Phase II Trial of Preoperative Chemoradiation with a Hyperfractionated RT Boost in Locally Advanced Rectal Cancer

Heather Jones, MD
University of Pennsylvania Cancer Center
Last Modified: November 4, 2001

Presenter: H. Diratzouian
Affiliation: Fox Chase Cancer Center, Philadelphia, PA

Studies have reported a dose response relationship for preoperative radiation therapy. The Fox Chase group has previously reported the results of a phase I dose escalation trial demonstrating the tolerability of preoperative chemoradiation with a hyperfractionated (Hfx) RT boost to 61.8 Gy. The purpose of this phase II study was to prospectively determine the efficacy (pathologic response, downstaging, and survival) of this regimen in locally advanced rectal cancer.

Materials and Methods

  • Patients had to have adenocarcinoma of the rectum <12 cm from the anal verge, clinically staged as T4 or T3 (but > 4 cm or > 40% of the bowel circumference).
  • Radiation (RT) consisted of 45 Gy to the pelvis (1.8 Gy per fraction) followed by 1.2 Gy BID (to the gross target volume) to a total RT dose of 61.8 Gy.
  • 5-FU was infused at 1 g/m2/24 hours for four days during the 1st and sixth weeks of RT (concurrent with the Hfx boost).
  • Surgical resection was planned 4-6 weeks later.
  • Adjuvant chemotherapy (5-FU/leucovorin) was scheduled for 4 cycles at 28-day intervals (days 1-5 beginning 4 wks post-surgery).


  • 22 patients with bulky primary tumors (21 fixed or tethered T3 lesions; 1 T4; 17/22 < 6 cm from anal verge) were enrolled.
  • All but 2 patients received the full 61.8 Gy and all but 2 patients received the preop chemotherapy per protocol
  • Acute toxicities from the preop chemoRT included grade (gr) 4 nausea (1 pt), gr 3 infection (2 patients), gr 3 proctitis (1 pt), and gr 3 diarrhea (1 pt).
  • Pathologic downstaging was achieved in 43% of patients.
  • Surgical resection consisted of APR in 12 pts, LAR in 7, and colo-anal anastomosis in 2.
  • A significant relationship was found between tumor distance from the anal verge (>6 cm vs <=6 cm) and the type of surgery (sphincter sparing vs not), p=0.0048.
  • Of the 21 patients S/P surgery, 9 (43%) had evidence of pathologic downstaging - - 5 (24%) had a near-complete pathologic response (>90% treatment effect with only residual cells of unclear etiology) and 4 patients (19%) had a moderate (30-90%) treatment effect.
  • With a median f/u of 27 months (7-135), the 1, 2, and 3 yr actuarial rates for all patients (n=22) of OS were 95%, 90% and 75%; of DFS 86%, 80% and 48%; and of LC 90%, 90% and 80%, respectively.
  • 3/21 pts (14%) had positive margins, all of whom developed a local failure (p<0.0001). Margin status also predicted for DFS (p=0.003) and OS (p=0.022). Metastatic disease (M+) found at surgery predicted for DFS (p=0.0007) and OS (p=0.008).
  • Other predictors of DFS included grade (0.04) and the degree of pathologic response (>30% vs none, p=0.025). Pathologic nodal disease predicted for LC (0.016).

Author's Conclusions
This regimen of high dose preop chemoradiation with a Hfx RT boost (to 61.8 Gy) is feasible and results in significant downstaging in patients with bulky, locally advanced rectal cancer. Negative margins are a prerequisite for local control, and the degree of pathologic response predicts for DFS.

Clinical/Scientific Implications
This study attempts to address the need for increased dose to the volume most at risk by using hyperfractionated RT for the final boost. The use of proper imaging and biologic markers may in future help us best predict the patients that would most benefit form such a boost. We also anxiously await the FACT questionnaire data from this cohort of patients at gain some insight into their bowel function after such attempt to dose escalate.