July 7, 2009 – Palliative sedation therapy used for the control of refractory symptoms in cancer patients with very advanced disease does not hasten death, a new prospective study concludes.
The study is reported in the July issue of the Annals of Oncology and is described as an "important contribution" to the field in an accompanying editorial.
When palliative sedation therapy is used to relieve refractory distress at the end of life, the question of whether it hastens death is a significant one, say the researchers. This is a concern for both oncologists and palliative specialists administering the treatment, as well as for the patients and/or the relatives who agree to it.
The concern is that this therapy could be a disguised form of euthanasia because death often comes fairly rapidly after sedation, the researchers comment.
"I think that many physicians think that palliative sedation therapy is or could be a form of 'slow' or 'soft' euthanasia,' " lead author Marco Marco Maltoni, MD, director of the Valerio Grassi Hospice, in Forlimpopoli, Italy, commented to Medscape Oncology.
But the results of this new study show that the therapy does not have a detrimental effect on survival, and they should be reassuring, he commented. "I would say that our results may help physicians and patients who do not accept euthanasia to have a good clinical practice, so that no patient is forced to reach death in a symptomatic way."
First Trial to Match Patients Prospectively
There have been previous trials showing that palliative sedation therapy does not accelerate the demise of the patients, but they have been criticized for methodology. "These data were indicative but not conclusive, insofar as there was a possibility that the patient populations were intrinsically different, with different prognoses and different anticipated trajectories of demise," notes the editorialist Nathan Cherny, MD, head of the palliative medicine unit at the Shaare Zedek Medical Center, in Jerusalem, Israel.
This latest trial is the first — as far as the authors are aware — that prospectively matched sedated patients with nonsedated patients in such a way that the 2 cohorts differed only in terms of 1 characteristic (ie, sedation).
Dr. Maltoni and colleagues recruited 518 patients from 4 hospices in the Emilia-Romagna region of Italy. The overall prevalence of palliative sedation therapy in the patients who were admitted to these hospices was 25.1%, with very little variability among the centers (+5%).
Patients in the 2 cohorts were matched for age, sex, Karnofsky performance status, reason for hospice admission, and predicted survival. In addition, there were no statistically significant differences in the location of the primary tumor or metastases. The most common cancers were lung, colorectal, stomach, breast, and pancreas, and the most common metastases were in the liver, lymph nodes, and bone.
Drugs used for palliative sedation included neuroleptics (used in 84.2% of patients) such as chlorpromazine, promethazine, and haloperidol, benzodiazepines (54.3%) such as lorazepam, midazolam, and diazepam, and opioids (25.5%) such as morphine.
Delirium and/or agitation were cited the most often as reasons for this therapy (in 78.7% of patients), followed by dyspnea (in 19.5% of patients), pain (in 11.2%), and vomiting (in 4.5%). Refractory psychological distress was cited in 18.7% of patients, but the majority of this group (37 of 50 patients) also presented with physical refractory symptoms, the researchers comment.
The mean duration of sedation was 4 days, while the median duration of sedation was 2 days (range, 0 – 43 days).
Overall survival was not statistically significant different in the 2 cohorts. The median survival of patients in the sedated group was 12 days, while that of unsedated patients was 9 days (P = .33; unadjusted hazard ratio, 0.92; adjusted hazard ratio, 0.86). The overall survival curves of the 2 cohorts were superimposable, the researchers commented.
"Palliative sedation therapy does not shorten life when used to relieve refractory symptoms," the researchers conclude.
Important and Necessary Therapy
This study shows that, even when matched for adverse prognostic variables, sedated patients in this setting did not have an accelerated demise, notes Dr. Cherny.
However, he says, it is important to note that the majority of patients in this study were lightly sedated. The same may not apply to sudden deep sedation.
Another issue that is unresolved is whether or not to continue hydration in patients who are sedated. This question was not evaluated in the current trial, Dr. Cherny points out.
But the researchers comment that "even if hydration had been interrupted in a higher number of sedated patients with respect to the nonsedated group, this would, at most, have had a detrimental effect on the former cohort . . . [but] this effect was not observed."
"For oncologists and palliative care specialists, sedation is an important and necessary therapy in the care of selected patients with otherwise refractory and severe distress at the end of life," Dr. Cherny writes in the editorial.
However, he adds that as "sedation has the capacity to harm as well as to help, the manner in which this therapeutic tool is applied is important."
A number of procedural guidelines for the use of sedation in the management of palliative care have already been published, and a framework for developing such guidelines is currently being developed by the European Association for Palliative Care, he notes.
No Need for Doctrine of Double Effect
These latest results confirm findings from previous studies of a lack of effect of palliative sedation therapy on survival, the researchers comment. Hence, it does not need the "doctrine of double effect" to justify its use from an ethical point of view, they add.
Dr. Maltoni explained to that this doctrine of double effect is a bioethical principle. "This doctrine says that if doing something morally good has a morally bad adverse effect, it is ethically acceptable to do it provided the bad effect was not intended. This is true even if it is foreseen that the bad effect would probably happen."
In the case of palliative sedation therapy, a previous study has suggested around 3% to 4% of patients may have a serious adverse event, even death. But as the treatment is beneficial, and this adverse event is not wanted and not predictable in an individual patient, the therapy "is ethically acceptable from any point of view and ethical perspective," Dr. Maltoni told Medscape Oncology.
"Unfortunately, serious adverse effects are frequent in all medical acts, but they cannot stop appropriate care and therapies," he added.
No conflicts of interest were reported.
Ann Oncol. 2009;20:1163-1169 Abstract, 1153-1155. Abstract
Παρασκευή 10 Ιουλίου 2009
Τετάρτη 8 Ιουλίου 2009
BRAIN METASTASES IN EPITHELIAL OVARIAN CANCER
- Int J Gynecol Cancer. 2009 Jul;19(5):856-9.
Brain metastases in epithelial ovarian and primary peritoneal carcinoma.
Ratner ES, Toy E, O'Malley DM, McAlpine J, Rutherford TJ, Azodi M, Higgins SA, Schwartz PE.
Department of Obstetrics, Gynecology and the Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520-8063, USA. elena.ratner@yale.edu
OBJECTIVES: Central nervous system metastases are believed to be becoming more clinically evident as long-term survival for epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC) has improved. Our objective was to report our experience with managing brain metastatic disease (BMD) in patients with EOC and PPC. METHODS: A retrospective review was performed on patients with EOC and PPC diagnosed with BMD from 1983 to 2007 at our institution. RESULTS: Twenty-four patients were identified. Patients with multiple brain lesions (n = 16) had a shorter median time to diagnosis of BMD than patients with single lesions (n = 8; 22.5 vs 39 months). Radiation therapy was included in the treatment of BMD for 19 patients (78%). Fourteen patients received whole-brain radiation therapy (WBRT) only (survival, 6 months [range, 1-51 months]). Three patients received a combination of gamma knife radiosurgery and WBRT (survival, 20 months [range, 17-67 months]), and 1 patient received gamma knife radiosurgery alone (survival, 10 months). Four patients underwent craniotomy with 3 receiving postoperative WBRT (survival, 8.5 months [range, 2-97 months]). Two patients elected for palliative care only. The median survival from the diagnosis of BMD was 8.5 months (range, 1-97 months) with a 42% 1-year survival and 16% 2-year survival. Patients with single lesions had a significantly longer survival than patients with multiple lesions (17 months [range, 3-97 months] vs 6 months [range, 3-67 months], respectively). CONCLUSIONS: Our report provides the largest single-institution experience of brain metastasis from EOC and PPC in patients receiving predominantly platinum and paclitaxel therapy. Patients with BMD from EOC and PPC have a poor prognosis overall; however, prolonged survival is possible in a small subset of patients.
AN INTERESTING REGIMEN FOR ADVANCED CHORDOMA
- Ann Oncol. 2009 Jul 1. [Epub ahead of print]
Response to imatinib plus sirolimus in advanced chordoma.
Stacchiotti S, Marrari A, Tamborini E, Palassini E, Virdis E, Messina A, Crippa F, Morosi C, Gronchi A, Pilotti S, Casali PG.
Department of Cancer Medicine.
BACKGROUND: Imatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, sirolimus, to IM in IM-resistant advanced chordoma. PATIENTS AND METHODS: Since July 2007, 10 progressive advanced chordoma patients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis. RESULTS: The mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (>/=10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit [RECIST complete response + PR + SD >/=6 months] was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off. CONCLUSION: In addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.
FIRST MAINTENACE THERAPY FOR ADVANCED LUNG CANCER APPROVED BY THE FDA
July 6, 2009 — The US Food and Drug Administration (FDA) has approved pemetrexed (Alimta, Eli Lily) for the maintenance therapy of advanced or metastatic nonsquamous non–small-cell lung cancer (NSCLC). Pemetrexed is the first drug indicated as a maintenance therapy in this setting.
"This drug represents a new approach in the treatment of advanced non–small-cell lung cancer," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, in a press statement. "Typically, patients whose tumors respond to chemotherapy do not receive further treatment after four to six chemotherapy cycles. This study demonstrates an advantage in overall survival in certain patients who received Alimta for maintenance therapy."
In a phase 3 trial recently presented at the American Society of Clinical Oncology (ASCO) meeting, patients received either pemetrexed (n = 441) or placebo (n = 222), along with the best supportive care. Patients had advanced or metastatic (stage 3B or 4) NSCLC (both squamous and nonsquamous subtypes) that had not progressed after 4 cycles of initial platinum-based chemotherapy.
For all patients in the study, the pemetrexed treatment group had an overall survival of 13.4 months, compared with 10.6 months for the placebo group. However, for the nonsquamous subgroup, overall survival was 15.5 months for patients taking pemetrexed and 10.3 months for patients taking placebo. The difference was statistically significant (P = .002).
However, as reported by Medscape Oncology from ASCO, 2 lung-cancer experts attending the meeting questioned the appropriateness of using pemetrexed as a maintenance therapy. Neither was involved with this phase 3 trial.
"I don't think we have the answer as to when it is best to start pemetrexed. Should we start immediately after standard chemotherapy or later on? All you can say is that it improves survival in nonsquamous-cell patients. In my clinic, I will present maintenance therapy as an option," said Julie Brahmer, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, in Baltimore, Maryland.
"I endorse the use of pemetrexed as a second-line therapy for advanced non–small-cell lung cancer, but I don't think that all patients need immediate maintenance therapy following first-line treatment," said Nasser H. Hanna, MD, from the department of medicine at Indiana University, in Indianapolis, adding that the trial design did not allow it to definitively establish pemetrexed as a maintenance therapy.
Dr. Hanna explained the phase 3 trial was not designed to indicate whether maintenance therapy was superior to using pemetrexed at time of disease progression.
"Only 19 patients who were on placebo received pemetrexed at time of disease progression because, in part, the drug was not available at all of the centers involved in the study. In short, we know the drug improves survival but not that maintenance therapy is the best way to use it," he said.
A form of chemotherapy, pemetrexed is a folate analog metabolic inhibitor, which means that it disrupts metabolic processes that depend on the B-vitamin folate, a necessary ingredient for cell replication.
In the phase 3 study presented at ASCO, severe adverse effects (grade 3 or 4) were more common in the pemetrexed than in the placebo group, including fatigue (5% vs 0.5%) and low white-blood-cell counts (2.9% vs 0%).
Other reported adverse events included nausea, loss of appetite, tingling or numbness in the hands and feet, and skin rash, according to the FDA statement.
Δευτέρα 6 Ιουλίου 2009
FOLLOW UP OF PATIENTS TAKING BIPHOSPHONATES FOR OSTEOPOROSIS-NO USE OF BMD IN THE FIRST THREE YEARS
July 2, 2009 — Monitoring bone mineral density (BMD) in postmenopausal women in the first 3 years after starting treatment with a potent bisphosphonate is not needed and may even be misleading, according to the results of a study reported in the June 24 Online First issue of the BMJ.
"Guidelines for treatment of postmenopausal osteoporosis differ in their recommendations for monitoring after starting bisphosphonates," write Katy J.L. Bell, from the University of Sydney in Sydney, Australia, and colleagues from the Fracture Intervention Trial. "The US National Osteoporosis Foundation and the American Association of Clinical Endocrinologists recommend routine monitoring of bone mineral density within two years of starting treatment....The UK guidelines recommend that further research is needed and the North American guidelines recommend that treatment should not be stopped or changed because of a modest observed loss in density."
The goal of this secondary analysis of trial data using mixed models was to determine the value of monitoring response to bisphosphonate treatment by BMD measurement. The Fracture Intervention Trial was a randomized controlled trial comparing the effects of alendronate vs placebo on BMD after menopause. Between May 1992 and May 1993, a total of 6459 postmenopausal women with low BMD were enrolled and underwent measurement of hip and spine BMD at baseline and at 1, 2, and 3 years after randomization. The primary endpoints of the study were variation in hip and spine BMD, both between-person (treatment related) and within-person (measurement related).
After 3 years' treatment with alendronate, there was an increase in hip BMD by 0.030 g/cm2. Although there was some between-person variation in the effects of alendronate, this was small vs within-person variation. In most patients (97.5%), increases in hip BMD of 0.019 g/cm2 or more were attributed to alendronate treatment.
"Monitoring bone mineral density in postmenopausal women in the first three years after starting treatment with a potent bisphosphonate is unnecessary and may be misleading," the study authors write. "Routine monitoring should be avoided in this early period after bisphosphonate treatment is commenced."
Although improved adherence to treatment is sometimes cited as a reason for BMD monitoring, the study authors note that most adverse events occur within 3 months of starting treatment and that discussing any complaints with a healthcare professional a few months after starting therapy improves compliance.
In an accompanying editorial, Juliet Compston, from the University of Cambridge in Cambridge, United Kingdom, notes that biochemical markers of bone turnover could potentially be used for monitoring because they change rapidly in response to treatment and predict fracture risk better than BMD. However, within-person and measurement variability are too high for these markers to allow their routine use in clinical settings.
"If true non-responders to antiresorptive treatment do exist they are rare, and most cases of non-response are caused by failure to persist with treatment," the study authors write. "This is best tackled by carefully explaining the treatment to patients before they start and follow-up after about three months to discuss problems related to treatment. Routine monitoring of bone mineral density during the first few years of antiresorptive treatment cannot be justified because it may mislead patients, lead to inappropriate management decisions, and waste scarce healthcare resources."
PEMETREXED FOR OVARIAN CANCER
Phase II Evaluation of Pemetrexed in the Treatment of Recurrent or Persistent Platinum-Resistant Ovarian or Primary Peritoneal Carcinoma: A Study of the Gynecologic Oncology Group
From the University of Texas Southwestern Medical Center, Dallas, TX; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo; Long Island Gynecologic Oncologists, Smithtown, NY; Dana-Farber Partners Cancer Care, Massachusetts General Hospital, Boston, MA; University of Oklahoma, Oklahoma City, OK; Abington Memorial Hospital, Rosenfeld Cancer Center, Abington, PA; University Hospital Case Medical Center, Cleveland, OH; and Virginia Commonwealth University, Richmond, VA.
Corresponding author: David Scott Miller, MD, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, J7.124, Dallas, TX 75390-9032; e-mail: david.miller@utsouthwestern.edu.
Purpose To estimate the antitumor activity of pemetrexed in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer and to determine the nature and degree of toxicities.
Patients and Methods A phase II trial was conducted by the Gynecologic Oncology Group. Patients must have had cancer that had progressed on platinum-based primary chemotherapy or recurred within 6 months. Pemetrexed at a dose of 900 mg/m2 was to be administered as an intravenous infusion over 10 minutes every 21 days. Dose delay and adjustment was permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects.
Results From July 6, 2004, to August 23, 2006, 51 patients were entered. A total of 259 cycles (median, four; range one to 19 cycles) of pemetrexed were administered, with 40% of patients receiving six or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15% of patients. No treatment-related deaths were reported. One patient (2%) had a complete and nine patients (19%) had partial responses, with a median duration response of 8.4 months. Seventeen patients (35%) had stable disease for a median of 4.1 months. Eighteen patients (38%) had increasing disease. Three patients (6%) were not assessable. Median progression-free survival was 2.9 months, and overall survival was 11.4 months.
Conclusion Pemetrexed has sufficient activity in the treatment of recurrent platinum-resistant ovarian cancer at the dose and schedule tested to warrant further investigation.SORAFENIB AND SUNITINIB FOR SOFT TISSUE SARCOMAS
Phase II Study of Sorafenib in Patients With Metastatic or Recurrent Sarcomas
From the Departments of Medicine, Pathology, Radiology, and Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center; Rockefeller University, New York, NY; Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago; Evanston Northwestern Health Care, Evanston, IL; Carolinas Hematology-Oncology and University of North Carolina, Charlotte, NC; Division of Hematology and Oncology, University Hospitals Case Medical Center, Case Comprehensive Cancer Center, Cleveland, OH; Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center, San Antonio, TX; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC; and the University of Colorado Cancer Center, Aurora, CO.
Corresponding author: Robert G. Maki, MD, PhD, Melanoma-Sarcoma Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Howard 909, New York, NY 10065; e-mail: makir@mskcc.org.
Purpose Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma.
Patients and Methods We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued.
Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies.
Conclusion As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.
Supported by the National Cancer Institute (NCI) Program Project Grant No. CA47179, NCI phase II contract CM62202, Cycle for Survival, the Shuman Family Fund for GIST research, and the Sarcoma Research Fund.
Presented in part in oral format at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.Multicenter Phase II Trial of Sunitinib in the Treatment of Nongastrointestinal Stromal Tumor Sarcomas
From the Dana-Farber Cancer Institute; Massachusetts General Hospital; Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA; and the Memorial Sloan-Kettering Cancer Center, New York, NY.
Corresponding author: Suzanne George, MD, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, 44 Binney St, D1210, Boston, MA 02115; e-mail: suzanne_george@dfci.harvard.edu.
Purpose To evaluate the potential benefit of continuous daily dosing sunitinib in patients with advanced nongastrointestinal stromal tumor (GIST) sarcomas.
Patients and Methods A total of 53 patients with advanced non-GIST soft tissue sarcomas received sunitinib 37.5 mg daily. Primary end point was Response Evaluation Criteria in Solid Tumors defined response. Secondary end points were stable disease at 16 and 24 weeks. [18F]-fluorodeoxyglucose positron emission tomography was performed on a subset of 24 patients at baseline and after 10 to 14 days of therapy.
Results Forty-eight patients were eligible for response. One patient (desmoplastic round cell tumor [DSRCT]) achieved a confirmed partial response (PR) and remained on study for 56 weeks. Ten patients (20%) achieved stable disease for at least 16 weeks. Metabolic PR was seen in 10 (47%) of 21 of patients. Metabolic stable disease was seen in 11 (52%) of 21. There were no unexpected toxicities observed.
Conclusion Sunitinib demonstrated notable evidence of metabolic response in several patients with non-GIST sarcoma. The relevance of disease control observed in subtypes with an indolent natural history is unknown, however, the durable disease control observed in DSRCT, solitary fibrous tumor, and giant cell tumor of bone suggests that future evaluation of sunitinib in these subtypes may be warranted.
Supported in part by Pfizer Inc; the Virginia and Daniel K. Ludwig Trust for Cancer Research; Cycle for Survival and NCI program project CA47179 (R.G.M., G.K.S.) and correlative studies supported by National Comprehensive Cancer Network, protocol No. NCCN-S109.
Presented in part at the 13th Annual Connective Tissue Oncology Society Conference, Seattle, WA, October 31 to November 3, 2007; and the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30 to June 3, 2008.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Clinical Trials repository link available JCO.org.ANOTHER IRINOTECAN ADJUVANT FAILURE
- Ann Oncol. 2009 Jun 30. [Epub ahead of print]
A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer.
Ychou M, Hohenberger W, Thezenas S, Navarro M, Maurel J, Bokemeyer C, Shacham-Shmueli E, Rivera F, Kwok-Keung Choi C, Santoro A.
CRLC Val d'Aurelle, Montpellier, France.
BACKGROUND: Studies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting. PATIENTS AND METHODS: LMCRC patients were randomized to receive every 14 days, FA, 400 mg/m(2) infused over 2 h, followed by 5-FU as a 400 mg/m(2) i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m(2) over 46 h (LV5FUs) with or without irinotecan: 180 mg/m(2) infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety. RESULTS: Treated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI [hazard ratio (HR) 0.89, log-rank P = 0.44]. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%). CONCLUSION: FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.
SORAFENIB FOR THYROID CANCER
Some patients with advanced thyroid cancer may benefit from sorafenib
26.06.09
Category: Scientific News
Response not related to histology and worse in patients with bone metastases
Nearly 8,000 attendees from more than 75 countries attended Endocrine Society meeting in Washington, DC, 10-13 June, 2009. The strong relevance of science and clinical practice at the annual meeting brought together unparalleled access to the most sought after experts sharing groundbreaking innovations and progressive clinical treatments, and meeting endocrinology’s emerging challenges.
Almost two-thirds of patients with advanced thyroid cancer benefited from treatment with the tyrosine kinase inhibitor sorafenib according data from a small clinical trial presented during the meeting. Of the 26 patients in the study, 19 (62%) had partial responses or stable disease during 26 weeks of treatment. Median progression-free survival exceeded a year, and 14 patients remained alive after a median follow-up of 63 weeks.
Karen Heemstra, MD, of Leiden University in the Netherlands presented data from the phase II clinical trial involving 31 patients, median age 65, who had differentiated thyroid cancer that could not be treated with surgery or radioiodine ablation. All patients received sorafenib 400 mg twice a day for a maximum of 26 weeks, and response was assessed at baseline and at 26 weeks by CT scan and thyroglobulin measurement. Patients who completed the study could remain on treatment during an open-ended extension phase. Median time from diagnosis was three years. Only one patient had localized disease. Papillary and follicular histology accounted for 90% of the cases.
Of the 13 patients with papillary disease, 12 had the BRAFV600E mutation and one had NRAS mutation. Among the 14 patients with follicular histology, 10 had Hurtle-cell metaplasia and one had mutated NRAS. At the end of 26 weeks, five patients had withdrawn because of adverse events. An additional four patients had progressive disease.
Of the 22 patients who entered the open-phase extension, six had progressive disease and two withdrew because of adverse events. Eight patients had partial responses and 11 others had stable disease, resulting in a total clinical benefit of 62% (19 of 26).
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 (P=0.04). All patients with progressive disease had bone metastases. Progression-free survival was 69 weeks without bone metastases and 47 weeks in patients who had bone metastases.
Toxicity was common. A majority of patients had hand-foot syndrome, weight loss, diarrhea, alopecia, and rash/mucositis, and almost half had treatment-emergent hypertension and hypocalcemia. Almost 60% of patients required temporary sorafenib dose reductions.
VINFLUNINE IS HERE
EMEA adopted positive opinion for vinflunine intended for the treatment of carcinoma of urothelial tract
30.06.09
Category: Scientific News
Extended indication for bevacizumab in combination therapy with docetaxel to the first-line treatment of metastatic breast cancer
At the June, 2009 the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted positive opinion, recommending the granting of a marketing authorisation, for the following medicines:
- vinflunine ditartrate, from Pierre Fabre Medicament, intended for the treatment of carcinoma of urothelial tract. The review began on 27 February 2008, with an active review time of 196 days.
The Committee also adopted positive opinion for the following generic medicine, for which a reference medicine is already authorised in the European Union:
- topotecan hydrochloride, from Teva Pharma B.V., a generic of Hycamtin®, intended for the treatment of ovary carcinoma, small cell lung cancer and carcinoma of the cervix.
The Committee gave positive opinion for application for the extension of indication, adding new treatment options, for the following medicine:
- bevacizumab, from Roche Registration Ltd., to extend the indication to add combination therapy with docetaxel chemotherapy to the first-line treatment of metastatic breast cancer. Bevacizumab is already authorised in this indication in combination with paclixatel. It is also authorised for first-line combination therapy of patients with certain types of cancer of the colon or rectum, the kidney and non-small cell lung cancer.
FDA MAY RESTRICT ACETAMINOPHEN
July 1, 2009 — The FDA should put new restrictions on acetaminophen, an advisory committee recommended Tuesday, saying the move would protect people from the potential toxicity that can cause liver failure and even death.
The FDA does not have to follow its advisory committees’ recommendations, but it usually does. It will likely be months before the FDA makes a final decision on the drug.
One of the nation’s top drugs for pain relief, acetaminophen is found in many over-the-counter products -- including Tylenol, aspirin-free Anacin, Excedrin, and numerous cold medicines. It's also found in many prescription drugs.
Billions of doses of acetaminophen are used safely every year. But acetaminophen-related overdoses cause 56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths annually, according to studies done between 1990 and 1998.
Some people inadvertently take more than is recommended. Others -- such as people with underlying liver disease -- are more at risk of liver injury from acetaminophen use. Because acetaminophen is in so many products, people sometimes take two or more products containing acetaminophen without realizing it. That risk extends to children, who may be poisoned because they swallow the medication. Sometimes caregivers mistakenly give children too much acetaminophen.
Acetaminophen: Limiting Dosage Amounts
The advisory committee voted that the single adult acetaminophen dose should be no more than 650 milligrams, significantly less that the current 1,000 milligrams often contained in two tablets of certain over-the-counter pain products. The panel of 37 doctors and other experts also said that the maximum total dose for 24 hours, now at 4,000 milligrams, should be decreased.
Some advisory committee members said the move should help lower the overall amounts of acetaminophen that people take. Some on the panel said they were influenced by research indicating there are changes in liver function in some people who had taken only the currently recommended levels.
Call to Eliminate Some Acetaminophen Products
In a recommendation that would be a real change for the prescription industry, the committee voted 20 to 17 that prescription products that combine acetaminophen with other medications should be eliminated. Today, billions of doses of products are prescribed in which acetaminophen is combined with narcotics, according to the FDA. Some brand-name pain prescriptions containing acetaminophen include Vicodin, Lortab, Maxidone, Norco, Zydone, Tylenol with codeine, Percocet, Endocet, and Darvocet.
The combination of hydrocodone and acetaminophen, for instance, has been the most frequently dispensed drug since 1997, according to the FDA.
Richard DeNisco, MD, MPH, medical officer at the National Institute of Drug Abuse and a panel member, said that so much acetaminophen is going out to people in hydrocodone/acetaminophen mixes that he is uncertain why there is not more liver damage.
Prohibiting these combined products “would rock the system,” he said, but the two products should be prescribed separately, if necessary.
The combination prescription products, which have rapidly increased in use in the last five years, are clearly the biggest cause of the acetaminophen overdose, said Marie Griffin, MD, professor of preventive medicine at Vanderbilt University. But she worried that people will simply turn to plain narcotics, if the combinations are eliminated. “We need a broader answer to chronic pain, because these drugs are being used extensively in the older population," Griffin said during the meeting. "And I am not sure that practitioners feel like they have many other choices.”
On the other hand, the committee declined to vote for eliminating combination acetaminophen products that are sold over the counter.
Karl Lorenz, MD, who is with the VA Los Angeles Healthcare System, said that many people are being creative in managing low level chronic pain. “I just think we have to be cautious about eliminating an entire category of products that many people find useful,” he said.
Black Box Warning Advised for Acetaminophen Combination Products
The advisory committee also voted overwhelmingly to recommend that the FDA require a boxed warning -- often called a black box warning -- on the labels of prescription acetaminophen combination products, with members noting this is considered the highest precaution the agency can give.
They also called for limiting formulations of liquid over-the-counter acetaminophen to only one concentration level in order to reduce confusion when people give the medicine to children.
Linda Suydam, president of the Consumer Healthcare Products Association, which represents companies that make over-the-counter products, objected to the committee’s recommendations for new limits on acetaminophen in over-the-counter products.
“CHPA strongly believes that patients and physicians need to have a wide range of dosing available for patients who need their acetaminophen-containing products,” she said, asserting there is little data to support the idea that patients are harmed at current levels.
NOVEL PACLITAXEL FORMULATION
NEW YORK (Reuters Health) Jun 25 - In patients with unresectable pancreatic cancer, the combination of gemcitabine and a novel cationic liposomal formulation of paclitaxel called EndoTAG-1 substantially prolongs survival compared to gemcitabine therapy alone, according to a study presented this week.
EndoTAG-1, developed for the treatment of solid malignancies, targets activated negatively-charged endothelial cells of tumor blood vessels, Dr. Matthias L�hr of the Karolinska Institute, Stockholm, and colleagues explain in materials for the European Society for Medical Oncology's (ESMO) 11th World Congress on Gastrointestinal Cancer in Barcelona, Spain.
In a phase II study, the research team randomized 200 patients with locally advanced or metastatic pancreatic cancer to first-line treatment with weekly gemcitabine (1000 mg/m�) and twice weekly EndoTAG-1 at three different dose levels (11, 22, or 44 mg/m�) or to gemcitabine alone.
"The key finding is that the median survival time is dramatically prolonged in patients with advanced (inoperable) pancreatic cancer," Dr. L�hr told Reuters Health.
Tumor response after 7 weeks, according to RECIST (Response Evaluation Criteria in Solid Tumors), showed a higher proportion of patients with non-progressive disease in the combination arm (60%, 65%, and 52%, respectively, for gemcitabine plus low, medium, and high doses of EndoTAG-1) than in the gemcitabine only arm (43%).
Median progression-free survival, the researchers report, was "markedly higher" with combination therapy than monotherapy. Median progression-free survival was 18, 20, and 19 weeks, respectively, in the gemcitabine/EndoTAG-1 low, medium, and high dose groups, compared with 12 weeks in the gemcitabine monotherapy group.
Median overall survival was 7.2 months with gemcitabine alone versus 8.4, 8.7, and 9.4 months with gemcitabine plus low, medium, and high dose EndoTAG-1. Twelve-month survival rates were 17% with gemcitabine alone versus 22%, 36% and 33% for gemcitabine plus low, medium and high dose EndoTAG-1.
The study team also noted a dose-dependent improvement in pain scores on a standard quality of life questionnaire during treatment in the gemcitabine plus EndoTAG-1 groups. "Adverse events related to combination therapy were predominantly chills and pyrexia of mild to moderate intensity," the authors report.
Based on these data, Dr. L�hr told Reuters Health, the team is planning a phase III study of EndoTAG-1, which is being developed by German biotech company MediGene.
LANTUS IS OUT
July 1, 2009 — Three of 4 observational studies suggest an increased risk for cancer associated with use of insulin glargine (Lantus, sanofi-aventis), although these findings warrant further follow-up studies to confirm an association, according to the US Food and Drug Administration (FDA).
The FDA is currently reviewing many sources of safety data for insulin glargine, including these newly published observational studies, according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program.
The FDA currently is recommending that patients not stop taking insulin glargine without consulting a healthcare professional. No guidance regarding action to be taken by healthcare professionals has been issued.
Insulin glargine is approved to control blood glucose in patients with type 1 and type 2 diabetes.
The observational studies were published in the June 30 issue of Diabetologia,, the journal of the European Association for the Study of Diabetes (EASD). According to an EASD press release, one data analysis of 127,000 insulin-treated patients reported a statistically significant link between cancer and insulin glargine use compared with those using similar doses of human insulin. Among those receiving insulin glargine, there was an increase of 1 person with cancer for every 100 people receiving human insulin.
This study, conducted in Germany, also indicated a dose-dependent increase in cancer risk; 10 U of insulin glargine increased the risk by 9% whereas 50 U increased the risk by 31%.
As a result of these findings, studies were also conducted in databases from Sweden, Scotland, and the United Kingdom. The Swedish study found that compared with patients on other forms of insulin, patients receiving insulin glargine alone had a 2-fold increased risk for breast cancer. The Scottish study found a nonsignificant increased risk for breast cancer, whereas the UK study found no link between insulin glargine and any type of cancer.
According to the FDA, further studies are underway “to better understand the risk, if any, for cancer associated with use of [insulin glargine].”
More information is available on the FDA's MedWatch Web site.
Adverse events related to use of insulin glargine therapy should be communicated to the FDA's MedWatch reporting program by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.
EVERYDAY PRACTICE IN GREECE
June 26, 2009 (Lafayette, Louisiana) — An interventional cardiologist who implanted stents in patients who did not need them has been sentenced to 10 years in federal prison for healthcare fraud. Dr Mehmood Patel, formerly of Our Lady of Lourdes Hospital and Lafayette General Hospital in Louisiana, was convicted on 51 counts of billing private and government health insurers for unnecessary medical procedures and received the maximum sentence.
Our Lady of Lourdes Hospital and Lafayette General Hospital both suspended Patel's privileges in late 2003 or early 2004 as a result of their own internal investigations. Elisabeth Arnold, a spokesperson at Our Lady of Lourdes Regional Medical Center, told heartwire that the hospital reached legal closure on the issue long before Patel's sentencing.
The hospital paid $3.8 million in 2006 to settle a US Department of Justice false-claims lawsuit and also paid an additional $7.4 million to settle a class-action lawsuit brought by Patel's former patients. Arnold noted that in the past several years, the hospital has "increased physician leadership in our organization, implemented more stringent policies, and improved peer-review initiatives."
Patel's trial began in October 2008 and lasted 11 weeks. The 64-year-old doctor was initially indicted on 91 charges of fraud involving 75 patients. During his trial, 80 government witnesses testified, as did experts from Emory University, the University of Pennsylvania, Mount Sinai Hospital in New York, and the University of California, Los Angeles. The medical experts testified about a small number of procedures performed by Patel during a three-year period covered by the indictment, but their testimony stated that Patel performed tests and procedures in patients with little or no disease, according to the Department of Justice [1].
Testimony during the trial also revealed that Patel falsified patient symptoms in medical records, including chest pain when patients never complained of such pain, and falsified findings on medical tests. From 1999 to 2003, Patel billed Medicare and private insurance companies more than $3 million, according to the Advocate, a Baton Rouge, LA newspaper [2]. During this time, he was the top cardiology biller in the state and personally pocketed more than $500 000.
US District Court Judge Tucker Melançon called Patel "a brilliant and talented physician" and stated he was unsure whether the doctor was driven by pure greed or ego. Regardless, Melançon had little sympathy for Patel when sentencing him, noting that the doctor lied during his 19 days of testimony, contradicting findings made by the government witness, according to the Advocate.
Patel, who had been in clinical practice in Louisiana for 25 years, begins serving his sentence on July 6, 2009 at a federal facility in Oakdale, LA. He plans to appeal his conviction.
GASTRIC ADENOCARCINOMA MORE AGGRESIVE IN YOUNG PATIENTS
NEW YORK (Reuters Health) Jun 25 - Patients aged 35 years or less with gastric adenocarcinomas appear particularly at risk of having advanced disease at diagnosis, as well as more aggressive tumors, Californian researchers report in the June issue of the Archives of Surgery.
Dr. Bruce E. Stabile of University of California, Los Angeles, Medical Center, Torrance, and Dr. Brian R. Smith of the University of California, Irvine Medical Center, Orange point out that clinical observation has suggested that very young patients have a far worse prognosis than their older counterparts. "The relatively high mortality is largely attributable to the advanced stage of disease at diagnosis regardless of age," they note.
To investigate whether they also had biologically more aggressive disease, the researchers retrospectively reviewed data on 350 patients diagnosed with the condition.
In all, 30 (9%) were aged 35 years or less, and compared to older patients, they were significantly more likely to have histologic findings of diffuse tumor types (93% versus 69%). This was also true of adjacent organ invasion (74% versus 29%) as well as nodal and distant metastases. They were also more likely to have stage IV disease (90% versus 64%).
Despite similar operation rates, potentially curative gastrectomy was achieved in only 17% of the younger patients compared to 58% of older patients. The younger patients also had higher postoperative mortality (22% versus 2%).
In addition, mean survival was 33.4 months in older patients compared to 11.6 months in younger patients.
Given these findings, the researchers conclude that "strategies for earlier diagnosis together with effective new therapies are desperately needed to attenuate the extreme lethality in these uniquely unfortunate patients."
Arch Surg 2009;144:506-510.
SELENIUM AND AGGRESIVE PROSTATE CANCER
July 1, 2009 — "If you already have prostate cancer, it may be a bad thing to take selenium," says the senior author of a new study published online June 15 in the Journal of Clinical Oncology.
Selenium supplements have been sold and promoted as a means of preventing prostate cancer, but the large SELECT prevention trial recently showed no effect on the incidence rate. Now this latest study suggests the potential for harm in patients who already have prostate cancer.
In the study, Philip Kantoff, MD, director of genitourinary oncology at the Dana-Farber Cancer Institute at the University of California, San Francisco, and colleagues found that having a high level of selenium in the blood was associated with a slightly elevated risk of aggressive prostate cancer.
But the risk was particularly elevated in men who also had a certain variant of the gene coding for manganese superoxide dismutase (SOD2). For these men, who made up 75% of the study population, having "high selenium levels might increase the likelihood of having worse characteristics," the researchers concluded.
The results were unexpected, and they are the first to raise concern about potentially harmful consequences of taking supplemental selenium. Until further data are available to sort out which men can safely take the supplement, Dr. Kantoff told Medscape Oncology that he would advise patients with prostate cancer not to take supplements containing selenium.
Interaction Between Selenium and Genotype
The study involved 489 patients who had been diagnosed with prostate cancer at the Dana Farber Center between 1994 and 2001. These men had a mean age of 62 years and mean level of prostate specific antigen (PSA) of 6.0 ng/mL. More than half had good-risk disease, while about a third had intermediate-risk disease, the researchers comment.
The team examined banked blood samples for selenium levels and also for genomic DNA, in particular genotyping for the SOD2 polymorphism: 25% of patients were found to carry the A form of the gene, and 75% carried the V form of the gene.
Dr. Kantoff and colleagues found that having higher vs lower selenium blood levels was associated with a slightly increased likelihood of presenting with aggressive disease (relative risk, 1.35). The mean selenium level (121.4 ng/mL) in this patient population was similar to that reported in several other studies (ranging between 108 and 141 ng/mL), the researchers comment.
There was no way of knowing which patients had been taking selenium supplements, the researchers comment. But they note that the levels measured in this study were substantially lower than the median level (252 ng/mL) in men who were taking selenium supplements in the large SELECT prevention study.
This study found no effect of SOD2 genotype on disease aggressiveness, although this effect has been reported previously both by this team and others.
However, there was evidence of an interaction between the SOD2 genotype and selenium levels.
Among men with the AA genotype, higher selenium levels were associated with a 40% reduced risk of presenting with aggressive disease (relative risk, 0.60), while among men with the V allele (either VV or VA genotype), higher selenium levels were associated with an almost doubling of the risk of aggressive disease (relative risk, 1.82; P = .007 for the interaction).
"It is possible that selenium helps some and may harm others," Dr. Kantoff commented to Medscape Oncology. "Genetic studies will help sort this out. Until then, I would not advise taking selenium supplements," he said.
Potential Harm Not Previously Reported
The direct relation of higher selenium with more aggressive disease among V-allele carriers was "unexpected and has not been previously reported," say the researchers.
"One explanation may be that in men with established cancer, antioxidants may promote cancer-cell survival through an antiapoptotic mechanism by neutralizing the higher levels of reactive oxygen species found in cancer cells," they speculate. However, there could be other explanations, and the finding may also be due to chance and so needs confirmation, they add.
"These data suggest that the relationship between circulating selenium levels at diagnosis and the prognostic risk of prostate cancer is modified by the SOD2 genotype and indicate caution against broad use of selenium supplementation for men with prostate cancer," the authors conclude.
Prevention Study Found No Benefit
These new findings are also "interesting, particularly in light of the recent negative results from the SELECT prevention study," Dr. Kantoff commented in a statement.
The SELECT study set out to discover whether taking selenium and vitamin-E supplements would offer protection against prostate cancer, but the trial was stopped early in October 2008 because of an apparent lack of benefit and a possibility of harm, as reported by Medscape Oncology.
Selenium supplements' reputation for prevention, sold and promoted as a means of preventing prostate cancer, is largely based on observational studies that found a higher risk for prostate-cancer incidence and mortality in geographical areas that were naturally low in selenium. But studies with selenium as a preventive have shown mixed results.
However, after announcing the results from the huge SELECT study, which involved 35,000 men, lead author Larry Baker, MD, professor of medicine at the University of Michigan Medical School, in Ann Arbor, said: "This is the definitive study, and anyone who argues against it is ignoring the facts."
Dr. Kantoff tells Medscape Oncology that it is now "essential" to go back and genotype the samples in the SELECT trial. "There may be some people who benefit and some who do not or are even harmed."
No conflicts of interest were reported.
J Clin Oncol. Published online June 15, 2009. Abstract
PET-CT FOR PREOPERATIVE STAGING OF LUNG CANCER
PET-CT also reduced the total number of thoracotomies and improved diagnostic accuracy compared with conventional staging.
However, the use of this more expensive technology in the staging of these patients did not significantly affect overall survival, write the authors of the study in the July 2 issue of the New England Journal of Medicine.
Nevertheless, the authors of the study emphasize the benefits of PET-CT, including the fact that improved diagnostic accuracy can help avoid "resections of benign nodules and early local and distant relapse after surgery with curative intent." The authors were led by Barbara Fischer, PhD, from the department of oncology at the Odense University Hospital, in Copenhagen, Denmark.
The primary end point of the study, futile thoracotomy, is "controversial" in so far as it does not have a completely agreed-upon definition in the field, suggest the authors. In the study, a thoracotomy was considered futile in the event of any of the following clinical findings or results: a benign lung lesion, pathologically proven mediastinal lymph node involvement (stage IIIA [N2]), stage IIIB or IV disease, inoperable T3 or T4 disease, or recurrent disease or death from any cause within 1 year of randomization.
If that definition is accepted and futile thoracotomy is indeed considered a valid end point, write the authors, "the significantly higher number of early deaths and relapses in the conventional-staging group than in the PET-CT group was not due to chance or more successful surgery in the PET-CT group but instead reflects a better selection of patients for surgery in the PET-CT group."
Specifically, after staging, 60 patients in the PET-CT group (out of a total of 98) and 73 in the conventional-staging group (out of a total of 91) were considered to have operable disease and underwent thoracotomy.
Of the 60 patients in the PET-CT group, the thoracotomy was futile in 21 (35%), and of the 73 patients in the conventional-staging group, the procedure was futile in 38 (52%) (P = .05).
For the PET-CT group, the diagnostic accuracy and sensitivity were 79% and 64%, respectively. For the conventional-staging group, the accuracy and sensitivity were 60% and 32%, respectively.
Confirms Another Study
The new study's findings are similar to the results of another trial. That study, led by Harm van Tinteren, MD, from the Comprehensive Cancer Center Amsterdam, in the Netherlands, involved a similar number of patients (188) with NSCLC, although 70% of these patients had localized disease vs 34% in the latest study. Nevertheless, that study yielded a similar result and showed that staging with stand-alone PET resulted in an absolute risk reduction of futile thoracotomy by 20% (van Tinteren H et al. Lancet. 2002;359:1388-1393).
But there is 1 other trial that is comparable to these 2 studies that had different results. In an Australian study of 184 patients, 92% of whom had localized disease, there was no difference in number of thoracotomies between the 2 randomized comparison groups: patients who underwent staging with stand-alone PET and those who underwent conventional staging (Viney RC et al. J Clin Oncol. 2004;22;2357-2362).
However, this Australian study did not use confirmatory invasive procedures — only 10 of the 184 patients underwent mediastinoscopy, the authors of the latest study point out. In their own study, 94% of the patients underwent mediastinoscopy, which was "one of the strengths of the study," Dr. Fischer and colleagues comment. Eleven percent of the patients had positive lymph nodes on mediastinoscopy. Thus, these patients were considered to have inoperable disease in the current study but would have not been so classified in the Australian study; in short, the lack of mediastinoscopy weakens the Australian findings, Dr. Fischer and colleagues suggest.
One of the limitations of the current study is that it did not meet enrollment goals and was closed due to slow accrual.
The study was designed so that 215 patients would be randomized to each group (for a total of 430 patients), thus allowing enough power to detect a difference of 15% in the number of futile thoracotomies between the 2 groups, write the authors. However, the study was closed after enrolling only 189 patients. The published study is the first analysis of the data.
No Significant Difference in Survival
The staging of NSCLC was 1 of the first approved indications for PET, the authors observe. The combined PET-CT "has rapidly replaced stand-alone PET" since 2001, they add. The diagnostic capability has been proven to be superior to either PET or CT alone, they add. The advantage is mainly based on the superior assessment of tumor stage, the authors write.
Despite being the standard of care, there has been uncertainty about whether or not improved diagnostic accuracy translates into improved management of patients. The findings of the current study suggest that management is improved. However, there were no significant differences in survival between the 2 groups, with a median survival of 31 months in the PET-CT group and 49 in the conventional staging group (P = .29).
The study was supported by grants from the Danish Cancer Society and the Danish Center for Health Technology Assessment. One of the coauthors has received lecture fees from AstraZeneca. No other financial relationships were disclosed.
New Engl J Med. 2009;361:32-39.
VEGF INHIBITORS AND METASTASIS
Therapies aimed at inhibiting angiogenesis by targeting the vascular endothelial growth factor A (VEGFA)-VEGFR2 (VEGF receptor 2) pathway have been beneficial in treating several types of cancers. However, the benefits are often short lived, and various adaptive mechanisms eventually lead to tumour progression. Two papers in Cancer Cell have shown that, despite positive effects on established localized tumours, inhibition of angiogenesis can result in increased tumour invasion and metastasis.
Oriol Casanovas, Douglas Hanahan and colleagues studied the response to VEGFA-VEGFR2 pathway inhibition of pancreatic neuroendocrine cancer in the RIP1-Tag2 mouse model and glioblastoma multiforme (GBM) in an orthotopic mouse model. One week of treatment of tumour-bearing immunocompromised RIP1-Tag2 mice with the anti-VEGFR2 antibody DC101 resulted in significantly more invasive tumours, an effect that was intensified by longer treatment: 6% of tumours in control mice were categorized as highly invasive compared with 54% and 62.5% in mice treated for 1 week and 4 weeks, respectively. This phenotype was not reversible, as invasiveness persisted for at least 3 weeks after treatment was stopped. Furthermore, in immunocompetent RIP1-Tag2 mice, short-term DC101 treatment significantly increased the number of mice with long-term lymph node (fourfold) and liver (twofold) metastases, and the number of liver metastases per animal. The authors noted a significant increase in hypoxia in DC101-treated tumours and metastases, suggesting one possible molecular mechanism for the increased invasion. Similar data were observed with sunitinib, a Vegfr and platelet-derived growth factor receptor (Pdgfr) kinase inhibitor currently in clinical use, when administered continuously for 5 weeks, with the interesting exception of the increased incidence of lymph node metastases. The authors speculate that this could be because sunitinib, but not DC101, also inhibits VEGFR3 in lymphatic vessels. Finally, in a model of GBM, treatment with either sunitinib or the Vegfr-selective kinase inhibitor SU10944 increased invasion, which is consistent with several recent clinical studies in GBMs.
Robert Kerbel and colleagues also found a relationship between anti-angiogenic drugs and metastasis using a different approach. In agreement with preclinical and clinical efficacy of Vegfr inhibitors, they showed that sunitinib can inhibit the growth of localized orthotopically grown tumours from 231/LM2-4LUC+ metastatic human breast cancer cells, MeWo human melanoma cells or B16 mouse melanoma cells. However, short-term treatment of mice with sunitinib for 7 days either before or after tail vein injection of 231/LM2-4LUC+ cells accelerated metastatic disease progression and significantly reduced median survival compared with vehicle treatment. Similar results were obtained with short-term treatment using the Vegfr inhibitors sorafenib or SU10944 prior to 231/LM2-4LUC+ cell injection. The authors also found increased metastasis when mice were treated with short-term sunitinib before intravenous injection of MeWo cells. These data suggest that Vegfr inhibitors might precondition the host microenvironment, making it favourable for metastasis.
It is important to emphasize that both studies clearly recapitulate the clinical data that anti-angiogenic therapies can have significant, albeit transitory, effects on localized tumour growth. However, they raise interesting questions about the timing of anti-angiogenic therapy and whether combining these agents with chemotherapy or other targeted agents can counteract the observed unfavourable effects. Further studies to understand the mechanisms behind these dual effects of Vegfr inhibitors should help the development of more effective therapeutic options.
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Original Research Papers
• Pàez-Ribes, M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15, 220-231 (2009)
• Ebos, J. M. L. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232-239 (2009)
Further Reading
• Bergers G. & Hanahan D. Modes of resistance to anti-angiogenic therapy. Nature Rev. Cancer 8, 592-603 (2008)
AN INTERESTING DIAGNOSIS
Eur J Cancer Care (Engl). 2009 Jun 22. [Epub ahead of print] Related Articles, LinkOut
Supraclavicular lymph node metastases of unknown origin: HPV-typing identifies the primary tumour.
Kuemper C, Burges A, Hillemanns P, Mueller-Egloff S, Lenhard M, Ditsch N, Strauss A.
Department of Obstetrics and Gynecology, Kiel University Hospital, Arnold-Heller-Strasse 3, 24105 Kiel, Germany.
KUEMPER C., BURGES A., HILLEMANNS P., MUELLER-EGLOFF S., LENHARD M., DITSCH N. & STRAUSS A. (2009) European Journal of Cancer Care Supraclavicular lymph node metastases of unknown origin: HPV-typing identifies the primary tumourCancers of unknown primary origin (CUP) account for 0.5-10% of all malignancies. CUP patients with metastases have a median survival of approximately 6 months, despite therapy. Identification of the primary tumour site may offer the opportunity of a specific and more efficient treatment. The case of a 45-year-old woman with supraclavicular lymph node metastases of a squamous cell CUP is reported. A staging laparoscopy with multiple biopsies and a loop diathermy excision of the cervix were performed. Human papillomavirus (HPV)-testing in the tissues revealed the tumour cells as metastases of an occult cervical cancer. Primary platin-based chemotherapy combined with paclitaxel leads to a complete apparative remission. Twelve months later, staging positron emission tomography with 2-[(18)F]fluoro-2-deoxy-D-glucose in combination with computed tomography identified an isolated left renal lymph node metastasis. The patient received targeted radiation therapy, combined with cisplatin. To date, 19 months after diagnosis, she is doing well without any evidence of disease. The presented case report addresses the difficulties involving the identification of CUP. HPV-DNA is found in over 95% of cervical cancers. As the presented case illustrates, testing for this virus DNA in human tissues can be a useful diagnostic tool in patients with CUP where cervical cancer is the possible primary tumour.
TANDEM HDCT FOR REFRACTORY GERM CELL TUMORS
| Urol Oncol. 2009 Jun 23. [Epub ahead of print] | Related Articles, LinkOut |
Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features.
De Giorgi U, Rosti G, Salvioni R, Papiani G, Ballardini M, Pizzocaro G, Marangolo M.
Department of Oncology and Hematology, Istituto Oncologico Romagnolo-Santa Maria delle Croci Hospital, Ravenna, Italy.
OBJECTIVE: High-dose chemotherapy (HDCT) represents an option as salvage treatment for patients with resistant/refractory germ cell tumor (GCT). The objective of this retrospective analysis was to evaluate the long-term results of a single-center experience with salvage HDCT for GCT patients, and to validate the prognostic model proposed by Einhorn and colleagues [9]. MATERIALS AND METHODS: Between 1986 and 2003, 100 GCT patients received salvage HDCT consisting of high-doses of carboplatin, etoposide +/- cyclophosphamide, or ifosfamide. Twenty-four patients underwent a second HDCT cycle, and in 1 case, a third cycle was given with a median interval time of 6 weeks (range, 5-10). RESULTS: With a median follow-up of 8 years (range, 3-17); 6 of 32 (19%) patients with resistant GCT and 1 of 19 (5%) patients with cisplatin-refractory disease have been continuously disease-free, while none of the 16 patients with absolutely cisplatin-refractory GCT were alive at 1 year from HDCT treatment. In the PBPC era, HDCT appeared to be inapplicable in 32% of patients, mainly due to progressive disease during the induction/mobilizing phase. The prognostic model by Einhorn et al. for tandem HDCT did categorize our patients treated with a single HDCT cycle or low-dose intensity regimens in a very similar manner, but with inferior overall results. CONCLUSIONS: Long-term results with a single HDCT cycle or a low dose-intensity multicycle HDCT regimen remained poor in patients with adverse prognostic features. The tandem HDCT regimen represents a major option for refractory GCTs and relapsed tumors in third-line or later therapy, while a single course of HDCT should be abandoned for these patients.
INTRAVESICAL INSTILLATION OF GEMCITABINE NOT EFFECTIVE FOR BLADDER CARCINOMA
Eur Urol. 2009 Jun 21. [Epub ahead of print] Related Articles, LinkOut
Single Postoperative Instillation of Gemcitabine in Patients with Non-muscle-invasive Transitional Cell Carcinoma of the Bladder: A Randomised, Double-blind, Placebo-controlled Phase III Multicentre Study.
Böhle A, Leyh H, Frei C, Kühn M, Tschada R, Pottek T, Wagner W, Knispel HH, von Pokrzywnitzki W, Zorlu F, Helsberg K, Lübben B, Soldatenkova V, Stoffregen C, Büttner H; on behalf of the S274 Study Group.
Department of Urology, Helios Agnes Karll Hospital, Bad Schwartau, Germany (on behalf of the German AUO Trial Group).
BACKGROUND: Recurrence prophylaxis with intravesical gemcitabine (GEM) was effective and safe in patients with non-muscle-invasive bladder cancer (NMIBC); efficacy as single-shot instillation remains to be proved. OBJECTIVE: To compare the efficacy of a single GEM instillation versus placebo (PBO) immediately after transurethral resection (TUR) of tumour in patients with histologically confirmed NMIBC (pTa/pT1,G1-3). DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1-3). Of 355 patients randomised at 24 urologic centres, 328 underwent TUR and received instillation (92.4%; GEM/PBO: 166/162). In case of nonmalignancy, carcinoma in situ (CIS), >/=pT2 disease, or intraoperative complications, patients were discontinued. INTERVENTION: We used a single, postoperative 30-40-min instillation of GEM (2000mg/100ml of saline) or PBO (100ml of saline) followed by continuous bladder irrigation for >/=20h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guérin (BCG) instillations were allowed. MEASUREMENTS: Primary outcome was recurrence-free survival (RFS). Secondary outcomes included type of recurrence and adverse events. To detect a difference in RFS, 191 recurrences were required (80% power, log-rank-test, alpha=0.050). RESULTS AND LIMITATIONS: Two hundred forty-eight patients (69.9%, GEM, PBO: 124, 124) had histologically confirmed pTa/pT1 G1-3 Gx tumour and were eligible for efficacy (GEM: 76.6% male; median age: 65 yr; PBO: 83.1% male; median age: 67 yr). Treatment groups were balanced (pTa: 75.0%, 71.0%; G1-G2: 85.5%, 87.9%; recurrent tumour: 24.2%, 21.0%; BCG: 10.5%, 16.9%). After a median follow-up of 24 mo, there were only 94 recurrences and 11 deaths. The study was terminated early based on predefined decision criteria. RFS was high in both groups (12-mo RFS [95% confidence interval (CI)]: GEM: 77.7% [68.8-84.3]; PBO: 75.3% [66.3-82.3]). There was no significant group difference (hazard ratio [HR]: 0.946 [0.64-1.39], log-rank test, p=0.777). CONCLUSIONS: In this study of NMIBC, the immediate single instillation of GEM 2000mg/100ml of saline after TUR was not superior to PBO in terms of RFS. Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups.
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