March 17, 2011 — The latest results from the ongoing Herceptin Adjuvant (HERA) trial confirm that treatment with adjuvant trastuzumab (Herceptin) is beneficial to women with HER2-positive early breast cancer. Patients who received trastuzumab for 1 year after chemotherapy had significantly better disease-free survival than patients who did not (observation group).
The authors of a study published in the March issue of the Lancet Oncology found that 4-year disease-free survival in the trastuzumab group was 78.6%, compared with 72.2% in the observation group (hazard ratio [HR], 0.76; P < .0001).
"These findings confirm that adjuvant trastuzumab given sequentially to chemotherapy is associated with significant and persisting benefits, and remains an appropriate treatment modality in patients with HER2-positive early breast cancer," conclude the authors, led by Luca Gianni, MD, from the San Raffaele Institute, Milan, Italy.
There was no significant difference in the risk for death between the trastuzumab and observation groups (4-year overall survival, 89.3% vs 87.7%; P = .11). However, these results are probably heavily influenced by the fact that 52% of patients crossed over from observation to trastuzumab, notes Heikki Joensuu, MD, PhD, in an accompanying commentary.
Fewer Events in Crossover Group
Dr. Joensuu, who is from the Helsinki University Central Hospital in Finland, points out that there were fewer disease-free survival events in the crossover group than in those who remained in the observation group. This was despite the late start of trastuzumab treatment in the crossover group, which began a median of 22.8 months after randomization.
When the HERA trial was designed, the preference was for trastuzumab to be administered in the same fashion as endocrine therapy — as a single drug after chemotherapy for a long period of time, notes Dr. Joensuu. But growing evidence suggests that the concomitant administration of trastuzumab and chemotherapy is more effective than trastuzumab given after chemotherapy.
He points out that although the crossover data from HERA "are provocative," they cannot be regarded as sufficient evidence to recommend deferring the start of trastuzumab 1 to 3 years after chemotherapy is completed. The results seen in the HERA trial were "probably confounded by patient selection, and thus supportive evidence, preferably from randomized trials, is needed before deferred trastuzumab can be accepted as standard therapy," he writes.
"The best way to integrate trastuzumab with chemotherapy and the optimum duration of trastuzumab are not known, but inclusion of a period of concomitant trastuzumab and chemotherapy in the treatment regimen seems a reasonable choice," says Dr. Joensuu.
Interim Data Showed Positive Results
HERA is an ongoing phase 3 trial designed to compare trastuzumab treatment for 1 and 2 years with observation, following the administration of standard neoadjuvant/adjuvant chemotherapy in women with HER2-positive early breast cancer. Between December 2001 and June 2005, more than 5000 women from 39 countries were enrolled and randomly assigned to observation only, trastuzumab for 1 year, or trastuzumab for 2 years.
In 2005, a planned interim analysis at a median follow-up of 1 year showed that the addition of trastuzumab to standard adjuvant chemotherapy significantly improved disease-free survival, compared with chemotherapy alone (HR 0.54; 95% confidence interval [CI], 0.43 to 0.67) (N Engl J Med. 2005;353:1659-1672).
A second intention-to-treat analysis, at a median follow-up of 2 years (Lancet. 2007; 369:29-36), confirmed that trastuzumab is associated with a significant improvement in disease-free survival (HR, 0.64; 95% CI, 0.54 to 0.76) and an improvement in overall survival (HR, 0.66; 95% CI, 0.47 to 0.91), compared with chemotherapy alone.
Beneficial Over the Long Term
Dr. Gianni and colleagues reported on the outcomes at a median follow-up of 4 years, and assessed the effect on outcome measures of the extensive crossover of patients.
For this analysis, the cohort consisted of 1698 patients in the observation group and 1703 in the trastuzumab group. In the observation group, 1354 patients were alive and disease free as of May 16, 2005, and eligible for selective crossover to trastuzumab. A total of 885 (52%) crossed over to trastuzumab; the median time from randomization to the first dose of trastuzumab in the crossover group was 22.8 months (range, 4.5 to 52.7). This corresponded to a median time from original diagnosis of 30.9 months (range, 9.1 to 58.3).
A total of 827 disease-free survival events were recorded: 458 (27%) in the observation group and 369 (21.7%) in the trastuzumab group. Distant recurrence was the most common first disease-free survival event, affecting 320 in the observation group (18.8%) and 251 in the trastuzumab group (14.7%). In a nonrandomized comparison, patients in the crossover group had fewer disease-free survival events than those who remained in the observation group (adjusted HR, 0.68; 95% CI, 0.51 to 0.90; P = .0077).
A total of 182 patients in the trastuzumab group and 213 in the observation group died; the unadjusted HR for risk for death was 0.85 (95% CI, 0.70 to 1.04; P = .11).
Cardiotoxicity Continuing Concern
There was a higher incidence of grade 3/4 and fatal adverse events in the trastuzumab group. The most common were (each in less than 1% of patients) congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhea. One cardiac death occurred in the observation group, and more patients in the trastuzumab group had symptomatic congestive heart failure and a confirmed significant drop in left ventricular ejection fraction (LVEF).
There were fewer cases of symptomatic congestive heart failure and confirmed significant LVEF drops in the crossover group than in the trastuzumab group.
The risk for serious and life-threatening cardiotoxicity with combination anthracyclines and trastuzumab has been an ongoing concern.
In a second accompanying commentary, Evandro de Azambuja, MD, PhD, from the Institut Jules Bordet and Université Libre de Bruxelles, Belgium, and colleagues remind the oncology community that the "concurrent use of trastuzumab and anthracycline-based chemotherapy significantly increases the risk of cardiac toxicity, even if administered for brief periods in the neoadjuvant setting."
They argue that there is insufficient evidence to safely promote the concurrent use of trastuzumab and anthracyclines in patients with primary HER2-positive breast cancer.
A trial is needed that compares the sequential and concomitant administration of trastuzumab and anthracycline-based chemotherapy. Previous large trials of the sequential approach have suggested that a 50% reduction in the risk for relapse at the expense of a risk for congestive heart failure of up to 4% is an acceptable risk–benefit ratio, they write.
"To put this outcome into perspective, a new strategy that entails the combined use of anthracyclines and trastuzumab should achieve a higher risk–benefit ratio," Dr. de Azambuja and colleagues note. "Until this result is convincingly shown, we strongly discourage the concurrent use of trastuzumab and anthracycline-based regimens in clinical practice outside of the context of a clinical trial."
The study was funded by F. Hoffmann-La Roche and the Michelangelo Foundation. Several of the study authors report monetary relationships with Roche, the manufacturer of trastuzumab. Dr. de Azambuja and 2 of his coauthors report relationships with Roche. Dr. Joensuu has disclosed no relevant financial relationships.
Lancet Oncol. 2011;12:203-204, 209-211, 236-244. Abstract, Abstract, Abstract
The authors of a study published in the March issue of the Lancet Oncology found that 4-year disease-free survival in the trastuzumab group was 78.6%, compared with 72.2% in the observation group (hazard ratio [HR], 0.76; P < .0001).
"These findings confirm that adjuvant trastuzumab given sequentially to chemotherapy is associated with significant and persisting benefits, and remains an appropriate treatment modality in patients with HER2-positive early breast cancer," conclude the authors, led by Luca Gianni, MD, from the San Raffaele Institute, Milan, Italy.
There was no significant difference in the risk for death between the trastuzumab and observation groups (4-year overall survival, 89.3% vs 87.7%; P = .11). However, these results are probably heavily influenced by the fact that 52% of patients crossed over from observation to trastuzumab, notes Heikki Joensuu, MD, PhD, in an accompanying commentary.
Fewer Events in Crossover Group
Dr. Joensuu, who is from the Helsinki University Central Hospital in Finland, points out that there were fewer disease-free survival events in the crossover group than in those who remained in the observation group. This was despite the late start of trastuzumab treatment in the crossover group, which began a median of 22.8 months after randomization.
When the HERA trial was designed, the preference was for trastuzumab to be administered in the same fashion as endocrine therapy — as a single drug after chemotherapy for a long period of time, notes Dr. Joensuu. But growing evidence suggests that the concomitant administration of trastuzumab and chemotherapy is more effective than trastuzumab given after chemotherapy.
He points out that although the crossover data from HERA "are provocative," they cannot be regarded as sufficient evidence to recommend deferring the start of trastuzumab 1 to 3 years after chemotherapy is completed. The results seen in the HERA trial were "probably confounded by patient selection, and thus supportive evidence, preferably from randomized trials, is needed before deferred trastuzumab can be accepted as standard therapy," he writes.
"The best way to integrate trastuzumab with chemotherapy and the optimum duration of trastuzumab are not known, but inclusion of a period of concomitant trastuzumab and chemotherapy in the treatment regimen seems a reasonable choice," says Dr. Joensuu.
Interim Data Showed Positive Results
HERA is an ongoing phase 3 trial designed to compare trastuzumab treatment for 1 and 2 years with observation, following the administration of standard neoadjuvant/adjuvant chemotherapy in women with HER2-positive early breast cancer. Between December 2001 and June 2005, more than 5000 women from 39 countries were enrolled and randomly assigned to observation only, trastuzumab for 1 year, or trastuzumab for 2 years.
In 2005, a planned interim analysis at a median follow-up of 1 year showed that the addition of trastuzumab to standard adjuvant chemotherapy significantly improved disease-free survival, compared with chemotherapy alone (HR 0.54; 95% confidence interval [CI], 0.43 to 0.67) (N Engl J Med. 2005;353:1659-1672).
A second intention-to-treat analysis, at a median follow-up of 2 years (Lancet. 2007; 369:29-36), confirmed that trastuzumab is associated with a significant improvement in disease-free survival (HR, 0.64; 95% CI, 0.54 to 0.76) and an improvement in overall survival (HR, 0.66; 95% CI, 0.47 to 0.91), compared with chemotherapy alone.
Beneficial Over the Long Term
Dr. Gianni and colleagues reported on the outcomes at a median follow-up of 4 years, and assessed the effect on outcome measures of the extensive crossover of patients.
For this analysis, the cohort consisted of 1698 patients in the observation group and 1703 in the trastuzumab group. In the observation group, 1354 patients were alive and disease free as of May 16, 2005, and eligible for selective crossover to trastuzumab. A total of 885 (52%) crossed over to trastuzumab; the median time from randomization to the first dose of trastuzumab in the crossover group was 22.8 months (range, 4.5 to 52.7). This corresponded to a median time from original diagnosis of 30.9 months (range, 9.1 to 58.3).
A total of 827 disease-free survival events were recorded: 458 (27%) in the observation group and 369 (21.7%) in the trastuzumab group. Distant recurrence was the most common first disease-free survival event, affecting 320 in the observation group (18.8%) and 251 in the trastuzumab group (14.7%). In a nonrandomized comparison, patients in the crossover group had fewer disease-free survival events than those who remained in the observation group (adjusted HR, 0.68; 95% CI, 0.51 to 0.90; P = .0077).
A total of 182 patients in the trastuzumab group and 213 in the observation group died; the unadjusted HR for risk for death was 0.85 (95% CI, 0.70 to 1.04; P = .11).
Cardiotoxicity Continuing Concern
There was a higher incidence of grade 3/4 and fatal adverse events in the trastuzumab group. The most common were (each in less than 1% of patients) congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhea. One cardiac death occurred in the observation group, and more patients in the trastuzumab group had symptomatic congestive heart failure and a confirmed significant drop in left ventricular ejection fraction (LVEF).
There were fewer cases of symptomatic congestive heart failure and confirmed significant LVEF drops in the crossover group than in the trastuzumab group.
The risk for serious and life-threatening cardiotoxicity with combination anthracyclines and trastuzumab has been an ongoing concern.
In a second accompanying commentary, Evandro de Azambuja, MD, PhD, from the Institut Jules Bordet and Université Libre de Bruxelles, Belgium, and colleagues remind the oncology community that the "concurrent use of trastuzumab and anthracycline-based chemotherapy significantly increases the risk of cardiac toxicity, even if administered for brief periods in the neoadjuvant setting."
They argue that there is insufficient evidence to safely promote the concurrent use of trastuzumab and anthracyclines in patients with primary HER2-positive breast cancer.
A trial is needed that compares the sequential and concomitant administration of trastuzumab and anthracycline-based chemotherapy. Previous large trials of the sequential approach have suggested that a 50% reduction in the risk for relapse at the expense of a risk for congestive heart failure of up to 4% is an acceptable risk–benefit ratio, they write.
"To put this outcome into perspective, a new strategy that entails the combined use of anthracyclines and trastuzumab should achieve a higher risk–benefit ratio," Dr. de Azambuja and colleagues note. "Until this result is convincingly shown, we strongly discourage the concurrent use of trastuzumab and anthracycline-based regimens in clinical practice outside of the context of a clinical trial."
The study was funded by F. Hoffmann-La Roche and the Michelangelo Foundation. Several of the study authors report monetary relationships with Roche, the manufacturer of trastuzumab. Dr. de Azambuja and 2 of his coauthors report relationships with Roche. Dr. Joensuu has disclosed no relevant financial relationships.
Lancet Oncol. 2011;12:203-204, 209-211, 236-244. Abstract, Abstract, Abstract
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