Strategies to improve adjuvant and neoadjuvant treatment regimens

The role of anthracyclines and taxanes in the treatment of women with early stage breast cancer is well-established. Several trials have investigated whether the addition of agents such as gemcitabine or capecitabine to the standard anthracycline-taxane based adjuvant regimens can further improve prognostic outcome. Moebus et al.[1] presented the results of the phase III German Adjuvant Intergroup Node study that randomized approximately 3000 patients with node positive breast cancer (≥4 positive nodes) to either intense dose dense epirubicin, paclitaxel and cyclophosphamide regimen (IDD ETC) or epirubicin and cyclophosphamide followed by paclitaxel and capecitabine (EC-TX). The authors reported that at a median follow up of 74 months 5-year disease free survival was 80% and 82% among those receiving the IDD ETC and EC-TX regimens respectively essentially showing no additional benefit to the addition of capecitabine. Janni et al.[2] presented the final results of the phase III SUCCESS: A study that evaluated nearly 4000 patients with high risk breast cancer randomized to receive either fluorouracil (5 FU), epirubicin, and cyclophosphamide (FEC) followed by docetaxel or FEC, followed by docetaxel and gemcitabine. The authors reported a 5-year disease free survival and overall survival of 87% and 93% respectively for both arms of the study thereby concluding that the addition of gemcitabine did not improve prognostic outcome in the cohort study. The results of this study are in line with prior neoadjuvant (NEOTANGO and NSABP 40) and adjuvant (TANGO and NSABP 38) studies that have also failed to show a benefit of the addition of gemcitabine to a standard anthracycline and taxane based regimen. Data from studies such as these tell us that as of now the chemotherapy backbone of adjuvant regimens remains anthracyclines and taxanes. Future research studies will need to focus not on adding to this standard backbone, but perhaps modifying it according to tumor biology.

American Society of Clinical Oncology 2005 was a momentous occasion for the oncology fraternity in that the results of adjuvant treatment of patients with HER-2 positive breast cancer with trastuzumab were presented at a special session. For the first time in decades the addition of a targeted therapy (trastuzumab) was shown to reduce the risk of death from breast cancer by approximately 50%. Since then several anti-HER-2 agents have been introduced with hope of further improving prognostic outcome among women with HER-2 positive breast cancer. The NEOALLTO and NEOSPHERE studies both showed a significant increase in pathological complete response rates (pCR) when lapatinib or pertuzumab respectively were combined with trastuzumab and chemotherapy. Based on the belief that pCR functions as a surrogate marker of long-term outcome pertuzumab was approved in combination with trastuzumab in the neoadjuvant setting by the Food and Drug Administration in 2013. The question arose as to whether dual blockade actually has an impact on prognostic outcome. Piccart et al.[3] presented the results of the phase III randomized ALLTO trial that tried to answer this question. Patients with early stage HER-2 positive breast cancer were randomized to receive adjuvant trastuzumab for 1 year, lapatinib for 1 year, trastuzumab with lapatinib for 1 year or 3 months of tarastuzumab followed by 9 months of lapatinib. Anti-HER-2 therapy could be initiated concurrently with chemotherapy or following completion of all chemotherapy. Three years ago the single agent lapatinib arm of the trial was closed for futility. At median follow-up of 4.5 years no significant difference in the disease free survival and overall survival was observed across the three remaining arms of the study. As such at this time there is no role for the dual blockade in the adjuvant setting. We await the results of the phase III APHINITY trial that is looking at the role of adjuvant dual blockade with a combination of pertuzumab and trastuzumab.

The addition of tamoxifen to the adjuvant treatment of women with hormone receptor positive breast cancer has been shown to reduce the risk of death from breast cancer by 30% among women in the premenopausal age group. The use of luteinizing hormone-releasing hormone agonist has been shown in meta-analysis to have a small additional benefit when used after chemotherapy or in combination with tamoxifen. Adjuvant aromatase inhibitors have been shown among postmenopausal women with hormone receptor positive breast cancer to improve disease free survival compared to tamoxifen. Pagani et al.[4] presented the results of the combined results of the SOFT and TEXT trials that randomized premenopausal women with hormone receptor positive breast cancer to either adjuvant tamoxifen and ovarian function suppression or exemestane and ovarian function suppression asking the question of superiority of aromatase inhibitor compared with tamoxifen in this cohort. Women were allowed to receive adjuvant chemotherapy. The authors demonstrated an absolute improvement in disease free survival of 3.8% at 5 years favoring the group of patients receiving exmestane and ovarian function suppression. No significant difference in overall survival was seen although the results were still premature and longer follow-up is required. Based on these results should we be offering the option of an aromatase inhibitor and ovarian function suppression to our premenopausal patients? This option would be associated with increased cost as well as associated toxicity that comes with an aromatase inhibitor and ovarian function suppression. Furthermore, the results of this trial conflicts with the updated results of the ABCSG 12 trial that revealed no difference in disease free survival among between patients receiving tamoxifen and ovarian suppression and those receiving anastrozole and ovarian suppression. Despite this the use of an aromatase inhibitor and ovarian function suppression may be an option to consider among premenopausal women at high risk of relapse. Certainly longer follow-up of this trial is needed. The question of the added benefit of ovarian function suppression compared to no suppression among women receiving tamoxifen will be addressed by the SOFT trial with results expected to be presented later on this year.

Strategies to improve adjuvant treatment regimens

An important question addressed this year was whether the addition of oxaloplatin to fluoropyramidine based adjuvant therapy decreases risk of disease recurrence among patients with rectal cancer. Hongchao et al.[7] presented the results of the phase II ADORE study that randomized 321 patients with curatively resected rectal cancer whose postoperative stage was ypII or III to receive either adjuvant FOLFOX or 5 FU/leucovorin. The authors reported an improvement in 3 year disease free survival from 62.9%-to 71.6%-favoring the group of patients receiving adjuvant FOLFOX. Rodel et al.[8] presented results of a phase III trial where 637 patients with cT3/T4 or CN+ rectal cancer were randomized to receive either preoperative chemoradiation therapy with 5 FU followed by surgery followed by four cycles of adjuvant 5 FU or preoperative chemoradiation therapy with 5 FU and oxaloplatin followed by surgery followed by eight cycles of adjuvant FOLFOX. The authors reported an improvement in 3 year disease free survival from 71.2% to 75.9%-(P = 0.03) favoring the group receiving oxaloplatin. Both studies indicate a potential role for the use of adjuvant oxaloplatin/5 FU based treatment in patients with rectal cancer at high risk of recurrence.

The presence of microsatellite instability (MSI) in colon cancer is associated with a low recurrence rate postsurgery and resistance to chemotherapy with 5 FU chemotherapy. Tougeron et al.[9] presented the results of the multicenter retrospective AGEO study the aim of which was to look at the efficacy of adjuvant chemotherapy with either 5 FU or FOLFOX amongst patients with either high risk stage II or stage III colon cancer. The authors reported a 3 year relapse free survival of 75%, 66% and 84% among patients undergoing surgery alone, receiving adjuvant 5 FU or receiving adjuvant FOLFOX, respectively (P = 0.02) essentially indicating that the addition of adjuvant oxaloplatin to a 5 FU back bone chemo sensitivity among patients with MSI colon cancer.