Rethinking Combination Chemotherapy: Concomitant vs Sequential Drug Treatment for Breast Cancer

Abstract & Commentary

Synopsis: Epirubicin and paclitaxel were administered either in combination or sequentially to 202 patients with metastatic breast cancer to demonstrate noninferiority of the sequential approach. Response rates and survival were comparable in the 2 groups, but toxicity was greater (neutropenia and neuropathy) in those that received the drugs sequentially rather than in combination. Thus, sequential treatment with epirubicin and paclitaxel is an effective approach, but at the doses used in the current protocol, the approach is associated with greater, not less, toxicity.

Source: Conte PF, et al. Cancer. 2004;101:704-712.

Systemic chemotherapy remains the primary treatment for metastatic breast cancer, particularly for those with hormone-resistant tumors. Combinations, including those of anthracyclines with taxanes are commonly used in this setting. In the current report, a group of Italian oncologists performed a randomized trial to evaluate whether the results of sequential, rather than concomitant administration of drug would result in equivalent (non-inferior) results. The drugs selected were epirubicin (90 mg/m2) and paclitaxel (200 mg/m2) given in combination for a for a total of 8 cycles (concomitant arm, n = 108) or epirubicin at a dose of 120 mg/m2 for 4 cycles followed by paclitaxel at a dose of 250 mg/m2 over 3 hours for 4 cycles every 21 days (sequential arm, n = 94).

The median progression free and overall survival were 11 months (95% confidence interval [95% CI], 9.7-12.3) and 20 months (95% CI, 17.2-22.6) respectively, in the concomitant arm, and 10.8 (95% CI, 7.9-13.6) and 26 months (95% CI, 18.1-33.8) respectively in the sequential arm (P = not significant). Patients who received the sequential regimen experienced a higher incidence of Grade 3/4 neutropenia (62/2% of courses vs 50.62%; P = 0.03), whereas 6 patients who received the concomitant regimen developed Grade II cardiotoxicity. Quality-of-life analyses revealed no significant differences between the 2 regimens. Conte et al were therefore confident in rejecting the null hypothesis that the sequential treatment is less active than the standard concomitant regimen in this clinical setting.

Comment by William B. Ershler, MD

Since the introduction of MOPP chemotherapy for Hodgkin’s disease several decades ago, there has been a deeply seated dogma, based upon sound rationale, experimental data and clinical trial experience supporting the notion of combined, rather than single agent chemotherapy for malignant disease. The rationale is based upon the expectation that efficacy is likely to be greater if drugs with different mechanisms of activity are used, and that acquired drug resistance would be less. Indeed, in both the adjuvant and metastatic disease treatment setting, combined drug regimens usually prove superior to single drug treatments.1-3 However, with the introduction of newer, and potentially more powerful agents, the issue of single-agent treatment has arisen again. In fact, in the treatment of lung cancer, single agents therapy is commonly selected based upon a number of phase II and III trials demonstrating comparable efficacy and improved tolerability when compared to the more intensive combinations.4 Sequential therapy has been introduced to capitalize on certain of the benefits of combination therapy but with the hopeful expectation of reduced toxicity, and possibly expense.

In this regard, the current report is quite interesting. Metastatic breast cancer patients were randomized to a standard paclitaxel/epirubicin either in combination (standard) or in sequence (experimental arm). The doses of each agent were lower when used in combination. In fact, when used alone (sequential arm), the doses selected were at, or near the maximum tolerated dose (120/mg2 for epirubicin and 250/m2 for paclitaxel).

What was observed is that sequential single-agent treatment was no less effective than the combination, but, unfortunately, it was no less toxic either. In fact, Grade 3/4 neutropenia (during the epirubicin phase) and Grade 2 to 4 neurotoxicity (during the paclitaxel phase) were both more common during in the sequential treatment arm. Furthermore, quality-of-life measures did not reveal either arm to be superior. Thus, the trial succeeded in demonstrating that active drugs in sequence may be comparable to combined therapy, but there was no advantage in terms of tolerability or quality of life.

Physicians need to be cautious about adopting the concept of sequential therapy but using lower doses, such as what would be used in combined regimens. Although reduced toxicity would be likely, the data indicating that such an approach has the same level of success with regard to survival, or even response rates are yet to be established. Hopefully, this group or others will examine lower doses of single agents, used sequentially to provide this clinically important benchmark.

References

1. Slamon DJ, et al. N Engl J Med. 2001;344:783-792.

2. Robert N, et al. Breast Cancer Res Treat. 2002;76:s37.

3. O’Shaughnessy J, et al. Proc Am Soc Oncol. 2003;22:7.

4. Hurria A, Kris MG. CA Cancer J Clin. 2003;53:325-341.

William B. Ershler, MD INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC is Editor of Clinical Oncology Alert.