ASCO 2009-CO8 STUDY SHOWS NO USE OF BEVACIZUMAB FOR ADJUVANT TREATMENT OF COLON CANCER PATIENTS

Background: The primary aim of this two-arm randomized prospective study was to determine whether mFOLFOX6 plus bevacizumab (mFF6+B) would prolong disease-free survival (DFS) compared to mFOLFOX6 (mFF6) alone. Methods: Between September 2004 and October 2006, 2,672 patients with follow-up (1,338 and 1,334 in respective arms) with stage II (24.9%) or III carcinoma of the colon were randomized to receive either mFF6 (oxaliplatin 85 mg/m² IV d1, leucovorin 400 mg/m² IV d1, 5-FU 400 mg/m² IV bolus d1, and 5-FU 2400 mg/ m² CI over 46 hrs (d1+2) q14d x 12 cycles) or mFF6+B (same mFF6 regimen + bevacizumab 5 mg/kg IV q 2 wks x 1 yr). The primary end point was DFS. Events were defined as first recurrence, second primary cancer, or death. Results: The median follow-up for patients still alive was 36 months. The hazard ratio (HR: FF6+B vs. mFF6) was 0.89; 95% CI (0.76-1.04); p=0.15. Data censored at intervals disclosed an initial benefit for bevacizumab that diminished over time: The smoothed estimate of the DFS HR over time indicated that bevacizumab significantly reduced the risk of a DFS event during the interval from 0.5 to 1.0 year. There was no evidence that patients receiving bevacizumab had a worse DFS compared to those receiving mFF6 alone following treatment. Conclusions: The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS. There was a transient benefit in DFS during the one-year interval that bevacizumab was utilized. Consideration may be given to clinical trials assessing longer duration of bevacizumab administration. Supported by PHS grants U10CA-12027, -69974, -37377, and -69651 from the NCI and a grant from Genentech, Inc.

	N	Ev	3yDFS	P		Yr	1	1.5	2	2.5	3
mFF6	1338	312	75.5			HR	0.60	0.74	0.81	0.85	0.87
mFF6+B	1334	291	77.4	0.15		P	0.0004	0.004	0.02	0.05	0.08

ASCO 2009-RIBBON-1 A NEGATIVE STUDY?

Abstract:

Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m² x 14d), taxane (T) (nab-paclitaxel [260 mg/m²] or D [75 or 100 mg/m²], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies.

	Cap (n=615)		T + Ant (n=622)
	Pl (n=206)	B (n=409)	Pl (n=207)	B (n=415)
PFS, HR (95% CI)	0.688 (0.564, 0.840)		0.644 (0.522, 0.795)
Log-rank p-value	0.0002		<0.0001
Median (months)	5.7	8.6	8.0	9.2
ORR* (%)	38 (23.6)	115 (35.4)	67 (37.9)	177 (51.3)
p-value	0.0097		0.0054
OS, HR ( 95% CI)	0.847 (0.631, 1.138)		1.032 (0.774, 1.376)
Log-rank p-value	0.2706		0.8298
Median (months)	21.2	29.0	23.8	25.2

ASCO 2009-HERCEPTIN IN GASTRIC CANCER-PRACTICE CHANGING DATA

June 3, 2009 (Orlando, Florida) — About 22% of patients with advanced gastric cancer were found to have tumors that overexpress human epidermal growth-factor receptor 2 (HER2), and these patients had significantly improved overall survival when trastuzumab (Herceptin) was added to chemotherapy, compared with chemotherapy alone.

These findings, reported here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting, were hailed as "practice changing" by several experts, including the outgoing ASCO president, Richard Schilsky, MD, professor of medicine at the University of Chicago in Illinois, and a medical oncologist specializing in gastrointestinal cancers.

Experts agreed that all patients with advanced gastric cancer should now be tested for HER2 and, if found to be positive, should be treated with a combination of trastuzumab and chemotherapy.

"These results will quickly have an impact on the management of patients," Dr. Schilsky told journalists. "Until these data came out, we didn't know that we had to consider HER2 in stomach cancer."

The situation now is likely to follow what happened in the breast cancer field, where trastuzumab has become a mainstay in the treatment of HER2-positive disease. "[Gastrointestinal] oncologists clearly have a lot to learn from breast cancer," said David Cunningham, MD, from the Royal Marsden Hospital in the United Kingdom.

"In breast cancer, HER2 overexpression is found in 15% to 25% of patients and is correlated with poor prognosis. Trastuzumab has been shown to be active both alone and in combination with chemotherapy and improves survival in both the metastatic and adjuvant settings."

Results from the ToGA study

The new results come from the ToGA study, which was conducted in 594 patients with HER2-positive disease, who were identified after nearly 4000 patients with advanced gastric cancer were screened, noted lead author Eric van Cutsem, MD, from University Hospital Gasthuisberg in Leuven, Belgium. All of the patients received chemotherapy (most commonly cisplatin and capecitabine [Xeloda], but sometimes cisplatin and 5-fluorouracil) and half were randomized to also receive trastuzumab (6 mg/kg every 3 weeks until progression). The trial was stopped early (after a median follow-up of 17 months) because of the benefit seen.

The improvement in overall survival was 2.7 months, from 11.1 months in the chemotherapy group to 13.8 months in the trastuzumab group (hazard ratio, 0.74, P = .0046).

This 2.7-month improvement in overall survival is "modest, but it is clinically meaningful in this group of patients who have a poor prognosis," said Dr. Cunningham, who was discussant for the paper. As a result, he recommended that trastuzumab plus chemotherapy should be considered for all HER2-positive patients.

Dr. Cunningham also noted that the overall survival in both groups was "impressive," and suggested this might be because a large proportion of the patients were Asian, a population that tends to have a better prognosis and might have a biologically distinct disease from Westerners. The median overall survival seen in previous studies in such patients has been around 10 months.

The ToGA study was conducted in 24 countries, spanning Europe, Asia, Australia, South and Central America, and South Africa. When asked how the results would extrapolate to patients in the United States, Dr. van Cutsem said that he predicts similar findings, and that "there is no reason to expect any differences."

"We should now test all of our advanced gastric cancer patients for HER2-positive disease," said Dr. van Cutsem. This has not been standard practice until now, because before this trial, "there was no reason to do so," he added. But these results have changed the situation — they show that testing for this receptor and using targeted therapy significantly improves the outcome for these patients, he said.

In addition to the impact on survival, trastuzumab improved all of the secondary end points, he noted, including progression-free survival (increased from 5.2 months to 6.7 months; P = .002) and overall response rate (increased from 34.5% to 47%; P = .0017), which is "statistically significant and clinically meaningful," he said.

The addition of trastuzumab did not affect safety, Dr. van Cutsem explained; the overall rate of grade 3/4 adverse events was similar in both groups. There were 3 treatment-related deaths in the trastuzumab group and 1 in the chemotherapy group. In particular, there was no concern over cardiac toxicity, he added. The incidence of cardiac failure was very rare (<1%>

Gastric Cancer Subtype Populations

Dr. Cunningham also noted that HER2 overexpression varied with the site of the tumor and histology. Although overall, 22% of patients were HER2-positive, overexpression was found in 35% of those with tumors at the OG junction, 33% of those with intestinal pathology, 6% of those with diffuse pathology.

In addition, he commented on the testing for HER2 that was used in the trial, which was carried out with both fluorescence in situ hybridization (FISH) and in situ hybridization (ICH) techniques. When the criteria in the ToGA trial for HER2-positive gastric cancer are limited to those used for breast cancer (i.e., FISH-positive and ICH3-positive, as recommended in 2007 ASCO guidelines), only 256 patients would have been included in the trial, but in these patients, the magnitude of benefit was even greater, with overall survival improved from 12.3 months to 17.89 months (hazard ratio, 0.58).

Future Trials

Several of the experts agreed that practice should be changed on the basis of this 1 trial, because it had been well conducted and because the results showed a clear-cut significant benefit.

To repeat this same study would be a waste of resources and would not be helpful for patients, said Jennifer Obel, MD, from NorthShore University HealthSystem in Evanston, Illinois. This is a practice-changing trial, she said, adding "I will take it into my clinic tomorrow." She told Medscape Oncology that she had already phoned her assistant to arrange HER2 testing for one of her advanced gastric cancer patients. Testing for HER2 is now commonplace; pathology labs are already geared up to carry out this testing for breast cancer. She noted that the overall survival improvement shown in the trial was significant in a disease that is "challenging to treat."

Dr. van Cutsem said the results were so clear-cut that he saw no value in repeating this trial, but would rather "move onward." The next study should look at trastuzumab as adjuvant therapy in patients with earlier gastric cancer after surgery, he suggested.

"The prognosis for these patients is still poor," Dr. van Cutsem said. "We have now raised the bar to over 1 year, but we need to raise it still further," he said.

Dr. Cunningham suggested that future studies should look at trastuzumab continuation after progression in association with second-line therapy, which is how the drug is used in breast cancer, where it has been shown to be of considerable value.

Dr. van Cutsem reports having received research funding from Roche. Dr. Obel has served as an advisor or consultant to Onyx. Dr. Schilsky has disclosed no relevant financial relationships. Dr. Cunningham reports acting as an advisor to Roche, and receiving honoraria from Merck, Roche, and Sanofi-Aventis.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract LBA4509. Presented June 2, 2009.

BE CAREFUL WITH PPIs USE

June 3, 2009 — Proton-pump inhibitor use is linked to increased risk for hospital-acquired pneumonia, according to the results of a large, hospital-based pharmacoepidemiologic cohort study reported in the May 27 issue of the Journal of the American Medical Association.

"The use of acid-suppressive medication has been steadily increasing, particularly in the inpatient setting, despite lack of an accepted indication in the majority of these patients," write Shoshana J. Herzig, MD, from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues. "Recent data in the outpatient setting suggest an increased risk for community-acquired pneumonia in current users of acid-suppressive medication (both proton-pump inhibitors and histamine₂ receptor antagonists)."

The goal of this prospective study was to evaluate the association between acid-suppressive medication and hospital-acquired pneumonia. The study cohort consisted of all patients who were admitted to a large, urban academic medical center in Boston, Massachusetts, from January 2004 through December 2007, who were 18 years or older and hospitalized for 3 or more days without being admitted to the intensive care unit.

Any order for a proton-pump inhibitor or histamine₂ receptor antagonist was considered as use of acid-suppressive medication. Potentially confounding factors were controlled through traditional and propensity-matched multivariable logistic regression. The primary endpoint of the study was the incidence of hospital-acquired pneumonia, defined with codes from the International Classification of Diseases, Ninth Revision, Clinical Modification, in patients using vs not using acid-suppressive medication.

Of 63,878 admissions in the final cohort, hospital-acquired pneumonia developed in 2219 admissions (3.5%). In more than half of admissions (52%), acid-suppressive medication was ordered (27,236 received proton-pump inhibitors and 7548 received histamine₂ receptor antagonists). Most of these medications (89%) were ordered within 48 hours of admission.

Compared with patients not exposed to acid-suppressive medications, those who were exposed had a higher unadjusted incidence of hospital-acquired pneumonia (4.9% vs 2.0%; odds ratio, 2.6; 95% confidence interval [CI], 2.3 - 2.8).

In the group exposed to acid-suppressive medication, the adjusted odds ratio of hospital-acquired pneumonia was 1.3 (95% CI, 1.1 - 1.4), based on multivariable logistic regression. Findings were identical with use of matched propensity-score analyses. Although the association was significant for proton-pump inhibitors (odds ratio, 1.3; 95% CI, 1.1 - 1.4), it was not significant for histamine₂ receptor antagonists (odds ratio, 1.2; 95% CI, 0.98 - 1.4).

"In this large, hospital-based pharmacoepidemiologic cohort, acid-suppressive medication use was associated with 30% increased odds of hospital-acquired pneumonia," the study authors write. "In subset analyses, statistically significant risk was demonstrated only for proton-pump inhibitor use."

Limitations of this study include inability to determine the potential benefits of acid-suppressive medication in preventing gastrointestinal tract bleeding, concerns regarding the validity of International Classification of Diseases, Ninth Revision, Clinical Modification, coding, and lack of information on the temporal association between use of acid-suppressive medication and diagnosis of hospital-acquired pneumonia. Other limitations include possible unmeasured confounders and insufficient power to exclude a small but increased risk associated with histamine₂ receptor antagonists.

"These results occur in the context of an increasing body of literature suggesting an association between acid-suppressive medication and pneumonia," the study authors conclude. "Further scrutiny is warranted regarding inpatient prescribing practices of these medications."

The study authors have disclosed no relevant financial relationships. Dr. Herzig was funded by the Health Resources and Services Administration of the Department of Health and Human Services to support the Harvard Medical School Fellowship in General Medicine and Primary Care. The study contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Health and Human Services.

JAMA. 2009;301:2120-2128.

June 4, 2009 (Chicago, Illinois) — A case–control study of nearly 34,000 patients with hip fractures taking proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) shows that the risk for hip fracture is approximately 30% higher than in matched controls not taking these medications, researchers announced here at Digestive Disease Week 2009.

Principal investigator Douglas A. Corley, MD, PhD, MPH, assistant clinical professor of medicine at the University of California at San Francisco (UCSF) and staff gastroenterologist at Kaiser Permanente in San Francisco, and colleagues analyzed the Kaiser Permanente database to quantify hip-fracture risk with these drugs.

They identified 33,752 patients with hip fractures and 130,471 age-, sex-, and race-matched controls. Patients with hip fractures were 30% more likely than controls to have taken PPIs for at least 2 years (odds ratio [OR],1.30; 95% confidence interval [CI], 1.21 - 1.39).

Risk for hip fracture was 18% higher in those taking H2RAs for 2 or more years (OR, 1.18; 95% CI, 1.08 - 1.28).

Higher dosages for longer durations increased risk in a linear fashion. Patients who took more than 1.5 PPIs daily for 8 to10 years had an OR of 2.39 (95% CI, 1.40 - 4.08). Patients who took 0.01 to 0.74 pills a day for 8 to10 years had an OR of 0.99 (95% CI, 1.75 - 1.32; P < .001 for both PPIs and H2RAs).

An increased risk was seen even in people taking medications for only 1 year.

The greatest relative increase in risk for more than 2 years of PPI use was among people 50 to 59 years of age, whose risk was more than doubled (OR, 2.31; 95% CI, 1.67 - 3.18).

The largest number of fractures was among those aged 80 to 89 years and, although the actual number of fractures was greater, "this group had a lower relative risk associated with PPIs," Dr. Corley reported (OR, 1.19; 95% CI, 1.06 - 1.33).

"These findings could be coincidental or confounded, even though we controlled for other risk factors for hip fractures, including use of steroids and thyroid medications, and even thiazide diuretics, which are associated with a decreased risk of hip fracture," Dr. Corley said.

"Risk was increased with increasing duration of use, with larger doses, and with advancing age," Dr. Corley told Medscape Gastroenterology. "But since there was no real dose-response, the relationship is probably not causal."

"These [PPIs and H2RAs] are very effective medications for reflux disease, and there are not a lot of alternatives, but they are not completely without risk."

"Physicians should make sure there is a clear indication for PPIs, and they should not be given in perpetuity," the UCSF physician advised.

Moderator Nicholas J. Shaheen, MD, MPH, associate professor of medicine and epidemiology and director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill, told Medscape Gastroenterology that "PPIs are not entirely benign."

"A possible risk of hip fracture is a pretty important question, since these drugs are so widely used. Oftentimes, once a patient is prescribed them, they are on them forever. Since their safety profile is pretty good, physicians may not think to re-evaluate the continued need [for PPIs]."

And as to whether PPIs are overprescribed, the answer is an unequivocal yes!" Dr. Shaheen said.

Dr. Corley's study received no commercial funding. Dr. Shaheen receives some funding from manufacturers of PPIs.

Digestive Disease Week (DDW) 2009: Abstract 414. Presented June 3, 2009.

ASCO 2009-CAELYX AND CARBOPLATIN MORE TOXIC THAN PACLITAXEL CARBOPLATIN BUT WITH THE SAME EFFICACY

Preliminary results from the Multicentre Italian Trials in Ovarian Cancer (MITO-2) (Abstract LBA5508) presented during Sunday’s Gynecologic Cancer Oral Abstract Session showed that combination therapy with carboplatin plus pegylated liposomal doxorubicin (C+PLD) has a similar effect on disease activity but markedly different toxicities compared with carboplatin plus paclitaxel (C+P), the standard first-line therapy for advanced ovarian cancer.

Sandro Pignata, MD, PhD, of the Istituto Nazionale Tumori, Italy, presented this multicenter, randomized phase III study in which 820 patients with advanced ovarian cancer were randomized 1:1 to C+P (C area under the curve [AUC] = 5 + P 175 mg/m², day 1 every 21 days) or to C+PLD (C AUC5 + PLD 30 mg/m², day 1 every 21 days). The treatments were repeated every 3 weeks, rather than the more standard interval of 4 weeks, for six cycles. Although patients with International Federation of Gynecology and Obstetrics stage IC through stage IV disease were included, slightly more than 80% of patients had stage III or IV disease in both study arms. In the experimental and control arms, 82% and 88% of patients, respectively, completed all six cycles of treatment.

The toxicity profiles of the chemotherapy regimens differed considerably. C+PLD was associated with a significantly higher incidence of anemia (68% vs. 59% for C+P, respectively; p = 0.007) and thrombocytopenia (48% vs. 19% for C+P; p < 0.001), although transfusions rarely were required. However, delays in treatment cycles as a result of hematologic toxicities were higher with C+PLD. There also was a significantly higher incidence of stomatitis (20% vs. 9% for C+P, respectively; p < 0.001) and skin toxicity (20% vs. 6%; p < 0.001) for patients in the experimental arm compared with the control group, although these were rarely severe. However, there was a significantly lower incidence of hair loss (14% vs. 63%, respectively; p < 0.001) and neurotoxicity (15% vs. 47%, p<0.001) with C+PLD.

Both therapies showed similar effects on disease activity. Of the subset of women eligible for analysis using Response Evaluation Criteria in Solid Tumors (RESIST) criteria (having ? 1 target lesion), 59% (92/156) who received C+P and 57% (76/134) who received C+PLD had an objective complete or partial response, demonstrating no significant difference in response rate between treatments (p = 0.70). Similarly, there were no significant differences observed for women whose disease activity could not be analyzed using RECIST criteria: complete response was observed in 33% (27/83) of patients taking C+P and in 29% of patients (29/99) taking C+PLD (p = 0.64). Among women with elevated CA125 only, 83% (73/88) on standard treatment and 86% (69/80) receiving the experimental therapy experienced normalization of CA125 (p = 0.56).

The primary endpoint of this study, progression-free survival, was not presented because the number of events required for final analysis (632) has not been reached yet. As of May 4, 2009, 531 progressions have been recorded (median follow-up, 35 months). Dr. Pignata noted that the final analysis for progression-free survival will be conducted as soon as the required number of events has been reached.

Discussant Jonathan A. Ledermann, MD, of Cancer Research UK, United Kingdom, commented on the preliminary results of the MITO-2 study. He said that it was not surprising to learn that giving C+PLD every 3 weeks produced more hematologic toxicities, but he noted the benefit of less hair loss and neurotoxicity. Without having seen the results for progression-free survival, he noted, it is difficult to predict final results. Dr. Ledermann concluded that when looking at MITO-2 in the context of the many previous trials of triplet therapies in ovarian cancer, it is “a moderate-sized fish in very big sea of studies that have so far been entirely negative…The concern is, what do we do if MITO-2 is positive? How do we interpret those data?”

STEREOTACTIC BODY RADIOTHERAPY FOR SPINAL METASTASES

June 2, 2009 (San Diego, California) — Stereotactic body radiosurgery is showing promise for patients with spinal metastases, report researchers. Presenting here at the American Association of Neurological Surgeons 77th Annual Meeting, investigators showed that the approach yields high 6-month and 1-year progression-free survival rates and reduces symptoms, including pain.

"This approach is safe and can achieve a high rate of tumor control," presenter Eric Chang, MD, from the University of Texas MD Anderson Cancer Center, in Houston, said during an interview. "The effect was a bit more dramatic than we anticipated we might see," he noted.

Presenting at the plenary, Dr. Chang showed that stereotactic body radiosurgery achieved a 90% progression-free survival at 6 months and 84% at 1 year. "It can also lead to significant reductions in the amount of pain patients experience," he said.

An estimated 40% of all cancer patients will develop spinal metastases. These patients typically present with pain and possible neurological complications. Conventional irradiation has been useful for palliation, but its effectiveness can be limited by spinal-cord tolerance. Another problem is that reirradiation by conventional means is not possible.

Stereotactic body radiosurgery is an emerging technique that uses image guidance to deliver radiation and create a steep dose gradient between the spinal cord and tumor.

Emerging Technique

Asked by Medscape Neurology & Neurosurgery to comment, Michael Fehlings, MD, from the Toronto Western Hospital, in Ontario, called this "an attractive modality" and suggested that the rates of spinal metastases in cancer patients may be even higher than 40%.

Dr. Fehlings said that while these results appear promising, they are based on a small series, and he looks forward to the results of larger studies. The single-institution study was not randomized and had no control group.

Investigators evaluated 121 patients. They completed magnetic resonance imaging of the spine within 30 days of enrollment, every 3 months for the first year, and every 6 months after that. The researchers used the Brief Pain Inventory and the MD Anderson Symptom Inventory to assess patients at baseline and at each follow-up.

Patients underwent intensity-modulated, near-simultaneous, computed-tomography (CT) image-guided stereotactic body radiosurgery. They received 3 separate 9-Gy fractions to a total dose of 27 Gy. Investigators limited the spinal cord dose to 9 Gy.

Cancer types included renal cell, breast, sarcoma, lung, melanoma, and colon. The median tumor volume was 40.6 cm³. At the time of analysis, 39% of patients were alive with a median follow-up time of 13 months. The median survival time of the study population was 21.4 months.

The top 5 most severe symptoms patients reported were fatigue, pain, sleep disturbance, drowsiness, and distress. At 6 months, investigators said these symptoms declined.

Decreases in Symptoms at 6 Months

Symptom	Reduction on MD Anderson Symptom Inventory	P
Fatigue	-0.7	.03
Pain	-1.6	.001
Sleep disturbance	-1.2	.0001
Drowsiness	-1.3	.0001
Distress	-1.0	.0004

Dr. Chang and his team showed that acute toxicities were infrequent and manageable. There were no cases of grade 4 toxicities, but some grade 3 problems did occur. These included nausea, vomiting, diarrhea, fatigue, noncardiac chest pain, dysphagia, neck pain, and pain associated with severe tongue edema and trismus. No cases of radiation myelopathy have been observed to date.

Discussant Phillip Tibbs, MD, from the University of Kentucky, in Lexington, congratulated the researchers on the work. "Stereotactic body radiosurgery has a promising role in managing pain and controlling metastasis," he said at the meeting.

"I can tell you that at the University of Kentucky we are using it now," Dr. Tibbs noted. "It is a wonderful tool, and I think sometimes enthusiasm can lead to overuse. But I believe we have identified an appropriate indication for a suitable group of patients."

Dr. Tibbs pointed out the symptom inventories used in the study are subjective. "But I don't think that's a particular limitation here, and patient perception is appropriate."

The researchers have disclosed no relevant financial relationships.

American Association of Neurological Surgeons 77th Annual Meeting: Abstract 900. Presented May 6, 200

COMBINATION TREATMENT MAKES LIVER METASTASES FROM COLON CANCER RESECTABLE

NEW YORK (Reuters Health) May 29 - Combining hepatic artery infusion of floxuridine/dexamethasone with systemic oxaliplatin and irinotecan can make liver metastases from colorectal cancer resectable in about half of patients.

The findings, reported in the May 26th issue of the Journal of Clinical Oncology, are based on a study of 49 patients, 23 of whom had never been treated with chemotherapy before.

Lead author Dr. Nancy E. Kemeny, from Memorial Sloan-Kettering Cancer Center, New York, told Reuters Health that while the present study is not the first to examine treatments to increase resectability, it is different from many of its predecessors in that the subjects truly had unresectable disease.

"In many other studies using chemotherapy prior to resection...some of the patients really were resectable at first or did not have very extensive disease," she explained. "For example, some studies used six metastases as a reason that the patient can not go to resection."

By contrast, the patients in the current study, she noted, were clearly unresectable: 95% had 6 or more liver segments involved with tumor, 98% had bilobar disease, 89% had lesions greater than 5 cm, and 72% had synchronous disease.

Eight percent of patients had a complete treatment response and 84% had a partial response, the authors note. The overall conversion to resectability was 47%, while the rate in chemotherapy-nave patients was 57%.

The median survival periods from the initiation of hepatic artery infusion for patients with and without prior chemotherapy exposure were 35 and 50.8 months, respectively. Female gender was the only baseline characteristic that predicted resectability. Variables indicating the extent of anatomic disease did not predict resectability.

Dr. Kemeny said that future research should examine whether systemic therapy alone could achieve the same results seen in the present study.

J Clin Oncol. Published online May 26, 2009.

ASCO 2009-PEMETREXED EXTENDS SURVIVAL IN NON -SQUAMOUS NSCLC

June 3, 2009 (Orlando, Florida) — Pemetrexed (Alimta, Eli Lilly) following standard chemotherapy improves overall survival in patients with advanced nonsmall-cell lung cancer (NSCLC), according to study results presented here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting.

The study also confirms that this benefit is primarily limited to those with the nonsquamous subtype of NSCLC.

"This is the first single-agent maintenance therapy to show significant survival benefit in advanced nonsmall-cell lung cancer. Other studies of maintenance therapies have not shown this benefit," said the study's lead author, Chandra P. Belani, MD, from the Penn State Cancer Institute in Hershey, Pennsylvania, at a press conference.

In the study, among the 482 patients with nonsquamous NSCLC, pemetrexed resulted in significantly better overall survival than placebo (15.5 vs 10.3 months; P = .002).

"Pemetrexed maintenance therapy is a new treatment paradigm for patients with advanced nonsmall-cell lung cancer who respond to initial chemotherapy," said Dr. Belani.

However, other lung cancer experts attending the meeting differed on the appropriateness of using the drug as a maintenance therapy.

"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 nonsmall-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.

Drs. Brahmer and Hanna were both interviewed by Medscape Oncology.

Dr. Hanna was a discussant at a session in which the study was presented. He was also lead author of a study comparing pemetrexed with docetaxel that was presented at ASCO in 2003, which served as the basis for the drug's approval by the US Food and Drug Administration, he said. Dr. Hanna pointed out that the drug is not indicated as a maintenance therapy, but is for use either in combination with cisplatin for the initial treatment of advanced nonsquamous NSCLC or as a second-line single agent.

Another lung cancer expert at the meeting was more enthusiastic. "I think we should be adopting this in our practices in patients with the nonsquamous-cell histology that is responsive," said Bruce Johnson, MD, director of the Dana-Farber/Harvard Cancer Center Lung Cancer Program in Boston, Massachusetts, who was speaking at a Highlights of the Day session.

Dr. Johnson's advice was in contrast with his comments on 2 other maintenance-therapy studies presented at the meeting involving nonchemotherapy targeted agents—the ATLAS and SATURN trials. Both showed that the impact of these agents was limited to progression-free survival and, unlike the pemetrexed trial, the 2 trials had no data on overall survival, as reported by Medscape Oncology. "It's not clear yet that the patients in these 2 trials are living longer and better," he said.

Maintenance Therapy or Second-Line Therapy: Why It Matters

The distinction between maintenance and second-line therapy is important because the latter means that patients will receive a treatment break after initial chemotherapy, said Dr. Hanna. That, in turn, allows clinicians to find out which patients with advanced disease will immediately progress (that is, within 2 to 3 months), and which will not.

"About 30% of patients will not progress for quite some time. If you give maintenance therapy following initial chemotherapy to everyone, you will overtreat the group of patients who do not progress immediately," he said.

Dr. Hanna believes that this overtreatment is detrimental because pemetrexed has adverse events, including grade 1 and 2 nonhematologic toxicities, such as diarrhea, rash, and fatigue. "We must be careful not to trivialize these," he said, noting that they affect quality of life. He also acknowledged that a quality-of-life analysis of patients on pemetrexed, presented at ASCO in 2008, concluded that there was "no deterioration of quality of life" with the drug. However, for patients with severely limited life spans, Dr. Hanna believes quality of life is especially important. "I want to see improved quality of life," he emphasized.

He also said that the 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.

Despite his objections about pemetrexed maintenance therapy, Dr. Hanna believes "some patients do benefit from it."

So how does a clinician decide which patients should immediately get pemetrexed maintenance therapy?

According to Dr. Hanna, the approach is "especially well-suited" for patients who are "troubled" by their lung cancer symptoms and who have "pretty well-tolerated" chemotherapy. In other words, for such patients, starting pemetrexed immediately after the completion of initial chemotherapy will prolong the interval of progression-free survival. That is a "good thing" because such patients get very upset about their symptoms, he explained. However, for most patients who have completed initial chemotherapy, starting maintenance therapy immediately afterward is probably unnecessary, said Dr. Hanna.

He explained that most patients will have stabilized disease for a few months after initial chemotherapy. "If they take maintenance therapy, it's hard to tell what is at work: Is it maintenance therapy, or a durable response to chemotherapy, or is it indolent disease?," he wondered.

Study Details

In this randomized double-blind multicenter phase 3 study, 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. In a previous report, the investigators indicated that pemetrexed had better progression-free survival (P < .00001) than placebo.

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. As noted above, for the nonsquamous subgroup (482 patients), overall survival was 15.5 months for patients taking pemetrexed and 10.3 months for patients taking placebo.

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%).

Dr. Belani is a consultant to Eli Lilly, the manufacturer of pemetrexed, and has received honoraria from the company. Some of his coauthors are employees of Eli Lilly. Dr. Johnson has acted as a consultant to Genzyme; holds stock ownership in Boston Scientific, Celgene, and Johnson & Johnson; and receives royalty payments on a license to Genzyme for carrying out EGFR mutation testing. Dr. Brahmer has acted as an adviser to AstraZeneca, Eli Lilly, and ImClone. Dr. Hanna has received honoraria from Eli Lilly and Genentech.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract CRA8000. Presented May 31, 2009.

ASCO 2009- DO NOT IGNORE BREAST CANCER MICROMETASTASES

June 4, 2009 (Orlando, Florida) — Don't ignore micrometastases.

That is the main message from a Dutch study of women with early-stage breast cancer presented here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting.

One of the groups of women studied had micrometastases (nodal disease that measures 0.2 to 2.0 mm) discovered by sentinel lymph node biopsy (SLNB).

These women had a significantly higher rate of recurrence in the axillary nodes if they did not receive follow-up treatment, according to study results.

Follow-up treatment was either completion axillary lymph node dissection (cALND) or, less commonly, axillary radiation.

After 5 years, there was a 5% rate of axillary recurrence for the women with micrometastases who only had a SLNB (n = 141) and no follow-up treatment, compared with a 1% rate for those who had either cALND or radiation (n = 887; hazard ratio, 4.39).

"This 5-year recurrence rate is much too high. And it will likely increase with longer follow-up," said lead author Vivianne Tjan-Heijnen, MD, PhD, at a meeting press conference. She is professor of medical oncology at the Maastricht University Medical Center in the Netherlands.

The new Dutch study, dubbed MIRROR (Micrometastases and Isolated Tumor Cells: Relevant and Robust or Rubbish?), conflicts with a recent large American study. The latter found that follow-up treatment with cALND did not improve either axillary recurrence or survival for patients with microscopic disease, as reported by Medscape Oncology. The senior author of the American study said: "We have relied upon [cALND] too much."

However, Dr. Tjan-Heijnen told Medscape Oncology that there are a number of important differences between her study and the American study, all of which strengthen the authority of her group's findings.

She also noted that ASCO guidelines support her findings. "Completion axillary lymph node dissection is recommended in patients with micrometastases," she said, acknowledging that the procedure is associated with an increased rate of lymphedema.

An American breast cancer expert attending the meeting felt swayed by the Dutch findings. "We might have to be more aggressive with micrometastases — they should not be ignored," Julie Gralow, MD, told Medscape Oncology. Dr. Gralow is a member of the Fred Hutchinson Cancer Research Cancer in Seattle, Washington, and serves on the ASCO Communications Committee.

"We have struggled with what to do with micrometastases," observed Dr. Gralow. "Should we avoid further surgery and use radiation? It's important to know that axillary radiation is separate from breast radiation and also produces lymphedema," she added, noting that the standard of care in this situation has been cALND, but clinical judgment comes into play.

In the end, Dr. Gralow was impressed by the new findings: "I am going to use these data with my patients."

Another American clinician at the meeting felt similarly. "We have never known exactly how to approach these cases. The MIRROR study helps us have a further educated discussion with our patients," said Jennifer Obel, MD, a medical oncologist from the NorthShore University HealthSystem in Evanston, Illinois, and also a member of the ASCO Communications Committee

Dr. Gralow pointed out that, in early breast cancer, the majority of women can avoid any follow-up treatment because the SLNB is negative.

Isolated Tumor Cells and Micrometastatic Disease: The Differences

One of the key differences between the recent American and Dutch studies is that they worked with different definitions of the small amounts of disease that can be found by SLNB.

The difference here is not just an academic matter, it is a key to understanding how to proceed clinically, suggested Dr. Tjan-Heijnen.

In the Dutch study, the investigation separated microscopic disease into 2 groups: the smaller isolated tumor cells (<0.2>

The American study did not separate the 2 classifications because, before 2002, both categories were "lumped together," and thus were analyzed as "microscopic" disease, said Dr. Tjan-Heijnen, explaining that the American study's outcome findings date from before 2002.

The Dutch findings show that isolated tumor cells and micrometastases produce different outcomes and should not be treated the same way by clinicians.

Specifically, in the Dutch study, after 5 years, patients who were found to have isolated tumor cells by SLNB and who did not subsequently undergo cALND (n = 732) did not have a significantly higher rate of axillary recurrence than similar patients (n = 125) who did undergo cALND (2.3% vs 1.6%).

In other words, it's okay to not do a follow-up treatment in patients with isolated tumor cells, said Dr. Tjan-Heijnen.

However, Dr. Tjan-Heijnen qualified this recommendation a bit further: "These patients should have favorable tumor characteristics," she said, explaining that any patient with a grade 3 tumor should have follow-up treatment for any kind of nodal disease.

The Dutch study found that patients with micrometastases all need follow-up treatment, as noted above.

The quality of data in the Dutch study was superior in other ways, said Dr. Tjan-Heijnen. Data used in the American study were obtained from a cancer registry and did not undergo a central pathology review, whereas the Dutch data did undergo a central pathology review. According to Dr. Tjan-Heijnen, the authors of the American study admitted that their data on axillary recurrence were incomplete; the Dutch study had axillary recurrence data for all patients.

More About MIRROR

The Dutch MIRROR study is the largest cohort study on micrometastases and isolated tumor cells in the sentinel node era, say the study authors.

"The sentinel node is intensively examined to prevent false negatives," said Dr. Tjan-Heijnen. She also said that this intensity has led to increased detection of micrometastases and isolated tumor cells.

The study was supported by the Netherlands Organization for Health Research and Development (ZonMw) and the Dutch Breast Cancer Trialists' Group (BOOG). The authors have disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract CRA506. Presented May 30, 2009.

ASCO 2009-AVOID SSRIs WITH TAMOXIFEN

June 2, 2009 (Orlando, Florida) — Until there are more data, patients who are taking tamoxifen to reduce their risk for breast cancer recurrence should avoid concomitant use of selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft).

This was the advice from experts here at the American Society of Clinical Oncology 45th Annual Meeting, even though 2 presentations on the topic reported contradictory results.

As well as being used for the treatment of depression, SSRIs are used for hot flashes, which can be an adverse effect of tamoxifen therapy. However, some of these drugs are potent inhibitors of the cytochrome P450 2D6 enzyme that converts tamoxifen to its active metabolite, endoxifen. By inhibiting the enzyme, these drugs reduce the blood levels of this active metabolite, and so reduce the efficacy of tamoxifen in protecting against breast cancer recurrence.

Adverse Effect of SSRIs

One of the studies presented at the meeting showed that women who were taking SSRIs that were moderate to potent inhibitors of the 2D6 enzyme had a 2-fold increase in the risk for breast cancer recurrence, compared with women who were not taking these drugs concomitantly.

he difference was significant — the risk for breast cancer recurrence was 7% in women who were not taking SSRIs and 16% in women who were taking SSRIs that were moderate to potent inhibitors of the 2D6 enzyme (hazard ratio, 2.2, P = .0002). These drugs include fluoxetine, paroxetine, and sertraline.

However, SSRIs that had only a weak inhibitory effect on the enzyme did not have a significant effect; in this instance, the risk for breast cancer recurrence was 8.8%, not significantly different from the 7.5% seen in women who did not take these drugs. Weak inhibitors of the 2D6 enzyme include citalopram (Celexa), escitalopram (Lexapro), and fluvoxamine (Luvox).

"The implication from these findings is that women on tamoxifen should avoid the SSRIs that are moderate to potent inhibitors, as they interfere with the beneficial effects of tamoxifen, but the SSRIs that are weak inhibitors are probably okay," said senior author Robert Epstein, MD, chief medical officer at Medco Health Solutions, a pharmacy benefit management company in the United States.

The study, conducted in collaboration with researchers from Indiana University, used Medco's 11 million member database to identify 945 women older than 50 years and who were at least 70% compliant with tamoxifen therapy for 2 years or more. The researchers identified an additional 353 such women were also taking an SSRI (most commonly paroxetine or fluoxetine); the median overlap during which they were taking both drugs was 255 days.

No Effect of SSRIs

However, a similar study, also presented at the meeting, showed no effect of SSRIs on the risk for breast cancer recurrence in women taking tamoxifen. This study was conducted in the Netherlands, and involved 1962 women who were taking tamoxifen after surgery for early-stage breast cancer. About 11% had also taken an SSRI (most commonly fluoxetine and paroxetine) at some point.

Although this study showed no difference in the risk for breast cancer recurrence between women who took SSRIs and those who did not, lead author Vincent Dezentje, MD, a trainee in oncology at Leiden University Medical Center in the Netherlands, said "doctors and patients should be cautious about using these drugs together."

The number of women who used both drugs in the Dutch study was small, so the study could have been underpowered to show a significant effect, said Julie Gralow, MD, assistant professor of oncology at the University of Washington School of Medicine in Seattle

Dr. Gralow, who moderated the press conference at which the 2 studies were highlighted, told reporters that the message she will be taking back to her clinic is to avoid the SSRIs that could interfere with tamoxifen's action. She noted that the Medco study suggested the risk for breast cancer recurrence was 2-fold higher in women who were taking these drugs concomitantly. There are other drugs that that can be used instead, so "it's better to play it safe," she said.

The same message was given by the discussant of these 2 papers, Vered Stearns, MD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland. Despite the contradictory presentations, and also previous studies that have produced conflicting results, Dr. Stearns said that the use of SSRIs and other drugs with potent inhibitory effects on this enzyme should be limited in this patient population, if at all possible, and alternative drugs should be used.

However, a major limitation of both of these studies, she said, was that neither took into account the individual genetic variation in the 2D6 enzyme. Some women are poor metabolizers of tamoxifen, and they may already have reduced blood levels of the active metabolite because of their genetic predisposition.

"Ironically, it is the women who are good metabolizers of tamoxifen and who are getting the most benefit from the drug in terms of protection against breast cancer recurrence who are also the most likely to experience side effects from the drug, such as hot flashes. So these women are likely to take an SSRI for those hot flashes, but this drug interferes with the metabolism of tamoxifen and reduces its efficacy," Dr. Epstein told Medscape Oncology.

Dr. Epstein also noted that SSRIs are commonly used for hot flashes in the United States, with about 30% of women on tamoxifen taking these drugs. This is a different scenario from Europe, where these drugs are used mainly for the treatment of depression and appear to be used less commonly, he said, noting that the Dutch study found that only 11% of women taking tamoxifen were also taking these drugs.

Dr. Gralow added that the findings are important because tamoxifen is "a good drug and is still in clinical use." Although it has been superseded to some extent by aromatase inhibitors in the postmenopausal patient population, many women taking aromatase inhibitors develop adverse effects and consider switching to tamoxifen; for premenopausal women with breast cancer, tamoxifen remains the only option.

Dr. Epstein is employed by Medco Health Solutions. Dr. Dezentje has disclosed no relevant financial relationships. Dr. Gralow reports receiving honoraria from Genentech, Novartis, and Roche; and research funding from Amgen, Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, and Sanofi-Aventis.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstracts CRA508 and CRA509. Presented May 30, 2009.

ASCO 2009-AUTOLOGOUS VACCINE IN FOLLICULAR LYMPHOMA

June 4, 2009 (Orlando, Florida) — It has been nearly 10 years in coming, but at last there is a positive result with a vaccine approach to follicular lymphoma. Two other phase 3 clinical trials have failed, but the one that succeeded was reported during a plenary session here at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting.

The results come from a study funded by the National Cancer Institute that involved 177 patients with follicular lymphoma who had achieved and maintained a complete response for 6 months after induction chemotherapy. From this group, the patients who were randomized to receive the vaccine showed a significantly improved median disease-free survival, compared with those who received a control vaccine — the improvement was 47% from 30 months to 47 months (hazard ratio, 1.6; P = 045).

The vaccine, known as BiovaxID (under development by BioVest International), is personalized for each patient to include a tumor-derived idiotype protein. It has been granted fast-track status by the US Food and Drug Administration and orphan-drug status by the European regulatory authority.

"We now have a new therapeutic agent with clinical activity that may be applicable to our patients," said lead author Stephen Schuster, MD, director of the Lymphoma Program at the University of Pennsylvania School of Medicine in Philadelphia. The vaccine induces cellular immunity, and so has a different mechanism of action from existing immunotherapies. Logically, it could be added on to both chemotherapy and other immunotherapy, although to "ascertain clinical benefit would require another clinical trial," he told Medscape Oncology.

This question of where the new vaccine fits alongside existing therapy is the main issue with these new data, said Ron Levy, MD, chief of oncology at Stanford University in California, and a pioneer in the field of idiopathic vaccine development.

In a discussion of the paper also held during the plenary session, Dr. Levy concluded that the question of whether the vaccine was effective would get a "qualified yes," in that the data were "positive in those patients in whom it was tested." But the answer to whether there is a role for this vaccine in today's treatment of follicular lymphoma is more of a "maybe," he said, adding that "there may be a role for this vaccine, but further evidence will be needed."

Chemotherapy Used Is Now Out of Date

One of the issues with the trial was that the chemotherapy regimen used to induce remission in these patients, which was popular at the time the trial started 8 years ago, has now been superseded. The trialists used PACE (prednisone, doxorubicin, cyclophosphamide, and etoposide), which was standard in 1990s, Dr. Schuster noted.

However, in more recent years, immunotherapy with rituximab (Rituxan) has become the standard of care for use in induction schedules. It has had a huge impact on the treatment of follicular lymphoma, as previously reported by Medscape Oncology.

Dr. Schuster wondered how the vaccine will fit into therapy in the postrituximab era, and whether there will be a role for it. He said that another trial is now planned in patients who will be treated with rituximab and chemotherapy. He made the point that "the vaccine uniquely recruits the patient's immune system to seek and destroy only tumor B cells," and also noted that the vaccine was very well tolerated. In contrast, rituximab depletes the body of all B cells — healthy B cells in addition to the tumor B cells — which can result in toxicity.

Another issue with the trial was that of patient selection. Dr. Levy pointed out that 234 patients were originally enrolled, but the randomized trial was conducted in the 177 patients who responded to induction chemotherapy with a complete remission and who managed to sustain that complete remission for at least 6 months before receiving the vaccine (some maintained it for up to a year). So the patients who made it into the trial were "the best of the best," he said.

Dr. Levy pointed out that the positive result came from a modified intent-to-treat analysis of the 177 patients who received the vaccine, and not of the original 234 patients enrolled in the study. But he added that this "seems like a logical thing to do, to consider only the patients who received the treatment."

Despite the reservations, Dr. Levy highlighted the fact that this vaccine trial was positive, whereas 2 others in follicular lymphoma have both been negative.

Dr. Schuster speculated that the reason his group succeeded is that they used the vaccine in patients who were in complete remission and who remained in remission for at least 6 months. In these patients, it appears that the vaccine managed to hold the residual disease in check. In contrast, previous trials used vaccine in patients who had achieved partial or complete responses, but not necessarily remission.

The positive results from this trial — and for another vaccine in melanoma patients — that were presented at this ASCO meeting spell "the end of the beginning" for cancer vaccine therapies, Dr. Schuster told Medscape Oncology. He predicted that vaccine approaches will now be tested with more enthusiasm, and that the newer techniques of immunomodulation now available will enhance the results that have been seen so far.

Dr. Schuster reported receiving research funding from BioVest International. Dr. Levy has disclosed no relevant financial relationships..

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract 2. Presented May 31, 200

ASCO 2009-INVESTIGATIONAL TARGETED THERAPY FOR METASTATIC MELANOMA SHRINKS TUMORS

June 4, 2009 (Orlando, Florida) — The targeted-therapy revolution in oncology could be coming to melanoma, especially if the results of a phase 1 trial of an investigational agent are followed by similar results in subsequent trials, according to melanoma experts attending the American Society of Clinical Oncology 45th Annual Meeting.

"We are on the verge of a paradigm shift for melanoma therapy," said melanoma expert Boris Bastion, MD, from the University of California at San Francisco, who was not involved in the trial. "This is a decisive step toward personalized medicine," he added.

Dr. Bastion was a discussant at a meeting session on melanoma at which studies of 2 targeted therapies for malignant melanoma were presented, 1 of which is the investigational PLX4032 (Plexxicon Inc). This oral agent targets the oncogenic BRAF gene mutation known as V600E, which occurs in about 60% of malignant melanoma patients, according to the study authors.

In a dose-escalation, proof-of-concept study, more than half of metastatic melanoma patients with this BRAF mutation who received high doses of PLX4032 had tumor shrinkage, said lead study author Keith T. Flaherty, MD, from the Abramson Cancer Center of the University of Pennsylvania in Philadelphia.

"We were able to give enough drug to block mutated BRAF, and that resulted in clinical benefit in a majority of patients treated at higher doses," Dr. Flaherty told Medscape Oncology. Specifically, 9 out of 16 patients with BRAF mutations had an objective response by RECIST criteria. Of the remaining 7 patients, 5 had tumor shrinkage, but not enough to count as an objective response, and 2 had growth, he added.

Among the 16 patients with BRAF mutations, median progression-free survival "appears to be 6 months," said Dr. Flaherty, adding that the time period is "likely to change" as more data are collected.

"These early responses happen with remarkable reliability," Dr. Flaherty told the audience, adding that the agent is not useful for patients without the BRAF mutation.

"The magnitude of response is better than we expected," he continued.

PLX4032 is important because it represents an advance in targeting BRAF, explained another melanoma expert, David Fisher, MD, PhD, from Massachusetts General Hospital Cancer Center in Boston.

"Others have attempted to use kinase inhibitors to block the BRAF gene. This agent was designed to specifically block the oncogenic mutated form of BRAF," Dr. Fisher, who was also not involved in the study, told Medscape Oncology.

Historic Change, Quickly

Before entering the meeting room for the late afternoon session, the attendees buzzed with conversation. When asked by Medscape Oncology if the attendees were excited about his study, Dr. Flaherty laughed: "They might be or they might be hungry for dinner."

Nevertheless, Dr. Flaherty acknowledged that the treatment of melanoma is moribund. "Eight-five percent of patients don't respond to the 2 available drugs. It's almost as if we are starting off from ground zero in terms of treating the disease," he said.

Dr. Bastion suggested the same. "In 1840, advanced melanoma was described as untreatable," he said, adding that not much has improved since. "I feel this is about to change," he continued.

The development of targeted therapies for malignant melanoma has occurred rapidly, said Dr. Bastion. "It took 7 years to move from the discovery of the target to drug development," he said, contrasting this timeline with the 30-plus years that it took for the same activity to occur in chronic myelogenous leukemia.

Dr. Bastion also reminded the audience that the findings were "early results with many questions to be answered."

Further Details

In the study, supported by Plexxicon, 55 cancer patients were enrolled, 49 of whom had melanoma. Of these 49 melanoma patients, 28 received doses too low to determine efficacy; the other 21 received sufficiently high doses (at least 240 mg twice daily). Five of these patients did not have BRAF mutations and did not respond to PLX4032. However, 16 did have the mutation and therefore were suited to the drug. As noted above, 9 of the 16 were responders and 7 were not.

However, Dr. Flaherty noted that some of the 28 patients who received low doses of PLX4032 had "some evidence of benefit."

The agent was well tolerated, with adverse events that were dose-related and that tended to be mild, said Dr. Flaherty. For instance, the most common event, rash, occurred in 29% of patients, but it was of grade 3 in only 2%.

V600E BRAF is also found in colorectal carcinomas (10%), some anaplastic and papillary thyroid carcinomas, and low-grade serous ovarian carcinomas, the study authors noted.

Dr. Flaherty has served as a consultant to Plexxikon and Hoffman-LaRoche; some of his coauthors are employees of Hoffmann-La Roche and Plexxikon Inc. Dr. Bastion disclosed relationships with Novartis and Alnylam. Dr. Fisher has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract 9000. Presented May 30, 2009.

ASCO 2009-CT SCREENING FOR LUNG CANCER HAS LOW SPECIFICITY

June 4, 2009 (Orlando, Florida) — Individuals who undergo lung cancer screening with low-dose computed tomography (LDCT) are at high risk for false-positive results, according to the results of a study presented here at the American Society of Clinical Oncology 45th Annual Meeting.

The risk for a false-positive result was 21% after undergoing 1 LDCT scan, and 33% after undergoing a second LDCT. The false-positive risk, however, was lower for screening with chest x-ray. People undergoing chest x-ray screening had a false-positive risk of 9% after 1 screen and of 15% after 2 screens.

"The risks of false-positive lung cancer screening tests are substantial after just 2 exams," said lead author Jennifer M. Croswell, MD, acting director of the National Institutes of Health Office of Medical Applications of Research in Bethesda, Maryland. "There were only 2 rounds of screening, so this is a conservative risk of annual screening programs."

When evaluating whether or not lung cancer screening can reduce related mortality, several studies have reported a high incidence of noncalcified nodules in people who were screened. This study, however, is the first to quantify the cumulative risk for a false-positive result.

"We have seen an increasing promotion of LDCT screening to consumers, and the advertisements are saying that they can alleviate anxiety among smokers and former smokers," said Dr. Croswell, "but we don't have any real information about the efficacy of screening in early diagnosis."

Julie Gralow, MD, associate professor of medical oncology at the University of Washington in Seattle, pointed out that it is necessary to look at both the benefits and harms. "The gold standard in cancer screening should be an improvement in survival, but we haven't seen that yet in any screening for lung cancer," said Dr. Gralow, who moderated the press briefing in which the data were highlighted.

"However, depending on the benefit, some improvement in morbidity, such as finding it earlier so that you can have a smaller surgery or avoid chemotherapy — that counts too," she said.

But the gold standard is fewer deaths because it is found earlier, she emphasized. "Actually, very few screening tests have met that standard," she said. Mammography is 1 example in which multiple randomized studies have shown a reduction in death.

High Rate of Diagnostic Follow-Up

This study was a feasibility trial for the ongoing National Lung Screening Trial (NLST), a definitive randomized controlled trial comparing LDCT and single-view chest x-ray conducted at 6 NLST centers. The NLST itself was launched in 2002, has enrolled nearly 50,000 participants, is slated to collect and analyze data for 8 years, and will examine the risks and benefits of CT scans and chest X-rays. The goal of the NLST is to determine if either test is better at reducing lung-cancer-related mortality.

"We estimated the cumulative risk of receiving 1 false-positive test and other potential burdens associated with false-positive screening tests," explained Dr. Croswell.

The feasibility study looked at 3190 current or former smokers who were offered a baseline LDCT (n = 1610) or chest x-ray (n = 1580) and 1 repeat annual screen. The participants were followed for 1 year after their initial screening.

A positive screen was defined as any noncalcified nodule of 4 mm or more or any other radiographic finding deemed suspicious for cancer. A false-positive screen was defined as a completed negative work-up or a follow-up of 12 months or more without a cancer diagnosis.

There were a total of 38 screen-detected true cancers and 504 false positives. Of the people with false positives, 61% had at least 1 other type of screening exam, and 6.6% underwent some type of invasive procedure, Dr. Croswell pointed out.

Diagnostic Follow-Up of False-Positive Findings

Procedure	Number of LDCT Scans	False-Positive LDCT Scans (%)	Number of Chest X-rays	False-Positive Chest X-rays (%)
Imaging exams	307	61	110	51
Minimally invasive procedure	25	5.0	6	2.8
Moderately invasive procedure	20	4.0	7	3.2
Major surgical procedure	8	1.6	4	1.9
Any invasive procedure	33	6.6	9	4.2

On multivariable analysis, a higher risk for a false-positive result with LDCT was associated with increased age (>64 years), and being a current smoker vs a former smoker trended toward higher false-positive odds (odds ratio, 1.22; 95% confidence interval, 0.95 - 1.56).

"Given the high burden of false positives with LDCT for lung cancer screening, careful investigation of economic, psychosocial, and physical burdens is warranted," she said.

James Marshall, PhD, senior vice president for Cancer Prevention and Population Sciences, Roswell Park Cancer Institute in Buffalo, New York, agreed that advertising LDCT as a lung cancer screening tool to the public is problematic. "Some people will get the idea that they can go ahead with their 2 packs of Camels a day, and we can go ahead and catch it early, like polyps," said Dr. Marshall, who served as a discussant of the paper.

But he questioned the actual burden that receiving a false positive placed on the study participants. "These are modest burdens. Were they put at great risk by LDCT? I'm not sure."

The burden of false positives appears to be relatively modest, and consumers of screening services need to be fully informed, said Dr. Marshall.

More Emphasis Needed for Smoking Prevention/Cessation

Dr. Gralow feels it would be prudent to wait for the results from the National Lung Screening trial to see if there is a reduction in mortality. But the larger issue itself is tobacco use, she pointed out.

"Recent statistics suggest that 20% of adults in the [United States] smoke," she said, and lung cancer is just 1 of many risks that have been associated with smoking. "We should be putting efforts into prevention and cessation of smoking."

The NLST is sponsored by the National Cancer Institute. Dr. Croswell and Dr. Marshall have disclosed no relevant financial relationships. Dr. Gralow has received honoraria from Genentech, Novartis, and Roche; and has received research funding from Amgen, Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, and Sanofi-Aventis.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract CRA1502. Presented May 30, 2009.

PRIMARY HYPERPARATHYROIDISM MAY LEAD TO INCREASED CANCER RISK

June 3, 2009 (Houston, Texas) — Patients diagnosed with primary hyperparathyroidism (PHPT) may have a higher risk for cancer and a higher risk for death from any cause, according to an observational study presented here at the American Association of Clinical Endocrinologists 18th Annual Meeting and Clinical Congress. However, questions need to be answered before risk can be accurately determined.

"People have tended to think [PHPT is] a pretty benign, innocuous disease, but that might not be so," lead investigator Sujoy Ghosh, MD, clinical teaching and clinical research fellow at the Ayr Hospital in Scotland, told Medscape Diabetes & Endocrinology.

The study followed 3039 patients diagnosed with PHPT from 1981 through 2007 and looked at the prevalence of new cancers and deaths in these patients. They compared the results with the risk for cancer and mortality in the general Scottish population. Patients with pre-existing cancer or cancer diagnosed within 1 year of the PHPT diagnosis were excluded from the analysis, resulting in a cohort of 2706 patients. Patients were identified from the Scottish Morbidity Records and linked to the Scottish Cancer Registry and Scottish Mortality Records databases. Of these patients, 77% were women, and the mean age was 63.5 years.

Of the 2706 patients with PHPT, during an average follow-up of 15.1 years, 440 patients with PHPT were diagnosed with cancer (standardized incidence rate, 2.026; 95% confidence interval [CI], 1.841 - 2.224; P < .001). A total of 1601 patients died during the study (standardized incidence rate, 3.085; 95% [CI], 2.936 - 3.240; P < .001). For these patients with PHPT, this correlates to a 2-fold increased risk of developing cancer and a 3-fold increased risk for death, compared with the general population.

Dr. Ghosh said the findings have important implications for cancer screening and treatment in patients with PHPT. About 40% to 50% of patients with PHPT undergo surgery now in the most severe cases, but "in the next 4 to 5 years, at the most 10 years down the line, everyone will and should have surgery." He thinks that surgery will reduce the overall cancer rate as well as improve all-cause mortality, compared with patients with PHPT who do not undergo surgery.

Harmeet Singh Narula, MD, FACP, FACE, assistant professor of medicine at Stony Brook University Medical Center in New York and judge of the poster session, told Medscape Diabetes & Endocrinology that "PHPT has a lot of associations — hypertension, cardiac death, and cancer. This is something really important because people don't realize that a lot of associations with PHPT could be cancer. We need a really large number of people to see if treatment of PHPT would reduce the number of cancers."

Dr. Narula cautioned that the current findings are only observational. "That's all it is, and it's an important observation to keep in mind. The question then becomes: Is it the [high] calcium that's . . .a problem, is it the primary hyperthyroidism hormone that's high that's the problem, or is it something completely different? This study has shown that patients with PHPT have cancers more often, and there's a clear risk." But does treating the PHPT get rid of the cancer risk? "We don't know that," he said.

Dr. Ghosh agreed that to confirm the results of this study would require a large number of treatment centers working together for at least 10 years. Most countries would not be able to replicate this study because few countries have national databases similar to those used in this study. "The only countries would be the Scandinavian countries and Scotland," he said.

"It's very difficult to prevent cancers," Dr. Ghosh added. "Some very small studies in the past have indicated an increased rate of cancer [in patients with PHPT], and patients that had surgery had less chance of cancer, but more studies are needed to say with certainty" whether surgical treatment of PHPT would decrease the risk for cancer.

American Association of Clinical Endocrinologists (AACE) 18th Annual Meeting and Clinical Congress: Abstract 511. Presented May 15, 2009.

SEVERE DERMATITIS WITH CETUXIMAB AND RADIOTHERAPY

1: Am J Clin Oncol. 2009 May 29. [Epub ahead of print]

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Severe Radiation Dermatitis in Patients With Locally Advanced Head and Neck Cancer Treated With Concurrent Radiation and Cetuximab.

Koutcher LD, Wolden S, Lee N.

From the Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY.

OBJECTIVES:: A phase III trial has shown the superiority of concurrent cetuximab and radiotherapy versus radiotherapy alone for the treatment of locally advanced head and neck cancer (HNC). We evaluated our institution's experience of patients treated with concurrent cetuximab and radiotherapy to determine the rate of serious (>/=grade 3) radiation dermatitis. We also sought to more fully describe and characterize the grade 4 dermatitis that these patients develop. METHODS:: We performed a retrospective review of HNC patients who were treated with concurrent cetuximab and radiation. We included patients treated in either the definitive or loco-regionally recurrent setting with nonmetastatic disease who received their first dose of cetuximab from March 1, 2006 to January 1, 2008. We found 115 patients who fit our search. RESULTS:: Serious radiation dermatitis was noted in 26 (23%) patients, with 22 patients developing grade 3 dermatitis and 4 patients developing grade 4 dermatitis. All 4 patients who developed grade 4 dermatitis did so within the radiation field. The dermatitis was manifested by spontaneous bleeding from the involved skin, and in 1 case, skin necrosis. These toxicities developed during the fifth week of treatment. CONCLUSIONS:: Treatment with concurrent radiation and cetuximab for locally advanced HNC is a relatively new treatment modality, and the toxicities of this regimen are becoming better understood. We believe that the serious skin toxicities that these patients develop when treated with concomitant cetuximab occur more frequently than when patients are treated with concurrent cisplatin, although further study is needed to confirm this.

RECLAST APPOVED TO PREVENT OSTEOPORORSIS

June 4, 2009 — The FDA this month has approved zoledronic acid infusion (Reclast, Novartis Pharmaceuticals Corp) for the prevention of postmenopausal osteoporosis during a 2-year period.

"It is very important to treat postmenopausal women with low bone mass to help prevent them from progressing to osteoporosis," said Mone Zaidi, MD, PhD, in a company news release. "The dosing of Reclast for the prevention of postmenopausal osteoporosis offers an advance over existing therapies since it can be given once every two years, instead of daily, weekly, or monthly."

Dr. Zaidi is professor of medicine, geriatrics, and physiology and director of the Mount Sinai Bone Program at Mount Sinai School of Medicine in New York City.

The FDA's approval was based on data from a 2-year, randomized, multicenter, double-blind clinical study (n = 581) showing that zoledronic acid significantly increased bone mineral density at the lumbar spine relative to placebo for osteopenic women in early and late menopause (6.3% and 5.4%, respectively; P < .0001 vs placebo for both). An increase in hip bone mineral density was also observed for both groups (4.7% and 3.2%, respectively; P < .001 vs placebo for both).

The recommended prophylactic regimen of zoledronic acid is a single 5-mg dose every 2 years, administered intravenously during a period of at least 15 minutes. Daily supplementation with 500 to 1200 mg elemental calcium plus 400 to 800 U vitamin D is recommended.

Adverse events most commonly associated with treatment include pyrexia, myalgia, headache, arthralgia, and pain in extremity; other clinically important events were flu-like illness, nausea, vomiting, diarrhea, and eye inflammation. Treatment should be withheld for severe bone, joint, and/or muscle pain.

The FDA warns that zoledronic acid has been linked to a risk for renal impairment that may be elevated in patients receiving concomitant nephrotoxic medications or diuretic therapy and those with severe dehydration. Monitoring of serum creatinine is recommended before each dose.

Osteonecrosis of the jaw has been reported rarely during treatment with bisphosphonates, including zoledronic acid. A routine oral examination is recommended before initiation of therapy.

Zoledronic acid previously was approved for the treatment of osteoporosis to reduce the incidence of hip, vertebral, and nonvertebral fractures in postmenopausal women and to increase bone mass in men.

Other indications include the treatment and prevention of glucocorticoid-induced osteoporosis in patients expected to receive glucocorticoids for at least 1 year and the treatment of Paget's disease of bone in men and women.

THE USE OF BIPHOSPHONATES IN MULTIPLE MYELOMA

Ann Oncol. 2009 May 22. [Epub ahead of print]

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The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network.

Terpos E, Sezer O, Croucher PI, García-Sanz R, Boccadoro M, San Miguel J, Ashcroft J, Bladé J, Cavo M, Delforge M, Dimopoulos MA, Facon T, Macro M, Waage A, Sonneveld P.

Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra University Hospital, Athens, Greece.

BACKGROUND: Bisphosphonates (BPs) prevent, reduce, and delay multiple myeloma (MM)-related skeletal complications. Intravenous pamidronate and zoledronic acid, and oral clodronate are used for the management of MM bone disease. The purpose of this paper is to review the current evidence for the use of BPs in MM and provide European Union-specific recommendations to support the clinical practice of treating myeloma bone disease. Design and methods: An interdisciplinary, expert panel of specialists on MM and myeloma-related bone disease convened for a face-to-face meeting to review and assess the evidence and develop the recommendations. The panel reviewed and graded the evidence available from randomized clinical trials, clinical practice guidelines, and the body of published literature. Where published data were weak or unavailable, the panel used their own clinical experience to put forward recommendations based solely on their expert opinions. RESULTS: The panel recommends the use of BPs in MM patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable; however, oral administration can be considered for patients unable to make hospital visits. Dosing should follow approved indications with adjustments if necessary. In general, BPs are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. Initial therapy of ONJ should include discontinuation of BPs until healing occurs. BPs should be restarted if there is disease progression. CONCLUSIONS: BPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ.