**3. Novel strategies in neoadjuvant therapy for locally advanced rectal cancer**

The trimodal approach of neoadjuvant chemoradiotherapy and surgery is generally associated with high rates of local-regional control for patients with locally advanced rectal cancer [9]. However, there is room for improvement in the oncologic outcomes of the most locally advanced tumors, and also great interest in increasing the rate of complete pathologic responses to chemoradiotherapy, which may allow for increased utilization of non-operative management.

A variety of chemotherapy and targeted agents have been studied as part of novel neoadjuvant regimens in an attempt to improve on results obtained with fluoropyrimidine-based chemo‐ radiation. Although early-phase studies have shown modest improvements in tumor respons‐ es; this has often been at the expense of increased toxicity.

#### **3.1. Oxaliplatin**

There has been much interest in particular in the use of oxaliplatin concurrent with radiation. The ACCORD 12/0405 PRODIGE 1 study randomized patients with locally advanced rectal cancer to preoperative treatment with radiation (45 Gy in 25 fractions) plus capecitabine or radiation (50 Gy in 25 fractions) plus capecitabine and oxaliplatin [10;11]. High-grade toxicity rates were higher in the oxaliplatin-treated patients (25 versus 11%), and there were no significant differences between the two arms with respect to rates of pCR, local control, and overall survival. In the STAR-01 trial, over 700 patients with locally advanced rectal cancer were randomized to neoadjuvant treatment with radiation (50.4 Gy total dose) plus infusional 5-FU with or without weekly oxaliplatin, followed by surgery [12]. The addition of oxaliplatin increased the rate of high grade toxicity (24% versus 8%) but did not improve the pathologic complete response rate (equal in the two arms at 16%). In the PETACC-6 trial, 1094 patients with locally advanced rectal cancer were randomized to preoperative radiation plus capeci‐ tabine followed by surgery and adjuvant chemotherapy versus the same regimen with oxaliplatin delivered during the chemoradiation course as well as the adjuvant course [13]. The use of oxaliplatin again increased toxicity rates, with no disease-free survival benefit.

The NSABP R-04 trial is a four-arm study that compared infusional 5-FU and capecitabine, with and without the use of oxaliplatin, during neoadjuvant chemoradiotherapy for rectal cancer [14]. Capecitabine in place of 5-FU yielded a different toxicity profile with similar rates of pCR, local-regional control, and overall survival. Patients treated with oxaliplatin had higher rates of high-grade toxicity without significant improvements in local-regional control or overall survival. Finally, in the CAO/ARO/AIO-04 trial, patients with locally advanced rectal cancer were randomized to treatment with radiation with concurrent 5-FU, surgery, and adjuvant bolus 5-FU versus radiation plus 5-FU, oxaliplatin, surgery, and adjuvant mFOL‐ FOX6 [15]. There were no substantial differences in rates of pathologic complete response or margin-negative surgery. However, 3-year disease-free survival was higher in the oxaliplatin group (75.9% versus 71.2%). The independent contribution of the oxaliplatin delivered in the neoadjuvant setting is unclear.

#### **3.2. Targeted therapies**

Incorporation of novel targeted drug agents into trimodality regimens is also an area of dynamic clinical investigation. Bevacizumab is an anti-VEGF antibody. Willett et al. reported on 32 patients who underwent one cycle of bevacizumab followed by radiation, infusional 5- FU, further bevacizumab and subsequent surgery [16]. Local control was 100% at 5 years; disease-free survival was 75% at 5 years. Landry et al. reported on the phase 2 ECOG 3204 study, which combined capecitabine, oxaliplatin, and bevacizumab for patients with operable T3 and T4 rectal cancer [17]. Of the 49 patients who proceeded to surgery, 17% had a pathologic complete response. Surgical complications were common and may have been related to the addition of bevacizumab. Bevacizumab has also been associated with delayed wound healing in other studies [18;19].

Work is also underway evaluating combinations of the anti-EGFR agents panitumumab and cetuximab with chemoradiation. When combining such agents with conventional chemother‐ apy and radiation therapy, appropriate sequencing of these treatments may be of critical importance to optimize oncologic efficacy [17;20].

#### **3.3. Novel scheduling modalities**

**3.1. Oxaliplatin**

262 Updates on Cancer Treatment

neoadjuvant setting is unclear.

**3.2. Targeted therapies**

in other studies [18;19].

There has been much interest in particular in the use of oxaliplatin concurrent with radiation. The ACCORD 12/0405 PRODIGE 1 study randomized patients with locally advanced rectal cancer to preoperative treatment with radiation (45 Gy in 25 fractions) plus capecitabine or radiation (50 Gy in 25 fractions) plus capecitabine and oxaliplatin [10;11]. High-grade toxicity rates were higher in the oxaliplatin-treated patients (25 versus 11%), and there were no significant differences between the two arms with respect to rates of pCR, local control, and overall survival. In the STAR-01 trial, over 700 patients with locally advanced rectal cancer were randomized to neoadjuvant treatment with radiation (50.4 Gy total dose) plus infusional 5-FU with or without weekly oxaliplatin, followed by surgery [12]. The addition of oxaliplatin increased the rate of high grade toxicity (24% versus 8%) but did not improve the pathologic complete response rate (equal in the two arms at 16%). In the PETACC-6 trial, 1094 patients with locally advanced rectal cancer were randomized to preoperative radiation plus capeci‐ tabine followed by surgery and adjuvant chemotherapy versus the same regimen with oxaliplatin delivered during the chemoradiation course as well as the adjuvant course [13]. The use of oxaliplatin again increased toxicity rates, with no disease-free survival benefit.

The NSABP R-04 trial is a four-arm study that compared infusional 5-FU and capecitabine, with and without the use of oxaliplatin, during neoadjuvant chemoradiotherapy for rectal cancer [14]. Capecitabine in place of 5-FU yielded a different toxicity profile with similar rates of pCR, local-regional control, and overall survival. Patients treated with oxaliplatin had higher rates of high-grade toxicity without significant improvements in local-regional control or overall survival. Finally, in the CAO/ARO/AIO-04 trial, patients with locally advanced rectal cancer were randomized to treatment with radiation with concurrent 5-FU, surgery, and adjuvant bolus 5-FU versus radiation plus 5-FU, oxaliplatin, surgery, and adjuvant mFOL‐ FOX6 [15]. There were no substantial differences in rates of pathologic complete response or margin-negative surgery. However, 3-year disease-free survival was higher in the oxaliplatin group (75.9% versus 71.2%). The independent contribution of the oxaliplatin delivered in the

Incorporation of novel targeted drug agents into trimodality regimens is also an area of dynamic clinical investigation. Bevacizumab is an anti-VEGF antibody. Willett et al. reported on 32 patients who underwent one cycle of bevacizumab followed by radiation, infusional 5- FU, further bevacizumab and subsequent surgery [16]. Local control was 100% at 5 years; disease-free survival was 75% at 5 years. Landry et al. reported on the phase 2 ECOG 3204 study, which combined capecitabine, oxaliplatin, and bevacizumab for patients with operable T3 and T4 rectal cancer [17]. Of the 49 patients who proceeded to surgery, 17% had a pathologic complete response. Surgical complications were common and may have been related to the addition of bevacizumab. Bevacizumab has also been associated with delayed wound healing

Work is also underway evaluating combinations of the anti-EGFR agents panitumumab and cetuximab with chemoradiation. When combining such agents with conventional chemother‐ A more recent area of clinical study has been to incorporate systemic therapy prior to chemo‐ radiation or to eliminate radiation as a component of neoadjuvant therapy for selected patients with locally advanced disease (Figure 2). Chua et al. reported, on a phase 2 study, incorporating induction chemotherapy prior to neoadjuvant chemoradiotherapy [21]. Patients had locally advanced rectal cancers that were considered high-risk by MRI criteria (including tumors with threatened mesorectal resection margin, extensive mesorectal fat involvement, and T4 and/or N2 tumors). Patients were treated with 12 weeks of capecitabine and oxaliplatin. This was followed by radiation (total dose of 54 Gy) and concurrent capecitabine for six weeks and finally total mesorectal excision (Figure 2 B). One hundred and five patients were enrolled. Twenty percent of the patients had a pathological complete response, and 3-year progressionfree and overall survival were 68% and 83% respectively. In a similar approach, a recent randomized phase II trial incorporating induction capecitabine and oxaliplatin showed no difference in histopathologic downstaging compared to patients treated with chemoradiation alone [22]. The authors of these studies suggest that more data is needed before approaching induction chemotherapy as a standard of care for high risk patients.

Schrag et al. recently reported on 32 patients with stage II or III rectal cancer treated with 6 cycles of FOLFOX, with bevacizumab delivered during cycles 1-4, without planned radiation therapy (Figure 2 C) [23]. Thirty of the 32 patients proceeded to surgery without undergoing preoperative irradiation. Of the 32 patients, 25% had a pathologic complete response. The 4 year local recurrence rate was 0% and the 4-year disease-free survival rate was 84%. This strategy of neoadjuvant chemotherapy without planned use of radiation therapy (without use of bevacizumab) is under further study in the randomized N1048 study. However, these studies are in the initial stages of assessment at this time.

A. Conventional tri-modality treatment for rectal cancer

Figure 2. Novel strategies in neoadjuvant therapy for locally advanced rectal cancer. Conventional treatment (A). Induction chemotherapy followed by chemoradiation (B). Elimination of radiation (C). **Figure 2.** Novel strategies in neoadjuvat therapy for local advanced rectal cancer. Conventional treatment (A). Induc‐ tion chemotherapy followed by chemoradiation (B). Elimination of radiation (C).
