PREDICTION MODEL FOR GEMCITABINE TOXICITY

J Clin Oncol. 2009 Mar 16. [Epub ahead of print]

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Identification of a Predictive Biomarker for Hematologic Toxicities of Gemcitabine.

Matsubara J, Ono M, Negishi A, Ueno H, Okusaka T, Furuse J, Furuta K, Sugiyama E, Saito Y, Kaniwa N, Sawada J, Honda K, Sakuma T, Chiba T, Saijo N, Hirohashi S, Yamada T.

Chemotherapy Division, National Cancer Center Research Institute; Hepatobiliary and Pancreatic Oncology Division and Clinical Laboratory Division, National Cancer Center Hospital; Project Team for Pharmacogenetics, National Institute of Health Sciences; BioBusiness Group, Mitsui Knowledge Industry, Tokyo; Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital East, Kashiwa; and Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

PURPOSE: Gemcitabine monotherapy is the current standard for patients with advanced pancreatic cancer, but the occurrence of severe neutropenia and thrombocytopenia can sometimes be life threatening. This study aimed to discover a new diagnostic method for predicting the hematologic toxicities of gemcitabine. PATIENTS AND METHODS: Using quantitative mass spectrometry (MS), we compared the baseline plasma proteomes of 25 patients who had developed severe hematologic adverse events (grade 3 to 4 neutropenia and/or grade 2 to 4 thrombocytopenia) within the first two cycles of gemcitabine with those of 22 patients who had not (grade 0). RESULTS: We identified 757 peptide peaks whose intensities were significantly different (P < .001, Welch t test) among a total of 60,888. The MS peak with the highest statistical significance (P = .0000282) was revealed to be derived from haptoglobin by tandem MS. A scoring system (nomogram) based on the values of haptoglobin, haptoglobin phenotype, neutrophil count, platelet count, and body-surface area was constructed to estimate the risk of hematologic adverse events (grade 3 to 4 neutropenia and/or grade 2 to 4 thrombocytopenia) with an area under curve value of 0.782 in a cohort of 166 patients with pancreatic cancer. Predictive ability of the system was confirmed in two independent validation cohorts consisting of 87 and 52 patients with area under the curve values of 0.655 and 0.747, respectively. CONCLUSION: Although the precise mechanism responsible for the correlation of haptoglobin with the future onset of hematologic toxicities remains to be clarified, our prediction model seems to have high practical utility for tailoring the treatment of patients receiving gemcitabine.

IMATINIB FOR GRAFT VERSUS HOST DISEASE

Blood. 2009 Mar 16. [Epub ahead of print]

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Imatinib mesylate as salvage therapy for refractory sclerotic chronic graft-versus-host disease.

Magro L, Mohty M, Catteau B, Coiteux V, Chevallier P, Terriou L, Jouet JP, Yakoub-Agha I.

Service des Maladies du Sang, CHRU de Lille, Lille, France.

Imatinib is a promising candidate for the treatment of fibrotic diseases. This retrospective study evaluated the use of Imatinib for the treatment of refractory sclerotic chronic graft-versus-host disease (ScGVHD) in 14 patients with different hematological malignancies. Imatinib was started at a median of 44 (range, 16-119) months after transplantation, and was administered for a median of 5.9 (range, 2.1-74) months from time of initiation. With a median overall follow-up of 11.6 (range, 4.1-74) months from time of initiation of Imatinib, 4 patients (29%) had to stop Imatinib because of drug intolerance. All other adverse reactions were of mild-to-moderate grade and could be managed symptomatically. Overall, 7 patients responded to Imatinib (50%; 95%CI, 24-76%) with 4 patients improving their Rodman score >/=90%. In addition, Imatinib therapy allowed for a significant reduction of corticosteroids dosage. Despite its limited size, this cohort suggests some beneficial activity of Imatinib in ScGVHD warranting further prospective investigations.

TRASTUZUMAB BEYOND PROGRESSION

J Clin Oncol. 2009 Mar 16. [Epub ahead of print]

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Trastuzumab Beyond Progression in Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: A German Breast Group 26/Breast International Group 03-05 Study.

von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S.

GBG Forschungs GmbH, Neu-Isenburg; Dr.-Horst-Schmidt-Kliniken, Breast Unit, Wiesbaden; University Women's Hospital, Mainz; University Women's Hospital, Kiel; University Women's Hospital, Frankfurt/Main; Schwarzwald-Baar Klinikum, Villingen-Schwenningen; University Women's Hospital, Marburg; Klinikum Mutterhaus der Borromaeerinnen, Trier; Klinikum Deggendorf; and Gemeinschaftspraxis Papcke/Uleer, Hildesheim, Germany; Institute of Oncology, Ljubljana, Slovenia; Ikazia Ziekenhuis, Rotterdam; and Reinier de Graaf Gasthuis, Delft, the Netherlands; Clinical Division of Oncology, Department of Medicine I, Medical University Vienna and Central European Cooperative Oncology Group, Vienna, Austria; Rigshospitalet University Hospital, Copenhagen, Denmark; and University College London Hospitals, London, United Kingdom.

PURPOSE: Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. METHODS: Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. RESULTS: We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. CONCLUSION: Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.

TNF-a NATAGONISTS AND MELANOMA

Long term treatment of psoriasis with TNF-alpha antagonists : Occurrence of malignant melanoma; Kowalzick L, Eickenscheidt L, Komar M, Schaarschmidt E; Der Hautarzt (Mar 2009)

A 51-year-old white man developed de novo a cutaneous malignant melanoma (Stage Ia) after a 30-month treatment period with TNF-alpha-antagonists, consecutively using infliximab, adalimumab and etanercept because of a recalcitrant moderate to severe plaque psoriasis. The patient previously had been treated fumarates for 4 years, cyclosporine A for 2 months and methotrexate for 5 weeks. He also received cycles of cream PUVA and UVB before and then between systemic medications. A possible causal connection between development of melanoma and immunosuppressive treatment is discussed in the light of recent literature. The termination of TNF-alpha-antagonist therapy following development of melanoma is recommended

LETROZOLE SUPERIOR TO TAMOXIFEN

Title: Letrozole Superior to Tamoxifen in Postmenopausal Women With Endocrine-Responsive Breast Cancer: Presented at SGBCC
"Letrozole Superior to Tamoxifen in Postmenopausal Women With Endocrine-Responsive Breast Cancer: Presented at SGBCC"


By Mary Wessling ST. GALLEN, Switzerland -- March 19, 2009 -- Letrozole significantly prolongs disease-free survival (DFS) and time to distant recurrence compared with tamoxifen for postmenopausal women with endocrine-responsive breast cancer, researchers stated here at the St. Gallen Oncology Conferences: Primary Therapy of Early Breast Cancer International Conference (SGBCC). An update of the Breast International Group (BIG)-98 Primary Core Analysis presented on March 13 by lead author Beat Thürlimann, MD, Senologie-Zentrum Ostschweiz, Kantonsspital, St. Gallen, Switzerland, also suggests an overall survival benefit for letrozole over tamoxifen. The study included 8,010 postmenopausal women with endocrine-responsive breast cancer who were randomised to tamoxifen for 5 years (arm A); letrozole for 5 years (arm B); tamoxifen for 2 years followed by letrozole for 3 years (arm C); or letrozole for 2 years followed by tamoxifen for 3 years (arm D). Of the women in the study, 1,828 were randomised to a 2-arm option (A or B; March 1998-March 2000) and 6,182 were randomised to a 4-arm option (A, B, C, D; April 1999-May 2003). Events only up to the time of treatment switch are included for arms C and D. The primary endpoint was DFS and median follow up was 60.5 months. After the initial report of the superiority of letrozole in 2005, patients on tamoxifen alone were offered letrozole, and 619 patients of the 2,459 (25.2%) randomised to tamoxifen crossed over to letrozole. Intent-to-treat (ITT) results based on all patients and follow-up according to the original randomised assignment and analyses censoring tamoxifen patients who crossed over to letrozole at the time of the crossover were presented in this poster. DFS in the letrozole-treated patient population (n = 4,003) versus the tamoxifen-treated population (n = 4,007) was reported as follows for the ITT analysis and censored tamoxifen-crossover (TCO) analysis: events ITT, 585 versus 664 (hazard ratio [HR] = 0.86; 95% confidence interval [CI], 0.77-0.96) and TCO, 585 versus 643 (HR = 0.83; 95% CI, 0.74-0.93); Cox[ P = .008.Overall survival in the letrozole-treated patient population versus the tamoxifen-treated population was reported as follows for the ITT analysis and censored TCO analysis: events ITT, 330 versus 374 (HR = 0.87; 95% CI, 0.75-1.01) and TCO, 330 versus 369 (HR = 0.81; 95% CI, 0.70-0.94); Cox P = .07.

Time to distant recurrence in the letrozole-treated patient population versus the tamoxifen-treated population was reported as follows for the ITT analysis and censored TCO analysis: events ITT, 287 versus 357 (HR = 0.80; 95% CI, 0.68-0.92) and TCO, 287 versus 351 (HR = 0.78; 95% CI, 0.67-0.92); Cox P = .003.

Patients on tamoxifen had significantly more thromboembolic events, hot flushes, vaginal bleeding, night sweats, and endometrial events. Patients on letrozole had significantly more bone fractures, grade 3 to 5 cardiac events, hypercholesterolaemia, and arthralgia.

Analyses that consider the impact of the selective crossover of the 619 tamoxifen patients who received letrozole reinforce the significantly superior disease control for letrozole compared with tamoxifen, researchers concluded.

[Presentation title: Letrozole vs Tamoxifen as Adjuvant Endocrine Therapy for Postmenopausal Women With Receptor-Positive Breast Cancer. Update of the BIG 1-98 Primary Core Analysis. Abstract 0161]

SUNITINIB MAYBE THE MOST EFFECTIVE

Sunitinib Seems Most Effective for Metastatic Renal Cell Cancer

March 10, 2009 — New targeted therapies for metastatic renal cell cancer — both approved by regulatory authorities and unapproved — all offer better progression-free survival as first-line therapies than interferon-alpha or placebo, according to a new meta-analysis published online January 27 in BMC Cancer.

The agents — sunitinib (Sutent, Pfizer), sorafenib (Nevaxar, Bayer), bevacizumab (Avastin, Genentech), and temsirolimus (Torisel, Wyeth) — are part of what has been called a "new era" in the treatment of renal cell carcinoma.

However, which agent is most effective has not been established because none of the studies to date have done head-to-head comparisons, say the meta-analysis authors, led by Edward J. Mills, PhD, from Simon Fraser University, in Vancouver, British Columbia.

To address this unknown, the authors used indirect comparisons between the agents, and looked at studies in which these agents were used for first-line treatment of metastatic renal cell cancer.

In studies that used interferon-alpha as the comparator, the investigators found that sunitinib was superior to both sorafenib and bevacizumab used in combination with interferon-alpha.

They also found no significant difference between sorafenib and bevacizumab alone in a comparison of studies that used placebo as the comparator.

The remaining new therapy for metastatic disease, temsirolimus, was not included in the comparisons because the only randomized study with it in this setting is among patients who had poor prognoses, which is clinically different than the studies with the other agents, which were carried out in patients with favorable or intermediate risk.

"Our study represents a first step at determining the relative effectiveness of each new intervention," write the authors. They explain that new trials are now needed to compare the agents head to head or to comparatively combine the agents. They also admit that, foremost, the study is "hypothesis-generating."

High Cost Complicates Decision-Making

The investigators note that a clinician's decision-making about metastatic renal cell cancer treatment is complicated by cost. "In some settings [the drugs] are too expensive for public availability," they write.

For example, the United Kingdom's National Institute for Clinical Excellence (NICE) has issued provisional guidance not to recommend any of these 4 drugs on the National Health Service because of cost. NICE evaluated the cost of the drugs per quality-adjusted life-year and determined that all 4 were in excess of the £30,000 threshold (bevacizumab, £171,301; sorafenib, £102,498; sunitinib, £71,462; and temsirolimus, £94,385).

The proposal was widely criticized by cancer experts in the United Kingdom, as reported by Medscape Oncology.

NICE will issue final guidance on the drugs in May 2009, say the authors, who expect that 1 or more of the drugs will be recommended.

Indirect Comparison Needed

Improved understanding of the molecular mechanisms involved in the pathogenesis of metastatic renal cell carcinoma has allowed more advanced treatment options to emerge, note the authors.

The cancer is associated with overexpression of several proteins, including the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which are capable of promoting tumor growth and angiogenesis, they explain.

Three of the new targeted agents — bevacizumab, sorafenib, and sunitinib — act on VEGF, whereas the remaining agent, temsirolimus, has a different target and is an inhibitor of mammalian target of rapamycin kinase.

The clinical trials to date of these agents allowed the investigators to use the "adjusted indirect comparisons meta-analysis method."

The method will not be familiar to some readers of the study, admit the authors. However, they defend it as a method that has "demonstrated comparatively consistent findings between the indirect method and head-to-head trials."

In the analysis, the investigators included 7 randomized clinical trials (total patients = 3957): 3 with bevacizumab (2 with bevacizumab plus interferon-alpha), 2 with sorafenib, 1 with sunitinib, and 1 with temsirolimus. The trials used the new drug as a sole treatment or as adjunct treatment. Progression-free survival was used as the primary outcome.

Using trials that had interferon-alpha as the common comparator, the investigators found that sunitinib was superior to both sorafenib (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.38–0.86; P ≤ .001) and bevacizumab plus interferon-alpha (HR, 0.75; 95% CI, 0.60–0.93; P = .001). Sorafenib was not statistically different from bevacizumab plus interferon-alpha (HR, 0.77; 95% CI, 0.52–1.13; P = 0.23).

Using placebo as the common comparator, the investigators found no significant difference between sorafenib and bevacizumab alone (HR, 0.81; 95% CI, 0.58–1.12; P = .23).

Although it was not part of the indirect comparisons, temsirolimus provided significant progression-free survival in patients with poor prognosis (HR, 0.69; 95% CI, 0.57–0.85), they also note.

Patient-Prognosis Groupings Dependent on ECOG and Karnofsky Scores

The authors note that 3 patient groups existed in the studies examined in the analysis: treatment-naïve patients of favorable to intermediate risk, refractory patients of favorable to intermediate risk, and refractory patients of intermediate to poor risk.

Establishing a profile of the patients, and thus of the studies, was important to ensure that the meta-analysis comparisons were appropriate and fair, they suggest.

However, establishing prognosis of this metastatic disease is difficult, because there are a "variety of patient, tumor, and biochemical factors" that influence prognosis, they state. They based their division of prognosis into favorable, intermediate, and poor risk groups on ECOG (Eastern Cooperative Oncology Group) performance status or Karnofsky scores from the different studies.

"While they are not perfectly matched groups from a prognostic point of view, we felt that they were similar enough for inclusion in our analysis," they write.

"Further limitations of included trials based on more specific prognostic factors would have made any analysis impossible, given the variety of different prognostic scores available for metastatic renal cell carcinoma," they add.

RETSAS SPEAKING

Carboplatin, Paclitaxel, Bevacizumab Combination Promising for Stage IV Melanoma

NEW YORK (Reuters Health) Feb 06 - Triple therapy with monthly carboplatin, weekly paclitaxel and biweekly bevacizumab for patients with unresectable stage IV melanoma achieved "the best result ever in a clinical trial of metastatic melanoma conducted at the Mayo Clinic," investigators report.

Dr. Svetomir Markovic and colleagues in Rochester, Minnesota, conducted a two-stage phase II study of the triple chemotherapy regimen in 53 patients with unresectable stage IV melanoma. Carboplatin was given on day 1 of a 28-day cycle. Paclitaxel was given on days 1, 8 and 15. Bevacizumab was given on days 1 and 15. Treatment was continued until patients achieved remission or experienced intolerable toxicity.

The Mayo Clinic team reports in the January 1 issue of Cancer that nine patients (17%) achieved partial remission. Thirty patients (57%) achieved stable disease for at least 8 weeks.

Median progression-free survival was 6 months and median overall survival was 12 months. One patient died after eight treatment cycles from intracranial hemorrhage at the site of undiagnosed brain metastases.

Severe grade 3 or higher toxicities that limited treatment included neutropenia in 53%, thrombocytopenia in 11%, hypertension in 9% and anemia in 8%. Bevacizumab appeared to cause the most treatment-limiting toxicity, the researchers found.

"Based on our limited phase II data, the combination seems effective," Dr. Markovic said.

"An ongoing randomized Genentech-sponsored phase II study of Taxol/carboplatin compared with Taxol/carboplatin/bevacizumab in stage IV melanoma is under way," Dr. Markovic added. "If there is an advantage to the bevacizumab arm, as we would suspect, we would proceed with a randomized phase III clinical trial comparing the new combination with 'standard of care.'"

"The phase III study is already written and we will implement its final development upon release of the data from the randomized phase II study," Dr. Markovic concluded.

TB AND LUNG CANCER

TB Associated With Long-Term Risk of Lung Cancer

NEW YORK (Reuters Health) Mar 12 - Tuberculosis is an important risk factor for lung cancer in rural China, according to study findings published in the March issue of the International Journal of Cancer.

"Tobacco and indoor air pollution from smoky coal are major causes of lung cancer in rural Xuanwei County, China," Dr. Eric A. Engels, of the National Cancer Institute, Rockville, Maryland, and colleagues write. "It has been proposed that tuberculosis may increase the risk of lung cancer, because of lung inflammation and fibrosis that could induce genetic damage," they note.

The researchers used data from a retrospective cohort study of 42,422 farmers in Xuanwei to examine the association between tuberculosis and lung cancer risk. The subjects were followed from 1976, and deaths from lung cancer were ascertained through 1996. In 1992, the participants completed standardized questionnaires that included lifetime medical history as well as demographic and household characteristics and fuel and stove use.

TB was reported by 246 (0.6%) subjects. During follow-up, 2459 subjects (5.8%) died from lung cancer (mortality 3.1 per 1000 person-years), including 31 of the 246 patients with tuberculosis (mortality 25 per 1000 person-years).

The hazard ratio for lung cancer mortality was 6.1 for subjects with tuberculosis compared to those without TB, the report indicates.

The association between tuberculosis and lung cancer risk was especially pronounced in the first 5 years after diagnosis of tuberculosis (HRs ranging from 6.7 to 13). However, the association remained strong more than 10 years after tuberculosis diagnosis (HR 3.0).

Associations between tuberculosis and lung cancer were similar among men and women.

"In conclusion," Dr. Engels and colleagues write, "our study supports the possibility that tuberculosis may act through a process of localized pulmonary inflammation and fibrosis to initiate or promote the development of lung cancer, particularly in conjunction with other carcinogenic exposures."

They add, "The potential contribution of tuberculosis to the development of lung cancer points to the continuing need to develop and implement improved tuberculosis prevention and treatment programs, especially in the developing world."

TESTICULAR CANCER CHEMOTHERAPY AND ENDOTHELIAL INJURY

Long-Term Testicular Cancer Patients May Develop Endothelial Injury

NEW YORK (Reuters Health) May 28 - Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy have evidence of endothelial injury and dysfunction compared with testicular cancer patients who did not receive chemotherapy, according to the results of a study published in the May 1st issue of Cancer.

"Long-term survivors of testicular cancer who received cisplatin-based chemotherapy have an increased risk of cardiovascular disease," Dr. David J. Vaughn and colleagues from the University of Pennsylvania, Philadelphia, write.

In a cross-sectional study, the researchers assessed cardiovascular risk, subclinical atherosclerosis, and endothelial function in long-term survivors of testicular cancer who completed a testicular cancer-specific questionnaire regarding demographics and medical history.

The investigators also evaluated body mass index (BMI), Framingham relative risk (RR), soluble intercellular adhesion molecule-1 (sICAM-1), high sensitivity C-reactive protein, brachial artery flow-mediated dilatation, and other factors. In addition, the team performed flow cytometric analysis of peripheral blood for levels of endothelial progenitor cells and circulating endothelial cells.

Of the 39 patients included in the study, 24 had received cisplatin-based chemotherapy and 15 were chemotherapy-nave. Patients in the cisplatin-based chemotherapy group had a mean brachial artery flow-mediated dilatation of 5.63%, compared with 8.78% in the chemotherapy-nave group (p = 0.05).

Both groups had preserved nitrogen-induced dilatation, which suggests that impaired brachial artery flow-mediated dilatation was the result of endothelial dysfunction and not vessel wall smooth muscle dysfunction.

The cisplatin-based chemotherapy group also had significantly higher mean sICAM-1 levels compared to the chemotherapy nave group (p = 0.04).

There were no significant differences between the groups in BMI, Framingham RR, carotid intima-media thickness, or C-reactive protein.

Flow cytometry analysis was performed in a subset of five cisplatin-based chemotherapy patients and five chemotherapy-nave patients. Mean levels of endothelial progenitor cells did not differ between the groups. However, patients who had received chemotherapy had significantly increased levels of circulating endothelial cells.

The investigators point out that "validated biomarkers of endothelial dysfunction could potentially identify asymptomatic long-term testicular cancer survivors who are at increased cardiovascular risk years before an actual event occurs. This would provide the opportunity for interventions aimed at secondary prevention," they note.

These data also provide "a better understanding of the mechanisms of chemotherapy-induced endothelial injury," Dr. Vaughn's group adds, which "could potentially lead to primary prevention approaches."

DRUG OPTIONS FOR RENAL CANCER

NCCN 2009: Survival Increases as Drug Options Grow in Kidney Cancer

March 16, 2009 (Hollywood, Florida) — New treatments for kidney cancer have produced "much longer" overall survival with advanced disease and created a "very exciting time" in the treatment of the disease, said Robert J. Motzer, MD, from Memorial Sloan-Kettering Cancer Center, in New York City, here at the National Comprehensive Cancer Network (NCCN) 14th Annual Conference.

"There are lots of treatment options, and more are coming," he said during a session updating the NCCN's kidney cancer guidelines.

However, there are still many challenges in the field, including the high cost of the new targeted therapies and the fact that most advanced patients have an ongoing palliative need for the drugs, he added

Nevertheless, Dr. Motzer's great concern is that the word get out about new treatment options. "We have to make sure that patients are offered these drugs," he told Medscape Oncology. "There are still metastatic kidney cancer patients being treated soley by urologists, rather than by a team approach, for example," he said, suggesting that such patients would not likely receive the latest treatment options.

"The outlook for patients with metastatic renal cell cancer has been bleak," he added. About 30% of all patients will develop metastatic disease and the 5-year survival rate for those patients is less than 10%, he observed.

"But things have changed here," he explained.

For instance, in a study presented at the American Society of Clinical Oncology meeting in 2008, the targeted therapy sunitinib (Sutent, Pfizer) produced a median overall survival of 26.4 months in patients with metastatic disease, as reported by Medscape Oncology. "Previously [in studies of the older generation of drugs], average overall survival was 12 months," he said.

"A new bar for survival has been set in the treatment of metastatic disease," he said about the sunitinib trial.

The new targeted therapies are, for now, used exclusively in patients with metastatic disease. However, clinical trials in Europe and the United States are underway to test the new drugs in the adjuvant setting, following surgery. "There is considerable interest in using targeted therapies as an adjuvant to surgery," he added.

Guideline Changes: Targeted Therapies to the Fore

The "cornerstone" for stage 1, 2, and 3 local kidney cancers is surgical excision, either partial or radical, said Dr. Motzer. Patients with stage 4 disease, who are mainly those with metastatic disease, usually undergo surgery as well, but receive drug therapy after this primary treatment.

For those patients with local disease who relapse and for those with stage 4 disease, the first-line therapies with a category 1 designation from NCCN (highest recommendation) are sunitinib, temsirolimus (Torisel, Wyeth; category 1 for poor-prognosis patients only), and bevacizumab (Avastin, Genentech) plus interferon. The latter is approved in Europe but not the United States.

Dr. Motzer noted that these guidelines are for patients with clear cell histology. For those with nonclear cell histology, who are a small minority, the preferred first-line therapy is a clinical trial.

For patients who progress on first-line therapy, the next step is subsequent therapy. "Generally, we offer one therapy and then switch to another at the time of progression," explained Dr. Motzer. Second-line therapies include sorafenib (Nevaxar, Bayer), he said. However, subsequent or second-line therapy can include sunitinib if the patient was first receiving an older cytokine therapy, such as interferon.

Dr. Motzer noted that the NCCN guidelines for kidney cancer have "changed the most in metastatic disease in the past few years."

In effect, the new therapies have changed the model of care for kidney cancer, said Joan McClure, MS, from the NCCN. "Kidney cancer is actually moving into a continuum-of-care paradigm, much like that for colon cancer," she said in a statement. "Second-line therapies now exist for patients who have previously been treated with specific agents."

Predictors of Survival

The NCCN kidney cancer guidelines use a scoring system developed at Memorial Sloan-Kettering to help predict survival in all renal cell cancer patients.

The prognosis for patients with 3 or more of the following items is defined as poor, and such patients have a median survival of 5 months, said Dr. Motzer. The predictive items are:

• lactate dehydrogenase level of more than 1.5 times the upper limit of normal;
• hemoglobin level lower than normal;
• corrected serum calcium level of more than 10 mg/dL;
• interval of less than 1 year from original diagnosis to the start of systemic therapy;
• Karnofsky performance score of 70 or less; and
• 2 or more sites of organ metastasis.

Patients with none of these risk factors have a median survival of 30 months. Patients with 1 or 2 risk factors have a median survival of 14 months, said Dr. Motzer.

New Clinical Trials, New Agents

Among the new trials in advanced patients is a comparison of temsirolimus with sorafenib as a second-line therapy in patients who have failed first-line sunitinib. In the United States, phase 3 trial results for temsirolimus are currently limited to patients with a poor prognosis, even though the drug has a broad indication for the treatment of advanced kidney cancer. "There is a high level of interest in using this following sunitinib progression in patients with metastatic disease," said Dr. Motzer.

Other agents being tested in clinical trials in patients with metastatic disease are everolimus (Novartis), pazopanib (GlaxoSmithKline), and axitinib (Pfizer). All 3 products are still under development and not yet available.

INTRAOPERATIVE CHEMOTHERAPY FOR OVARIAN CANCER

Intraoperative Chemotherapy in Peritoneal Cavity Promising for Ovarian Cancer

NEW YORK (Reuters Health) Mar 12 - Intraoperative intraperitoneal chemotherapy with cisplatin appears to be a viable approach in patients with peritoneal carcinomatosis of ovarian cancer, French researchers report in a February 9th on-line paper in the World Journal of Surgical Oncology.

"Intraperitoneal chemotherapy is usually carried out by administering the chemotherapeutics using an external pump," investigator Dr. Bernard Royer told Reuters Health. "However, this kind of administration is impeded by inadequate diffusion in the peritoneal cavity related to adhesion barriers and anatomic niches, and even accompanied by adverse effects such as those which are catheter related."

"To circumvent some of these problems," he explained, "an 'open' perioperative intraperitoneal administration can be performed just after optimal cytoreductive surgery by filling the peritoneal cavity with chemotherapeutic agents."

To evaluate this technique, Dr. Royer of CHU Jean Minjoz, Besancon, and colleagues studied 47 patients with stage III ovarian cancer. They were treated with standard paclitaxel carboplatin intravenous chemotherapy and went on to debulking surgery.

After surgery, the peritoneal cavity was filled with 3 liters of isotonic saline and 90 mg of cisplatin, which was then hand stirred. The sequence was repeated twice over 2 hours.

"The administration during surgery," continued Dr. Royer, "confers optimal drug diffusion by manual mixing and eliminates catheter-related adverse effects."

"The present study," he concluded, "shows that this therapeutic strategy is well tolerated and investigation of its efficacy is currently ongoing in our centers."

GUIDELINES FOR BREAST CANCER UPDATED

NCCN 2009: Guidelines for Breast Cancer Updated

March 19, 2009 (Hollywood, Florida) — Genetic counseling is now recommended for women with either ductal carcinoma in situ or early invasive breast cancer when genetic testing indicates a high risk for hereditary breast cancer, said Beryl McCormick, MD, from the Sloan-Kettering Cancer Center, in New York City, in a presentation here at the National Comprehensive Cancer Network (NCCN) 14th Annual Conference.

Dr. McCormick said that the new NCCN recommendation was supported by a 2007 study that showed a dramatic increase in the decision to opt for a bilateral mastectomy (from 4% in 1998 to 11% in 2003) by women who present with unilateral disease and have a high genetic risk. "I suspect that if we looked again, the percentage would be up even higher," she said. The new recommendation will allow these women to make more informed decisions about local treatment.

"We are finding now that, in high-risk women in these populations, genetic testing following diagnosis can often lead to decisions to treat both the affected and unaffected breast," said Dr. McCormick.

She presented the updates to the NCCN's breast cancer guidelines along with Stephen Edge, MD, from Roswell Park Cancer Institute, in Buffalo, New York. The new counseling recommendation was 1 of a host of changes/additions, which include:

• revision of the status of a radiation boost in women with early invasive breast cancer to optional;
• new pathway for mastectomy in recurrent disease;
• use of magnetic resonance imaging (MRI);
• breast-reconstruction guidelines;
• local therapy in women who present with metastatic disease;
• ranking of chemotherapy and hormone-therapy options.

The breast cancer panel is the largest group of experts within the NCCN and meets annually for 3 days to review developments in breast cancer and the related guidelines, said Dr. McCormick.

Changes Regarding Radiation Therapy

In previous guidelines, women with early-stage breast cancer were all advised to receive a boost of radiation to the whole breast (by photons, brachytherapy, or electron beam). The guidelines now make that boost optional.

The revision is based in part on a large EORTC study, which indicated that the boost did not provide a significant advantage in preventing recurrence over 8 years for women older than 60 years. However, the advantage was "highly significant" in women younger than 40, said Dr. McCormick. She also noted there was some advantage to the boost in women aged 41 to 50 years and 51 to 60 years, but it was not as dramatic as it was for the young women. Hence, the guidelines present the boost as optional now, she said.

For clinicians treating women who have locally recurrent disease, there is now a new pathway to consider. If a woman has had no previous radiation therapy and was initially treated with mastectomy, the clinician should now consider (in addition to either surgical resection or total mastectomy and axillary dissection) another option — surgical resection plus radiation therapy to the chest wall and internal mammary nodes, said Dr. McCormick.

Surgery for Women Who Present With Metastatic Disease

A "very important footnote" to the new guidelines is in the treatment of women who present with metastatic disease, noted Dr. McCormick. These women may benefit from the performance of local breast surgery and/or radiation therapy. "Generally, this palliative local therapy should be considered only after response to initial systemic treatment," she said.

The support for this addition to the guidelines is from several recent retrospective studies that demonstrated improved survival when the primary tumor was removed with negative margins, she added.

"In the past, surgery was reserved for women with metastatic disease who progressed," said Dr. Edge. However, data from the National Cancer Data Base show that increasing numbers of women are now undergoing surgery at the time of the initial metastatic diagnosis (rather than when they progress). In women who are left with clear margins, this approach doubles the median survival time to about 2 years, compared with 12 months in women who have no surgery.

Dr. Edge also noted that these different approaches to surgery in the treatment of women who present with metastatic disease would be "best addressed" with a controlled trial, but this has not yet been done.

Guidance on Use of MRI

Guidance on the use of MRI is also addressed in the new NCCN document. However, the guidance is only a footnote and has not yet been codified into pathways, emphasized Dr. Edge. "This is a rapidly evolving area of practice and there is no firm consensus about MRI," Dr. Edge acknowledged.

Nevertheless, the new footnote spells out the role of MRI in breast cancer. MRI is now recommended for screening women at high risk, for evaluating the extent of disease (especially screening for second lesions), for defining response to adjuvant therapy, and for evaluating breasts with an axillary node with adenocarcinoma and a normal mammogram.

"Lesions identified by MRI must be biopsied because of the high rate of false positives," Dr. Edge emphasized, noting that about 75% to 80% of the lesions identified on MRI are benign. He also noted that in 1 study of women with breast cancer undergoing an MRI in case of a second lesion, the MRI caught more false positives (24%) than second tumors (10%).

MRI may also lead to increased use of mastectomy, Dr. Edge said. However, there is no evidence that these MRI-related mastectomies have any impact on local recurrence or survival in women, he emphasized.

Adjuvant Therapy and Breast Reconstruction

In its section on adjuvant chemotherapy, the NCCN's breast cancer guidelines now rank the therapies. "It's not just pick-as-you-choose anymore," said Dr. Edge.

For women who are not treated with trastuzumab (Herceptin, Genentech) regimens, the preferred regimens are:

• TAC (docetaxel [Taxotere] plus doxorubicin [Adriamycin] plus cyclophosphamide);
• dose-dense AC (doxorubicin plus cyclophosphamide) followed by paclitaxel every 2 weeks;
• TC (docetaxel plus cyclophosphamide);
• AC (doxorubicin plus cyclophosphamide).

For women who are treated with trastuzumab, the preferred adjuvant regimens are:

• AC (doxorubicin plus cyclophosphamide) followed by T (docetaxel) plus concurrent trastuzumab;
• TCH (docetaxel, carboplatin, trastuzumab).

The new guidelines also now have a section on the principles of breast reconstruction following surgery. In general, these guidelines apply only to surgeons who have experience with both plastic surgery and breast cancer surgery, said Dr. McCormick. They note that reconstructive surgery can be completed either at the time of mastectomy or subsequently.

NO BENEFIT OF ADDING A THIRD DRUG

Additional Chemo Agent No Benefit in Advanced-Stage Ovarian Cancer

NEW YORK (Reuters Health) Mar 13 - The addition of a third cytotoxic agent to a standard treatment regimen of paclitaxel and carboplatin does nothing to improve overall or progression-free survival in women with advanced epithelial ovarian carcinoma, according to a multinational phase III trial published ahead of print on February 17 by the Journal of Clinical Oncology.

"The possible addition of a third cytotoxic drug to a core regimen of carboplatin and paclitaxel was an objective shared by multiple international phase III trials over the last 10 years," Dr. Michael A. Bookman of the Fox Chase Cancer Center, Philadelphia, told Reuters Health. "Although the hypothesis was based on good preclinical data ... none of the phase III trials have shown an advantage for adding a third drug."

"However," he added, "all of these drugs continue to have a potential role in the management of recurrent disease, either alone, or in combination with carboplatin, depending on the timeframe of recurrence."

The current study enrolled 4312 women over a period of 3.5 years. Participants had a confirmed histologic diagnosis of epithelial ovarian carcinoma or primary peritoneal carcinoma, stage III or IV, and had either optimal or suboptimal residual disease following cytoreductive (debulking) surgery.

The subjects were randomized to a reference arm, which received paclitaxel and carboplatin only, or one of four experimental arms in which a third agent was added to standard therapy. There were two gemcitabine arms, a topotecan arm and a liposomal doxorubicin arm. Nearly 80% of the women completed 8 cycles of the assigned therapy.

A prespecified interim analysis was triggered by a combination of total progressions and deaths among the participants. The researchers found no statistically significant difference in either progression-free or overall survival associated with any of the four experimental regimens, versus 8 cycles of carboplatin and paclitaxel.

While noting the efficiency of the multiarm trial design, the researchers conclude: "The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes of women with advanced epithelial ovarian carcinoma."

PROSTATE SCREENING AND SURVIVAL

EUA 2009: European Data Provide Proof of Prostate Cancer Screening Benefit, Say Experts

March 19, 2009 — The new data from the European study that showed a reduction in mortality from prostate cancer in men who were screened for the disease provide proof of the benefits of screening, said the lead investigator.

Clinicians can now tell their patients there is proof that screening for prostate cancer will decrease their probability of dying from the disease, Fritz Schröder, MD, from the Erasmus Medical Center, in Rotterdam, the Netherlands, told Medscape Oncology. Before this study, clinicians would have to admit to their patients that they did not know whether prostate cancer screening reduced the rate of death from prostate cancer, he said in an interview here at the European Association of Urology (EAU) 24th Annual Congress, where he presented the data.

The study, known as the European Randomized Trial of Screening for Prostate Cancer (ERSPC), found that prostate-specific antigen (PSA) screening was associated with a 20% reduction in the rate of death from prostate cancer. It showed an absolute reduction of approximately 7 prostate-cancer-related deaths per 10,000 men screened.

The results were published online March 18 in the New England Journal of Medicine, and have already been reported by Medscape Oncology. However, published at the same time was a large study from the United States that found no reduction in mortality from prostate cancer screening. An accompanying editorial noted that prostate cancer screening remains a controversial issue because it is so difficult to weigh the benefits against potential harms, which include overtreatment.

It is well known that, for some patients, a diagnosis of prostate cancer can lead to unnecessary treatment, which can be associated with major adverse effects, Dr. Schröder explained. Some cases of prostate cancer are very slow growing and may not warrant treatment, but instead can be followed with active surveillance or "watchful waiting."

"For this reason, overtreatment resulting from overdiagnosis is unwarranted and represents a major clinical problem," he said. "Now, the patient can be told that if he considers screening, then he would have a chance of decreasing the probability of his dying of prostate cancer by about 25%. That is a major change in the present clinical situation."

Dr. Schröder agreed that the controversy over unnecessary treatment remains very much open. However, he pointed out that researchers are getting closer to developing a reliable way to distinguish indolent from aggressive cancers. "We would really like to have a test, like the PSA test, that allows us to selectively identify those aggressive cancers, but we don't just now. What we do have, however, are nomograms that use a number of different indicators and allow us to decrease the number of biopsies, specifically in the low PSA ranges, where most of these potentially harmless cancers are found."

According to Schröder, the use of a nomogram can identify almost one third of the cases of indolent cancers. "This is also listed in our paper. If you apply that prostate-risk indicator, you identify 30% of men who can be advised not to be treated but to be managed by active surveillance. This is what we recommend at this time to decrease that enormous amount of overdiagnosis. Such nomograms can be found on the European Association of Urology's Web site."

Screening Shows Benefit for First Time

Approached for an independent comment, Freddie C. Hamdy, MD, from the Oxford Radcliffe Hospital, in the United Kingdom, agreed that for the first time, screening asymptomatic 55- to 69-year-old men appears to show benefit. But, he insisted, that benefit comes at a price.

"To prevent some men from dying of prostate cancer, you are diagnosing many, many men and, by doing so, and this is something that many people do not realize — you are giving them the label of a cancer patient. These are healthy men, they are leading good lives, they are happy, and suddenly they become a cancer patient. The effect of that is underestimated," he told Medscape Oncology in an interview during the EAU meeting.

A further analysis of the ERSPC study will delve into quality-of-life issues, and the results should be very interesting, Dr. Hamdy said.

Most men, when faced with a diagnosis of prostate cancer, want treatment, that is their gut reaction, Dr. Hamdy said. But, he pointed out, "only a small proportion of men with screen-detected prostate cancer are going to die from prostate cancer. It takes a lot of explanation to convince a patient that, yes, he has cancer, but that he doesn't need treatment, he needs to be followed up. Compounding that difficulty is the fact that we don't have reliable methods for following these men that will tell us they are safe or if they now need treatment."

Both Dr. Schröder and Dr. Hamdy agree that developing a reliable fail-safe method to let clinicians know just when to initiate treatment is key. "This is probably the most urgent area of research we need to focus on," said Dr. Hamdy.

Right now, physicians and their prostate cancer patients remain on the horns of a dilemma. And, said Dr. Hamdy, studies such as the ERSPC are not taking that dilemma away. "It is continuing. I don't think that governments are going to jump on the evidence and say, fantastic, we are now going to screen for prostate cancer. I don't think they will do that. I hope that they are not going to do that, because the cost of that, to society and to men, is going to be very considerable."

In the United Kingdom, the new results have led to a prostate cancer charity calling for nationwide screening, which at present is not offered as a standard (unlike mammograms for breast cancer screening). In the United Kingdom, men older than 45 years can ask their family doctor for a PSA test, but only an estimated 6% of men do so. Health minister Ann Keen said that she will ask the UK National Screening Committee to review the new evidence and make recommendations, says a news report on the National Health Service website.

A NEW FRONTIER FOR SURGEONS

First Pediatric Case of Multi-Abdominal Organ Removal, Autotransplantation

March 12, 2009 — Locally invasive and inflammatory tumors are often considered unresectable, but according to the first pediatric case report, en bloc multiple organ removal, ex vivo resection, and autotransplantation could provide a novel treatment strategy for patients who are deemed inoperable. An advantage of the technique is that it obviates the need to wait for a donor and also eliminates the need for postoperative immunosuppressants.

Tomoaki Kato, MD, from NewYork-Presbyterian Morgan Stanley Children's Hospital, New York City, led a team of 7 surgeons on the first pediatric case. Dr. Kato previously performed the surgery on an adult woman with a surgical team led by Andreas G. Tzakis, MD, at the University of Miami in Florida.

The surgery, performed on a 7-year-old girl with inflammatory myofibroblastic tumor, involved the removal of 6 major organs (the liver, pancreas, stomach, spleen, and small and large intestines), ex vivo resection, autotransplantation of salvageable organs, and reconstruction of the vasculature. Surgery lasted 23 hours. The team was able to successfully resect the liver and small and large intestines, but it was unable to salvage the pancreas, stomach, and spleen. New vascular conduits were established with jugular vein and Goretex.

Moving Beyond Conventional Boundaries

"What we have done is move beyond the conventional boundaries of surgery, opening up a new way of thinking about organ surgery," Dr. Kato told Medscape General Surgery. "Other than that, we have to do more cases." The best treatment candidates are patients with slow-growing, locally invasive tumors that are unlikely to metastasize distantly, he explained.

The tumor's location and strangulation of the blood vessels going through and around the organs made it unsuitable for conventional surgical techniques. Dr. Kato described the challenges this way: "The tumor occupied much of the abdomen, and it encased the blood vessels. It was touching the liver, pushing down on the abdominal aorta, and...encased the celiac artery and superior mesenteric artery. The splenic vein and portal artery were occluded."

A month has elapsed since the surgery, and the girl is doing well. She has a temporary iliostomy that will be closed in 3 months. Yet there are hurdles ahead. The girl has brittle diabetes, and lacking a spleen, she is at increased risk for infection.

Douglas Farmer, MD, director of the intestinal transplant program at the University of California at Los Angeles Medical Center, commented to Medscape General Surgery: "The advantages are real. You are giving someone back their own organs and you don't have to maintain them on immunosuppressants."

Although the surgery is not an entirely new concept, Dr. Farmer added, "What he has done is take it a step further, dissecting away the organs and sewing back the vasculature."

Patient Selection Is Complex

Even though experts agree on general patient selection criteria — tumors that are locally invasive, nonaggressive, and unlikely to metastasize — selecting the ideal patient is no simple matter.

"What you base your decision on are the various scans you review. If you think that there is enough intestine and liver that can be preserved and the vasculature can be reconstructed, then it can be successful," Charles Miller, MD, director of liver transplantation at the Cleveland Clinic in Ohio, told Medscape General Surgery. "Knowing that ahead of time is a set of judgments that can be very tricky."

Dr. Miller stressed that this is a very innovative surgery applicable to a very small group of patients. In addition, "the surgery is so innovative, unusual, and so complex" that he advised considering it only at a strong liver and intestine transplant center.

Dr. Farmer laid out other important criteria: "The patient must be in good shape, have good pulmonary function, and be able to sustain hours of dissecting." He stressed that young patients will tolerate the surgery best, and that it would be most suitable for desmoid and gastrointestinal stromal tumors not likely to metastasize and unsuitable for aggressive pancreatic and colon cancers.

Careful preoperative planning is crucial, he explained. "You need to study and make sure that you can salvage the most vital organs, for example, the liver. There is no dialysis for the liver." (In this case, the girl's father was available as a donor if needed.) Also, he explained, "If you can't salvage the intestines, the patient will be on total parenteral nutrition."

Ultimately, it will come down to how well the patient survives the procedure and whether the patient is able to avoid immunosuppression, Dr. Farmer said. Also, he cautioned that the recurrence rate is not well known and that because the surgeries were performed fairly recently, patients have not yet been followed for a long time.

TEMOZOLOMIDE AND SURVIVAL IN GLIOBLASTOMA

Long-Term Results Confirm Survival Advantage of Adding Temozolomide to Radiation in Glioblastoma

March 12, 2009 — The final results from a phase 3 study, with a median follow-up of more than 5 years, have confirmed the survival advantage of adding temozolomide (Temodar, Schering-Plough) to radiotherapy in adult patients with newly diagnosed glioblastoma.

"A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients 60 to 70 years," according to a report published online March 9 in the Lancet Oncology.

In addition, the long-term results confirm earlier findings that patients with a tumor containing a methylated promoter for the gene encoding 0-6-methylguanine-DNA methyltransferase were more likely to benefit from the addition of temozolomide. This has also been seen with temozolomide in other brain tumors, such as gliomatosis cerebri, as reported recently by Medscape Oncology.

"We have identified the first marker in brain tumors that allows selection of patients who will benefit most from treatment with temozolomide and radiotherapy," say the researchers, headed by Roger Stupp, MD, from the University of Lausanne, in Switzerland.

Survival Improved, But Did Not Plateau

When results from this trial were first reported in 2004, with a median follow-up of just over 2 years, they were described as "the most markedly positive" results in patients with glioblastoma in 20 years, and were predicted to change clinical practice (Nat Clin Pract Oncol. 2005;2:334-335).

Until that time, postoperative radiotherapy had been the standard treatment for glioblastoma. Since then, combined treatment with radiotherapy and temozolomide, given both concomitantly and after the radiotherapy, has become the standard.

The new results show that survival advantage was maintained over the long term. Overall survival was significantly improved at 2, 3, 4, and 5 years in patients who were treated with temozolomide plus radiotherapy, compared with those treated with radiotherapy alone.

Overall Survival With Combined Therapy (Temozolomide Plus Radiotherapy) or With Radiotherapy Alone

Overall Survival	Combined Therapy	Radiotherapy Alone
2 years, %	27.2	10.9
3 years, %	16.0	4.4
4 years, %	12.1	3.0
5 years, %	9.8	1.9

Despite this improvement, however, most of the patients died during the 5-year follow up — 254 of 287 patients (89%) in the combined-therapy group and 278 of 286 patients (97%) in the radiotherapy-alone group.

"Survival does not plateau, and combined treatment is unlikely to be curative for many patients," the researchers write.

They add that an analysis of recurrence showed no difference between initial radiotherapy alone and the combined treatment, which supports the hypothesis that combined therapy might effectively reduce tumor bulk and aggressiveness, but does not modify the disease course.

"Many patients with glioblastoma survive for several years," they add. "However, true long-term survival and cure are not possible."

Further research is needed and ongoing trials are investigating the addition of other treatments to the combination of temozolomide plus radiotherapy, the researchers note. These include studies with the angiogenesis inhibitor bevacizumab, inhibitors of integrins, such as cilengitide, and inhibitors of epidermal growth-factor receptor, such as erlotinib.

"Until better treatments are available, radiotherapy with concomitant and adjuvant chemotherapy is the current standard of care," Dr. Stupp and colleagues conclude

A NEW STANDARD OF CARE FOR SMALL RENAL TUMORS?

SIR 2009: Percutaneous Cryoablation May Be New Standard of Care for Small Renal Tumors

March 11, 2009 (San Diego, California) — Interventional cryoablation is an effective treatment for small renal tumors, and should be the gold standard or first treatment option for all patients with lesions that are 4 cm in size or smaller, researchers say.

It might also be a viable option for larger tumors, up to about 7 cm in size, for patients who wish to avoid or cannot have surgery, according to a study presented here at the Society of Interventional Radiology (SIR) 34th Annual Scientific Meeting.

"These new types of procedures are game changers, and they change the way we think," said Brian Stainken, MD, president-elect of SIR, who was not involved in the study. "But it is important to know that we have good data before we offer game-changing solutions."

Based on a preponderance of data, this technique is ready to be used in general clinical practice, he told Medscape Oncology in an interview. "More than three quarters of individuals with kidney cancer have tumors that are 4 cm or less in size," he said. "For patients with small tumors, this procedure can take the place of removing the entire kidney. It can replace having to undergo significant surgery, and might even be possible to conduct on an outpatient basis."

In this study, Christos Georgiades, MD, PhD, from the Division of Vascular & Interventional Radiology at Johns Hopkins Hospital, in Baltimore, Maryland, presented efficacy data from 90 cryoablation procedures that were performed on 84 patients with renal tumors ranging in size from 1 to 10 cm. The procedures were conducted at Johns Hopkins Hospital from April 2006 through December 2008, and patients were followed every 3 months during the first year, and annually thereafter.

Usage Varies Among Facilities

At last year's SIR meeting, Dr. Georgiades presented preliminary data from the study, which was reported by Medscape Oncology. At that time, Dr. Georgiades said that he initially performed cryoablation on patients who could not undergo surgery because of comorbidities, but now offers the procedure as an alternative to patients who can undergo surgery.

Stephen Solomon, MD, a cryoablation specialist from Memorial Sloan-Kettering Cancer Center, in New York City, spoke with Medscape Oncology last year. Cryoablation was "still relatively far from becoming the standard of care," he said, and "many surgeons still prefer to cut out the tumor."

Dr. Solomon, who was not involved in the study, also told Medscape Oncology that the proportion of kidney tumors treated with cryoablation varies among institutions; some do not use it at all, whereas others treat 15% of tumors smaller than 4 cm with this method. The technology is widely available, with 2 companies involved (Endocare and Galil), and the market is growing, he said.

At this year's presentation, Dr. Georgiades reported that interventional cryoablation has now become the first-line treatment for small tumors at Hopkins.

Small Tumors Had 100% Response

Dr. Georgiades noted that they didn't initially set a threshold of 4 cm or less as the optimal size for the procedure. "We have treated patients with tumors up to 10 cm — admittedly, these are patients who could not have surgery for whatever reason," he said during a press briefing. "But we found that patients with tumors that were 4 cm or smaller were the ones with a 100% response, so that's why our recommendation stops at 4 cm."

"We have had equally good results with lesions up to 7 cm, but we've only treated between 5 and 10 patients with lesions that size, so I cannot make a generalized conclusion for larger tumors," he added.

Within this cohort, 88 tumors were treated completely, without any evidence of cancer remaining. Two patients had a small amount of residual disease (~1 cm), and 1 patient was retreated with a complete response. The other patient refused further treatment.

Follow-up data are available in a subgroup of patients for 2.5 years, explained Dr. Georgiades. "Efficacy is still 100% and none have shown any local tumor recurrence or metastatic disease," he said.

There are major advantages to percutaneous cryoablation, compared with other procedures. "There is no surgery, no incision, and no general anesthesia," Dr. Georgiades explained. "There is some pain when the tumor begins to thaw, and some inflammation, but we can easily address that."

Most patients go home the same day or the following morning, he added. Compared with surgery, there are also fewer complications and lower cost. "In the unlikely case that cryoablation fails, the patient can still undergo surgery," he said.

Strong Safety Profile Reported

In a related safety study, Dr. Georgiades evaluated the results of 81 computed tomography (CT)-guided percutaneous cryoablations conducted in 73 patients who either couldn't undergo surgery or who elected to undergo the interventional radiology treatment. Patients were followed in the clinic at 3, 6, and 12 months, and annually thereafter.

The lesions ranged in size from 1 to 10 cm, and 13 (16%) were benign. All peri-procedural and long-term complications were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE).

Overall, the researchers found that CT-guided percutaneous cryoablation had an "excellent safety profile." They observed a total of 6 (7.4%) CTCAE category >1 complications, including cryoshock, bleeding, pleural effusion, pneumothorax, and fistula. In addition, 22 (27%) self-limiting CTCAE category 1 events were noted; there were no procedure-related deaths.

"There is always going to be a role for more aggressive and conventional therapies," said Dr. Stainken. "What we need to do now is sort out when minimal is best and when conventional is best. But all of these choices need to be available to patients."

RITUXIMAB MAINTENANCE

Rituximab Maintenance Improves Progression-Free Survival in Indolent Lymphoma

March 19, 2009 — In patients with advanced indolent non-Hodgkin's lymphoma, maintenance rituximab after chemotherapy significantly prolongs progression-free survival to a far greater extent than has been achieved by any previous strategy, and with minimum toxicity. These conclusions come from the E1496 study, conducted in the United States by the Eastern Cooperative Oncology Group and funded by the National Cancer Institute, and published online March 2 in the Journal of Clinical Oncology.

These results add to a "substantial body of evidence that the combination of rituximab with chemotherapy is a new standard for patients with indolent lymphoma who require treatment," say the authors.

These are the first data from a phase 3 trial for maintenance rituximab in this setting, they note, and they have already resulted in a US Food and Drug Administration–approved indication for the use of rituximab (Rituxan, Genentech; MabThera, Roche) as maintenance therapy in patients with indolent lymphoma.

Free of Disease for 3 Times Longer

The study followed 311 patients with advanced-stage indolent lymphoma (of whom 282 had follicular lymphoma) for a median of more than 4 years. Patients were initially treated with the chemotherapy combination of cyclophosphamide, vincristine, and prednisone, and were then randomly assigned to observation or maintenance therapy with rituximab 375 mg/m² once weekly for 4 weeks every 6 months for 2 years.

Compared with patients who were observed after chemotherapy, the group treated with maintenance rituximab had a median progression-free survival that was more than 3 times longer (4.3 vs 1.3 years), and a 60% reduction in progression risk.

However, the effect on overall survival was of borderline statistical significance (92% with maintenance vs 86% with observation rituximab at 3 years; P = .05).

Patients with low-grade lymphoma can live for many years, said lead author Howard Hochster, MD, professor of medicine at the New York University School of Medicine, in New York City.

"No 1 treatment to date has been able to show benefit on long-term survival," he said in a statement. "This reasonably nontoxic antibody can improve disease-free survival by several years, and can possibly effect overall survival. In this group of patients, even 10 years of observation is a little too soon to show survival benefits, but the trend is present," he added.

However, in extrapolating these results to clinical practice, several points should be borne in mind, say the researchers.

"First, indolent lymphoma has a variable clinical course and patients with favorable status were underrepresented in our study," they write. "Although such patients had longer [progression-free survival] with maintenance rituximab, the overall survival in the observation arm was 99% at 2 years, a figure that will be difficult to improve on." They add that "watchful waiting" remains an option for asymptomatic patients with favorable status.

Second, this trial — which began in 1997 — used chemotherapy without rituximab for the initial treatment; since then, practice has changed and chemotherapy with rituximab is commonly used for induction. Hence, this trial cannot answer questions about the benefit of rituximab maintenance in patients who were initially treated with chemotherapy plus rituximab, the researchers comment.

This issue is being addressed in an ongoing study, they add. The international European Primary Rituximab and Maintenance (PRIMA) study has recently finished accrual, and the first interim analysis is due out in 2009, according to an accompanying editorial.

Results Similar to Those From European Study

Editorialist Anton Hagenbeek, MD, from the University of Amsterdam, the Netherlands, writes that the improvement in progression-free survival seen in this American trial is very similar to that seen in a European phase 3 trial (Blood. 2006;108:3295-3301), even though the rituximab maintenance regimens were different. The American study used 16 infusions of rituximab, whereas the European study used only 8 infusions.

The European study was also conducted in a slightly different patient population (465 relapsed/refractory follicular non-Hodgkin's lymphoma patients) and a different induction chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], with or without rituximab). Nevertheless, the improvement in progression-free survival of 36.6 months was "strikingly similar" to the 36 months seen in the American study, says Dr. Hagenbeek.

One could hypothesize that, in the European study, the same result was achieved with much less rituximab because the initial induction therapy (CHOP) resulted in a more efficient lymphoma cell kill, he comments. "From this it may be deduced that the more effective the reduction in tumor load is before rituximab therapy is initiated, the more effective rituximab maintenance will be," Dr. Hagenbeek writes. "This strategy would be in concert with the idea that immunotherapy is most effective in patients with a small tumor load."

Another explanation may lie in the timing of the rituximab infusions, which were administered every 3 months in the European trial but every 6 months in the American trial. These longer intervals might have left the American patients without therapeutic levels of rituximab for a couple of months or so, which might have allowed lymphoma cells to regrow, the editorialist speculates.

"The optimal rituximab maintenance regimen remains to be established," Dr. Hagenbeek states. In addition, how long maintenance should be continued is still unclear — most trials to date have used 2 years, but an ongoing Swiss trial is investigating the safety and efficacy of 5 years of maintenance therapy.

Could Be Some Time Before a True Plateau Is Seen

So far, rituximab maintenance treatment of indolent lymphoma has certainly been shown to maintain remissions, Dr. Hagenbeek notes. However, viable lymphoma cells in residual disease remain, and it is unlikely that rituximab maintenance will eradicate this minimal residual lymphoma, even if it is applied for prolonged periods of time, mainly because some lymphoma cells will become refractory to rituximab.

Thus, it might be necessary to combine rituximab maintenance therapy with other treatment modalities, he says. One example may be the radio-immunotherapeutic ⁹⁰yttrium ibritumomab tiuxetan (Zevalin, Bayer Schering Pharma). The results from a large phase 3 study (J Clin Oncol. 2008;26:5156-5164) suggest this is the "the most effective single drug with a favorable toxicity profile in the treatment of follicular non-Hodgkin's lymphoma," Dr. Hagenbeek says.

"Combining these most active ingredients may finally lead to a true plateau in the overall survival curve of patients with advanced-stage indolent lymphoma," he writes. "However, one should realize that it might take quite some years before this can ultimately be proven."

BRIASOULIS TYPE OF DESIGN

Ann Oncol. 2009 Mar 10. [Epub ahead of print]

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Tan EH, Rolski J, Grodzki T, Schneider CP, Gatzemeier U, Zatloukal P, Aitini E, Carteni G, Riska H, Tsai YH, Abratt R.

Department of Medical Oncology, National Cancer Centre, Singapore, Malaysia.

BACKGROUND: The study compared the efficacy of a first-line treatment with day 1 i.v. vinorelbine (NVBiv) and day 8 oral vinorelbine (NVBo) versus docetaxel (DCT) in a cisplatin-based combination in advanced non-small-cell lung cancer, in terms of time to treatment failure (TTF), overall response, progression-free survival (PFS), overall survival (OS), tolerance and quality of life (QoL). METHODS: Patients were randomly assigned to receive cisplatin 80 mg/m(2) with NVBiv 30 mg/m(2) on day 1 and NVBo 80 mg/m(2) on day 8 every 3 weeks, after a first cycle of NVBiv 25 mg/m(2) on day 1 and NVBo 60 mg/m(2) on day 8 (arm A) or cisplatin 75 mg/m(2) and DCT 75 mg/m(2) on day 1 every 3 weeks (arm B), for a maximum of six cycles in both arms. RESULTS: From 2 February 2004 to 1 January 2006, 390 patients were entered in a randomised study and 381 were treated. The patient characteristics are as follows (arms A/B): metastatic (%) 80.5/84.8; patients with three or more organs involved (%) 45.3/40.8; median age 59.4/62.1 years; male 139/146; squamous (%) 34.2/33.5; adenocarcinoma (%) 41.6/39.3; median TTF (arms A/B in months) [95% confidence interval (CI)]: 3.2 (3.0-4.2), 4.1 (3.4-4.5) (P = 0.19); overall response (arms A/B) (95% CI): 27.4% (21.2% to 34.2%), 27.2% (21.0% to 34.2%); median PFS (arms A/B in months) (95% CI): 4.9 (4.4-5.9), 5.1 (4.3-6.1) (P = 0.99) and median OS (arms A/B in months) (95% CI): 9.9 (8.4-11.6), 9.8 (8.8-11.5) (P = 0.58). The median survival for squamous histology was 8.87/9.82 months and for adenocarcinoma 11.73/11.60 months for arms A and B, respectively. Main haematological toxicity was grade 3-4 neutropenia: 24.4% (arm A) and 28.8% (arm B). QoL as measured by the Lung Cancer Symptom Scale was similar in both arms. CONCLUSIONS: Both arms provided similar efficacy in terms of response, time-related parameters and QoL, with an acceptable tolerance profile. In the current Global Lung Oncology Branch trial 3, NVBo was shown to be effective as a substitute for the i.v. formulation. This can relieve the burden of the i.v. injection on day 8 and can optimise the hospital's resources and improve patient convenience.

CETUXIMAB AND HEMODIALYSIS

Head Neck. 2009 Mar 12. [Epub ahead of print]

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Cetuximab in hemodialysis: A case report.

Aldoss IT, Plumb T, Zhen WK, Lydiatt DD, Ganti AK.

Department of Internal Medicine, Creighton University Medical Center, Omaha, Nebraska.

BACKGROUND.: Concurrent chemoradiotherapy with cisplatin is the standard therapy for patients with unresectable locally advanced head and neck squamous cell carcinoma. However, cisplatin administration in patients on hemodialysis is complicated by the need to perform hemodialysis immediately after the infusion. Concurrent chemoradiation with cetuximab has been approved in definitive treatment of locally advanced head and neck cancer. Although cetuximab is not excreted via the kidneys, its use in patients on hemodialysis has not been reported. METHODS AND RESULTS.: We present the case of a 65-year-old man undergoing hemodialysis, with stage IVA squamous cell carcinoma of the hypopharynx. Given the logistics of performing hemodialysis immediately postcisplatin, he received concurrent chemoradiotherapy with cetuximab. He tolerated treatment well with minor side effects. CONCLUSION.: Cetuximab can be safely used in patients with renal impairment. This is the first reported case of the use of cetuximab in a patient undergoing hemodialysis. (c) 2009 Wiley Periodicals, Inc. Head Neck, 2009.

GEFITINIB AND HEAD AND NECK CANCER

Cancer. 2009 Mar 13. [Epub ahead of print]

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Neoadjuvant chemotherapy/gefitinib followed by concurrent chemotherapy/radiation therapy/gefitinib for patients with locally advanced squamous carcinoma of the head and neck.

Hainsworth JD, Spigel DR, Burris HA 3rd, Markus TM, Shipley D, Kuzur M, Lunin S, Greco FA.

Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee.

BACKGROUND:: The authors evaluated the feasibility, toxicity, and efficacy of gefitinib added to first-line combined-modality therapy for patients with locally advanced squamous carcinoma of the head and neck. METHODS:: Patients with biopsy-proven locally advanced squamous carcinoma of the head and neck who had low expected cure rates with local treatment modalities alone were eligible for this treatment. All patients received a 6-week induction course of docetaxel, carboplatin, infusional 5-fluorouracil, and gefitinib (250 mg daily). Gefitinib was continued while patients received concurrent weekly docetaxel and radiation therapy. After the completion of radiation therapy, gefitinib was continued until patients developed disease progression or for a maximum of 24 months. RESULTS:: Sixty-two patients (53% with stage IV disease) received protocol treatment, and 50 patients (81%) were able to complete the regimen. The addition of gefitinib increased the incidence of grade 3/4 mucositis (27%) and diarrhea (16%) during induction therapy but did not appear to add substantially to toxicity during concurrent chemoradiation. The estimated 3-year progression-free and overall survival rates for the entire group were 41% and 54%, respectively. CONCLUSIONS:: The addition of gefitinib was associated with a moderate increase in toxicity with this combined modality regimen, particularly during induction therapy. Although this regimen was efficacious, the survival results overlap with results reported with chemoradiation alone. The role of epidermal growth factor receptor inhibitors in first-line, combined-modality therapy for patients with head and neck cancer remains undefined. Cancer 2009. (c) 2009 American Cancer Society.