Cytotoxic Chemotherapy for Breast Cancer: Are We Done Tweaking It?


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While novel targeted agents may grab the headlines in the treatment of breast cancer, oncologists still debate the optimal delivery of conventional cytotoxic chemotherapy, still a vital component of treatment. At the Best of ASCO Boston meeting, Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital in Boston, commented upon the new data in this field that can help guide everyday practice.

End of an Era of Cytotoxic Trials?

National Surgical Adjuvant Breast and Bowel Project (NSABP) B-38 asked whether adding gemcitabine to a taxane-based adjuvant regimen could improve outcomes in patients with node-positive breast cancer, but the final analysis found no benefit. The addition of gemcitabine (G) to a dose-dense regimen of doxorubicin/cyclophosphamide (AC) followed by paclitaxel (P) was no better than AC→P alone or the standard docetaxel/doxorubicin/cyclophosphamide (TAC) regimen.1

The study enrolled 4,894 women with operable, node-positive breast cancer, randomly assigning them to (1) AC × 4 followed by paclitaxel × 4 every 2 weeks, (2) the same plus gemcitabine given with the paclitaxel, or (3) TAC every 3 weeks × 6. Disease-free survival at 5 years was 82.2% with dose-dense AC→P, 80.6% with dose-dense AC→PG, and 80.1% with standard TAC. Overall survival was approximately 90% in all arms. However, the toxicity profiles, with more neuropathy and anemia observed on the dose-dense arms and more diarrhea and febrile neutropenia on TAC.

“How do we move forward?” Dr. Isakoff asked. “As Dr. Kathy Miller noted during her discussion of this abstract at ASCO, it is unlikely that any third-generation regimen will prove superior, and there is something in these results for everyone. There are regional variations in treatment, and all are reasonable. Personal preferences may prevail, and that’s okay. My own choice is dose-dense AC→P. Patients finish treatment faster, and there is less febrile neutropenia.”

Major improvements are unlikely with additional standard cytotoxics, or further modifications of dose and schedule, he added. “The era of large and broad adjuvant trials is over, and our focus should be on biologics and targeted therapy.”

Benefit of Maintenance Chemotherapy in Subsets

In patients with metastatic breast cancer who respond to paclitaxel/gemcitabine (PG), maintenance with the same regimen doubled the time to progression and improved overall survival vs observation in a phase III Korean Cancer Study Group (KCSG)-BR 0702/NCT00561119 study of 324 patients.2 Patients received six cycles of PG, and the responders were randomly assigned to observation or to continued treatment with the regimen. Certain subsets of patients were found to benefit from continued treatment.

Maintenance PG chemotherapy after six cycles should be considered in patients with metastatic hormone receptor–negative tumors, visceral disease, high tumor burden, young age (< 50), and premenopausal status, the investigators concluded.

From the time of randomization, median progression-free survival was 3.8 months in the observation arm and 7.5 months in the maintenance arm, for a 27% reduction in risk (P = .026). Six-month progression-free survival was 36% vs 59.7% (P = .00023), respectively, and median overall survival was 28 vs 36.8 months, respectively (P = .048).

While pointing out several methodologic issues with this study, Dr. Isakoff noted that the overall results are consistent with prior studies showing that longer duration of treatment has superior disease-free and overall survival.

“The study provides additional data that maintenance was quite effective, but it came with a cost,” he said. “There was an increase in nearly all toxicities, including nausea, emesis, diarrhea, constipation, neutropenia, anemia, and neuropathy. However, using validated EORTC instruments, the investigators found no detriment on quality of life.”

Weekly Paclitaxel Holds Its Own

Weekly paclitaxel proved superior to newer, more expensive microtubule agents in a comparison of weekly regimens plus bevacizumab (Avastin) for the treatment of metastatic breast cancer in the phase III open-label Cancer and Leukemia Group B (CALGB) 40502/North Central Cancer Treatment Group (NCCTG) N063H trial of 799 chemotherapy-naive patients.3

Weekly ixabepilone (Ixempra) at 16 mg/m2 was significantly less effective than weekly paclitaxel at 90 mg/m2, and weekly nab-paclitaxel (Abraxane) at 150 mg/m2 was no better than weekly paclitaxel. Overall tolerability was also best with paclitaxel.

The study closed after the second interim analysis, when ixabepilone and nab-paclitaxel had both crossed the futility boundary for superiority.

The study concluded that at these doses and schedules, the newer agents offer no advantage but they do increase toxicity. At a median follow-up of 12 months, median progression-free survival was 10.6 months with weekly paclitaxel, 9.2 months with nab-paclitaxel, and 7.6 months with ixabepilone (nab-paclitaxel vs paclitaxel, HR = 1.19, P = .12; ixabepilone vs paclitaxel, HR 1.54, P < .0001).

Overall survival was not significantly different among the arms, with approximately 50% of patients alive at 2 years, though it was numerically lowest with ixabepilone. Grade 3 or 4 hematologic and nonhematologic toxicities were lowest with weekly paclitaxel.

“CALGB 40502 convincingly showed that not only is there no improvement with novel microtubule agents, but they performed worse. It is hard to know why,” Dr. Isakoff commented.

“It is unlikely that this occurred by chance, or that activity for bevacizumab differs when paired with the different agents. Is there less potent microtubule inhibition with the newer agents? Preclinical studies suggest they are actually more potent. Were the drugs given on the wrong dose and schedule? Doses were based on data from previous trials, though ixabepilone given weekly is backed by less strong data,” he said.

“The most likely explanation is that toxicity attenuated exposure to the drug,” he suggested. Discontinuation rates were higher with the newer regimens (approximately 45% vs 25% with paclitaxel), and 45% of patients receiving nab-paclitaxel had been dose-reduced by the third cycle.

Ki-67 Is Predictive and Prognostic

Postchemotherapy expression of the proliferative Ki-67 marker in the residual tumor was prognostic for disease-free survival in a correlative analysis of the GeparTrio trial,4 which evaluated neoadjuvant response-guided TAC (docetaxel, doxorubicin, cyclophosphamide) regimens in 2,072 patients with operable or locally advanced breast cancer. The study found benefit for response-guided therapy primarily in the estrogen receptor–positive subgroup.

Ki-67 was measured in 1,165 prechemotherapy core biopsies and in 676 postchemotherapy surgical samples. Residual tumors with the highest proliferation expression (> 35% staining) had very poor outcomes, while those with the lowest (0%–15% staining) had better disease-free survival. The hazard ratios for patients with the highest Ki-67 expression were 1.64 for disease-free survival (P < .0001) and 1.82 for overall survival (P < .0001). Patients who achieved a pathologic complete response had the best outcomes overall, superior even to those with the lowest Ki-67 expression in the residual tumor.

The same patterns were observed in hormone receptor–positive and –negative patients, but the curves were shifted downward in hormone receptor–negative patients, reflecting worse outcomes overall.

“Centrally assessed post-treatment Ki-67 adds independent and additional prognostic information of the outcome after surgery,” Dr. Isakoff commented, “but in real practice, I think that heterogeneity causes challenges.” There is no standard for reading Ki-67 in the clinic, many pathologists don’t report Ki-67, there can be heterogeneity in the tumor bed, and there is no standard cut-off for Ki-67 expression levels, he explained.

“But the study does show that the post-treatment Ki-67 fraction identifies a group at high risk for relapse, for whom we clearly need better treatments,” he added. “Studies are ongoing to determine how to manage patients with residual disease, and these correlative markers may be useful in them.” ■

Disclosure: Dr. Isakoff is a consultant or advisor for Abbott Laboratories.

References

1. Swain SM, Tang G, Geyer CE, et al: NSABP B-38: definitive analysis of a randomized adjuvant trial comparing dose-dense AC→ paclitaxel plus gemcitabine with DD AC→P and with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer. ASCO 2012. Abstract LBA1000. Presented June 5, 2012.

2. Im YH, Park YH, Jung KH, et al: A phase III, multicenter, randomized trial of maintenance versus observation after achieving clinical responses in patients with metastatic breast cancer who received six cycles of gemcitabine plus paclitaxel as first-line chemotherapy. 2012 ASCO Annual Meeting. Abstract 1003. Presented June 5, 2012.

3. Rugo H, Barry WT, Moreno-Aspitia A, et al: CALGB 40502/NCCTG N063H: Randomized phase III trial of weekly paclitaxel compared to weekly nanoparticle albumin bound nab-paclitaxel or ixabepilone +/- bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. 2012 ASCO Annual Meeting. Abstract CRA1002. Presented June 4, 2012.

4. Von Minckwitz G, Mueller B, Blohmer JU, et al: Prognostic and predictive impact of Ki-67 before and after neoadjuvant chemotherapy on pCR and survival: Results of the GeparTrio trial. 2012 ASCO Annual Meeting. Abstract 1023. Presented June 4, 2012.



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