Colorectal Chemoprevention Pilot Study (SWOG-9041), randomized and placebo controlled: the importance of multiple luminal lesions.

BACKGROUND: Colorectal cancer is common worldwide and chemoprevention has the potential of reducing the number of individuals who may suffer and perish from this disease. METHODS: A randomized placebo controlled pilot study in colorectal cancer patients was performed using calcium carbonate as the test agent in a multi-institutional oncology study group. RESULTS: Two hundred twenty volunteers were randomized in the study. The primary goals of compliance, accrual, and toxicity monitoring are presented. Presence of multiple adenomas at study entry and subsequent development of metachronous adenomas were recorded and found to be associated with synchronous adenomas. The secondary endpoint of recurrent adenomas indicated lower rates of new adenoma in the volunteers randomized to the calcium group. CONCLUSION: This pilot study indicates the feasibility of enrolling survivors of colorectal cancer as study volunteers in a colorectal neoplasm chemoprevention clinical trial and oral calcium continues to be a potentially effective drug in reducing colorectal adenomas.

The surgeon's role in cancer prevention. The model in colorectal carcinoma.

Cancer Prevention is an emerging field, capturing the old traditional concept of anticipating the development of a major disease and preventing its full impact by early detection, treatment, or aborting the tumorigenic process by a "molecular vaccine" and alleviating the full impact of the disease. Surgeons are important clinician scientists who can carry this discipline forward and develop its full potential in the clinics and in the community. Advances in molecular biology, genetics, and other technologies have permitted seminal understanding of the carcinogenic pathways and identification of targets and intermediate end points in neoplasia. In this review, we will see that we have the means of preventing significant numbers of colorectal carcinomas (CRC).

A phase I trial of (90)Y-DOTA-anti-CEA chimeric T84.66 (cT84.66) radioimmunotherapy in patients with metastatic CEA-producing malignancies.

PURPOSE/OBJECTIVE: Previous radioimmunotherapy (RIT) clinical trials at this institution with (90)Y-labeled cT84.66 anti-CEA (carcinoembryonic antigen) evaluated the antibody conjugated to diethylenetriaminepentaacetic acid (DTPA). The aim of this phase I therapy trial was to evaluate cT84.66 conjugated to the macrocyclic chelate (90)Y-DOTA and labeled with (90)Y in a comparable patient population. EXPERIMENTAL DESIGN: Patients with metastatic CEA-producing cancers were entered in this trial. If antibody targeting to tumor was observed after the administration of (111)In-DTPA cT84.66, the patient then received the therapy infusion of (90)Y-DOTA-cT84.66 1 week later. Serial nuclear scans, blood and urine collections, and computed tomography (CT) scans were performed to assess antibody biodistribution, pharmacokinetics, toxicities, and antitumor effects. RESULTS: Thirteen (13) patients were treated in this study. Dose-limiting hematologic toxicity was experienced at initial starting activity levels of 12 and 8 mCi/m(2). Subsequent patients received systemic Ca-DTPA at 125 mg/m(2) every 12 hours for 3 days post-therapy to allow for a dose escalation to 16 mCi/m(2), where hematologic toxicity was observed with an associated maximum tolerated dose (MTD) of 13.4 mCi/m(2). Tumor doses ranged from 4.4 to 569 cGy/mCi, which translated to 97-12,500 cGy after a single infusion of (90)Y-DOTA-cT84.66. Human anti-chimeric antibody (HACA) response developed in 8 of 13 patients and prevented additional therapy in 4 patients. CONCLUSIONS: This study demonstrates the feasibility of using (90)Y-DOTA-cT84.66 for antibody-guided radiation therapy. Immunogenicity of the DOTA-conjugated cT84.66 antibody was not appreciably greater than that observed with (90)Y-DTPA-cT84.66 in previous trials. Dose-limiting hematopoietic toxicity with (90)Y-DOTA-cT84.66 decreased with Ca-DTPA infusions post-therapy and appears to be comparable to previously published results for (90)Y-DTPA-cT84.66. The highest antibody uptake and tumor doses were to small nodal lesions, which supports the predictions from preclinical and clinical data that RIT may be best applied in the minimal tumor burden setting.

Clinicopathologic significance of synchronous and metachronous adenomas in colorectal cancer.

PURPOSE: Colorectal cancers (CRCs) evolve from a multiple-step tumorigenesis and, morphologically, are characterized by adenoma. Colorectal cancers with adenomas have distinct clinical features, including reports of improved survival. It is hypothesized that this survival advantage is related to biologic differences in CRC with adenomas rather than earlier diagnosis or earlier stage of disease presentation. PATIENTS AND METHODS: A retrospective chart review of 569 patients treated from 1983 through 2002 was conducted. Data on age, sex, and survival; CRC stage, location, and recurrence; adenoma number, size, histology, and location; and colonoscopy history were analyzed. RESULTS: The mean patient age was 62 years (range, 17-90 years), and 54% of patients were men. The majority of CRCs were left-sided (67%). The American Joint Committee on Cancer stage distribution was 0/I (12%), II (21%), III (34%), and IV (33%). Colorectal cancer with synchronous adenoma was seen in 33% of cases; overall, CRC with adenoma comprised 42% of cases. The event-free survival and overall survival favored CRC with adenoma. After adjusting for age, disease stage, sex, and total number of colonoscopic examinations, the relative risk for an event was 1.51 (P < 0.003) for patients without adenomas versus those with adenomas. CONCLUSION: Colorectal cancer with adenoma represents a distinct population of patients with CRC. The apparent association seems to confer a survival advantage that is not based on age, sex, or disease stage. The survival benefit, although slightly less dramatic, remained significant even when controlled for the number of colonoscopies.

Clear cell sarcoma in the era of sentinel lymph node mapping.

Clear cell sarcoma of the tendons and aponeuroses (CCSTA) are rare aggressive soft tissue tumors with tendency for lymph nodes dissemination. Lymph node involvement is a correlate for prognosis. We present three patients with CCSTA in whom simultaneous sentinel lymph biopsy (SLNB) and resection was performed. Sentinel lymph node mapping may have a role in clear cell sarcoma from a prognostic standpoint. Further investigations are needed for validation.

Pilot trial evaluating an 123I-labeled 80-kilodalton engineered anticarcinoembryonic antigen antibody fragment (cT84.66 minibody) in patients with colorectal cancer.

PURPOSE: The chimeric T84.66 (cT84.66) minibody is a novel engineered antibody construct (V(L)-linker-V(H)-C(H)3; 80 kDa) that demonstrates bivalent and high affinity (4 x 10(10) m(-1)) binding to carcinoembryonic antigen (CEA). The variable regions (V(L) and V(H)) assemble to form the antigen-combining sites, and the protein forms dimers through self-association of the C(H)3 domains. In animal models, the minibody demonstrated high tumor uptake, approaching that of some intact antibodies, substantially faster clearance than intact chimeric T84.66, and superior tumor-to-blood ratios compared with the cT84.66 F(ab')(2) fragment, making it attractive for further evaluation as an imaging and therapy agent. The purpose of this pilot clinical study was to determine whether (123)I-cT84.66 minibody demonstrated tumor targeting and was well tolerated as well as to begin to evaluate its biodistribution, pharmacokinetics, and immunogenicity in patients with colorectal cancer. EXPERIMENTAL DESIGN: Ten patients with biopsy-proven colorectal cancer (6 newly diagnosed, 1 pelvic recurrence, 3 limited metastatic disease) were entered on this study. Each received 5-10 mCi (1 mg) of (123)I-labeled minibody i.v. followed by serial nuclear scans and blood and urine sampling over the next 48-72 h. Surgery was performed immediately after the last nuclear scan. RESULTS: Tumor imaging was observed with (123)I-labeled minibody in seven of the eight patients who did not receive neoadjuvant therapy before surgery. Two patients received neoadjuvant radiation and chemotherapy, which significantly reduced tumor size before surgery and minibody infusion. At surgery, no tumor was detected in one patient and only a 2-mm focus was seen in the second patient. (123)I-labeled minibody tumor targeting was not seen in either of these pretreated patients. Mean serum residence time of the minibody was 29.8 h (range, 10.9-65.4 h). No drug-related adverse reactions were observed. All 10 patients were evaluated for immune responses to the minibody, with no significant responses observed. CONCLUSION: This pilot study represents one of the first clinical efforts to evaluate an engineered intermediate-molecular-mass radiolabeled antibody construct directed against CEA. cT84.66 minibody demonstrates tumor targeting to colorectal cancer and a faster clearance in comparison with intact antibodies, making it appropriate for further evaluation as an imaging and therapy agent. The mean residence time of the minibody in patients is longer than predicted from murine models. We therefore plan to further evaluate its biodistribution and pharmacokinetic properties with minibody labeled with a longer-lived radionuclide, such as (111)In.

The role of pelvic exenteration in the management of recurrent rectal cancer.

BACKGROUND: Use of extirpative surgery in the setting of recurrent rectal cancer is controversial given the poor overall outcome of such patients and the morbidity associated with exenteration. METHODS: A retrospective review of patients treated for recurrent rectal cancer from 1990 to 2002 was performed. RESULTS: Twenty-two patients underwent pelvic exenteration. Seventeen underwent potentially curative resection, 5 were for palliation only. There was 1 operative death. Fifteen suffered at least 1 complication; 9 suffered multiple complications. Ten patients required readmission to the hospital. The overall disease-free interval was 11 months. Potentially curative and palliative resections resulted in median survivals of 20.4 and 8.4 months, respectively (P = 0.049). CONCLUSIONS: While patients may derive oncologic and palliative benefits from exenteration, the price in terms of operative morbidity remains high. Newer measures of operative morbidity are necessary to better appraise the value of this radical approach to recurrent rectal cancer.

A Phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer.

PURPOSE: Targeted systemic radiation therapy using radiolabeled antibodies results in tumor doses sufficient to produce significant objective responses in the radiosensitive hematological malignancies. Although comparable doses to tumor are achieved with radioimmunotherapy (RIT) in solid tumors, results have been modest primarily because of their relative lack of radiosensitivity. For solid tumors, as with external beam radiotherapy, RIT should have a more important clinical role if combined with other systemic, potentially radiation-enhancing chemotherapy agents and if used as consolidative therapy in the minimal tumor burden setting. The primary objective of this trial was to evaluate the feasibility and toxicities of systemic 90Y-chimeric T84.66 (cT84.66) anti-carcinoembryonic antigen RIT in combination with continuous infusion 5-fluorouracil (5-FU). EXPERIMENTAL DESIGN: Patients with chemotherapy-refractory metastatic colorectal cancer were entered. The study was designed for each patient to receive 90Y-cT84.66 anti-carcinoembryonic antigen at 16.6 mCi/m2 as an i.v. bolus infusion combined with 5-FU delivered as a 5-day continuous infusion initiated 4 h before antibody infusion. Cohorts of patients were entered at 5-FU dose levels of 700, 800, 900, and 1000 mg/m2/day. Upon reaching the highest planned dose level of 5-FU, a final cohort received 90Y-cT84.66 at 20.6 mCi/m2 and 5-FU at 1000 mg/m2/day. For all patients, Ca-diethylenetriaminepentaacetic acid at 125 mg/m2 every 12 h was administered for the first 72 h after 90Y-cT84.66. Patients were eligible to receive up to three cycles of 90Y-cT84.66/5-FU every 6 weeks. RESULTS: Twenty-one patients were treated on this study. All had been heavily pretreated with 19 having previously received 5-FU and 16 having failed two to four chemotherapy regimens. A maximum-tolerated dose of 16.6 mCi/m2 90Y-cT84.66 combined with 1000 mg/m2/day 5-FU was reached. These dose levels are comparable with maximum-tolerated dose levels of each agent alone. Thirteen patients received one cycle and 8 patients two cycles of therapy. Hematopoietic toxicity was dose-limiting and reversible. RIT did not appear to increase nonhematopoietic toxicities associated with 5-FU. Two of 19 patients assayed developed a human anti-chimeric antibody immune response after the first cycle of therapy, which is significantly less than that observed in a previous trial evaluating 90Y-cT84.66 alone. No objective responses were observed. However, 11 patients with progressive disease entering the study demonstrated radiological stable disease of 3-8 months duration and 1 patient demonstrated a mixed response. CONCLUSIONS: Results from this trial are encouraging and demonstrate the feasibility and possible advantages of combining continuous infusion 5-FU with 90Y-cT84.66 RIT. The addition of 5-FU does not appear to significantly enhance hematological toxicities of the radiolabeled antibody. In addition, 5-FU reduces the development of human anti-chimeric antibody response, permitting multicycle therapy in a larger number of patients. Future efforts should continue to focus on integrating radiation therapy delivered by radiolabeled antibodies into established 5-FU regimens.

The surgical treatment of cancer: a comparison of resource utilization following procedures performed with a curative and palliative intent.

BACKGROUND: Costs associated with the provision of medical care continue to escalate. Therefore, providers must evaluate the cost-effectiveness and benefit to individual healthcare practices. The authors evaluated the immediate and short-term resource utilization needs of patients undergoing surgical intervention with curative or palliative intent. METHODS: Three hundred two patients undergoing surgery with therapeutic intent were observed from the time of admission for intervention until the time of death or until 6 months from the time of the surgical procedure. Surgeons preoperatively identified each case as either curative or palliative in intent. Demographic information, as well as the nature of all interactions with the cancer center, was recorded. RESULTS: Surgeons identified 58 (19%) procedures as palliative and 244 (81%) as curative in intent. Demographic characteristics between the two groups were similar, although recurrent or metastatic disease was more often present in palliative rather than curative patients (P = 0.0078) and palliative intent patients were more likely to have received previous therapy. During the 6-month period, 4690 encounters occurred with the cancer center. The mean number of encounters per patient in each group was similar, although curative intent patients were more likely to have visits with therapeutic intent including chemotherapy administration (P = 0.01), radiation (P = 0.003), or repeat surgical procedures (P = 0.006). In contrast, palliative patients were more likely to be admitted for management of symptoms (P = 0.0001) and had fewer hospital-free days than did curative patients (P = 0.0069). CONCLUSIONS: The average number of encounters for patients undergoing treatment of disease was not significantly different, suggesting that patients undergoing surgery with palliative intent do not require a greater amount of resources than curative intent patients. The nature of the interactions, however, was different, suggesting that resource needs are different and may need to be anticipated in the assessment of how better quality outcomes can be achieved in the palliative surgery setting.

Concerns of family caregivers of patients with cancer facing palliative surgery for advanced malignancies.

PURPOSE/OBJECTIVES: To describe the concerns of family caregivers of patients undergoing palliative surgeries for advanced malignancies. DESIGN: Descriptive study with repeated measures. SETTING: A National Cancer Institute-designated Comprehensive Cancer Center in the western United States. SAMPLE: Family caregivers (N = 45) of patients with cancer. METHODS: Family caregivers were assessed prior to planned palliative surgery and at two weeks and six weeks postsurgery. Quantitative assessment of caregiver quality of life (QOL) occurred at each interval. A subset of nine caregivers also participated in a structured interview presurgery and at two weeks postsurgery. MAIN RESEARCH VARIABLES: Caregiver concerns, QOL, decision making. FINDINGS: Family caregivers have important QOL concerns and needs for support before and after surgery for advanced disease. Psychological issues were most pronounced, and common concerns included uncertainty, fears regarding the future, and loss. Family caregivers have concerns about surgical risks and care after surgery and voiced recognition of the declining status of patients. CONCLUSIONS: Surgery is an important component of palliative care and profoundly impacts family caregivers of patients with cancer. The needs of family caregivers are multiple and complex, requiring ongoing assessment to provide interventions that help them cope and ultimately improve their QOL. This important topic requires further research and clinical attention. IMPLICATIONS FOR NURSING: Findings suggest that family caregivers experience their own trajectory during the course of their loved ones' cancer, with surgery being a part of the course. This includes their profound emotions that may swing like a pendulum from one minute to the next. Nurses need to assess family caregivers in addition to patients to provide support and resources that will help increase caregivers' QOL.

Online exclusive: patient and surgeon decision making regarding surgery for advanced cancer.

PURPOSE/OBJECTIVES: To describe a program of research related to outcomes of palliative surgery and focus on one phase of this research involving decision making by patients and surgeons considering surgery for advanced disease. DESIGN: Descriptive. SAMPLE: 10 patients undergoing surgery and 3 oncology surgeons. METHODS: Qualitative interviews were conducted with patients and their surgeons pre- and postoperatively. Transcripts were content analyzed to identify major themes in patient and surgeon interviews based on study questions. MAIN RESEARCH VARIABLES: Decision making, palliative surgery, quality of life. FINDINGS: The study findings highlight the issues of greatest concern to patients and surgeons considering palliative surgery. This phase was an important component of the overall program of palliative surgery research. CONCLUSIONS: Comprehensive care for patients with advanced cancer seeks to achieve a balance of providing aggressive care, ensuring optimum symptom management, and maintaining a focus on comfort. Further study of palliative surgery as an aspect of interdisciplinary care is warranted. IMPLICATIONS FOR NURSING: Patients undergoing surgery for advanced disease require expert nursing care to address quality-of-life concerns. Further research is needed in this area.

Adenoma recurrences after resection of colorectal carcinoma: results from the Southwest Oncology Group 9041 calcium chemoprevention pilot study.

BACKGROUND: Colorectal adenomas are the usual precursors to carcinoma in sporadic and hereditary colorectal cancers (CRC). METHODS: A total of 220 CRC patients (stages 0, I, and II) were randomized prospectively in a double-blind pilot study of calcium chemoprevention by using recurrent colorectal adenomas as a surrogate end point. This trial is still in progress, and we report the preliminary findings on adenoma recurrence rates. RESULTS: Synchronous adenomas were present in 60% of patients, and cancer confined in a polyp was present in 23% of patients. The overall cumulative adenoma recurrence rate was 31% (19% in the first year, 29% for 2 years, and 35% for 3 years). The recurrence rates were greater for patients with synchronous adenomas: 38% at 3 years (P =.01). Lower stage was associated with higher adenoma recurrence rates (P =.04). Factors including age, sex, site of primary cancer, and whether the cancer was confined to a polyp were not significantly associated with differences in adenoma recurrence rates. CONCLUSIONS: The substantial adenoma recurrence rate in patients resected of CRC justifies colonoscopic surveillance on a periodic basis. Patients with higher rates of adenoma recurrences, such as CRC with synchronous adenomas, are ideal subjects for chemoprevention trials.

A prospective evaluation of palliative outcomes for surgery of advanced malignancies.

BACKGROUND: We prospectively evaluated the effectiveness of major surgery in treating symptoms of advanced malignancies. METHODS: Fifty-nine patients were evaluated for major symptoms of intent to treat and were followed up until death or last clinical evaluation. Surgeons identified planned operations before surgery as either curative or palliative and estimated patient survival time. An independent observer assessed symptom relief. A palliative surgery outcome score was determined for each symptomatic patient. RESULTS: Surgeons identified 22 operations (37%) as palliative intent and 37 (63%) as curative intent. The median overall survival time was 14.9 months and did not differ between curative and palliative operations. Surgical morbidity was high but did not differ between palliative (41%) and curative (44%) operations. Thirty-three patients (56%) were symptomatic before surgery, and major symptom resolution was achieved after surgery in 26 (79%) of 33. Good to excellent palliation, defined as a palliative surgery outcome score >70, was achieved in 64% of symptomatic patients. CONCLUSIONS: Most symptomatic patients with advanced malignancies undergoing major operations attained good to excellent symptom relief. Outcome measurements other than survival are feasible and can better define the role of surgery in multimodality palliative care. A new outcome measure to evaluate major palliative operations is proposed.

Quality of life in patients with colorectal metastasis and intrahepatic chemotherapy.

BACKGROUND: Liver metastasis from colorectal cancer remains an oncological challenge. Hepatic chemotherapy has been used; however, rigorous quality of life (QOL) measurements are lacking. The aim of this study was to describe unique QOL issues to formulate a specific tool for this population. METHODS: A purposive sample was identified of patients treated with intrahepatic chemotherapy. Consenting patients completed a demographic tool and the City of Hope QOL Scale/Cancer Patient survey. An in-depth interview on QOL concerns was conducted, taped, and transcribed verbatim. The data from the interviews were coded to identify recurrent themes. RESULTS: Sixteen patients participated. Physical well-being was maintained. Significantly lower subscale scores were noted for psychological, social, and spiritual domains compared with nonpatient norms (City of Hope volunteers; n = 169). Patients found intrahepatic chemotherapy convenient but were unable to pursue vigorous activity, and their sleep habits changed. Psychologically, patients felt reassured to receive specific therapy to their liver. CONCLUSIONS: Pilot evaluation of QOL in this population revealed changes in physical, psychological, social, and spiritual dimensions. Both disease- and treatment-specific concerns were identified, and the results provide evidence for items to include in a QOL questionnaire specific to this population.