Stockholm, Sweden—Radiotherapy can be given between or during chemotherapy cycles, rather than sequentially (ie, after or before chemotherapy), for women with early breast cancer, according to a large study from the United Kingdom presented at the 2011 European Multidisciplinary Cancer Congress.

In fact, patients who received “synchronous” radiotherapy and chemotherapy had a reduced risk of local recurrence, though no improvement in survival, reported Indrajit Fernando, MD, of University Hospitals Birmingham NHS Foundation Trust.

“With this approach, patients are also able to avoid the delay of radiotherapy, to potentially shorten the treatment time, which is very important to them,” Fernando said.

The randomized phase III SECRAB trial enrolled 2296 women who underwent breast-conserving surgery or mastectomy. All received chemoradiation after surgery, either sequential (n = 1146) or synchronous (n = 1150). With the synchronous approach, radiotherapy was given in the time interval between chemotherapy cycles, either sandwiched between cycles (when 3 weeks of radiotherapy was prescribed) or given concomitantly (when >3 weeks of radiotherapy was prescribed). The women were followed for a median time of 8.8 years.

The chemotherapy regimens were CMF (cyclophosphamide/methotrexate/fluorouracil) or anthracyclineâ”€CMF. CMF was chosen because it is considered the most acceptable regimen for combining with radiotherapy, Fernando explained.

A number of radiotherapy schedules were considered suitable; more than 60% of patients received 40 Gy in 15 fractions over 3 weeks.

The 5-year local recurrence rate was significantly improved with the synchronous approach: 2.8% versus 5.1% with sequential chemoradiation, which was a 35% reduction in risk (

He noted the importance of this seemingly small but statistically significant difference. “According to the Early Breast Cancer Trialists’ Collaborative Group, one breast cancer death can be avoided for every four local recurrences prevented. Therefore, even a 2.3% reduction in local recurrence rates will have an impact worldwide when we consider that this is a very common cancer.”

There was no difference, however, in locoregional recurrence rates, which were 6.8% with the synchronous approach and 8.2% with the sequential approach, a nonsignificant 17% reduction in risk.

Closer examination of this outcome showed that most of these recurrences were observed in tissue outside the radiation field. The in-field locoregional recurrence rate was 2.9% with the synchronous approach and 5.3% with the sequential approach, for a significant 35% reduction in risk (

There was a “modest” increase in acute skin toxicity in patients in the synchronous arm, 24% versus 15% (

 < .001), he noted, and borderline significant difference in moderate to severe telangiectasia, 2.5% versus 1.3% (

 = .05). There were no differences in other late effects of radiotherapy. There were no differences in global quality of life.

Fernando suggested that with more modern radiotherapy techniques, the incidence of acute toxicity would be much lower.

Lori J. Pierce, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, commented that at the present time the results of the SECRAB trial show no improvement in disease-free survival or overall survival with the synchronous approach, but the absolute benefit in local control might spark conversation between clinicians and their patients.

“Are the results practice-changing? Perhaps,” Pierce commented. “With longer follow-up, if survival gains are observed, absolutely. If subgroups are identified who derive a greater absolute local benefit, it’s very likely.”

Articles

Radiotherapy can be given between or during chemotherapy cycles, rather than sequentially, for women with early breast cancer.

Synchronous Radiotherapy With Chemotherapy Improves Local Control in Early Breast Cancer Patients

A number of radiotherapy schedules were considered suitable; more than 60% of patients received 40 Gy in 15 fractions over 3 weeks. The 5-year local recurrence rate was significantly improved with the synchronous approach: 2.8% versus 5.1% with sequential chemoradiation, which was a 35% reduction in risk (

There was no difference, however, in locoregional recurrence rates, which were 6.8% with the synchronous approach and 8.2% with the sequential approach, a nonsignificant 17% reduction in risk. Closer examination of this outcome showed that most of these recurrences were observed in tissue outside the radiation field. The in-field locoregional recurrence rate was 2.9% with the synchronous approach and 5.3% with the sequential approach, for a significant 35% reduction in risk (

Radiotherapy can be given between or during chemotherapy cycles, rather than sequentially for women with early breast cancer.

Stockholm, Sweden—In a global phase III trial, the addition of aflibercept to the standard FOLFIRI chemotherapy regimen improved progression-free survival (PFS) and overall survival (OS) in previously treated patients with metastatic colorectal cancer, Josep Tabernero, MD, of Vall D’Hebron University Hospital in Barcelona, Spain, reported at the 2011 European Multidisciplinary Cancer Congress.

“Adding aflibercept to FOLFIRI in metastatic colorectal cancer patients previously treated with oxaliplatin-based regimens resulted in OS and PFS benefits that are both statistically significant and clinically meaningful,” Tabernero said in his presentation at the Presidential Session.

Aflibercept is a new fusion protein of key domains from human vascular endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A isoforms, VEGF-B and placental growth factor (PIGF) as well, binding with high affinity.

The VELOUR study randomized 1226 patients with previously treated metastatic disease to  1-hour intravenous aflibercept (4 mg/kg) or placebo, plus FOLFIRI (folinic acid, 5-FU, oxaliplatin, irinotecan), every 2 weeks until progression.

The primary endpoint of OS was reached, with a hazard ratio [HR] of 0.82 (

 = .0032). Median OS in the intention-to-treat population was 12.1 months with FOLFIRI alone, and 12.5 months with FOLFIRI plus aflibercept.

Positive results were also observed for PFS, with a HR of 0.76 (

 = .00007). Median PFS was 4.7 with chemotherapy alone versus 6.9 months with the addition of aflibercept. Response rates were 11.1% versus 19.8%, respectively (

All subgroups benefited, especially patients with liver-only metastases

Prespecified subgroup analyses were planned to confirm the consistency of the effect of aflibercept on OS and PFS. Investigators assessed the impact by stratification factors (performance status, prior bevacizumab treatment), and patient characteristics (age, gender, geographic region, prior hypertension, number of metastatic sites, disease confined to the liver, location of primary tumor).  

“The preplanned subgroup analyses supported the consistency and robustness of the efficacy results across all domains, including prior treatment with bevacizumab,” he reported.

A significant interaction was observed between treatment arm and the presence of liver metastases only, indicating a greater treatment effect in this group of patients, as compared with patients with disease not confined to the liver or no liver disease.

Among patients with liver metastases only, mortality was reduced by 35%, compared with an 11% risk reduction among other groups. PFS followed a similar pattern. For patients with prior bevacizumab treatment who received aflibercept, median PFS was 6.7 months, and OS was 12.5 months, which did not differ from overall study results.   

The incidence of grade 3-4 adverse events were as expected with the anti-VEGF class of agents, and were similar among patients with and without prior bevacizumab exposure. Grade 3-4 hypertension occurred in 16.6% and 20.5% of these groups, respectively.

“Prior treatment with bevacizumab does not appear to significantly impact the safety profile of aflibercept,” he noted.

David Kerr, MD of the University of Oxford, United Kingdom, who is also president of the European Society of Medical Oncology, called VELOUR a, “well designed and well conducted study,” in his comments at the Presidential Session.  He praised the investigators for conducting a preplanned subgroup analysis with 

 biologic rationale rather than “sifting through the data post hoc” to look for associations, but he added that the findings of subgroup analyses should always be considered hypothesis generating rather than practice changing.

However, he said the main findings from VELOUR do, “change the landscape” of the second-line treatment of advanced disease. “We have a new agent to consider for those patients who progress following frontline treatment with FOLFOX with or without bevacizumab,” he said.  

Aflibercept added to FOLFIRI chemotherapy improved PFS and OS in previously treated patients with metastatic colorectal cancer.

Aflibercept Improves Survival in Metastatic Colorectal Cancer Patients

Stockholm, Sweden—The addition of panitumumab to chemotherapy improved overall survival (OS) and progression-free survival (PFS) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck that were negative for the human papillomavirus (HPV), but no benefit was shown for HPV-positive tumors.

These results were presented in a subanalysis of the European SPECTRUM trial presented as a late-breaking abstract at 2011 European Multidisciplinary Cancer Congress (ECCO, ESMO, ESTRO).

The main results of SPECTRUM were reported at ESMO 2010, showing that patients who received panitumumab plus chemotherapy, versus chemotherapy alone, had a significant improvement in PFS but not OS.

The current sub-analysis is the first report of treatment outcomes related to HPV status with any drug in the first-line treatment of advanced squamous cell head and neck cancer, according to lead investigator Jan Vermorken, MD of Antwerp University Hospital in Belgium.

SPECTRUM evaluated panitumumab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), plus platinum-based chemotherapy (cisplatin + 5-FU) in 657 patients with recurrent or metastatic disease. Three hundred seventy-seven (57%) had samples evaluable for HPV status, of which 22% were HPV-positive (ie, had staining in at least 10% of cells), and 78% were HPV-negative.

PFS and OS Improved in HPV-Negative Subset Only

Median OS, in the HPV-negative subset, was 11.8 months in the panitumumab/chemotherapy arm versus 8.6 months in the chemotherapy arm, for a 27% statistically significant reduction in the risk of death (

 = 0.02). In contrast, in the HPV-positive subset, the addition of panitumumab was not associated with a survival benefit: median OS was 10.9 months with panitumumab/chemotherapy versus 12.1 months with chemotherapy alone (

“The survival was strikingly and significantly different in the HPV-negative patients who received panitumumab, and this was not the case in the HPV-positive patients,” he noted. The test for interaction, however, was not significant (

 = 0.332), possibly due to small numbers of patients in the HPV-negative group, he added.

Progression-free survival was also significantly, though not as strikingly, improved with panitumumab in the HPV-negative subset, where median PFS was 6.5 months with panitumumab/chemotherapy versus 5.1 months with chemotherapy alone (

 = .002). In the HPV-positive subset, median PFS was 5.5 and 5.3 months, respectively. Again, the test for interaction was not significant (

The effect of panitumumab in HPV-negative patients was consistent across all subsets, including patients with poor performance status and those with prior platinum chemotherapy. Adverse events in the panitumumab arm were as expected, with serious adverse events leading to study or drug discontinuation seen in 14% of the panitumumab arm and 12% of the chemotherapy-alone arm.

In the overall population, he added, there was a trend for a more favorable outcome in patients with HPV-positive disease; however, “this should be confirmed in an independent dataset,” he said.

“Although our data suggest that it may be worthwhile to use HPV status for stratification in future phase III trials with anti-EGFR treatment in recurrent/metastatic squamous cell carcinoma of the head and neck, it remains speculative and confirmation is first needed,” Dr. Vermorken said.

Jean Bourhis, MD, PhD, of the Institute Gustave Roussy, Villejuif, France, discussed the presentation, noting that HPV has become a major prognostic factor in locally advanced head and neck cancer (especially of the oropharynx); however, its prognostic value in recurrent and metastatic disease is unknown.

“The role of HPV in recurrent and metastatic disease for predicting response to EGFR monoclonal antibodies is also unknown,” he noted.

But the value of targeting EGFR with EGFR inhibitors, especially cetuximab, has been established, he said. “The amount of benefit in PFS is significant, and there is also a survival benefit for the first time in 30 years,” he said.

The SPECTRUM trial had a relatively similar design to the pivotal cetuximab trial, and it also demonstrated a significant PFS benefit but not an OS benefit, which was the primary endpoint, he noted. He also noted that in a phase II trial (unpublished) lapatinib, another EGFR inhibitor, has shown benefit in locally advanced disease.

“There are some clear limitations of the study,” according to Bourhis. It is a subgroup and retrospective analysis, only two thirds of the patients had HPV status evaluable, the analysis of HPV status was primarily performed on the primary tumor, and the test for interaction was nonsignificant. 

Nevertheless, this is the first description of EGFR inhibition activity specifically in HPV-negative disease, and the data are consistent with previous findings.

“There is a potentially important clinical impact of these findings,” he commented. “But because of some limitations in the study there is a need for confirmation and for generating additional evidence-based medicine (level 1) in recurrent/metastatic disease.”

Panitumumab + chemo improves OS and PFS in patients with metastatic carcinoma of the head and neck that were negative for HPV.

Panitumumab Extends Progression-Free Survival in HPV-Negative Subset of Advanced Head and Neck Cancer

Stockholm, Sweden—Patients with liver metastases from uveal melanoma had improved survival after treatment with percutaneous hepatic perfusion (PHP), in which chemotherapy is directly infused into the liver, University of Pittsburgh investigators reported at the 2011 European Multidisciplinary Cancer Congress (EMCC). 

“This is the first treatment to show a clinical benefit in patients with liver metastases from ocular melanoma,” said James Pingpank, MD, who presented the results at a press briefing.

The phase III trial randomized 93 patients to receive PHP or best alternative care (BAC), which could involve interleukin 2, ipilimumab, transcatheter arterial chemoembolization, systemic chemotherapy, or inclusion in a clinical trial.

Percutaneous hepatic perfusion saturates the liver with high doses of melphalan 3.0 mg/kg delivered via a 30-minute hepatic artery infusion, using specially designed catheters, with jugular venous return of filtered blood. Treatment was administered every 4 to 5 weeks, for up to 4 cycles.

The rationale for using melphalan is based on its history in limb perfusion, and its ability to produce high response rates with little toxicity in the liver, Pingpank explained.

“Melphalan is an effective agent for melanoma and other histologies because it gives good control, and you can dose-escalate to the level you need,” he said. “In the absence of severe liver disease it is very well tolerated.”

The adverse effects included more grade 3 and 4 neutropenia (61%), thrombocytopenia (74%), and anemia (47%), but these were transient. One patient died of hepatic failure, he said. Risk of progression reduced by 64%

The receipt of PHP significantly extended median progression-free survival (PFS), which was only 1.6 months with BAC, but reached 6.1 months with PHP, a 64%, highly significant, reduction in risk (

 < .001).  For patients with disease confined to the liver, median hepatic-only PFS was 1.6, versus 8.0 months (

“These were highly significant results in the experimental arm,” Pingpank noted.

But despite the fact that 58% of patients crossed over to the PHP arm, no survival differences were observed. Overall survival at one year was 26% with BAC and 29% with PHP, and median survival was 9.9 versus 11.4 months, respectively.  

Interestingly, patients who crossed over and received “late” PHP still experienced an improvement in PFS. Median PFS in this crossover group was 6.5 months overall and 9.2 months for patients with disease confined to the liver, he reported.

Alexander Eggermont, MD, director general of the Institut de Cancerologie Gustave Roussy in Paris, commented, “One of the interesting points is that those patients who crossed over from the BAC arm of the study had PFS after ‘late’ treatment with PHP that is about the same as when PHP was given upfront. Also, in the absence of identified targets for targeted drugs in uveal melanoma, one might consider testing the role of ipilimumab following PHP.”

PHP can potentially be used for liver metastases from other cancers as well, and the investigators are obtaining encouraging results in neuroendocrine tumors, Pingpank added.  The device that delivers and filters the melphalan is approved in Europe and is pending approval in the United States. 

Patients with liver metastases from uveal melanoma had improved survival after treatment with percutaneous hepatic perfusion (PHP).

By Sandra Hanner

Articles

Synchronous Radiotherapy With Chemotherapy Improves Local Control in Early Breast Cancer Patients

Synchronous Radiotherapy With Chemotherapy Improves Local Control in Early Breast Cancer Patients

Aflibercept Improves Survival in Metastatic Colorectal Cancer Patients

Panitumumab Extends Progression-Free Survival in HPV-Negative Subset of Advanced Head and Neck Cancer

Novel Infusion Approach Significantly Delays Progression in Uveal Melanoma Patients With Liver Metastases