A Phase II study combining short course radiotherapy, chemotherapy and resection of the rectum and metastases in primary metastasized rectal cancer.

DISEASE CHARACTERISTICS:

1. Histologically verified adenocarcinoma of the rectum;

2. Initial evaluation 4 weeks or less before inclusion.

PRIMARY RECTAL TUMOR:

1. Palpable rectal tumor OR;

2. Tumor below the level S1-2 as judged by sagittal CT or MRI slides;

3. R0 resection (circumferential margin > 1 mm) possible at time of presentation OR;

4. Locally advanced primary tumor in which an R0 resection is feasible after 5x5 Gy radiation therapy and a waiting period. This criterium will be judged based on CT scan or MRI of the pelvis. In general, tumors with lymph node metastases in the obturator fossa or above the promontory are not resectable, even after downsizing.



METASTATIC DISEASE:

1. Resectable or ablatable liver metastases. This criterium is judged on the following criteria:

A. No metastatic disease adjacent to or apparently involving all three major hepatic veins, the portal vein bifurcation or the retro hepatic vena cava;

B. No metastatic disease adjacent to or involving the main right or main left portal vein and the main hepatic vein of the opposite lobe;

C. No metastatic disease that would require more than a right or left trisegmentectomy;

D. No presence of six or more metastatic lesion distributed diffusely in both lobes of the liver;

E. No metastatic liver disease that would require a resection that would jeopardize postoperative liver function.

2. Resectable lung metastases. This criterium is judged on the size, number and location of lesions and on the condition and lung capacity of the patient;

3. No metastatic disease in more than two organs, based on CT scan or FDG-PET scan;

4. No peritoneal metastases as demonstrated on CT scan, FDG-PET scan or during laparotomy;

5. No clinical signs of brain metastases.



PATIENT CHARACTERISTICS:

1. GENERAL:

A. 18 years and above;

B. ECOG performance status 0 or 1;

C. Ability to withstand major operative procedure;

D. Written informed consent obtained prior to any study specific screening procedures;

E. Patient must be able to comply with the protocol.

2. HEMATOPOIETIC:

A. White blood cell count at least 3000/mm3.

B. Platelet count at least 100.000/mm3;

C. No bleeding diathesis or coagulopathy.

3. HEPATIC:

A. Total bilirubin less than 1.5 x upper limit of normal;

B. ASAT/ALAT less than 2,5 times upper limit of normal;

C. INR less than 1,5 (for patients receiving coumarin derivates).

4. RENAL:

A. Creatinine normal OR;

B. Creatinine clearance at least 50 ml/min;

C. Negative urine dipstick for protein OR;

D. Protein less than 1 g on 24-hour urine collection.

5. CARDIOVASCULAR;

A. No history of cerebrovascular attack or transient ischemic attack;

B. No uncontrolled hypertension (i.e., blood pressure > 150/100 mm Hg on medication);

C. No unstable angina pectoris;

D. No myocardial infarction within the past year;

E. No New York Heart Association class II-IV congestive heart failure;

F. No serious cardiac arrhythmia requiring medication;

G. No peripheral vascular disease ≥ grade II;

H. No other clinically significant cardiovascular disease;

I. No other unstable or uncompensated cardiac disease.

6. OTHER:

A. No unstable or uncompensated respiratory disease;

B. No pregnant or lactating women;

C. Fertile patients must use effective contraception;

D. No previous or concomitant malignancies within five years other than non-melanoma of the skin or carcinoma in situ of any organ;

E. No serious non-healing wound, ulcer, or bone fracture;

F. No significant traumatic injury within the past 28 days;

G. No serious active infections.




PRIOR AND CONCURRENT THERAPY
CHEMOTHERAPY:

1. No prior fluorouracil-based therapy for any malignancy;

2. No other concurrent chemotherapy.



ENDOCRINE THERAPY:

1. No concurrent hormonal therapy except the following:

A. Steroids for adrenal failure or allergic reactions;

B. Hormones for non-disease-related conditions (e.g., insulin for diabetes);

C. Intermittent dexamethason as an antiemetic.

RADIOTHERAPY:

1. No prior pelvic radiotherapy.



SURGERY:

1. More than 28 days since prior major surgery or open biopsy, surgical wounds should be completely healed;

2. More than 7 days since prior biopsy (except rectal cancer);

3. More than 7 days since prior placement of vascular access device;

4. No other concurrent planned major surgery.



OTHER:

1. More than 10 days since prior full-dose oral or parenteral anticoagulant or thrombolytic agents (except to maintain patency of preexisting, permanent indwelling IV catheters);

2. No prior treatment for this malignancy;

3. No concurrent chronic aspirin use (more than 325 mg/day);

4. No concurrent nonsteroidal anti-inflammatory medications (of the kind known to inhibit platelet function at doses used to treat chronic inflammatory diseases);

5. No other concurrent investigational agents.

See inclusion criteria.