Erectile dysfunction was also more common, reported by 85% of patients in the combination antiandrogen and radiotherapy group vs 72% in the antiandrogen group (P < .001).

"Considering the substantial survival benefit, the increase in symptoms seems to be acceptable and of small influence on quality of life 4 years after treatment," the researchers concluded.

The results suggest that radiotherapy should be offered in addition to antiandrogen therapy to men with locally advanced prostate cancer, Dr. Widmark commented. He said that he would encourage such men to talk to their clinicians.

T3N0 POSTMASTECTOMY RADIATION ONLY TO CHEST WALL

Post-Mastectomy Nodal Radiation Unnecessary for Node-Negative Breast Cancer

By Megan Rauscher

NEW YORK (Reuters Health) Sept 22 - Irradiation of axillary and supraclavicular lymph nodes is unnecessary in women whose axillary nodal status following mastectomy is negative, according to research presented Sunday at the 50th annual meeting of the American Society for Therapeutic Radiology and Oncology in Boston.

"This study demonstrates an extremely low rate of regional nodal failure in patients with pathologically node-negative breast tumors following complete dissection that are greater than 5 centimeters or have close/positive margins following mastectomy and adjuvant radiotherapy to the chest wall alone," the study team wrote in a meeting material abstract.

"Avoidance of regional node radiotherapy and its risks of lymphedema and pulmonary toxicity may be an acceptable approach in these selected patients," they concluded.

Mastectomy followed by radiation is currently recommended for women with breast tumors greater than 5 centimeters and negative lymph nodes, Dr. Penny Anderson, attending physician in the radiation oncology department at Fox Chase Cancer Center, Boston, explained in a statement.

"We typically irradiate the chest wall because it's been shown to improve survival. Out of an abundance of caution, many radiation oncologists also treat the surrounding lymph nodes, but there is little evidence that this improves outcome," she noted.

Dr. Anderson and her colleagues evaluated the need for lymph node irradiation in 64 patients with pathologic node-negative breast cancer treated by mastectomy and radiation from 1985 to 2006. Fifty-three patients received radiation therapy to the chest wall only and 11 patients received radiation to the regional lymph nodes in addition to the chest wall.

After a median follow up of 78 months, "we found an extremely low rate of recurrences in the lymph nodes among those who didn't have them irradiated," Dr. Anderson said.

Only 1 of the 53 patients who received chest wall radiation only developed a recurrence in an axillary lymph node. None of the patients who received chest wall and node radiation had a recurrence.

The 5-year overall survival rates were 91 percent for the women who received radiation to the chest wall only and 100 percent for those who also received radiation to chest wall and lymph nodes. There was no statistically significant difference noted between the local, regional or distant recurrence rates between the two groups.

CORONARY CT IN EMERGENCY EVALUATION

CTA in the ER Can Safely and Effectively Screen for Acute Coronary Syndrome

Findings from a new study suggest that computed tomography angiography (CTA) safely and effectively stratifies high- and low-risk patients admitted to the emergency room for chest pain [1]. Investigators screened patients admitted to the emergency room for acute coronary syndrome using high-resolution CTA and showed that negative scans were a quick and accurate way of identifying patients who were safe to be discharged from the hospital.

"If you look at the literature, CTA is a relatively new technology," said lead investigator Dr Anna Marie Chang (University of Pennsylvania, Philadelphia). "Most people aren't using it in the emergency department to make decisions about the patient. Most people using it in this way are still testing it out, trying to see if it's okay, but we're using CTA in the low-risk patient. These are patients who traditionally would come into the emergency department and we'd have to admit them to the hospital or send them to observation unit before they could be sent home. Now we can send them home immediately from the emergency department."

The results of the study were presented here at the Society of Academic Emergency Medicine (SAEM) 2008 Annual Meeting.

Cutting costs by sending low-risk patients home

Speaking with heartwire, Chang said that approximately 5% to 15% of individuals admitted to the hospital for chest pain have an acute coronary syndrome, but more than half of these patients are admitted to the hospital for observation and further testing. While previous studies have traditionally compared CTA with other ACS screening protocols to determine how well it stacked up against these traditional tests, Chang and colleagues wanted to determine whether CTA could be used clinically to quickly and accurately determine whether patients could be discharged.

Investigators evaluated 568 patients with chest pain admitted to the Hospital of the University of Pennsylvania for acute coronary syndromes. Of these patients, 285 received CTA immediately in the emergency department and 283 received coronary CTA after a brief observation period. Overall, 84% of patients were discharged home following coronary CTA.

Investigators report that negative scans were accurate and allowed investigators to safely discharge patients from the hospital. Thirty days after discharge, none of 285 patients who received a coronary CTA immediately in the emergency department and were discharged died from cardiac causes, had an MI [myocardial infarction], or returned to the hospital for revascularization.

In terms of cost, Chang and colleagues report that CTA is more cost-effective than traditional methods of identifying at-risk patients [2]. In another study of 643 patients, also presented at the SAEM meeting, investigators compared the costs of receiving CTA in the emergency room with the costs associated with CTA following time in an observation unit, as well as with the costs of stress tests and telemetry monitoring following hospital admission.

The cost of screening with immediate CTA in the emergency room was $1240, while the cost of stress testing, measuring serial biomarkers, and monitoring in the observation unit was more than $4000 per patient. The cost of usual care, defined as admission with serial biomarkers and hospital-directed evaluation, was $2913. Among these low-risk patients without ACS, immediate CTA helped discharge patients faster, with these patients discharged an average of eight hours following admission. Those who were screened with stress testing and received telemetry monitoring were kept, on average, 24 hours.

"Not only is it a safe test, but it's less expensive," said Chang. "Patients are getting out of the emergency department much faster, which is important because of issues related to overcrowding. If a patient can leave the department in eight hours rather than 20 hours or more while waiting for a bed, this can free up more time for us to see other patients."

Chang told heartwire that if a hospital has the technology and the hospital administration is supportive of CTA in the emergency department, with radiologists trained in cardiac imaging to read the CTA scan, the test can routinely be used in clinical practice.

She noted there is currently a debate about reimbursement, with the Center for Medicare & Medicaid Services voting in November 2007 to not reimburse CTA use in the emergency room, although this decision was overturned. As previously reported by heartwire, all 50 individual US states already provide Medicare coverage for patients undergoing cardiac CTA under local coverage determinations, but the overturned federal policy decision would have limited Medicare coverage of a diagnostic CT to just two indications and only in cases where the patient was enrolled in a clinical trial of cardiac CT.

NOVEL AGENTS FOR OVARIAN CANCER

Novel Agents Potentially Beneficial in Recurrent Ovarian Cancer

September 19, 2008 (Stockholm, Sweden) — Recurrent disease remains a considerable problem in ovarian cancer, even though most patients will respond initially to first-line therapy. Two novel therapeutic agents showed encouraging results in the treatment of recurrent ovarian cancer, according to data presented here at the 33rd European Society for Medical Oncology Congress.

The investigational angiogenesis inhibitor pazopanib (gw786034, GlaxoSmithKline) demonstrated significant biologic single-agent activity among patients with relapsed ovarian cancer. A greater-than-50% decrease in CA-125 levels was observed in 31% of the cohort, with a 113-day median duration of response.

"Chemotherapy has been the standard management for ovarian cancer for many years, but despite an enormous amount of effort, the overall prognosis for women with advanced disease is still poor, and the majority of women will unfortunately relapse," said lead author Michael Friedlander, MD, from the Prince of Wales Cancer Centre, in Sydney, Australia.

"But we now know that angiogenesis plays a critical role in ovarian cancer, and it is a very attractive target," he added.

Pazopanib is an oral, investigational angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit, which play an essential role in the angiogenic process. VEGF plays a major role in the biology of ovarian cancer, as it is overexpressed in the disease and associated with the formation of ascites and a poor prognosis, said Dr. Friedlander. Angiogenesis inhibitors have previously demonstrated single-agent activity in ovarian cancer.

CA-125 is an established and accepted biomarker in ovarian cancer for both response and progression, correlates with clinical response, and is widely used clinically. "We reasoned that patients with a rising CA-125, after relapsing after first- or second-line therapy with small-volume tumors, would present an ideal opportunity to look at a novel agent such as pazopanib, where we thought response rates would be higher," said Dr. Friedlander during a press briefing. "It is also interesting to speculate that with some of these newer agents, we may not always see objective responses because they can be cytostatic. That was the rationale for the study."

Within 3 to 9 months, CA-125 levels rise in most patients with recurrent ovarian cancer. Therefore, it is an attractive marker to use in assessing the efficacy of novel targeted therapy.

Dr. Friedlander and colleagues enrolled 35 patients with recurrent epithelial ovarian cancer or fallopian tube or primary peritoneal carcinoma, of whom 17 had measurable disease at baseline. Three-quarters of the patients were sensitive to their most recent platinum therapy, and 61% had 1 prior line of chemotherapy. More than two-thirds (33%) had relapsed within 6 months, 33% within 6 to 12 months, and 28% more than12 months from their last treatment.

The patients received 800 mg of pazopanib daily, and CA-125 responses were observed in 11 (31%) patients, with a median time to response of 29 days. Sixteen of the patients with measurable disease at baseline had evaluable data, and of this subgroup, 4 experienced stable disease by the Response Evaluation Criteria in Solid Tumors (RECIST) standard for more than 100 days.

Adverse events were similar to those generally experienced with angiogenesis or tyrosine kinase inhibitors and were predominantly hypertension, nausea, diarrhea, fatigue, and abdominal pain. Most of the reported adverse effects were grade 1 and 2.

"Patients continued on treatment until disease progression, withdrawal due to toxicity, or withdrawal due to consent," he said. "There are still 3 patients in the study, up to 2 years."

In light of these data, further studies are being planned, and a phase 3 trial is being considered at this time, he concluded.

Hypertension was lower with pazopanib than is seen with similar agents, commented Cristiana Sessa, MD, PhD, from the Istituto Oncologico della Svizzera Italiana, in Bellinzona, Switzerland, who served as a discussant of the paper. "That is a very important factor."

Pazopanib is a good inhibitor of VEGFR-1, -2 and -3; other tyrosine kinase inhibitors may be more useful than pazopanib for different targets, she said.

There are currently a number of compounds targeting VEGF that are being studied, said Dr. Sessa, "But optimal schedules for combination therapy still need to be designed."

Combination Trabectedin and PLD Improve Progression-Free Survival

The second trial investigated the use of a non–platinum-based doublet therapy for second-line recurrent ovarian cancer. Trabectedin (Yondelis, PharmaMar and Johnson & Johnson), a novel marine-derived alkaloid, was combined with pegylated liposomal doxorubicin (PLD), and the efficacy of the combination therapy was compared with PLD monotherapy. Women who received the combination therapy had a median progression-free survival of 7.3 months, compared to 5.8 months for those who received PLD alone.

Those on combination therapy who relapsed more than 6 months after receiving first-line therapy had a median progression-free survival of 9.2 months, vs 7.5 months for patients receiving PLD alone. The risk of disease progression was reduced by 21% in the group receiving combination therapy.

"The study was powered for overall survival," said lead author Bradley Monk, MD, an associate professor at the Chao Family Comprehensive Cancer Center at the University of California, Irvine. "But the data is not mature, and it is premature to give an analysis."

Trabectedin is a DNA minor groove-binding drug with a distinct mechanism of action and has been studied in the treatment of several malignancies, including sarcoma, and prostate, breast, and ovarian cancers. It has been approved in Europe for the treatment of advanced soft-tissue sarcoma but has not yet received Food and Drug Administration (FDA) approval in the United States.

Phase 1 and 2 trials in ovarian cancer have been favorable, explained Dr. Monk. "Phase 2 trials showed a 30% to 43% response in second- and third-line platinum-sensitive patients and 6% to16% in second-line platinum-resistant patients," he said.

In this phase 3 trial, Dr. Monk and colleagues randomized 672 women to PLD 30 mg/m² plus trabectedin 1.1 mg/m² every 3 weeks or to PLD alone, 50 mg/m² every 4 weeks. Treatment response was based on an independent radiology review using RECIST, and the primary end point was progression-free survival.

Fatigue, nausea and vomiting, and neutropenia were higher among patients who received trabectedin, while skin toxicities, including hand and foot syndrome, were lower in the combination-therapy group.

"Positive trials in recurrent ovarian cancer are rare and have almost always led to newly approved therapeutic regimens," Dr. Monk said in a statement. "This combination will undoubtedly be carefully monitored by the FDA and, if approved, would give women with ovarian cancer another much-needed option."

Dr. Sessa, who also served as a discussant for this paper, noted that the response to the second-line therapy correlated to the duration of response from the end of first-line treatment. "It is still a matter of debate," she said, "as to which is the best second-line treatment in the platinum-sensitive patient."

The role of trabectedin in the treatment of ovarian cancer is still unclear. Trabectedin possibly shows a therapeutic index better than standard therapies, she said, but it has not yet shown antitumor activity in resistant disease. Further studies will better define trabectedin's role in ovarian cancer and its possible benefit.

33rd European Society for Medical Oncology Congress: Abstracts 6630 and LBA4. Presented September 15, 2008.

CAUTION WITH ATROVENT

Drug Used for COPD Linked to Increased Mortality Risk

eptember 19, 2008 — Ipratropium used for chronic obstructive pulmonary disease (COPD) is associated with the risk for all-cause and cardiovascular death, according to the results of a nested case-control study reported in the September 16 issue of the Annals of Internal Medicine.

"Concerns exist regarding increased risk for mortality associated with some...COPD medications," write Todd A. Lee, PharmD, PhD, from the Hines Veterans Affairs Hospital in Hines, Illinois, and the Northwestern University Feinberg School of Medicine in Chicago, Illinois. "The extent to which these safety concerns exist and can be generalized to patients with COPD outside the context of clinical trials is unclear. Therefore, we sought to examine the association between medication use and risk for death, including respiratory and cardiovascular deaths, in a large population of patients with recently diagnosed COPD."

The study cohort of 32,130 case patients and 320,501 control participants was identified between October 1, 1999, and September 30, 2003, and followed up through September 30, 2004, with use of National Veterans Affairs inpatient, outpatient, pharmacy, and mortality databases; Centers for Medicare & Medicaid Services databases; and National Death Index Plus data.

For a random sample of 40% of those who died during follow-up, the cause of death was determined. Case patients were grouped in categories on the basis of all-cause, respiratory, or cardiovascular death. Mortality risk linked to use of COPD medication was determined by conditional logistic regression adjusted for comorbid conditions, healthcare use, and markers of COPD severity.

Relevant exposure was considered to be use of inhaled corticosteroids, ipratropium, long-acting beta-agonists, and theophylline in the 6 months before death. Of 11,897 patients for whom data on cause of death were available, 2405 case patients had respiratory deaths and 3159 case patients had cardiovascular deaths.

For all-cause mortality, adjusted odds ratios (ORs) were 0.80 (95% confidence interval [CI], 0.78 - 0.83) for inhaled corticosteroids, 1.11 (95% CI, 1.08 - 1.15) for ipratropium, 0.92 (95% CI, 0.88 - 0.96) for long-acting beta-agonists, and 1.05 (95% CI, 0.99 - 1.10) for theophylline. Although ipratropium was linked to a greater risk for cardiovascular deaths (OR, 1.34; 95% CI, 1.22 - 1.47), inhaled corticosteroids were associated with a lower risk for cardiovascular death (OR, 0.80; 95% CI, 0.72 - 0.88). Results were consistent across sensitivity analyses.

"The possible association between ipratropium and elevated risk for all-cause and cardiovascular death needs further study," the study authors write.

Limitations of this study include observational design, lack of data on current smoking status and lung function, and unknown misclassification of cause-specific mortality.

"Ipratropium may increase the risk for cardiovascular death; however, this risk may be attenuated by the concomitant use of inhaled corticosteroids, which were associated with reduction in the risk for all-cause and cardiovascular death," the study authors conclude. "The risk for death due to some medications must be weighed against potential benefits of these medications that are not captured in observational database studies, such as symptom relief, health status, or quality of life. It is not clear, however, that these benefits would outweigh the increased risk for death."

MAGNESIUM AND CISPLATIN

Eur J Cancer. 2008 Sep 14. [Epub ahead of print]

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Renal protection with magnesium subcarbonate and magnesium sulphate in patients with epithelial ovarian cancer after cisplatin and paclitaxel chemotherapy: A randomised phase II study.

Bodnar L, Wcislo G, Gasowska-Bodnar A, Synowiec A, Szarlej-Wcisło K, Szczylik C.

Department of Oncology, Military Institute of The Health Services, 128 Szaserow Street, 00-909 Warsaw, Poland.

BACKGROUND: The aim of this study was to examine the effect of magnesium supplementation on nephrotoxicity accompanying standard cisplatin-based chemotherapy in patients with epithelial ovarian cancer (EOC). PATIENTS AND METHODS: A double-blind, placebo-controlled, randomised study was conducted in which study arm magnesium sulphate (5g) was administered before each course of standard chemotherapy with paclitaxel (135mg/m(2)/24h) plus cisplatin (75mg/m(2)) every 3 weeks in patients with EOC. Magnesium subcarbonate (500mg), three times per day orally, was administered during the treatment intervals. The control arm was administered a placebo instead of both magnesium salts. Magnesium serum levels (sMg) and GFR markers: serum levels of creatinine (sCr), Cockroft-Gault (ClCG) and Modification Diet of Renal Disease (MDRD) formulae were recorded before each cycle, and 3 weeks after the sixth course. RESULTS: 41 EOC patients were randomised and 40 were eligible. sMg varied significantly between the supplemented and placebo groups (p<0.0001). The control group showed a significantly greater decrease of GFR assessed by: sCr (p=0.0069), ClCG (p=0.0077) and MDRD (p=0.032) formulae compared with the magnesium supplemented group. CONCLUSIONS: These results demonstrate the nephroprotective effect of magnesium supplementation during chemotherapy with cisplatin.

CAPECITABINE CARDIOTOXICITY

Hepatogastroenterology. 2008 Jul-Aug;55(85):1249-56.

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Capecitabine cardiotoxicity--case reports and literature review.

Manojlovic N, Babic D, Stojanovic S, Filipovic I, Radoje D.

Clinic for Gastroenterology and Hepatology, Military Medical Academy of Serbia, Crnotravska 17, 11000 Belgrade, Serbia. nmanojlovic@ptt.yu

This study presents 3 case reports of patients who experienced anginous pain during treatment with capecitabine. The interruption of capecitabine and sublingual or intravenous nitroglycerine treatment lead to recovery. Rechallenge of capecitabine with dose reduction of 30% lead to repeated anginous pain in 2 patients. Treatment with capecitabine had been replaced with weekly bolus 5FU-LV, without further cardiotoxicity. The literature contains data from about 50 patients who experienced cardiotoxicity during capecitabine treatment. The most frequent manifestations of capecitabine cardiotoxicity included: anginous pain in 38/53 (71.7%), arrhythmia in 6/53 (11.3%), myocardial infarction in 6/53 (11.3%). Cardiotoxicity of capecitabine lead to death in 6/53 (11.3%) patients. Risk factors for cardiotoxicity are associated with the grade 4 and the fatal outcome of cardiotoxicity (p = 0.035, p = 0.015), but not with the symptom recurrence upon capecitabine rechallenge (p = 0.18). The combination chemotherapy regimens are associated with the grade 4 of cardiotoxicity (p = 0.048), but not with the fatal outcome (p = 0.3). Rechallenge of capecitabine lead to symptoms recurrence in 10/16 patients. Neither the dose reduction of capecitabine (p = 0.18) nor the additional medical prophylaxis (p = 0.37) were important for the outcome of capecitabine rechallenge.

A GREEK STUDY FOR PANCREATIC CANCER

Cancer Invest. 2008 Sep 16:1. [Epub ahead of print]

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Gemcitabine Combined with Gefitinib in Patients with Inoperable or Metastatic Pancreatic Cancer: A Phase II Study of the Hellenic Cooperative Oncology Group with Biomarker Evaluation.

Fountzilas G, Bobos M, Kalogera-Fountzila A, Xiros N, Murray S, Linardou H, Karayannopoulou G, Koutras AK, Bafaloukos D, Samantas E, Christodoulou C, Economopoulos T, Kalogeras KT, Kosmidis P.

Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.

The combination of gemcitabine and gefitinib was evaluated in advanced pancreatic cancer. Totally, 53 patients were treated with a 7 week cycle of gemcitabine (1,000 mg/m(2) given weekly) followed by six 4 week cycles of gemcitabine given on days 1, 8 and 15. Gefitinib 250 mg was administered daily. Responses were seen in 6, and stabilization of the disease in 12 patients. The main toxicity was myelotoxicity (92%). The 6-month progression-free survival (PFS) was 30%. Median PFS was 4.1 months and median survival 7.3 months with a 1 year survival rate of 27%. The above combination demonstrated promising activity in advanced pancreatic cancer.

WEEKLY INCRETIN MIMETIC FOR DIABETES

Exenatide Once a Week Just as Effective as Twice Daily for Glycemic Control

September 10, 2008 — The antidiabetes drug exenatide (Byetta, Amylin Pharmaceuticals/Eli Lilly) works just as well for improving glycemic control in type 2 diabetics if taken once a week, instead of twice a day, results from the Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention with Exenatide ONce Weekly (DURATION-1) trial show [1]. According to Dr Daniel J Drucker (University of Toronto, ON) and colleagues, whose results are published online September 8, 2008 in The Lancet, the drug offers "a promising treatment option for the management of type 2 diabetes."

As previously reported by heartwire, exenatide is an incretin mimetic, a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster, a lizard native to the Southwest US, that eats only four times a year. Early studies of the drug showed that it works through the glucagon-like peptide 1 (GLP-1) receptor but is much more potent and has similar actions to human GLP-1, including stimulation of insulin secretion, slowing of gastric emptying, and inhibition of glucagon production by the alpha cells of the pancreas. Clinical studies of exenatide have shown that it is as effective as insulin glargine in patients who fail to reach blood glucose targets with common oral antidiabetics. While no cardiovascular-outcome studies have been performed with exenatide, the drug also appears to improve several important cardiovascular risk factors, likely due to its effects on body weight.

For the DURATION

In DURATION-1, Drucker et al sought to compare a long-acting-release formulation of exenatide (2 mg, injected once weekly) with 10-µg exenatide injected twice per day in 295 patients with type 2 diabetes. Patients could be on either no other antidiabetic drug or one or more oral agents.

At 30 weeks, Drucker et al reported that patients taking the once-a-week regimen had significantly greater changes in hemoglobin A1c (HbA_1c) than patients taking the twice-a-day regimen; they also were more likely to reach target HbA_1c levels (7.0% or less).

Authors also reported important changes in cardiovascular disease (CVD) risk factors. Compared with the twice-a-day regimen, patients receiving the once-per-week injections had greater reductions from baseline in mean total and low-density lipoprotein (LDL) cholesterol. Both groups experienced similar reductions in triglycerides from baseline, similar reductions in blood pressure, and similar weight loss.

Percent change from baseline with the two exenatide regimens

Risk factor	Once-a-week (%)	Twice-a-day (%)
Total cholesterol (mmol/L)	–0.31	–0.10
HDL (mmol/L)	–0.02	–0.03
LDL (mmol/L)	–0.13	+0.03
Systolic BP (mm Hg)	–4.7	–3.4
Diastolic BP (mm Hg)	–1.7	–1.7
Weight (kg)	–3.7	–3.6

Commenting on the study for heartwire, Drucker emphasized that this is the first once-weekly diabetes therapy to demonstrate beneficial effects on weight loss and blood pressure, with very low risk of hypoglycemia. "This has favorable implications for improvement of cardiometabolic risk," he noted.

Likewise, Dr John Buse (University of North Carolina, Chapel Hill), a coauthor on the study who is presenting some of the results here at the European Association for the Study of Diabetes 44th Annual Meeting, told heartwire that while it's too soon to appreciate the long-term effects of exenatide on the heart, at least some of the early signals are promising.

"This is an area where there is a lot of hope that, associated with the weight loss, there will be improvements in cardiovascular risk markers," he said. "Enough hope that many people, including myself, have called for the need for CV-outcomes studies, not because anyone thinks there will be any surprise in terms of safety, but because of all of the therapies we have in diabetes, this is the one that is perhaps most likely to improve CV outcomes. If the major focus or concern was to look at cardiovascular safety, then you would do a noninferiority trial comparing exenatide [with another antidiabetic drug]. But in this case, I think this is drug where it's probably worth doing a superiority trial with cardiovascular end points."

Whether the signal of benefit in terms of lipid and blood-pressure parameters is due completely to weight loss or is directly related to drug effects "has not been sorted out," he added.

Caution and hope

In a Comment accompanying the DURATION-1 results [2], Dr Andre J Scheen (University of Liège, Belgium) warns that longer-term data are needed for this new regimen. "Caution is needed as with any new drug developed for the treatment of type 2 diabetes. . . . Many glucose-lowering drugs were withdrawn from the market or their use became controversial despite early positive results. The success of any antidiabetic agent depends on efficacy for glucose control, good tolerance and safety profile, ease of use, cost (unknown for long-acting exenatide), and capacity to reduce complications."

That said, Scheen acknowledged that avoiding twice-daily injections would be a welcome change for diabetes patients. "When the once-a-week exenatide formulation becomes available, after confirmation and extension of today's positive results, this new strategy might substantially change the management of type 2 diabetes," he writes.

Exenatide is already approved for twice-daily injections in the US for use on top of metformin, sulfonylurea, or a thiazolidinedione (TZD) alone, on top of metformin plus sulfonylureas, or on top of metformin plus a TZD. It is not approved for monotherapy.

MONTHLY BIPHOSPHONATE THE SAME AS WEEKLY

Monthly Ibandronate as Effective as Weekly Risedronate or Alendronate

Alison Palkhivala

Medscape Medical News 2008. © 2008 Medscape

September 17, 2008 (Montreal, Quebec) � Monthly ibandronate therapy is as effective in the prevention of fractures as weekly therapy with risedronate or alendronate in a real-world setting, according to posters presented on September 14 and 15 here at the American Society for Bone and Mineral Research (ASBMR) 30th Annual Meeting.

"It's been our feeling all along that there are some patients who would prefer to take once-a-month therapy rather than once-a-week therapy, particularly if you look at [the administration regimen] of these compounds, where you have to take them on an empty stomach with plain water and wait," Steven T. Harris MD, FACP, clinical professor of medicine at the University of California at San Francisco, told Medscape Medical News. He is lead author of the first poster and senior author of the second. According to his research, "people don't have to apologize if they prefer to take a monthly dose [of bisphosphonate] because they're not sacrificing efficacy for convenience."

"Medication fatigue" associated with long-term bisphosphonate therapy is a common problem that can be at least partly remedied with once monthly-therapy, Robert Recker, MD, professor of medicine at Creighton University School of Medicine, in Omaha, Neraska, told Medscape Medical News. He attended the ASBMR conference but was not involved in this research. "It's hard to get people to take bisphosphonates for months and years when success means nothing happens. . . . People comply much better with a once-a-month therapy than a once-a-week therapy," he said, although he acknowledged that adherence to medication is tough to track.

For the Evaluation of Ibandronate Efficacy (VIBE) study, the researchers used medical-claims databases to identify 7345 women, 45 years or older, who were newly prescribed once-monthly ibandronate 150 mg and 56,837 prescribed once-weekly alendronate (35 mg or 70 mg) or risedronate (35 mg) between April and December 2005. The participants had been adherent to their therapy for at least 90 days and did not have cancer or Paget's disease. The researchers used regression analysis to compare fracture rates between the 2 groups, after adjustment for potential confounding factors. Mean follow-up was approximately 7 months.

The risk for hip fracture, nonvertebral facture, and all fracture was similar in both groups, with an all-fracture rate of 1.5% with weekly bisphosphonate therapy and 1.4% with monthly ibandronate. Interestingly, vertebral fracture rates were actually a little bit lower with monthly ibandronate (0.11% vs 0.24%; P = .006).

"The intent of this particular analysis is to do a whole bunch of sensitivity analyses, so that if you take out this subgroup of patients, or you take out that subgroup of patients, are findings the same? And the answer is yes," said Dr. Harris. Sensitivity analyses involved excluding patients taking estrogen, calcitonin, or raloxifene; patients taking glucocorticoids; patients who experienced a fracture; patients taking gastrointestinal medication; and patients on glucocorticoids and/or with osteopenia and/or on alendronate during the preindex period. None of these exclusions significantly affected the results.

A subanalysis presented in a separate poster involved only women 65 years or older. "There's been a concern that maybe among older patients efficacy might be different than among the younger prevention population," said Dr. Harris. "When you restrict your analysis to the over-65 group, you're enriching your population of osteoporotic patients, as opposed to patients who might be osteopenic or something of the sort." Once again, the findings were similar.

"It looks like the fracture rates for patients getting monthly [ibandronate] were very comparable to those of patients getting weekly [risedronate or alendronate]," said Dr. Harris. "If anything, interestingly, there's a little bit of a trend favoring a reduction of vertebral fractures for patients who got monthly [ibandronate]."

"It's good that [once-a-month ibandronate] is effective in all these types of patients," said Dr. Recker, "and it's not hugely unexpected. [These data] provide confirmation and reassurance."

AN INTERESTING PHARMOKINETIC INTERACTION

Anticancer Res. 2008 Jul-Aug;28(4C):2519-27.

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Paclitaxel and pegylated liposomal doxorubicin in recurrent head and neck cancer: clinical and unexpected pharmacokinetic interactions.

Airoldi M, Cattel L, Milla P, Pedani F, Garzaro M, Dosio F.

Medical Oncology Department, San Giovanni Antica Sede Hospital, Turin, Italy. airoldim@yahoo.com

BACKGROUND: The combination of paclitaxel (PTX) with pegylated liposomal doxorubicin (PLD) is an interesting treatment for recurrent head and neck cancer. The pharmacokinetic behavior may depend on the interval between the intravenous administration of the two drugs. This study evaluates the clinical efficacy, toxicity and any possible interval-dependent pharmacokinetic interactions. PATIENTS AND METHODS: Thirty patients were randomized to receive 80 mg/m2 PTX weekly and 12.5 mg/m2 PLD every two weeks at administration intervals of 0, 1, 3, 12 or 24 hours. Blood sampling was performed at day 1 and 15 and pharmacokinetics of PTX, PLD and Cremophor EL were evaluated by non-compartmental analysis. RESULTS: Neutropenia was the most frequent side-effect (100% of patients; 30% grade 3-4). Hand-foot syndrome was severe in only 3% of patients. Overall response rate was 30%, with 3% complete responses and 27% partial responses. Stable disease and progression were 43% and 27%, respectively. Median response duration and overall median survival were 5.5 and 10 months respectively. Co-administration of PLD markedly reduced Cmax and the area under the curve (AUC), and increased PTX clearance. The differences in the PTX AUC and clearance between the 0 h and the 24 h experimental arms were statistically significant. CONCLUSION: The PTX/PLD combination plays a palliative role (clinical benefit in 73% of patients) and has good tolerability. The PTX pharmacokinetic profile was unexpectedly affected by different administration time intervals; in the 0 h arm the AUC was reduced to one fourth, therefore a schedule with PTX on day one, PLD on day two may be preferred.

COST DOES NOT INTEREST US

Cancer Chemother Pharmacol. 2008 Sep 16. [Epub ahead of print]

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Phase I study of cetuximab, erlotinib, and bevacizumab in patients with advanced solid tumors.

Lin CC, Calvo E, Papadopoulos KP, Patnaik A, Sarantopoulos J, Mita AC, Preston GG, Mita MM, Rodon J, Mays T, Yeh IT, O'Rourke P, Takimoto CH, Dancey JE, Chen H, Tolcher AW.

Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA.

BACKGROUND: Complex interrelationships exist between the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor pathways. EGFR activation elicits cell proliferation and increased VEGF expression. To maximally inhibit EGFR and then downstream VEGF activity, this phase I study was initiated to determine the maximum tolerated dose (MTD) of erlotinib with fixed-dose cetuximab, and then combine with bevacizumab in patients with advanced malignancies. PATIENTS AND METHODS: Patients with advanced malignancies likely to express EGFR were treated with a full dose of cetuximab intravenous weekly, combined with various doses of oral erlotinib daily (Part 1). Once the MTD was determined in Part 1, escalating doses of bevacizumab were administered intravenously biweekly (Part 2). RESULTS: Forty patients were enrolled and received 155 courses over four dose levels. In Part 1, dose-limiting grade 3 rash occurred in two patients administered with erlotinib at 100 mg daily, and the MTD of erlotinib for this combination was 50 mg daily with standard-dose cetuximab (11 patients treated). Other adverse events included rash, diarrhea, fatigue, and hypomagnesemia. In Part 2, bevacizumab at 10 mg/kg intravenous every 2 weeks was safely added, with additional nondose-limiting headache, proteinuria, and hypertension. There was one partial response in a patient with renal cell carcinoma. Durable stable disease was observed in five patients for 6-11 months. CONCLUSIONS: The MTD for Part 1 was 50 mg daily of erlotinib combined with standard cetuximab. Bevacizumab at 10 mg/kg biweekly can be safely administered with the MTD for erlotinib and cetuximab combination.

CHEAPER IS THE SAME SO CHOOSE IT

Temozolomide No Better Than Dacarbazine in Advanced Melanoma

Zosia Chustecka

Medscape Medical News 2008. © 2008 Medscape

September 16, 2008 (Stockholm, Sweden) — One of the largest trials conducted in advanced melanoma to date has found that the oral drug temozolomide (Temodal, Schering-Plough) was no better than standard dacarbazine therapy, which is administered intravenously.

The trial, conducted in 859 patients with stage 4 melanoma, was reported here at the 33rd European Society for Medical Oncology Congress.

"Dacarbazine has been the standard therapy for this group of patients for the past 20 years or so," said lead investigator Poulam Patel, MD, from Nottingham University, in the United Kingdom, "and so far nothing has surpassed it. The results of this trial suggest that dacarbazine should remain the standard treatment."

This is the latest in a line of disappointments in the melanoma field, commented discussant Lorenz Jost, MD, from Kantonsspital Bruderholz, in Switzerland. There have been many red traffic lights on these roads, "so far we can't see a way that looks like a highway," he said.

Better Response, But No Effect on Survival

Stage 4 melanoma is generally incurable, and largely accounts for the 48,000 deaths from melanoma seen annually, Dr. Patel commented. It accounts for about 20% to 30% of all cases of melanoma that occur annually; many patients present with localized disease and can be cured with surgery.

Temozolomide is already marketed for use in various brain cancers, but in this trial it was administered at an escalated dose in an extended-dosage schedule (150 mg/m² orally for 7 days, repeated every 14 days). "This schedule allows much more of the drug to be given," Dr. Patel said, and "our trial showed that this dosing regimen was feasible."

Temozolomide showed a significantly better overall response rate than dacarbazine (14.4% vs 9.8%; P =.05). However, progression-free survival was very similar for both drugs (2.3 months for temozolomide vs 2.17 months for dacarbazine; P = .27), as was the median overall survival (9.13 vs 9.36; P = 1.0). Both of these survival rates are very similar to what has been seen in previous trials of dacarbazine, Dr. Patel commented.

Temozolomide was "slightly more toxic" than dacarbazine, but it had an acceptable safety profile, Dr. Patel said. There was a higher rate of lymphopenia (reported by 45% of patients on temozolomide and 9% on dacarbazine), although the rates for the other hematologic adverse events (leucopenia, anemia) and nonhematologic events (such as fatigue, nausea, and vomiting) were similar for both drugs. There were no treatment-related deaths in either group.

When asked whether temozolomide might be preferred because it is an oral drug and the results suggest it is about the same as dacarbazine, Dr. Patel replied: "This trial was designed to show an improvement in survival, and it would take a larger trial to show that the oral drug is equivalent to the intravenous drug."

In his discussion, Dr. Jost said clinicians could consider using the oral drug in patients who have problematic venous access, liver failure, or asymptomatic brain metastases (although a benefit here is not proven, he pointed out). "But only if cost is not an issue," he added.

Dr. Jost also made the point that dacarbazine, although a standard treatment in this patient population for years, is unproven. "There are no data comparing this drug with best supportive care, so we do not know whether it extends survival. Even worse, there is no proof that it doesn't shorten survival," he pointed out. "So temozolomide is no better than dacarbazine, but we don't know that dacarbazine is good," he said.

Genetic Variant Linked to Melanoma

In a separate presentation, a link was reported between the cyclin D1 gene and susceptibility to melanoma. The results come from a study of 1053 people, including 161 patients with melanoma and 892 healthy controls, reported by Raquel Catarino, PhD, and colleagues from the Portuguese Institute of Oncology, in Porto.

Dr. Catarino and colleagues found that people who carry 2 copies of the gene variant were 80% more likely to develop melanoma. "Our results indicate that the proportion of melanoma cases attributable to this genetic alternation is 14%," she added.

"Our study demonstrates that cyclin D1 polymorphism is associated with a higher risk of melanoma development, indicating that this genetic variation may confer a growth advantage to cancer cells," Dr. Catarino commented. Previous studies have suggested that cyclin D1 is an important oncogene in melanoma, making it a candidate for further evaluation as a therapeutic target in this disease, the researchers commented.

RADIATION THERAPY FOR MELANOMA?

Radiation Therapy as Primary and Adjuvant Treatment for Local and Regional Melanoma

Lawrence B. Berk, MD, PhDCancer Control. 2008;15(3):233-238. ©2008 H. Lee Moffitt Cancer Center and Research Institute, Inc.

Posted 09/11/2008

Abstract and Introduction

Abstract

Background: The role of radiation therapy as primary and adjuvant therapy for localized or locally advanced melanoma is controversial.
Methods: To develop evidence-based guidelines, PubMed was searched using the keywords melanoma AND (radiation OR radiotherapy). These references were reviewed and the relevant articles selected. The articles were then reviewed for further references. Because of the paucity of prospective or randomized trials, no attempt was made to classify the quality of the results.
Results: No phase III trials of nodal irradiation for prevention of regional recurrence are available. A phase III trial is being completed by the Tasman Radiation Oncology Group. A phase II trial has been completed by the group. Multiple retrospective series have been published. The available data appear to confirm that nodal radiation therapy is effective in preventing nodal recurrence. No dose response or fraction size response was found. According to generally accepted guidelines, radiation therapy should be offered for patients who have nodes greater than 3 cm, more than 3 involved nodes, or extracapsular extension. For radiation therapy for the treatment of metastatic disease, a phase III trial showed that 50 Gy in 2.5-Gy fractions was as effective as 32 Gy in 8-Gy fractions, with 25% complete remission and 35% partial remission. In contrast, the retrospective studies support that larger fraction sizes, at least 4 Gy, are more effective.
Conclusions: Adjuvant nodal irradiation appears to be effective for the prevention of nodal recurrence. Radiation therapy can also be effective for treatment of local disease, if surgery is not an option.