Recurrent Colorectal Cancers Research Articles

Assessment of biomarkers in paired primary and recurrent colorectal adenocarcinomas

Purpose: Recurrent colorectal cancers respond poorly to anticancer treatment including radiotherapy. To better understand the biological characteristics of the recurrent colorectal tumor, we investigated various biomarkers regulating cell proliferation and cell loss in paired primary and recurrent colorectal tumor specimens within each individual. Methods and Materials: From a total of 11 colorectal adenocarcinoma patients, 22 specimens of paired primary and recurrent tumors were obtained for analysis. Apoptosis was evaluated by TUNEL labeling of apoptotic DNA fragmentation. Other biomarkers including proliferating cell nuclear antigen (PCNA), p53, WAF1, p34cdc2, and cyclins B1 and D1 were analyzed by immunohistochemical stains. Results: PCNA index (PCNAI) showed an increase in 6 and a decrease in 5 recurrent tumors compared to primary tumors. Median PCNAI in primary and recurrent tumors were 33.5 and 48.3, respectively (p 5 0.16). In contrast, the apoptotic index (AI) decreased in 9 of 11 recurrent tumors compared to primary tumors. Median AI decreased from 4.3 in primary tumors to 1.4 in recurrent tumors (p 5 0.04). The p53 expression increased in more than half of recurrent tumors compared to primary tumors. Mean staining score increased from 0.7 in primary tumors to 1.2 in recurrent tumors (p 5 0.059). WAF1 and cyclin B1 did not show significant change. In contrast, both cyclin D1 and p34cdc2 increased significantly in recurrent tumors. These two biomarkers showed increased expression in 8 (cyclin D1) and 7 (p34cdc2) recurrent tumors, respectively, compared to their primary counterparts. Mean staining scores of both biomarkers in recurrent tumors increased by more than twofold compared to those in primary tumors and these differences were statistically significant (cyclin D1, p 5 0.007; p34cdc2, p 5 0.008). Conclusion: This study showed significantly decreased apoptosis in recurrent colorectal tumors compared to their primary counterparts. The underlying regulatory mechanisms included increased expression of p53 and altered cell cycle regulators such as increased cyclin D1 and p34cdc2. With further study, it may be used for developing a new therapeutic strategy for the treatment of recurrent colorectal cancer. © 1999 Elsevier Science Inc.

Indications for and Results of Combined Modality Treatment of Colorectal Cancer

Combined modality chemoirradiation is commonly used as a component of treatment in combination with maximum resection for both high-risk resectable and locally advanced primary or recurrent rectal cancers. With surgically resected but high-risk rectal cancers, postoperative chemoirradiation has been shown to improve both disease control (local and distant) and survival (disease-free and overall) and was recommended as standard adjuvant treatment at the 1990 National Institute of Health (NIH) Consensus Conference on Adjuvant treatment for patients with rectal and colon cancers. Subsequent intergroup trials are being conducted to help define optimal combinations of postoperative chemoirradiation for resected high-risk rectal cancers and to test sequencing issues of preoperative versus postoperative chemoirradiation. With locally unresectable primary or recurrent colorectal cancers, standard therapy with surgery, external beam irradiation (EBRT) and chemotherapy is often unsuccessful. When intraoperative electron irradiation (IOERT) is combined with standard treatment, local control and survival appear to be improved in separate analyses from the Mayo Clinic and the Massachusetts General Hospital (MGH). However, routine use of systemic therapy is also needed as a component of treatment, in view of high rates of systemic failure.

Accuracy of Computed Tomography in Determining Resectability for Locally Advanced Primary or Recurrent Colorectal Cancers

Aim: To determine the accuracy of computed axial tomography (CT) in determining tumor resectability in patients with locally advanced primary (T4) or locally recurrent colorectal cancer. Methods: Computed tomography scans of 84 patients with “resectable” locally advanced primary rectal cancer (n = 12) or recurrent colorectal cancer (n = 72) were compared with the operative findings to assess the accuracy of abdominal and pelvic CT in determining extent of disease and resectability. Results: At surgery, disease was confined to the pelvis in 63 patients, the abdomen in 7, and involved both the pelvis and abdomen in 14. Computed tomography correctly identified these anatomic sites of tumor in 87% of patients, with 89% and 80% accuracies for pelvic and abdominal disease, respectively. Tumor resection was performed in 71 patients (85%), but was not in 13 patients because of locally unresectable disease in 8 and metastatic disease in 5. The accuracy of predicting tumor-related operability was 85%. With regard to adjacent organ resection, CT was accurate in determining the need for sacrectomy or hysterectomy, but overestimated the need for urinary organ resection. Based on histological examination of resection margins, CT correctly staged (n = 45) or overstaged (n = 9) 54 patients (64%) and understaged the remaining 30. The ability of CT to preoperatively predict a locally advanced tumor after preoperative radiation therapy as not being fixed was 30%, fixed but resectable 75%, and fixed but not resectable 25%. Conclusions: Computed tomography is generally reliable at identifying disease as being confined to one region, and for predicting the need for adjacent organ resection. It is less discriminating for predicting local tumor resectability.

A flow cytometric analysis of the nuclear DNA content between primary and recurrent colorectal cancers

We compared the DNA content in both the primary and recurrent lesions of 12 cases with colorectal cancer. The DNA ploidy agreed in 10 cases (83.3%) between the primary and recurrent lesions. The mean DNA index was similar between both lesions. The DNA content seems to remain stable during recurrence in many cases of colorectal cancer. However, the existence of variations in the content also suggests that the specimens should be investigated for both primary and recurrent lesions in order to obtain more information on the biological or clinical behavior of the tumor.

Radiotherapy for palliation of symptoms in incurable cancer

Approximately one half of prescribed radiotherapy is given for palliation of symptoms due to incurable cancer. Distressing symptoms including pain, bleeding, and obstruction can often be relieved with minimal toxic effects. Painful osseous metastasis is common in oncologic practice. Ninety percent of patients with symptomatic bone metastases obtain some pain relief with a lowdose, brief course of palliative radiotherapy. One half of the responding patients may experience complete pain relief. A single dose of 800 cGy in the setting of painful bone metastasis may provide pain control comparable to more protracted treatment at a higher dose of radiation. Patients with lytic disease in weight-bearing bones, particularly in the presence of cortical destruction, should be considered for prophylactic surgical stabilization of their condition. Routinely a brief, fractionated course of radiotherapy is given postoperatively. Pain due to multiple bone metastases uncontrolled by analgesics can be managed with single doses of halfbody irradiation. Doses of 600 cGy delivered to the upper half-body (above the umbilicus) and 800 cGy to the lower half-body (from the umbilicus to the middle of the femur) will provide some pain relief in 73% of patients. Half-body techniques have been investigated as prophylactic treatment, as a complement to local-field irradiation, and as fractionated rather than singledose therapy. Although intravenous administration of strontium 89 has been associated with myelosuppression, this treatment has been shown (a) to relieve pain due to bone metastasis and (b) to delay development of new painful sites. Recent data from phase III trials demonstrated that bisphosphonates have a role in reducing skeletal morbidity due to bone metastasis. Bone pain was reduced, and the incidence of pathologic fracture and the need for future radiotherapy was decreased. Radiotherapy relieves clinical symptoms in 70% to 90% of patients with brain metastases. Brief treatment schedules (e.g., 2000 cGy in five fractions over 1 week) are as effective as more prolonged therapy. Patients with solitary brain metastasis and no extracranial disease or controlled extracranial disease should be considered for surgical resection, because phase III data indicate enhanced survival with such an approach. Whole-brain radiotherapy is routinely administered postoperatively. A phase III study is examining the impact of accelerated fractionated doses of radiotherapy (two treatments per day) on survival of patients with brain metastases. Stereotaxic radiosurgical treatment is becoming increasingly available and permits delivery of radiation to metastatic intracranial tumor with minimal exposure of normal surrounding brain This treatment is most commonly used at the time of a solitary recurrence of disease in patients who previously received whole-brain radiotherapy. A role for this modality in newly diagnosed brain metastases remains to be defined. Chest symptoms are common in patients with locally advanced lung cancer and are effectively palliated with one 1000 cGy or two 850 cGy one fraction doses of radiation to the thoracic inlet and mediastinum. Chest pain and hemoptysis are more effectively palliated than cough and dyspnea. In patients with stage III cancer there is no compelling evidence that radiotherapy confers a survival advantage, and it may be reasonable to administer thoracic radiotherapy only when the patient has significant symptoms and the goal is to achieve control of these symptoms. Approximately 75% of the cases of superior vena cava syndrome are due to lung cancer, and small-cell lung cancer is the most common histologic type. A histologic diagnosis should be obtained before treatment is started, because detection of lymphoma or small-cell carcinoma would necessitate systemic therapy. Eighty percent of the patients with vena cava syndrome due to malignant disease achieve symptom relief with a brief, fractionated, palliative course of rad

Intraoperative electron and external beam irradiation with or without 5-fluorouracil and maximum surgical resection for previously unirradiated, locally recurrent colorectal cancer.

1) Disease control and survival will be evaluated for treatment regimens containing intraoperative electron irradiation (IOERT) for locally recurrent, previously unirradiated colorectal cancers. 2) Various prognostic factors will be evaluated to determine whether they have an impact on disease control or survival. From April 1981 through August 1995, 123 patients with previously unirradiated locally recurrent colorectal cancers received IOERT at our institution, usually as a supplement to external beam irradiation (EBRT) and maximum resection. All received EBRT with or without concomitant 5-fluorouracil-based chemotherapy. Forty-five Gy in 25 fractions was given to the tumor or tumor bed plus 3-cm to 5-cm margins in 121 of 123 patients and a boost of 5.4 to 9 Gy in 3 to 5 fractions to the tumor plus 2-cm margins. Maximum resection was performed before or after EBRT. IOERT doses ranged from 10 to 20 Gy in 119 of 123 patients, with dose dependent on resection margins (130 fields in 123 patients). Maintenance chemotherapy was given to only two patients. Disease relapse and survival were evaluated. Central failure (within the IOERT field) was documented in 13 of 123 patients (11 percent) with a five-year actuarial rate of 26 percent. Local relapse (in EBRT field) occurred in 24 patients (20 percent); five-year rate was 37 percent. Distant metastases occurred in 66 patients (54 percent); five-year rate was 72 percent. Median survival was 28 months, with overall survival at two, three, and five years of 62, 39, and 20 percent, respectively. Tolerance data suggest a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (< or = 12.5 Gy, 2 of 29 or 7 percent; > or = 15 Gy, 19 of 101 or 19 percent; P = 0.12). Survival and disease control were analyzed as a function of potential prognostic factors. None of the prognostic factors had a significant impact on disease control or survival. Although there was a trend for reduction in local relapse rates with gross total vs. partial resection, this neither achieved statistical significance nor translated into improved survival. Patients with gross residual disease after maximum resection had three-year and five-year survival rates of 36 and 18 percent, respectively, which paralleled results for patients with gross total resection at 41 and 24 percent, respectively. Encouraging trends for improved local control with or without survival exist in separate locally recurrent colorectal IOERT analyses from our institution and other institutions. Therefore, continued evaluation of IOERT approaches seems warranted. Disease control within the IOERT and external fields is decreased when the surgeon is unable to accomplish a gross total resection. Therefore, it is reasonable to consistently add 5-fluorouracil or other dose modifiers during EBRT and to evaluate the use of dose modifiers in conjunction with IOERT (sensitizers and hyperthermia). In view of high systemic failure rates of > 50 percent in patients with locally recurrent disease, more routine use of systemic therapy is indicated as a component of IOERT-containing treatment regimens (use existent chemotherapy and/or develop effective immunotherapy and gene transfer therapy). Even with locally recurrent lesions, the aggressive multimodality approaches including IOERT have resulted in improved local control and long-term survival rates of 20 percent vs. an expected 5 percent with conventional techniques.

Advances in the treatment of early- to late-stage colorectal cancer: 20 years of progress

Numerous scientific and clinical advances have made significant changes in our understanding of the etiology of colorectal cancer and in the diagnosis and treatment of patients with large bowel malignancy or its precursor lesions. A personal view of 20 years of progress was presented at the Commission on Cancer lecture during the 1993 Clinical Convocation of the American College of Surgeons. Improvement in the diagnosis and treatment of early bowel cancers, significant benefit from multimodality therapy of more advanced resectable bowel cancers, and better articulated selection criteria in patients with recurrent colorectal cancers are reviewed. Most importantly, both physical and emotional consequences of our therapies are shown to have diminished without sacrificing the ability to cure. Perhaps the next major challenge is for the general surgeon to assume responsibility as the primary medical manager of any patient with gastrointestinal cancer from the time of diagnosis onward.

Pretargetted imaging of colorectal cancer recurrences using an 111In-labelled bivalent hapten and a bispecific antibody conjugate.

In 11 patients recurrence of colorectal cancer was suspected by a rise in serum carcinoembryonic antigen (CEA) (nine cases), by a subocclusive clinical situation (one case) or by endoscopy (on an anastomosis, one case). Two-step tumour targetting was performed by a first injection of 0.1 mg kg-1 of unlabelled bispecific antibody conjugate (an anti-CEA Fab' fragment chemically coupled to an anti-diethylene triamine pentaacetate (DTPA)-indium fragment) followed 4 to 5 days later by injection of the bivalent DTPA hapten labelled with 5 to 8 mCi 111In. Planar scintigraphy, single photon emission computed tomographic (SPECT) 360 degrees acquisitions and whole-body scans were obtained 4.5 and 24 h after injection of the radiolabelled hapten. Biodistribution was determined for eight patients at 48 h. The final diagnosis was confirmed histologically in nine patients (eight by second-look surgery, one by laparotomy). Overall, results were one true negative (1-year follow-up) and 10 true positive; however, for the three large liver metastases (3 to 6 cm), only the periphery of the metastasis had high uptake compared to normal liver. For pelvic recurrences, immunoscintigraphic (IS) contrast was better for small tumours. The highest tumour uptake was found for a 1 cm diameter pelvic recurrence (7.2% i.d. kg-1). Mean tumour-to-blood ratios were 6.4. Thus, this two-step tumour targetting technique, which uses a bispecific antibody conjugate and an 111In-labelled bivalent hapten injected sequentially without chasing the excess bispecific antibody, provided satisfactory results in this preliminary clinical trial for detection of recurrent colorectal cancers.

Site-specific phase I, II trials of hyperthermia at Kyoto University.

Site-specific phase I, II trials of locoregional hyperthermia undertaken at Kyoto University are briefly reviewed. Thermometry analysis demonstrated the usefulness of RF (radiofrequency) capacitive heating equipment in the treatment of various subsurface or deep-seated tumours including locally advanced breast cancers, soft tissue tumours, lung cancers involving the chest wall, liver tumours, unresectable or recurrent colorectal cancers, and invasive urinary bladder cancers. The difficulty in heating whole tumour volume or hypervascular tumours to therapeutic temperatures was also shown. Non-randomized trials for locally advanced breast cancers, unresectable or recurrent colorectal cancers and invasive urinary bladder cancers demonstrated a higher response rate in thermoradiotherapy than in radiotherapy alone. The complications associated with treatment were not generally serious except for chronic bowel damages in a trial for colorectal cancers. These promising phase I, II trials encourage the future phase III trials.

Anticarcinoembryonic antigen immunoscintigraphy with a 99mTc-Fab' fragment (Immu 4) in primary and recurrent colorectal cancer. A prospective study.

Forty-seven patients were submitted to 68 radioimmunoscintigraphic investigations for primary or recurrent colorectal cancer. Immunoscintigraphy with Immu-4 correctly detected 28 primary colorectal cancers of 29 and 12 of 12 recurrent colorectal cancers. Overall accuracy was 93.75 percent in primary and 91.6 percent in recurrent colorectal cancer. Immunoscintigraphy had a decisive influence on treatment planning in every third primary colorectal cancer patient and was by far superior to CT scan in the detection of early recurrences, especially in patients with a history of abdominoperineal or low anterior resection. Immu-4 scintigraphy is a safe and convenient diagnostic approach to colorectal cancer. Because radioactivity is acceptably low and the method is absolutely free of side effects, there are no objections to the repeated use of immunoscintigraphy which provides important information in primary diagnosis as well as in the follow-up of colorectal cancer patients.

Residual, inoperable or recurrent colorectal cancer: Interaction of surgery and radiotherapy

For irradiation of inoperable, residual or recurrent colorectal cancers, doses of 4,500 to 5,000 rads can achieve short-term palliation; doses must be increased to 6,000 to 7,000 rads or more, however, if long-term control of disease or possible cure is desired. The ability to achieve those dose levels safely depends on close interaction between the surgeon, the radiation oncologist and the diagnostic radiologist in defining and displacing normal and tumor tissues. Methods used at Massachusetts General Hospital from March 1976 to August 1979 are defined. They include the use of operative clips and pelvic reconstruction, diagnostic computed tomography and ultrasound, radiotherapy optimization including shrinking field techniques, radiation with bladder distention and single intraoperative boost doses given in combination with external beam.