TOP ESMO NEWS-PART II

1. Promising results suggest that the combination of bendamustine and rituximab could become the new standard, first-line treatment option for patients with advanced follicular, indolent, and mantle-cell lymphoma To further investigate the role of bendamustine and rituximab combination therapy, researchers from the German Study Group Indolent Lymphoma (StiL) initiated a multicenter, randomized, phase III study to compare the efficacy and safety of bendamustine plus rituximab versus CHOP plus rituximab as a potential first-line therapy for patients with follicular, indolent, and mantle-cell lymphoma. Study results revealed that bendamustine and rituximab combination therapy significantly improved progression-free survival and complete remission rates, while showing less toxicity than the current standard treatment. The results were presented at the 51st Annual Meeting of the American Society of Hematology (5–8 December 2009, New Orleans, USA) by lead author Dr Mathias J Rummel from the Department for Hematology at the University Hospital in Giessen, Germany. Read more…

2. Some patients with advanced thyroid cancer may benefit from sorafenib Dr Karen Heemstra of Leiden University, The Netherlands, reported at the Endocrine Society meeting (Washington, USA, 10–13 June 2009) that two-thirds of patients with advanced thyroid cancer benefited from treatment with the tyrosine kinase inhibitor sorafenib. This phase II clinical trial involved 31 patients with differentiated thyroid cancer who could not be treated with surgery or radioiodine ablation. Response to treatment was not related to histology. When grouped according to presence of bone metastases, patients in whom the cancer had not spread were significantly more likely to have objective responses or stable disease. Read more…

3. Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia In a phase III, open-label study, Dr Tony Mok of the Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, HKSAR, China, and colleagues from different East Asian sites, randomly assigned previously untreated patients with advanced pulmonary adenocarcinoma – either nonsmokers or former light smokers – to receive gefitinib or carboplatin plus paclitaxel. The researchers found that the presence in the tumor of a mutation of the epidermal growth factor receptor (EGFR) gene is a strong predictor of better outcome with gefitinib. Results were published in the 3 September 2009 edition of The New England Journal of Medicine. The resutls were presented first at the ESMO 2008 Congress in Stockholm, Sweden. Read more…

4. No survival benefit for early treatment of relapsed ovarian cancer based on CA125 levels only Findings from a multinational phase III trial – carried out by the Medical Research Council (MRC) and the European Organization for Research and Treatment of Cancer (EORTC) – indicate that early treatment of recurrent ovarian cancer based on rising CA125 biomarker levels does not improve overall survival compared with delaying treatment until symptoms emerge. Dr Gordon Rustin of the Mount Vernon Cancer Centre in Middlesex, UK, presented these results at the plenary session of the ASCO Annual Meeting (Orlando, USA, 29 May – 2 June 2009). They represent practice-changing data: CA125 levels should be assayed less frequently, with rapid access to CA125 measurement in patients who become symptomatic. Read more…

5. Clinical activity observed in a phase I dose escalation trial of an oral cMET and ALK inhibitor Results presented first at the ASCO Annual Meeting in Orlando, USA, this year and during the Best of 2009 session at the ECCO 15 – ESMO 34 Congress in Berlin by Dr Eunice Kwak of the Massachusetts General Hospital Cancer Center, Boston, USA, suggest that translocations for decades have been the hallmark of hematologic malignancies and that this represents a new finding in solid tumors. EML4-ALK possesses potent oncogenic activity both in vitro and in vivo. Discussing results of this first-in-humans, phase I dose escalation study, Prof. José Baselga of the Vall d’Hebron Hospital, Barcelona, Spain, said that 2009 will be remembered for the development of PF 02341066, a selective, ATP-competitive, small-molecule oral inhibitor of the cMET/HGFR and ALK receptor tyrosine kinases. Read more…

6. Denosumab in men receiving androgen-deprivation therapy for prostate cancer Dr Matthew R Smith of the Massachusetts General Hospital Cancer Center, Boston, USA, led a Denosumab HALT Prostate Cancer Study Group to investigate the denosumab effects on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand. Investigators published the study results in the 20 August 2009 issue of The New England Journal of Medicine and found that denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures. Read more…

7. PARP-inhibitors hold promise for patients with metastatic triple-negative breast cancer and BRCA 1/2 deficient breast cancer Treatment with BSI-201, a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, in combination with gemcitabine/carboplatin, prolonged both progression-free and overall survival for patients with metastatic triple-negative breast cancer. Dr Joyce A O’Shaughnessy of the Baylor Sammons Cancer Center, Dallas, US, presented the results of a randomized, multicenter, phase II trial on behalf of the US Oncology investigators during the plenary session of the ASCO Annual Meeting (Orlando, USA, 31 May 2009). The promising safety and efficacy results have prompted the initiation of a phase III study. A second phase II study found that 40% of women with advanced BRCA-deficient breast cancer experienced tumor shrinkage after receiving the PARP-inhibitor olaparib. The results were presented at the same meeting by Dr Andrew Tutt of Kings College London, UK. Read more…

TOP ESMO NEWS-PART I

1. Efficacy results from the ToGA trial show the clinical benefits of adding trastuzumab to first-line standard chemotherapy in HER2-positive advanced gastric cancer The ToGA study is the first randomized, prospective, multicenter, phase III trial to study the efficacy and safety of trastuzumab in HER2-positive gastric cancer. Study results indicate that trastuzumab plus chemotherapy is superior to chemotherapy alone in HER2-positive patients. Prof. Eric Van Cutsem of the Digestive Oncology Unit, Leuven University, Belgium, presented these results during the ASCO Annual Meeting (29 May – 2 June 2009, Orlando, USA). They represent practice-changing data with indication for HER2 assessment and a benefit for trastuzumab treatment in HER2-positive gastric cancer patients. This is the first cancer localization beyond breast, where anti-HER2 therapy shows benefit. Read more…

2. Radiotherapy plus short-term androgen suppression provides inferior survival compared with radiotherapy plus long-term suppression in locally advanced prostate cancer Dr Michel Bolla of the Department of Radiation Oncology, Grenoble University Hospital, France, and colleagues from the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology Group and Genito-Urinary Tract Cancer Group registered 1113 men, of whom 970 were randomly assigned: 483 to short-term suppression and 487 to long-term suppression. The 5-year overall mortality for short-term and long-term androgen suppression was 19.0% and 15.2%, respectively. Adverse events in both groups included fatigue, diminished sexual function, and hot flushes. Read more…

3. Three important abstracts confirmed the need to perform KRAS testing before prescribing anti-epidermal growth factor receptor (EGFR) monoclonal antibodies to patients with colorectal cancer The randomized, phase III study of panitumumab with FOLFIRI versus FOLFIRI alone showed significantly improved progression-free survival in patients with KRAS wild-type metastatic colorectal cancer (mCRC) who received panitumumab with chemotherapy as second-line treatment. Dr Marc Peeters of the Digestive Oncology Unit, University Hospital Ghent, Belgium, presented the results at the Joint ECCO 15 – 34 ESMO Congress on 20–24 September 2009 in Berlin, Germany. The results of the randomized, phase III study of panitumumab with FOLFOX4 compared with FOLFOX4 alone as first-line treatment for mCRC (PRIME trial) were reported by Dr Jean-Yves Douillard of the Medical Oncology Branch at Centre Rene Gauducheau in Nantes, France. In patients with mutated KRAS, panitumumab proved detrimental. Intermittent versus continuous oxaliplatin-based combination chemotherapy with cetuximab was tested in a randomized non-inferiority trial (MRC COIN) in patients with advanced CRC. Balanced against fewer side effects, patient survival was shorter with intermittent chemotherapy. Results were presented by lead author Dr Tim Maughan of Cardiff University, UK. Read more…

4. Combination of reduced dosage for induction therapy followed by maintenance therapy may be a novel approach in untreated patients over the age of 65 with multiple myeloma Melphalan with prednisone has been the gold standard for treating elderly multiple myeloma patients for the past 40 years, but novel combination therapies have emerged as superior options. In a study presented at the Plenary Scientific Session of the 51st Annual Meeting of the American Society of Hematology (5–8 December 2009, New Orleans, USA), 260 patients with a median age of 75 were randomized to receive a modified induction schedule of six cycles of bortezomib, melphalan, and prednisone (VMP) or bortezomib, thalidomide, and prednisone (VTP) as induction therapy, followed by maintenance therapy with bortezomib and thalidomide (VT) or bortezomib and prednisone (VP) for up to 3 years. Study results were presented by lead author Dr Maria-Victoria Mateos of the Hematology Department, Hospital Universitario de Salamanca, Spain. Read more…

5. Sunitinib significantly improves progression-free survival for patients with progressive well-differentiated pancreatic islet cell tumors Dr Eric Gregory from the Medical Oncology Service, Inter Hospitalier de Cancerologie Bichat-Beaujon in Clichy, France, presented new encouraging data at the ESMO Conference: 11th World Gastrointestinal Cancer Congress (Barcelona, 24–27 June 2009). During a 20-month period, 154 patients with progressive, well differentiated, malignant pancreatic islet cell tumors were randomized to receive best supportive care and either placebo or sunitinib. Progression-free survival in the sunitinib treated groups was 11.1 months, compared with 5.5 months for placebo. Read more…

6. RIBBON-2 is the first positive phase III study of bevacizumab in second-line metastatic breast cancer Dr Sarah Hurvitz from the University of California, Los Angeles, USA, presented on 12 December 2009 at the San Antonio Breast Cancer Symposium results from the RIBBON-2 trial – a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer. For the primary efficacy analysis, progression-free survival was 7.2 months in the bevacizumab treatment arm, compared with 5.1 in the placebo arm. Overall response rate was 39.5% in the bevacizumab arm versus 29.6% in the placebo arm. Overall survival rates for the bevacizumab arm and the placebo arm (18.0 months and 16.4 months, respectively) were not significantly different, but these are still early data. Read more…

7. In 2009, the European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) approved next new agents or extended indications for existing agents. The Committee: Extended the indication for rituximab to the first-line treatment of patients with chronic lymphocytic leukemia in combination with chemotherapy. Read more… Extended the indication for imatinib to the adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117)-positive gastrointestinal stromal tumors (GIST). Read more… Granted a marketing authorization for gefitinib to treat adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR). Read more… Granted a marketing authorization for everolimus to the second line treatment of advanced renal cell carcinoma in patients whose disease has progressed despite treatment with vascular endothelial growth factor (VEGF)-targeted therapy. Read more… Extended the indication for pemetrexed as a monotherapy maintenance treatment for locally advanced or metastatic NSCLC in patients whose disease has not progressed immediately following platinum-based chemotherapy. Read more… Granted a marketing authorization for vinflunine to treat carcinoma of the urothelial tract. Read more… Extended the indication, adding a new treatment option, for bevacizumab in combination therapy with docetaxel in the first-line treatment of metastatic breast cancer. Read more… Extended the indication for temsirolimus to include the treatment of adult patients with relapsed and/or refractory mantle cell lymphoma. Read more… Recommended patupilone as an orphan medicinal product for treating primary peritoneal cancer and fallopian tube cancer. Read more… Adopted a positive opinion for adding a new treatment option for trabectedin in combination with pegylated liposomal doxorubicin for treating patients with relapsed platinum-sensitive ovarian cancer. Read more… Extended the indication for trastuzumab to include the treatment of patients with HER2-positive metastatic adenocarcinoma of the stomach or gastro esophageal junction who have not received prior anti-cancer treatment for their metastatic disease in combination with capecitabine or 5-fluorouracil and cisplatin. Read more… Adopted a positive opinion for catumaxomab for the intraperitoneal treatment of malignant ascites in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible. Read more…

IT HAPPENS EVERYWHERE-BREAST CANCER SURGEONS DO NOT CONSULT OTHER CANCER EXPERTS

January 7, 2009 — Although a multidisciplinary approach is considered to offer the best quality of care, a new survey has found that many breast cancer surgeons do not routinely consult with other experts, such as medical or radiation oncologists or plastic surgeons, when developing treatment plans. Many also do not make use of patient decision-support activities, such as videos, websites, and patient-support programs.

The survey is reported in the January issue of Medical Care.

"Despite the mantra for multidisciplinary decision-making and care intake for patients, surgeons in the community are reporting relatively little of that in their practices," said lead author Steven Katz, MD, MPH, professor of internal medicine at the University of Michigan Comprehensive Cancer Center in Ann Arbor.

"Either doctors are not convinced that these elements matter or there are logistical constraints in terms of building these standards into their practices," he added.

However, Dr. Katz pointed out that the implications for patients are not known. The results from the survey suggest that it is the surgeons with high volumes of breast cancer patients who are most likely to have a more integrated practice. "But we don't know whether that matters with regard to patient decision-making, quality of life and satisfaction," he said in a statement.

Surgeon Plays Primary Role

For a patient newly diagnosed with breast cancer, the surgeon plays a primary role in clinical decision-making and delivery of treatment, the authors note. Investigating how surgeons go about this "can provide key insight about how care is organized for patients with breast cancer," the researchers write.

The researchers surveyed 318 surgeons who treat breast cancer in the metropolitan areas of Detroit, Michigan and Los Angeles, California. The researchers also surveyed 2268 breast cancer patients, and found a good correlation between the 2 sets of responses.

When asked about multidisciplinary physician communication, only one quarter to one third of surgeons said they had discussed the treatment plan with medical and radiation oncologists prior to surgery for a majority of their patients treated in the previous 12 months. Only 13% had consulted with a plastic surgeon. But a substantial proportion of surgeons reported that they frequently had outside pathology or imaging studies reviewed by their colleagues (for two thirds or more of their patients).

About two thirds of surgeons reported that few or almost none of their patients participated in patient decision-support activities arranged by the practice, such as attending a practice-based presentation, viewing web-based materials, or participating in peer-support programs.

Surgeons who treated mostly breast cancer patients were more likely to consult with other experts and to use patient decision-support tools than those who saw fewer breast cancer patients. About half of the surgeons (46.1%) surveyed said that 15% or less of their total practice was devoted to breast cancer, whereas 16.2% of surgeons said that half or more of their practice was devoted to breast cancer.

It might be that the surgeons in the more specialized practices, who reported more collaborative communication and patient decision-support activities, are more willing or have more opportunity to invest in infrastructure such as same-day appointments and weekly tumor boards. Surgeons who devote only a small proportion of their total practice to breast cancer might not feel that a large investment in infrastructure targeting these patients is justified, the authors note. These surgeons might benefit from virtual approaches, such as computer-based or internet-based methods of between-physician communication, they suggest.

Being part of a teaching program increased the likelihood of multidisciplinary collaboration, and this was independent of the level of specialization of the surgeon. "Practices that participate in surgical teaching programs may be more motivated to initiate innovations in practice, or these features may evolve more naturally due to the structure of the teaching programs," the authors write.

These results should be interpreted cautiously with regard to patient care, the authors warn. "One important caveat is that we do not know yet whether patients who received treatment from more experienced surgeons using more patient and practice management processes actually received better quality of care," they point out.

The study was supported by the Commission on Cancer of the American College of Surgeons. The researchers have disclosed no relevant financial relationships.

Med Care. 2010;48:45-51. Abstract

AN INTERESTING REGIMEN FOR COLORECTAL LIVER METASTASES

J Clin Oncol. 2010 Jan 4. [Epub ahead of print]

Alternating Systemic and Hepatic Artery Infusion Therapy for Resected Liver Metastases From Colorectal Cancer: A North Central Cancer Treatment Group (NCCTG)/ National Surgical Adjuvant Breast and Bowel Project (NSABP) Phase II Intergroup Trial, N9945/CI-66.

Alberts SR, Roh MS, Mahoney MR, O'Connell MJ, Nagorney DM, Wagman L, Smyrk TC, Weiland TL, Lai LL, Schwarz RE, Molina R, Dentchev T, Bolton JS.

Mayo Clinic Rochester, Rochester, MN; National Surgical Adjuvant Breast and Bowel Project Allegheny General Hospital, Pittsburgh, PA; National Surgical Adjuvant Breast and Bowel Project St Joseph Hospital, Orange; National Surgical Adjuvant Breast and Bowel Project City of Hope National Medical Center, Duarte, CA; Altru Health Systems, Grand Forks, ND; National Surgical Adjuvant Breast and Bowel Project Cancer Institute of New Jersey, New Brunswick, NJ; Iowa Oncology Research Association Community Clinical Oncology Program (CCOP), Des Moines, IA; and Ochsner CCOP, New Orleans, LA.

PURPOSE: Prior trials have shown that surgery followed by hepatic artery infusion (HAI) of floxuridine (FUDR) alternating with systemic fluorouracil improves survival rates. Oxaliplatin combined with capecitabine has demonstrated activity in advanced colorectal cancer. Based on this observation a trial was conducted to assess the potential benefit of systemic oxaliplatin and capecitabine alternating with HAI of FUDR. The primary end point was 2-year survival. PATIENTS AND METHODS: Patients with liver-only metastases from colorectal cancer amenable to resection or cryoablation were eligible. HAI and systemic therapy was initiated after metastasectomy. Alternating courses of HAI consisted of 0.2 mg/m(2)/d FUDR and dexamethasone, day 1 through 14 weeks 1 and 2. Systemic therapy included oxaliplatin 130 mg/m(2) day 1 with capecitabine at 1,000 mg/m(2) twice daily, days 1 through 14, weeks 4 and 5. Two additional 3-week courses of systemic therapy were given. Capecitabine was reduced to 850 mg/m(2) twice daily after interim review of toxicity. RESULTS: Fifty-five of 76 eligible patients were able to initiate protocol-directed therapy and completed median of six cycles (range, one to six). Three postoperative or treatment-related deaths were reported. Overall, 88% of evaluable patients were alive at 2 years. With a median follow-up of 4.8 years, a total of 30 patients have had disease recurrence, 11 involving the liver. Median disease-free survival was 32.7 months. CONCLUSION: Alternating HAI of FUDR and systemic capecitabine and oxaliplatin met the prespecified end point of higher than 85% survival at 2 years and was clinically tolerable. However, the merits of this approach need to be established with a phase III trial.

PEDIATRIC CANCER SURVIVORS AND CARDIOVASCULAR RISK

January 7, 2010 — Exposure to total-body irradiation or abdominal plus chest radiation and a sedentary lifestyle among survivors of childhood cancer are associated with the development of risk factors that can predispose them to metabolic syndrome and subsequent cardiovascular disease, according to new research published in the January issue of Cancer Epidemiology, Biomarkers & Prevention.

The new study is part of a growing body of evidence that indicates that childhood cancer survivors are at higher risk of developing metabolic syndrome than the general population.

The authors found that adult survivors of childhood cancer were about 1.9 times more likely to be taking medication for hypertension, 1.6 times more likely to be taking medication for dyslipidemia, and 1.7 times more likely to be taking medication for diabetes as those in the study's sibling comparison group.

Other studies have shown that pediatric cancer survivors are at high risk for a number of physical and psychosocial conditions as a result of the cancer and its treatment. These include stroke, problems with neurocognitive function and academic achievement, and subsequent malignant neoplasms, as previously reported by Medscape Oncology.

Recently published data from the Childhood Cancer Survivor Study (CCSS) found that nearly three quarters of survivors had at least 1 chronic health condition, the authors note. The risk for cardiovascular disease was approximately 10 times higher among survivors than among their siblings.

Lillian R. Meacham, MD, medical director of the Cancer Survivor Program and professor of pediatrics at Emory University, in Atlanta, Georgia, and colleagues used data from the CCSS to determine the prevalence of and factors associated with the development and clustering of cardiovascular risk factors.

More Likely to Develop Metabolic Syndrome

The authors defined Cardiovascular Risk Factor Cluster (CVRFC), which they used as a substitute for metabolic syndrome, as having at least 3 of the following 4 risk factors: obesity, hypertension, dyslipidemia, and diabetes mellitus or impaired glucose tolerance.

The CCSS is a multi-institutional study of individuals who survived 5 years after a childhood cancer that was diagnosed from 1970 to 1986. The current analysis includes 8599 of the cancer survivors and 2936 of their siblings who were evaluated for a body mass index of 30 kg/m² or more, based on self-reported heights and weights. The self-reported use of pharmacologic agents for the treatment of hypertension, dyslipidemia, and impaired glucose metabolism was also evaluated.

More than half of the survivors (59.2%) received radiation as part of their initial cancer therapy, 33.5% received 100 mg/m² or more of anthracyclines, and 4.7% were treated with platinum therapy.

Three of the hallmarks of metabolic syndrome (hypertension, dyslipidemia, and diabetes) were more commonly found in survivors than in their siblings, but there was no difference in the prevalence of obesity between the 2 groups (20.6% for survivors vs 20.8% for their siblings).

The authors noted that older age at the time of the questionnaire (40 years or older vs younger than 30 years) was associated with each cardiovascular risk factor, and a sedentary lifestyle was associated with CVRFC and each risk factor except for dyslipidemia.

Type of Treatment Influences Risk

In terms of risk and treatment modalities:

• Exposure to more than 100 mL/m² of an anthracycline was associated with a 50% increase in the odds of hypertension.
• Patients who received cranial radiation were more likely to be obese than those who did not receive radiation.
• Those who received more than 300 mg/m² of anthracyclines were less likely to be obese.
• Individuals who received either abdomen or chest radiation or who were currently receiving steroid therapy showed increased risk for hypertension.
• Total-body irradiation and radiation to the craniospinal axis, abdomen plus chest, and chest alone were associated with treatment for dyslipidemia.
• Diabetes was associated with total-body irradiation and radiation to the abdomen and to both the abdomen and chest.
• CVRFC was associated with total-body irradiation and abdominal plus chest radiation.

The authors also evaluated the association between the cardiovascular disease events reported in the 2000 follow-up survey and the cardiovascular risk factors that were observed in the most recent follow-up. Among the survivors, there were 83 reports of cardiac events (which included coronary artery disease, atherosclerosis, and myocardial infarction), and 151 patients reported a history of stroke at either the baseline or the first follow-up questionnaire. Except for stroke, all the previously reported cardiac events were associated with an increased risk of reporting CVRFC at second follow-up (P = .003).

"In light of the high prevalence of chronic health conditions, including cardiac disease and associated increased rates of death, it behooves all healthcare providers to be proactive in the early recognition and treatment of cardiovascular risk factors in this population," the authors conclude.

The Childhood Cancer Survivor Study is funded by the National Cancer Institute. Dr. Meacham reports receiving a commercial research grant from Genentech, Novo Nordisk, and Pfizer. Coauthor Charles Sklar, MD, from Memorial Sloan-Kettering Cancer Center in New York City, reports being a member of the consultant/advisory board of EMD Serono.

Cancer Epidemiol Biomarkers Prev. 2010:19:170-181.

EGFR POLYMORPHISM AND SKIN TOXICITY AND RESPONSE TO TREATMENT

Clin Cancer Res. 2010 Jan 1;16(1):304-10. Epub 2009 Dec 22.

Association of epidermal growth factor receptor polymorphism, skin toxicity, and outcome in patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment.

Klinghammer K, Knödler M, Schmittel A, Budach V, Keilholz U, Tinhofer I.

Department of Hematology and Oncology, Campus Benjamin Franklin and Laboratory for Translational Radiobiology & Radiooncology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

PURPOSE: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), has shown clinical efficacy in squamous cell carcinoma of the head and neck with prolonged progression-free (PFS) and overall survival (OS). In this study, we analyzed whether cetuximab-induced skin rash was correlated with distinct polymorphisms within the EGFR gene known to modulate EGFR expression, ligand binding, or signaling activity. EXPERIMENTAL DESIGN: Fifty-one patients enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with cetuximab/docetaxel were genotyped for two genetic variations in the EGFR gene, a point substitution G-->A in exon 13 resulting in an amino acid substitution in position 521 (EGFR-R521K) and a CA repeat (CA-SSR) polymorphism in intron 1. Association between genotypes and incidence/grade of skin rash was determined by Fisher's exact test. The predictive value of genotypes for PFS and OS was determined using the log-rank test. RESULTS: Overall, 21 patients (41%) developed skin rash with grade >1 within 6 weeks of treatment. The common EGFR-R521K genotype (G/G) was significantly associated with increased skin toxicity (P = 0.024) and showed a trend toward reduced risk of tumor progression (hazard ratio, 0.55; 95% confidence interval, 0.27-1.08; P = 0.08), whereas no correlation of the EGFR-R521K genotype with OS could be observed (P = 0.20). No significant interaction between CA-SSR polymorphism and skin toxicity, PFS, or OS could be detected. CONCLUSIONS: Our study revealed an influence of the EGFR-R521K genotype on skin toxicity and suggested its relation to clinical activity of cetuximab/docetaxel treatment.

ONCOTYPE FOR N+ PATIENTS?

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Lancet Oncol.. [Epub ahead of print] Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, Ravdin P, Bugarini R, Baehner FL, Davidson NE, Sledge GW, Winer EP, Hudis C, Ingle JN, Perez EA, Pritchard KI, Shepherd L, Gralow JR, Yoshizawa C, Allred DC, Osborne CK, Hayes DF; for The Breast Cancer Intergroup of North America. Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, IL, USA. BACKGROUND: The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. METHODS: The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. FINDINGS: There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0.006; hazard ratio [HR] 2.64, 95% CI 1.33-5.27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; p="0.97;">/=31; log-rank p=0.033; HR 0.59, 0.35-1.01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. INTERPRETATION: The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. FUNDING: National Cancer Institute and Genomic Health.

PMID: 20005174 [PubMed - as supplied by publisher]

EGFR MUTATION TESTING

January 8, 2010 — The targeted therapy gefitinib (Iressa, AstraZeneca) is not inferior to chemotherapy in terms of improving overall survival in pretreated patients with advanced nonsmall-cell lung cancer (NSCLC). However, there is also no evidence of a difference in overall survival between these 2 treatments.

These are among the new findings from the multinational 1466-patient clinical trial known as INTEREST (Iressa NSCLC Trial Evaluating Response and Survival Versus Taxotere), which were published online December 28 in the Journal of Clinical Oncology.

The study investigators also found that patients who tested positive for an epidermal growth factor receptor (EGFR) mutation had longer progression-free survival (hazard ratio, 0.16; 95% confidence interval, 0.05 - 0.49; P = .001) with gefitinib than with the chemotherapy docetaxel.

INTEREST is the third major trial to show that EGFR mutation predicts benefit with EGFR tyrosine kinase inhibitors (TKIs), which are much less toxic than chemotherapy, writes Ramaswamy Govindan, MD, in an editorial accompanying the new results.

"Taken together, the three recent representative studies (INTEREST, IPASS [IRESSA Pan-Asia Study], and SATURN) underscore the fact that the presence of EGFR [tyrosine kinase] mutation best identifies those who would derive the most benefit, as measured by [progression-free survival]," writes Dr. Govindan, who is from the Alvin J. Siteman Cancer Center at Washington University School of Medicine in St. Louis, Missouri.

Other biomarker tests in NCSLC, including that for KRAS mutations, have not been consistently predictive of the benefit from EGFR [tyrosine kinase] inhibition, adds Dr. Govindan.

Although EGFR mutation is clearly the best biomarker for predicting progression-free survival benefit with the TKIs, which also include erlotinib (Tarceva, Genentech/OSI Pharmaceuticals), this finding needs to be placed in its proper context, said H. Jack West, MD, a lung cancer expert approached for comment by Medscape Oncology. Dr. West is from the Swedish Cancer Institute in Seattle, Washington.

"These data don't say that everyone with NSCLC needs to be tested for the mutation," said Dr. West, who explained that heavy smokers or those with squamous cell carcinomas are very unlikely to have the mutation.

"The most suitable candidates for testing are never-smokers or those with a remote smoking history with an adenocarcinoma," he noted.

However, even when patient context is clarified, it is not yet clear how the testing changes clinical practice, Dr. West explained.

EGFR Testing Has "Very Real" Barriers

Dr. West endorses testing patients for the EGFR tyrosine kinase mutation. "If feasible, it is desirable to test for this," he said, explaining, as an example, that patients who do not have the mutation should definitely not receive an EGFR TKI as a first-line therapy.

He also believes that the use of the testing is "actively evolving" and that "practice patterns are probably changing quarterly."

"It has changed my practice," Dr. West added.

"EGFR-mutation testing tells us that someone with a mutation is highly likely to have a dramatic and often long-lasting response to an EGFR TKI whenever they get it," Dr. West has written in his Medscape blog, Blowing Smoke.

However, the testing is often not feasible because of "very real barriers," Dr. West said.

"There are a limited number of labs that perform the test, and it can take 3 to 4 weeks to get results," Dr. West said, adding that most patients with lung cancer and their clinicians are "uneasy" about delaying the start of therapy for that long.

Also, initial lung biopsies often do not yield sufficient tissue for testing, necessitating another biopsy, said Dr. West. In the IPASS trial, only one third of patients had biopsied tissue suitable for the testing, he noted.

In INTEREST, only 297 of the 1466 patients had tissue assessable for the test, and 44 of them (15%) were EGFR-mutation positive.

EGFR TKIs Should Ultimately Be Used in Most Patients Anyway

Dr. West also declared that, in NSCLC patients, chemotherapy — and not the EGFR TKIs — is the "well-established standard of care as first-line therapy in North America."

"There is still no evidence that people live longer with an upfront TKI," he added, citing the IPASS results and other data.

However, Dr. West also noted that there is no "penalty" in terms of overall survival when giving it as a second-line instead of first-line therapy, he added, citing the results of a recent Spanish study of erlotinib.

Still, Dr. Govindan believes there is a case for the upfront use of EGFR TKI.

"Does it really matter whether we give EGFR TKIs earlier (front-line/maintenance) in the course of the disease or later (in the second- or third-line setting)?" he asks in his editorial.

Dr. Govindan goes on to suggest that sequence does matter because, in patients with an EGFR mutation, it is "hard to make the case for delaying a therapy that is dramatically effective, convenient, and well tolerated compared with more toxic intravenous cyctoxic chemotherapy."

But Dr. West says that an EGFR TKI will offer the same quality-of-life benefits to an NSCLC patient eventually as a second-line therapy. "There is no evidence of what is the best sequence," he reiterated.

Despite his objections, Dr. West offers an EGFR TKI to all NSCLC patients who progress, even those who do not test positive for the EGFR mutation.

"Being EGFR wildtype, however, does NOT mean that someone will get no benefit from an EGFR TKI," he writes in Blowing Smoke.

The results of IPASS, Dr. West writes, strongly suggest that these wildtype patients will not receive a "major and prolonged benefit, but they are in the large proportion of patients who may experience a minor response or prolonged stable disease that translates to a survival benefit in the range of a few months."

The INTEREST trial was supported by AstraZeneca. Dr. Govindan reports being a consultant/advisor to Genentech Lilly Oncology and AstraZeneca, and receiving honoraria from the same companies. Dr. West has disclosed no relevant financial relationships.

J Clin Oncol. Published online December 28, 2009. Abstract, Abstract

DECITABINE FOR AML IN ELDERLY

NEW YORK (Reuters Health) Jan 06 - A substantial minority of older patients with acute myeloid leukemia (AML) responds to first-line treatment with the nucleoside analogue decitabine, researchers report in a December 21st on-line paper in the Journal of Clinical Oncology.

"In this Phase II study, the complete response rate of 24% was observed even in patients with high-risk disease features, like poor-risk cytogenetics and preceding myelodysplastic syndrome," lead author Dr. Amanda F. Cashen told Reuters Health by email.

"These encouraging findings justify investigation of this relatively well-tolerated therapy in larger, randomized studies in elderly AML patients," she added.

Dr. Cashen of Washington University School of Medicine, St. Louis, and her colleagues treated 55 treatment-na�ve AML patients, all at least 60 years old, with decitabine 20 mg/m2 intravenously for 5 consecutive days of a 4-week cycle. Study participants completed a median of 3 cycles.

The overall response rate was 25% and the complete response rate was 24%. Overall median survival was 7.7 months, and the 30-day mortality rate was 7%.

All patients had myelosuppression, 29% had febrile neutropenia, and 26% had fatigue. Twenty-six patients (47.3%) experienced at least one serious adverse event that appeared to be related to treatment.

Even so, the investigators considered the results to be promising, and treatment-related toxicity and mortality to be relatively low.

In an editorial, Dr. Charles A. Schiffer of Wayne State University School of Medicine, Detroit, comments on these and other data on AML therapy in the elderly.

Despite the age of these patients, he says, "the instinct should be to treat -- with the goal of achieving remission and/or improvement of blood counts -- rather than to search for reasons why treatment should not be given."

J Clin Oncol 2009.

NEW GENE MUTATIONS FOR RENALCANCER

January 6, 2010 — Mutations in genes modifying histone structure are associated with many cases of clear cell renal cell carcinoma (ccRCC), according to scientists at Wellcome Trust Sanger Institute and their international collaborators. Although most ccRCC — the most common type of kidney cancer in adults — involves mutations that inactivate VHL, the new findings point to greater genetic heterogeneity in this disease.

The study, by senior author P. Andrew Futreal, MB, PhD, from the Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom, and colleagues, was published online today in Nature.

The majority of ccRCC cases differ from other renal cell carcinomas by the presence of mutations that inactivate VHL, a gene coding for a tumor suppressor protein. Inactivation of VHL is associated with von Hippel-Lindau disease, and VHL mutations predispose people to a variety of tumors, both malignant and benign. Patients with ccRCC typically lack mutations in other genes associated with adult epithelial cancers. This study looked for genes other than VHL that might contribute to ccRCC.

Investigators screened 101 ccRCC samples from 96 primary tumors and 5 ccRCC cell lines. The tumor sources were 56 men and 40 women, with ages ranging from 32 to 85 years (median, 62 years). Tumors at diagnosis were at stage I (n = 44), stage II (n = 14), stage III (n = 34), stage IV (n = 2), or not available (n = 2); grade at diagnosis was 1 (n = 4), 2 (n = 35), 3 (n = 39), 4 (n = 16), or not available (n = 2). Consistent with other studies of ccRCC, 55% of the tumors demonstrated VHL mutations.

Two distinct phenotypes were identified among the tumors with respect to gene expression: 82% of the ccRCCs assessed showed greater activity of genes associated with cellular hypoxia, and 65% of this group had point mutations that inactivated VHL. The second phenotype was represented by the 18% of tumors that did not demonstrate a hypoxic gene expression pattern.

In tumors with increased hypoxia-related gene activity, EGLN3 was the most upregulated gene (a hypoxia response element is located in the region of EGLN3). SETD2 and JARID1C mutations were more common in tumors with hypoxic upregulation. Mutations in NF2 were found only in tumors without hypoxic upregulation.

Both SETD2 and JARID1C code for enzymes that modify histones — the main proteins that constitute chromatin and also influence gene expression. SETD2 encodes a "histone H3 lysine 36 methyltransferase," and JARID1C encodes a "histone H3 lysine 4 demethylase." The involvement of a third histone-modifying gene, UTX, which encodes a histone H3 lysine 27 demethylase, was previously reported by this research group.

Histone-Related Mutations Found

Histone-related mutations found in ccRCC in the initial screen, follow-up screen, and RCC cell-lines in this study include

• a total of 16 mutations in SETD2: 4 nonsense, 3 missense, 9 frameshift;
• a total of 14 mutations in JARID1C: 6 nonsense, 2 missense, 2 splice/deletions, and 4 frameshift; and
• a total of 12 mutations in UTX: 1 nonsense, 5 missense, 1 splice, 1 splice/deletion, 4 frameshift.

Seven NF2 mutations were also found: 1 nonsense, 4 frameshift, 1 splice, and 1 splice/deletion. Although this study identified somatic mutations in tumors and cell lines, NF2 germline mutations are known to predispose patients to neurofibromatosis II. Interestingly, none of the NF2 mutations found in this study occurred in tumors with VHL mutation or a hypoxic gene expression pattern. "These data indicate that somatic NF2 mutations may account for a proportion of this subset of cases," the authors note.

Quite different phenotypes were associated with expression of mutated SETD2 or JARID1C. Mutant SETD2 involved "large-scale transcriptional deregulation...with 298 genes showing significant differences in expression relative to other cancers analyzed," the study reports. In contrast, mutation of JARID1C "showed a much more restricted signature.... Eighteen genes showed significant expression changes in cancers with JARID1C mutations."

The authors conclude, "For ccRCC, the data presented here will provide insights into its pathogenesis and the opportunity to understand the role of genetic subtypes in clinical behavior and response to treatment."

In addition, their study indicates that "substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer."

Nature. Published online January 6, 2010.

TARGETS FOR BREAST CANCER BONE METASTASIS

Src

• Src activity regulates many pro-metastatic abilities of breast cancer cells and is also required for the generation of functional, bone-resorbing osteoclasts, making it an ideal candidate for therapeutic intervention for breast cancer bone metastasis.
• A Src-related gene expression signature has been identified in a subset of primary breast tumors and is highly predictive of the development of bone metastases. Several Src inhibitors are being tested in clinical trials, with many more in preclinical development.

TGF-β

• The TGF-β pathway is believed to exert opposing roles during cancer progression, acting as a growth inhibitor in normal epithelium and as a promoter of cancer invasiveness and metastasis as the disease progresses. Ample data exists to support both of these roles, and the diverse, often opposing effects, of TGF-β signaling on both cancer cells and cells within the tumor microenvironment make this a challenging pathway to target therapeutically. However, the large body of data pointing to the ability of this pathway to augment breast cancer metastasis will justify the continued development and testing of TGF-β inhibitors for use as anticancer agents.

Receptor activator of NF-κB ligand

• Receptor activator of NF-κB ligand (RANKL) is a critical mediator of osteoclast formation and is commonly deregulated during the process of breast cancer bone metastasis. Denosumab, a RANKL-neutralizing antibody, has demonstrated superior efficacy as an antiresorptive agent when compared with bisphosphonates. This agent is currently being investigated as an antibone metastatic therapy in PhaseIII clinical trials for patients with breast cancer or multiple myeloma.

Cathepsin K

• Cathepsin K is a proteolytic enzyme produced by osteoclasts, and contributes to the Collagen I degradation that occurs during bone resorption.
• Cathepsin K may facilitate breast cancer cell invasion.
• Odanacatib is a highly specific Cathepsin K inhibitor that is currently being investigated for its utility in treating numerous disorders that are characterized by excessive bone resorption.

CXCR4

• CXCR4 is a G-protein-coupled receptor commonly expressed in breast cancer cells that can facilitate the development of bone metastasis. It is also expressed by hematopoietic precursor cells and promotes their retention in the bone marrow.
• While CXCR4 inhibition may diminish the pro-metastatic abilities of breast cancer cells and promote the mobilization of hematopoietic precursor cells, it may also result in increased osteoclast activity. Thus, the effects of pharmacological CXCR4 inhibitors, such as plerixafor and CTCE-9908, should be investigated with respect to these undesirable effects on the promotion of bone resorption if they are to be used as antibone metastasis therapies.

Glycoprotein nonmetastatic B

• Glycoprotein nonmetastatic B (GPNMB) is a novel target expressed on the surface of breast cancer cells, which can promote bone metastasis in vivo. Its role in bone physiology is beginning to be elucidated and appears to be required for osteoblast and osteoclast function. CDX-011 is a GPNMB-targeted antibody drug conjugate that is yielding promising results in PhaseII trials for the treatment of metastatic breast cancer.

EGF-family ligands

• Recent data suggests that EGF initiated signaling can have profound effects on bone resident cells, including their ability to impair osteoblast differentiation and promote osteoclast formation. The net effect is to promote conditions that favor breast cancer induced osteolysis during the formation of breast cancer bone metastasis. A re-evaluation of therapeutic agents designed to impair EGFR signaling, which have displayed modest effects in treating primary breast cancer, may be warranted in the context of breast cancer metastasis to bone.

MELOXICAM FOR EXTRAABDOMINAL DESMOID TUMORS

January 5, 2010 — Meloxicam (Mobic), a cyclooxygenase (COX)-2 inhibitor drug used for arthritis, has shown promise as a treatment for extraabdominal desmoid tumors, according to the results of a small pilot study.

The study results, which were published online December 21 in the Journal of Clinical Oncology, showed that of 20 patients treated with meloxicam who were available for evaluation, 19 (95%) had a final status of stable disease or better.

Extraabdominal desmoid tumors are generally sporadic in nature and can occur in virtually any body site, note the authors. However, they are primarily found in the extremities, chest, abdominal wall, and neck. They can be locally aggressive and invasive to surrounding anatomic structures, leading to pain, functional impairment, and deformity.

Management usually involves a multidisciplinary approach that includes surgery and radiation, but these have potential associated morbidities. This has led to investigations of both cytotoxic and noncytotoxic chemotherapy, but because the tumors are rarely fatal, finding a pharmacologic treatment with fewer complications is desirable, according to the authors.

"We recommend meloxicam for patients with extraabdominal desmoid tumors, instead of surgery first," said lead author Yoshihiro Nishida, MD, PhD, from the Department of Orthopedic Surgery at Nagoya University Graduate School of Medicine in Japan.

"However, our study included only a small number of patients, so if tumors do not respond to meloxicam treatment, we would then use surgery or other modalities such as radiotherapy or chemotherapy," he told Medscape Oncology.

Meloxicam Induced Responses, Well Tolerated

The authors hypothesized, on the basis of previous studies, that COX-2 might be a potential therapeutic target. Experimental in vitro and in vivo research demonstrated decreased cell proliferation in desmoid cell cultures and small tumors when COX-2 was blockaded with pharmacologic agents.

In this study, between 1991 and 2003, Dr. Nishida and colleagues identified 30 patients who were surgically treated for extraabdominal desmoid tumors at their institutions (excluding those with intraabdominal, familial adenomatous polyposis-associated, and unresectable tumors). Because of the high rate of relapse after surgery (53%), 22 patients have been prospectively treated with meloxicam since 2003.

None of the 22 patients had a known history of gastrointestinal disorders, such as gastritis or gastric ulcer, and no one in the cohort was receiving hormonal medications. Baseline imaging of desmoid tumors by magnetic resonance imaging (MRI) was obtained prior to beginning treatment with oral meloxicam 10 mg/day.

Patients were followed with physical examinations and MRI and/or computed tomography every 3 to 6 months, and meloxicam was administered for a median of 20 months (range, 3 to 66 months). Of this group of 22, 2 patients discontinued treatment because of adverse events and were not included in the final evaluation.

Among the 20 patients evaluated, the researchers observed 1 complete response, 7 partial responses, 11 patients with stable disease, and 1 patient who had progressive disease. Although the 2 patients who discontinued treatment were not included in the evaluation, they had stable disease at the time they stopped the therapy. Patient sex, tumor size, tumor site, follow-up interval, and period of medication were not significant prognostic factors of responsiveness. However, age appeared to play a role; good responders were significantly older than poor responders (P = .0091).

Meloxicam was well tolerated and none of the patients in the final analysis experienced any adverse effects. Of the 2 patients who discontinued treatment, 1 did so because of mild gastritis, and the other was elderly with had a history of cerebral infarction and suffered from intermittent pneumonia and diarrhea.

Surgery remains the mainstay for resectable sporadic desmoid tumors, especially extraabdominal ones, the authors write, and there is growing evidence that chemotherapy might be effective in managing life-threatening intraabdominal desmoid tumors. "However, the significant morbidity of aggressive chemotherapy should be avoided in patients with extraabdominal desmoids tumors," they say.

The authors point out that this was a prospective and consecutive-case–control study with a small number of patients. Even though 95% of the patients achieved stable disease or better, they note that they still cannot conclude that these results were "solely attributable to the meloxicam itself."

However, they add that it was crucial to prove that meloxicam had potential for treating extraabdominal desmoid tumors before undergoing a large placebo-controlled trial.

Further investigations are needed, but on the basis of these results, the authors recommend "meloxicam as the initial treatment for patients with extraabdominal desmoid tumors."

Unfortunately, these results cannot be extrapolated to children. "In the pediatric population, a pilot study is necessary," said Dr. Nishida. "Currently, we do not recommend meloxicam treatment for pediatric patients with extraabdominal desmoids tumors."

The authors have disclosed no relevant financial relationships.

J Clin Oncol. Published online December 21, 2009. Abstract

CT IMAGING AND CANCER RISK

The use of computed tomographic (CT) scans has increased dramatically over the last few decades. Regardless of the recognized benefits from the radiologic definitions achieved with this technology, there is growing concern about radiation exposure associated with CT imaging, particularly with the lifetime attributable risk for radiation-related secondary cancer development. Conservative estimates are that more than 60 million CT examinations are done yearly in the United States, representing an estimated 70% of all medical x-ray exposure. Since the development of the first commercial CT scanners in 1972, CT has become the major source of medical radiation.

The potentially harmful consequences of ionizing radiation are divided into deterministic and stochastic effects.^[1] Deterministic effects of ionizing radiation result from cell and tissue death. Such changes occur only at doses above a certain threshold and are proportional to the dose given. Radiation doses from medical diagnostic procedures are usually far below this threshold, but adverse effects, such as skin burns, have been reported after interventional procedures that use fluoroscopy. The term stochastic radiation effect refers to irradiated cells that are modified rather than killed. Modified cells may develop into cancer after a latency period of years. In principle, stochastic effects have no threshold. Exposed individuals do not incur ill effects with certainty, but they have a higher statistical chance for toxicity, including cancer. The doses delivered in diagnostic procedures are large enough to cause stochastic radiation effects, and the probability increases with the magnitude of the dose.

Although exact risk estimates related to low doses of radiation exposure are difficult to ascertain, the ionizing radiation exposure from a single abdominal or chest CT scan may be associated with elevated risk for DNA damage and cancer formation.^[2] The seventh National Academy of Science report on Biological Effects of Ionizing Radiation estimated that a single dose of 10 mSv produces a lifetime risk of developing a solid cancer or leukemia of 1 in 1000.^[3]

Two recently published studies^[4,5] further addressed the issue of CT-related radiation exposure. A multicenter study sponsored by the US National Institutes of Health and the National Cancer Institute in Bethesda, Maryland, estimated the number of cancers that would arise from all CT studies performed in the United States during the year 2007.^[4] Risk models with organ-specific radiation exposures were used to estimate age-specific cancer risks for each type of CT scan. Overall, approximately 29,000 future cancers could be related to CT scans performed in 2007 alone. The largest contributions to incident cancers were from abdominal and pelvic scans (14,000 cancers), followed by chest CT (41,000 cancers), head CT (4000 cancers), and CT angiography (2700 cancers). One third of the projected cancers were the result of CT exposure from ages 35 to 54 years, and 15% were related to exposure in patients younger than 18 years of age.

A second retrospective cross-sectional study evaluated the radiation doses received by 1119 consecutive adult patients who had diagnostic CT.^[5] The study authors were surprised to find that radiation doses for common CT exams were higher and far more variable than previous estimates. Within each type of CT study, effective doses varied significantly both within and across institutions, with a mean 13-fold variation between the highest and lowest dose for each study type. The overall median dose of radiation for a routine abdomen/pelvis CT scan with contrast ranged from 12 mSv to 20 mSv, and for multiphase abdomen and pelvis CT scans, the dose ranged from 24 mSv to 45 mSv. These documented figures are considerably higher than those previously cited for abdominal CT radiation exposure (5-10 mSv). The investigators then estimated the number of patients who had each type of CT scan and the development of radiation-induced cancers. The risk for CT-related cancer varied by sex, age, and study type. There was a higher cancer risk in women and in patients with exposure at earlier ages. CT angiography was associated with the highest relative risk (1 cancer for every 150 examinations in 20-year-old women). The relative risks for CT of the abdomen are shown in the Table.

Table. Relative Risks for Cancer After Abdominal CT

CT Study	20 Years		40 Years		60 Years
	Female	Male	Female	Male	Female	Male
Abdomen/pelvis (with contrast)	1/470	1/620	1/870	1/942	1/1320	1/1250
Multiphase abdomen/pelvis	1/250	1/330	1/460	1/498	1/700	1/660

CT = computed tomography

Viewpoint

Advances in radiologic imaging have fundamentally changed the approach to diagnostic evaluation of patients with many disorders. With continuing growth in radiography, medical providers should be aware of the potential for radiation risk associated with CT scanning.

The popularity of CT imaging is high for many reasons, ranging from its speed and ease of use, to the relentless development of new imaging techniques, and finally to a growing body of evidence showing its images to be reliable for diagnosis. Unfortunately, drivers of increasing scan volumes also include financial rewards -- particularly for in-office procedures and the practice of defensive medicine -- resulting in unnecessary scans to minimize the threat of a lawsuit resulting from a missed diagnosis.

As these 2 studies made clear, radiation doses are higher than previously thought. They also demonstrated that radiation dose reduction is not yet a universal phenomenon and raised further doubt about whether the risk-benefit ratios and alternatives to CT scanning are seriously considered for every patient and CT scan.

In a recent article,^[6] we suggested that patients and physicians need to discuss the choice for radiologic imaging and the relative risks associated with this choice. This is particularly important for discussions of screening in asymptomatic patients. Furthermore, both physicians and patients need to be cognizant of previous radiation exposure as well as the age when the previous exposures occurred. Because radiation-related risks may be cumulative over time, this information should become a key element of the patient's medical history. Most healthcare providers do not think of potential "downstream" radiation-related consequences of diagnostic and screening radiologic imaging that may occur decades later. Therefore, it is time for a paradigm shift in the way in which we approach the use of CT imaging as we balance the risk-benefit profile for our patients!

GFR ESTIMATION

Question

Is a value of 150 or 160 mL/min really accurate when using the Cockcroft and Gault equation to calculate creatinine clearance (CrCl)?

Response from Michael J. Postelnick, BSPharm
Senior Infectious Diseases Pharmacist, Clinical Coordinator, Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois

An accurate estimate of a patient's glomerular filtration rate (GFR) is a critical element in the safe and effective dosing of renally eliminated medications. Serum creatinine, which is an endogenous marker of glomerular filtration, is commonly used to help estimate the GFR. The GFR estimate is derived using either the Cockcroft-Gault^[1] or modification of diet in renal disease (MDRD) equation.^[2] The MDRD equation estimates the GFR directly, whereas the Cockcroft-Gault equation estimates creatinine clearance (CrCl). CrCl is the parameter most often used in clinical trials to determine dose adjustments for renally eliminated medications.

Many problems are associated with using estimation equations^[3]:

1. The use of the filtration marker creatinine, which is generated by the breakdown of creatine in muscle, limits both estimation equations.
2. Patient-to-patient variation in muscle mass and diet have a significant effect on creatinine generation and subsequent clearance estimates produced by these equations.
3. CrCl slightly overestimates the GFR due to the fact that creatinine is not only filtered by the glomerulus but also secreted by the proximal tubule.
4. In patients with acutely increasing serum creatinine, the CrCl and GFR are overestimated, whereas in patients with declining serum creatinine, the CrCl and GFR are underestimated.
5. CrCl and GFR equations are less accurate at higher levels of the estimated CrCl and GFR.

Given the aforementioned list, there are reasons that clinicians should be circumspect of extremely elevated estimates:

1. The highest CrCl value for participants in the Cockcroft and Gault study was 130 mL/min^[1]; the highest value in the MDRD study was 90 mL/min/1.73 m².^[2] The accuracy of values higher than those from which the estimating equation was derived and tested is likely to be suboptimal.
2. Patients with altered muscle mass caused by poor nutrition, paralysis, amputation, or deconditioning due to chronic illness will have decreased creatinine production. This will result in lower serum creatinine values than would be expected for a similar patient without altered muscle mass. Estimating the CrCl or GFR using these values will result in an overestimate that can be quite significant.

Due to all the potential factors that affect calculated CrCl or GFR estimates, it is important for the clinician to use judgment when using these values to adjust drug dosages. Rather than blindly following recommendations derived from calculated estimates, careful assessment of the clinical status of the patient and the desired therapeutic outcomes as well as the risks associated with subtherapeutic or supratherapeutic doses of the pharmacologic agent must always be considered. When possible, drug level monitoring will give more accurate guidance to ensure appropriate dosing.

[ CLOSE WINDOW ]

References

1. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41. Abstract
2. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461-470. Abstract
3. National Kidney Foundation. Frequently asked questions about GFR estimates. Available at: http://www.kidney.org/professionals/kls/pdf/faq_gfr.pdf Accessed December 17, 2009.

ANTICOAGULANTS FOR PROSTATE CANCER?

November 5, 2009 (Chicago, Illinois) — Anticoagulants are indicated for the treatment of cardiovascular disease but might have a role to play in prostate cancer.

Anticoagulants, including aspirin, warfarin, and clopidogrel, were associated with improved biochemical control of localized prostate cancer in men treated with radiation therapy, according to a new retrospective study of 662 men.

The potential benefit is most pronounced in patients with high-risk localized disease, according to the study's lead author, who presented a poster here at the American Society for Radiation Oncology 51st Annual Meeting.

The current study looked only at men with prostate cancer treated with radiation, not with surgery, explained Kevin S. Choe, MD, PhD, from the University of Chicago Pritzker School of Medicine in Illinois.

The benefit seen in men who undergo radiotherapy while taking anticoagulants likely stems from an "interaction" between the radiation and the drugs, reported Dr. Choe.

At 4 years, biochemical control, or the absence of biochemical relapse as measured by prostate-specific antigen testing, was statistically significantly better in the group of prostate cancer radiotherapy patients receiving anticoagulants than in the group not receiving the blood-thinning therapy (91% vs 78%; P = .0002).

"We need more data before recommending that men undergoing radiotherapy consider taking anticoagulants," said Dr. Choe. However, the young investigator, who is a resident in radiation oncology at the University of Chicago, also put a positive spin on the results. "Those men with localized prostate cancer who already are on anticoagulants for cardiovascular disease may receive additional benefit when they undergo radiotherapy."

An expert in cancer and anticoagulants approached by Medscape Oncology for comment believes that the use of these agents holds considerable promise in oncology. "There is much that can be done that is low cost and effective," said Leo R. Zacharski, MD, from the White River Junction VA Medical Center in Vermont and the Dartmouth School of Medicine in Hanover, New Hampshire.

There is a "very large" literature on the subject, said Dr. Zacharski, citing the "dramatic effects" of anticoagulants on small-cell lung cancer as an example. "It is too bad that few people pay attention to the literature on this," opined Dr. Zacharski.

Dr. Zacharski also had a theory about the current findings. "In my opinion, the most likely explanation for the findings is that people who take anticoagulants tend to have slightly increased blood loss, which reduces the amount of iron in their bodies," he said.

In a randomized trial of iron reduction in men with peripheral arterial disease, Dr. Zacharski and colleagues found a statistically significant reduction in new cancer diagnosis and cancer-specific mortality (J Natl Cancer Inst. 2008;14:996-1002). The effect was seen for prostate cancer as well as other cancers, he said.

he current study was an outgrowth of another study in prostate cancer patients, in which Dr. Choe and colleagues investigated rectal bleeding. Prostate cancer patients treated with radiotherapy while taking anticoagulants had a significantly higher risk for this bleeding than patients not taking anticoagulants, he said.

Given this complication, if anticoagulants were ever to be recommended for use in these men, "it would need to be planned out very carefully," said Dr. Choe.

Subgroup Analysis: Benefit Only Significant in High-Risk Men

The new study looked at men with localized prostate cancer, Dr. Choe noted. This is appropriate, suggested Dr. Zacharski, who said that "established prostate cancer does not respond to anticoagulants."

The study cohort consisted of 662 patients with prostate cancer who were treated with radiotherapy at the University of Chicago from 1988 to 2005. Of these men, 243 were receiving warfarin, clopidogrel, and/or aspirin. Most of the men were receiving aspirin alone (n = 161) or warfarin alone (n = 42).

The men were treated with seed implants and/or external-beam radiation. The type of radiation received did not influence biochemical control outcomes, said Dr. Choe. About half the men also received short-term androgen-deprivation therapy.

Among the 243 patients, risk was low in 38%, intermediate in 38%, and high in 25%, according to National Comprehensive Cancer Network criteria.

In a subgroup analysis, the improvement in biochemical control was apparent among low- and intermediate-risk men taking anticoagulants, compared with the respective risk groups of men not taking the drugs.

However, biochemical control was only statistically significant in the high-risk men (n = 165). In that subgroup, the men taking anticoagulants (n = 52) had a 4-year rate of freedom from biochemical recurrence (i.e., biochemical control) of 82.4%, compared with 57.6% of those not taking anticoagulants (n = 113; P = .0007).

"The benefit of biochemical control appears to be most pronounced in men with localized high-risk disease," said Dr. Choe.

Anticoagulants had another benefit in the study: the drugs were associated with a reduced rate of metastasis.

The distant metastasis rate at 4 years was lower in the group taking anticoagulants than in the group not taking anticoagulants (1% vs 5%; P = .0248). "Anticoagulants may inhibit a tumor's ability to spread," said Dr. Choe, adding that "mounting preclinical evidence" supports this hypothesis.

Dr. Choe and Dr. Zacharski have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 51st Annual Meeting: Abstract 2269. Presented November 2, 2009