Prospective Phase II Study of Preoperative Radiotherapy and

Oral Capecitabine followed by Total Mesorectal Exicision (TME)

in Locally Advanced Rectal Cancer

JH Kim M.D.1, J Park M.D.1, EK Choi M.D.1, SD Ahn M.D.1

S Lee M.D.1, SS Shin M.D.1, JC Kim M.D.2, CS You M.D.2

HC Kim M.D.2, TW Kim M.D.3, HM Chang M.D.3, MH Ryu M.D.3

Department of 1Radiation Oncology, 2Surgery, 3Internal medicine

Asan Medical Center, College of Medicine, University of Ulsan

OBJECTIVES

To evaluate the tumor response, sphincter preservation

effect and acute toxicity of preoperative chemoradiation

therapy using oral capecitabine for locally advanced

rectal cancer

MATERIALS AND METHODS

• Prospective phase II trials

• January 2002 – February 2004

• Locally advanced rectal adenocarcinoma

• Preoperative radiotherapy and oral capecitabine

INCLUSION CRITERIA

• Histologically proven rectal adenocarcinoma

• Locally advanced rectal cancer in clinical evaluation

• Tumor distal border located within 10 cm from AV.

• ECOG performance score 0 – 2

• Adequate hematologic, renal, hepatic function

• Approved informed consent

PRETREATMENT EVALUATION

• History taking and physical examination

• CBC, serum chemistry, CEA

• Sigmoidoscopy or colonoscopy with biopsy

• Endorectal (or transrectal) ultrasound

• Abdominal pelvic CT

• Chest X ray

• Chest CT (CEA > 20ng/ml) , bone scan (CEA > 40ng/ml)

TREATMENT SCHEME( Chemotherapy )

• Preoperative

- 1,650 mg/m2/day, whole period of radiotherapy

- Given orally, divided into two doses

• Postoperative

- 2,500 mg/m2/day (D1-14, every 3 weeks) x 4

• 6, 15 MV photon

• Multiple field technique (3 or 4 portals)

• Whole pelvis 46 Gy / 23 Fr. with tumor boost 4 Gy

• 5 days / week

TREATMENT SCHEME( Radiotherapy )

TREATMENT SCHEME

#1 #2 #3 #4CT

RTSURGERY

Capecitabine1,650 mg/m2/day

50 Gy / 25 Fr.

Capecitabine2,500 mg/m2/day

0 4 8 12 16 20 24

PATIENT CHARACTERISTICS ( I )

Characteristics No. (%)

Patient number 95

Age (years) Median 55 Range 31 – 75

Sex M 68 (72) F 27 (28)

Performance status 1 95 (100) (ECOG)

Histologic Diff. W/D 21 (22) M/D 58 (61)

P/D 5 (5) Other 11 (12)

PATIENT CHARACTERISTICS ( II )

Characteristics No. (%)

Distance from AV (cm) Median 5 Range 0 - 10

Mobility Mobile 15 (16)

Tethered 44 (46) Fixed 31 (33) Unpalpable 5 (5)

Clinical stage * No. (%)

T3N0 13 (14)

T3N1-2 56 (59)

T4N0 4 (4)

T4N1-2 22 (23)

Total 95 (100)

PATIENT CHARACTERISTICS ( III )

* Based on EUS and CT evaluation

Modality No. (%)

Planned radiation dose

Complete 92 (97)

Incomplete 3 (3)

Planned chemotherapy dose

Complete 92 (97)

Incomplete 3 (3)

RESULTS: ComplianceRESULTS

Extent of resection No. (%)

Microscopically complete 92 (98)

Microscopically incomplete 2 (2)

Macroscopically incomplete 1 (1)

Total* (%) 94 (100)

RESULTS: Extent of resection

RESULTS

* One patient did not have surgery due to multiple metastasis.

RESULTS: Pathologic response I

pT

T stage pCR pT1 pT2 pT3 pT4

cT3 (n=68) 10 2 19 37 -

cT4 (n=26) 2 1 5 15 3

Total* (%) 12 (13) 3 (3) 24 (26) 52 (55) 3 (3)

RESULTS

- T down-stage: 54/94 (57%)* One patient did not have surgery due to multiple metastasis.

pN

N stage pN0 pN1-2

cN0 (n=17) 11 6

cN1-2 (n=77) 53 24

Total* (%) 64 (68) 30 (32)

- N down-stage: 53/77 (69%)

RESULTS: Pathologic response II

RESULTS

* One patient did not have surgery due to multiple metastasis.

T level down-stage

N level down-stage

Complete response

Overall down-stage

69 % (53/77)

76 % (71/94)

100 %

12 % (11/94)

57 % (54/94)

50 %

RESULTSRESULTS: Pathologic response III

RESULTS: Sphincter preservation

RESULTS

Tumor distance from anal verge (cm)

Op. 0 – 5 6 – 10

LAR 40* 37

APR 14 3

Total 54 40 * Sphincter preservation rate (AV ≤ 5 cm) : 74% (40/54)Elongation of distal tumor margin: 0.8 ± 1.3 cm (mean ± SD; 0 - 5.5 cm)

Safe sphincter preservation rate: 37% (20/54)

RESULTS: Acute toxicity (Hematologic)

RESULTS

Grade*

1 2 3 4

Leucopenia 41 (43%) 19 (20%) 1 (1%) -

Neutropenia 27 (28%) 5 (5%) 1 (1%) -

Anemia 46 (48%) 7 (7%) - -

Thrombocytopenia 1 (1%) - - -

Toxicity

*NCI CTC V2.0

RESULTS: Acute toxicity (Nonhematologic)

RESULTS

Grade*

1 2 3 4

Proctitis 33 (35%) 7 (7%) - -

Diarrhea 3 (3%) 3 (3%) 3 (3%) -

Hand-foot syndrome 9 (10%) 3 (3%) - -

Radiation dermatitis 1 (1%) 14 (15%) - -

Stomatitis 5 (5%) - - -

Nause 17 (18%) 2 (2%) - -

Vomiting 3 (3%) 1 (1%) - -

Weight loss 1 (1%) - - -

Toxicity

*NCI CTC V2.0

PERIOPERATIVE COMPLICATIONS

Complication * No. (%)

Mechanical ileus 1 (1)

Delayed wound healing 2 (2)

Wound infection 1 (1)

Wound dehiscence 2 (2)

Perianal abscess 1 (1)

Anastomotic leak 1 (1)

Total 8 (9) * Within 60 days from surgery

Results of Preoperative Chemoradiation with Capecitabine

Authors No. No. Staging RT dose Drug* T stage N stage Overall stage Cinical pCR†

T4 workup down down down response

Kim 45 4 EUS/CT 50.4 Gy XL 63% 90% 84% - 31%(2002) / 28 Fr. (24/38) (26/29) (32/38) (12/38)

Kocakova 34 NR‡ EUS 50.4 Gy X 100% 100% 100% - 21%(2003) / 28 Fr. (7/34)

Shi 31 1 - 52.5 Gy X - - 71% - 18%(2004) / 30 Fr. (20/28) (5/28)

Dunst 58 50% - 55.8 Gy X 74% - - 61% 4%(2004) / 31 Fr. (37/50) (30/49) (2/50)

Wong 18 0 EUS/CT 50.4 Gy X 28% 86% 50% - 17%(2004) /MRI / 28 Fr. (5/18) (6/7) (9/18) (3/18)

De Paoli 53 13% - 50.4 Gy X - - 57% 58% 24%(2004) / 28 Fr. (29/51) (31/53) (12/51)

Dupois 51 1 EUS/CT 45 Gy X 59% - - - 24%

(2004) /MRI / 25 Fr.

Current 95 26 EUS/CT 50 Gy X 57% 69% 76% - 12%trial / 25 Fr. (54/94) (53/77) (71/94) - (11/94)

*X=capecitabine, L=leucovorin, †pCR=pathologic complete remission rate, ‡Not reported

CONCLUSIONS

1. Preoperative chemoradiation with oral capecitabine and

conventionally fractionated radiotherapy achieved encoura

ging rates of tumor downstaging, enabling more sphincter

preservation, and reducing multivisceral resection with low

acute toxicity in this trial.

2. This combined modality was safe, effective, and convenien

t treatment for locally advanced rectal cancer