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Preoperative Chemoradiation for Locally Advanced Rectal Cancer: Emerging Treatment Strategies

Preoperative Chemoradiation for Locally Advanced Rectal Cancer: Emerging Treatment Strategies

ABSTRACT: Over the past decade, patients with locally advanced rectal cancer at The University of Texas M. D. Anderson Cancer Center have been managed with preoperative chemoradiation. Patients achieving a complete clinical response to preoperative chemoradiation have had better pelvic tumor control, sphincter preservation, and overall survival than those with gross residual disease. Some patients achieving a complete clinical response have even had rectal-preserving surgery (full-thickness local excision). These results emphasize the importance of maximizing tumor response. Further improvement in response and survival could be achieved by using novel chemotherapeutic agents or through tumor-selective molecular targeting strategies that enhance the effects of chemotherapy, radiotherapy, or both. Irinotecan (CPT-11, Camptosar) is a novel chemotherapy agent being evaluated clinically as a radiosensitizing agent in rectal cancer. Inhibition of several molecular targets—such as epidermal growth factor receptor, ras oncogene activation, the cyclooxygenase-2 (COX-2) enzyme, and neoangiogenesis—appears to be tumor-selective in preclinical models. COX-2 expression has been shown to enhance cytotoxic therapy in preclinical models. In vitro and in vivo studies show that selective COX-2 inhibition enhances the effects of radiotherapy as well as chemotherapy. COX-2 is also markedly upregulated in human colorectal cancer and appears to be associated with adverse patient prognosis. Thus, integration of molecular targeting, such as COX-2 selective inhibition with existing chemoradiation approaches, may provide selective tumor radiosensitization and chemosensitization, resulting in improved pelvic control, sphincter preservation, and overall survival. [ONCOLOGY 16(Suppl 5):39-44, 2002]

Preoperative chemoradiation has become a common
approach to treat stage II and III rectal cancer at many institutions, including
The University of Texas M. D. Anderson Cancer Center (MDACC) in Houston.[1-4] A
study from Uppsala, Sweden, has shown that preoperative radiation alone improves
pelvic control as compared with postoperative radiation alone.[5] Another
Swedish trial in patients with rectal cancer demonstrated improved pelvic
control and overall survival using preoperative radiotherapy compared with
surgery alone.[6] These studies, however, used preoperative radiotherapy without
concurrent chemotherapy.

Although a randomized trial has not been conducted to compare the efficacy of
preoperative chemoradiation to that of radiotherapy alone, concurrent
chemoradiation is commonly used in the United States. This practice is based on
extrapolation from trials in the postoperative setting[7,8] showing the
superiority of combined chemotherapy and radiotherapy over radiotherapy alone.
In this respect, the use of a protracted venous infusion of fluorouracil (5-FU)
has become the standard chemotherapy, based on data from a randomized trial
conducted by the Gastrointestinal Intergroup.[9]

Patients who have had a complete clinical response to preoperative
chemoradiation have had better pelvic tumor control, sphincter preservation, and
overall survival than those who have had gross residual disease. Some patients
achieving a clinical complete response have even had rectal preserving surgery
(full-thickness local excision). These results emphasize the importance of
maximizing tumor response. The improvement in overall survival could be due to
higher pelvic control rates, or the response may indicate increased sensitivity
of distant micrometasteses to chemotherapy. Any increase in the response of
local disease to chemoradiation or distant micrometasteses to chemotherapy would
logically further improve outcome.

Use of chemotherapeutic agents that may be more effective than 5-FU as
radiosensitizers or as systemic agents may also lead to further improvements in
response and survival rates. Alternatively, molecular targeting could be used to
selectively enhance the efficacy of chemoradiotherapy regimens. Irinotecan
(CPT-11, Camptosar) is among the newer chemotherapeutic agents being explored in
combination with radiotherapy. Phase I studies have determined the maximum
tolerated dose of irinotecan when used with preoperative chemoradiation in
rectal cancer patients.[10] The Radiation Therapy Oncology Group (RTOG) is
currently evaluating irinotecan as a radiosensitizer in rectal cancer.

Because the primary limitation of chemoradiation is toxicity to normal
tissues, an improvement in therapeutic ratio could also be achieved by
incorporating tumor-selective agents. A number of processes—such as epidermal
growth factor receptor signaling, ras oncogene activation, the cyclooxygenase-2
(COX-2) enzyme, and angiogenesis—appear to be tumor-selective in preclinical
models. Treatment with inhibitors of these molecular processes has shown
therapeutic efficacy in several preclinical tumor models, particularly when
combined with cytotoxic agents.[11]

Among molecular target therapeutic strategies, counteracting COX-2 enzyme
activity seems promising, and significant preclinical and clinical testing of
this approach has been initiated. COX-2 overexpression occurs in various types
of human cancer[12] and has been shown to correlate with poor prognosis.[13]
Study results have shown that treatment of tumor-bearing mice with selective
COX-2 inhibitors enhances tumor response to radiation[14] and chemotherapy.[15]
Cyclooxygenase inhibitors have been shown to prevent colon cancer[16,17] and to
reduce the number of polyps in patients with familial adenomatous polyposis.[18]
Therefore, COX-2 inhibition has the potential to improve outcome for rectal
cancer patients treated with preoperative chemoradiation.

Experience at
The University of Texas M. D. Anderson Cancer Center

Over the past decade at MDACC, patients with rectal cancer have been treated
with a preoperative radiotherapy dose of 45 Gy in 25 fractions prescribed to the
95% isodose line, with concomitant protracted venous infusion 5-FU at 300
mg/m2/d, Monday through Saturday morning. Since 1997, patients have been treated
in an ongoing prospective phase II trial that includes a concomitant boost
technique. With this technique, the same radiation dose is delivered to the
tumor and pelvic lymphatics (45 Gy) over 5 weeks, with an additional 1.5-Gy
boost as a second daily treatment separated from the first by 6 hours during the
fifth treatment week. The total dose to the primary tumor is 52.5 Gy prescribed
to the 95% isodose line. The boost is given to the gross tumor volume using a 3D
conformal technique, which minimizes normal tissue irradiation. Mesorectal
excision is carried out 4 to 8 weeks later. All patients receive four cycles of
adjuvant 5-FU and leucovorin after surgery.

Treatment Results

Pelvic Control

Between 1990 and 2000, 390 stage II and III rectal cancer patients were
treated with preoperative pelvic chemoradiation followed by surgery. Presence of
microscopic or no residual disease was shown to be a favorable predictor of
pelvic control on univariate analysis (P = .02, Figure
1
). A Cox regression
multivariate analysis showed a trend toward improved survival (P = .08,
unpublished observations). The only independently significant prognostic factor
for freedom from pelvic recurrence was clinical T stage. Actuarial freedom from
pelvic recurrence at 4 years was 90% for 354 patients with T3 disease vs 79% for
36 patients with T4 disease.[19] At MDACC, clinical T4 disease is defined as
objective evidence of adjacent organ involvement on computed tomography (CT)
scan, physical examination, or endoscopic ultrasound.

Sphincter Preservation

While the concept is not universally accepted, several investigators have
reported that significant numbers of patients who were initially thought to
require abdominoperineal resection were able to undergo sphincter-preserving
procedures following preoperative chemoradiation.[20] This phenomenon has been
demonstrated prospectively by preliminary results of the ongoing National
Surgical Adjuvant Breast and Bowel Project (NSABP) R-03 trial, in which patients
were randomly assigned to receive preoperative or postoperative chemoradiation.
Surgeons entering patients in the study were encouraged to decide prospectively
which operation would be necessary. A sphincter-preserving procedure was
possible in 23% of those patients initially felt to require abdominoperineal
resection.[21]

While studies have suggested that response to preoperative chemoradiation may
impact the rate of sphincter-preserving surgery,[2,22] those analyses were not
originally designed to answer that question. At MDACC, the sphincter
preservation rate in patients with low rectal cancer following preoperative
chemoradiation has increased with time and is currently greater than 60% for
tumors < 6 cm or less from the anal verge. A logistic regression analysis of
clinical, treatment-related, and pathologic factors among 238 patients with
tumors < 6 cm from the anal verge indicated that complete clinical response
to preoperative chemoradiation is an independent predictor of sphincter
preservation.[23]

Clinical complete response rate was 46%, and tumors < 3 cm or less from the anal
verge that responded completely to preoperative chemoradiation had the most
striking difference in sphincter-preserving surgery (44% vs 23%, P = .01)
compared to those who did not respond completely. Importantly, the pelvic
recurrence rate among patients undergoing sphincter-preserving surgery has been
less than 10% since 1993, and no increase in pelvic recurrence risk has been
observed with the use of sphincter-preserving procedures in the low rectum
(unpublished observations). Thus, increasing the response rate could lead to
increased rates of sphincter preservation or even rectal preservation.

Of 362 patients with T3 rectal cancer treated at MDACC with preoperative
chemoradiation and surgery over the past decade, 17 patients with localized
disease have been selected for local excision due to patient refusal of
abdominoperineal resection, medical comorbidity, physician preference after a
complete clinical response, or unknown reasons. Local excision was performed
after completion of chemoradiation. With a median follow-up of 34 months (range:
6 to 96 months), only 1 of 17 patients has had intrapelvic recurrence and
another has had disease recur in an inguinal lymph node. Two patients have died
of metastatic rectal cancer and one has died of unknown causes.

The 5-year actuarial overall survival at 5 years was 67%. Twelve of 17 (71%)
patients have achieved pathologic complete response, microscopic residual
disease was evident in 4/17 (24%), and gross residual disease was present in one
patient. This indicates that the response to preoperative chemoradiation may
have played a role in the decision to proceed with local excision rather than
abdominoperineal resection in some patients. Furthermore, it appears that
preoperative chemoradiation followed by local excision provides effective local
control in highly selected cases. This strategy should be studied prospectively
in patients with low rectal cancer who respond to chemoradiation.

Overall Survival

Previously, we reported that response to preoperative chemoradiation (defined
as evidence of microscopic or no residual disease) is a positive predictor of
improved overall survival (P = .07).[3] At the time of that analysis, the
follow-up duration and patient numbers were insufficient to demonstrate
statistical significance. We recently reported results involving a larger
patient cohort, which showed that response (defined as evidence for T-stage
down-staging without nodal positivity) is a positive predictor of
disease-free[24] and overall survival.[25] The presence of microscopic or no
residual disease also positively predicted survival on univariate analysis in
this updated experience (P = .002, Figure
2
). A Cox regression multivariate
analysis confirmed this finding as well as the negative influence of poor
differentiation on overall survival (unpublished observations).

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