J. David Beatty

Results of a prospective randomized trial of continuous regional chemotherapy and hepatic resection as treatment of hepatic metastases from colorectal primaries

One hundred patients were entered on a randomized prospective protocol to evaluate the effectiveness of hepatic resection of single as well as multiple hepatic metastases from colorectal primaries in combination with continuous hepatic artery infusion (CHAI) of fluorodeoxyuridine (FUDR) via the implantable pump (Infusaid, Intermedics Infusaid Inc., Norwood, MA). The eight patients with single metastases were randomized to hepatic resection alone (three patients) or hepatic resection plus CHAI (five patients). The 22 patients with resectable multiple metastases were randomized between receiving CHAI only (12) or CHAI after resection of all metastases (10). Patients who had positive portal lymph nodes (14) were all treated with CHAI. Patients with unresectable metastases (31) were randomized between intravenous 5‐fluorouracil or CHAI of FUDR. FUDR was alternately infused every 2 weeks at a dose of 0.1 mg/kg/24 hour escalated to .3 mg/kg/24 hour with heparinized saline as the alternative infusate. The median follow‐up of all patients was 20 months. All patients with multiple resectable metastases had at least a partial response (PR) to the CHAI (PR defined as ≤50% decrease of the sum of the products of the diameters of the lesions measured on computerized axial tomography scans), and four patients given CHAI only had no metastases in the liver on relaparotomy. Patients with resection and CHAI had a better survival than patients with CHAI only; however, the difference was not significant. Patients with positive portal nodes and CHAI had a lower PR (36%) than patients with unresectable disease treated with CHAI (52%). Patients with positive portal nodes or metastatic disease outside of the liver did significantly worse than patients with unresectable disease treated with CHAI.

A mouse model for calculating cross-organ beta doses from yttrium-90-labeled immunoconjugates

Background. The organs of laboratory mice used in radioimmunotherapy experiments are relatively small compared to the ranges of high‐energy yttrium‐90 (Y‐90) beta particles. Current Medical Internal Radiation Dose (MIRD) dosimetry methods do not account for beta energy that escapes an organ. A dosimetry model was developed to provide more realistic dose estimates for organs in mice who received Y‐90‐labeled antibodies by accounting for physical and geometric factors, loss of beta dose due to small organ sizes, and cross‐organ doses.

Tumor DNA content as a prognostic indicator in squamous cell carcinoma of the head and neck region

Our purpose in this study was to determine whether tumor DNA content is a prognostic factor independent of other standard clinical and histologic parameters in squamous cell carcinoma (SCC) of the head and neck region. Tumor DNA content was determined in 76 patients with primary resectable SCC of the oral cavity, larynx, or pharynx who were treated from 1978 to 1984 at the City of Hope. In addition, we measured various clinical and pathologic parameters in all patients. In comparison to patients with diploid SCC, those with aneuploid SCC had significantly decreased relapse-free and overall survival rates (p less than 0.001 for both). A Cox regression analysis demonstrated that tumor DNA content was a prognostic factor independent of all clinicopathologic features examined. By regression analysis, it was the single most important prognostic factor in determining relapse and death from SCC (p less than 0.001 for both).

Cancer of the breast after prophylactic subcutaneous mastectomy

We have reported a case of carcinoma of the breast in a patient that occurred after bilateral prophylactic subcutaneous mastectomy. We recommend that the patient and physician be aware of the limitations of prophylactic mastectomy in terms of cancer prevention and that patients who undergo prophylactic mastectomy continue to be carefully followed.

The effect of tumor CEA content and tumor size on tissue uptake of indium 111-labeled anti-CEA monoclonal antibody†

This study was undertaken to determine the effect of tumor size and tumor carcinoembryonic antigen (CEA) content on the uptake of indium 111 (111In)‐labeled anti‐CEA monoclonal antibody in nude mice bearing xenografts. The tumor cell lines were WiDr, SW403, and LS174T, human colon cancer derivatives. The murine breast carcinoma cell line EMT‐6 was used as a control. Tumor CEA levels (ng/g) of tumor standard error of the mean [SEM], measured by enzyme immunoassay (EIA) were: EMT‐6, 0; WiDr, 105 ± 5.7; LS174T, 2052 ± 198; SW403, 17,575 ± 1,785. The 111In‐labeled monoclonal antibody was injected intravenously into mice bearing a single tumor. At 48 hours postinjection, scintiscan was performed, and the mice were killed so that biodistribution studies could be performed. The uptake of the monoclonal antibody was expressed as percent injected counts per minute per gram of tissue ± SEM. The non‐CEA‐producing tumor, EMT‐6, showed the lowest tumor uptake (1.4 ± 0.3). WiDr, an intermediate CEA‐producing tumor, showed some tumor uptake (16.4 ± 1.5). The high CEA‐producing tumors, SW403 and LS174T, had high tumor uptake (29.5 ± 5.0 and 51.1 ± 6.1, respectively). Biodistribution and scintiscan quality were closely related. Although LS174T had the best tumor uptake, SW403 had the highest CEA tumor content, indicating tumor CEA content cannot entirely predict scintiscan and biodistribution results. Tumor‐to‐blood (T/B), tumor‐to‐liver (T/L), and liver‐to‐blood (L/B) ratios were calculated for each animal and compared with tumor size. It was found that T/L had a negative correlation with tumor size (r = −0.72) and L/B had a positive correlation with tumor size (r = 0.94). These ratios may be useful clinically to follow response to therapy.

Predicting the need for prolonged enteral supplementation in the patient with head and neck cancer

Nutritional support is an important consideration in the management of the head and neck cancer patient. In our series, characteristics significantly associated with the need for long-term postoperative nutritional support included stage IV cancers, primary pharyngeal tumors, combined treatment utilizing surgery and radiotherapy, and preoperative weight loss of more than 10 pounds. In planning nutritional support, nasogastric tube feeding is appropriate for short-term use. In contrast, gastrostomy tube feeding is preferable for those head and neck cancer patients with a high probability of requiring long-term nutritional support postoperatively.

Neoadjuvant chemotherapy of breast cancer: tumor markers as predictors of pathologic response, recurrence, and survival.

Abstract:  This study reports the value of the tumor markers estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in predicting the response of breast cancer to neoadjuvant chemotherapy. A community cancer center prospectively maintained breast cancer database containing over 8,000 patient records was used. Since 1989, 464 patients were treated with neoadjuvant chemotherapy followed by surgical resection and were tested for ER and PR. Estrogen receptor and/or PR positive patients were considered hormone receptor (HR) positive. Human epidermal growth factor receptor 2 status was available on 368 patients. Total, breast, and nodal pathologic complete response (pCR) rates, recurrence, and overall survival were assessed. Total and breast pCR rates were higher in HR negative (HR−) patients (26% and 32%, respectively) than in HR positive (HR+) patients (4% and 7%, respectively; p < 0.001). Compared to HR+ patients, HR− patients had higher recurrence rates (38% versus 22%; p < 0.001), a shorter time to recurrence (1.28 versus 2.14 years; p < 0.001), and decreased overall survival (67% versus 81%; p < 0.001). Human epidermal growth factor receptor 2 positive patients treated with neoadjuvant trastuzumab (NAT) demonstrated higher total pCR (34% versus 13%; p = 0.008), breast pCR (37% versus 17%; p = 0.02), and nodal pCR rates (47% versus 23%; p = 0.05) compared to HER2+ patients not treated with NAT. Furthermore, HER2+ patients who received NAT had lower recurrence rates (5% versus 42%; p < 0.001) and increased overall survival (97% versus 68%; p < 0.001). In conclusion, breast cancer HR status is predictive of total and breast pCR rates after neoadjuvant chemotherapy. Although HR− patients derive greater benefit from neoadjuvant chemotherapy in terms of pathologic response, they have worse outcomes in terms of recurrence and survival. Hormone receptor positive patients demonstrate significantly less response to neoadjuvant chemotherapy, but significantly better overall outcome. For both HR− and HR+, addition of NAT for HER2+ tumors results in both a superior response and outcome.

Impact of radiolabeled antibody imaging on management of colon cancer

One hundred patients with known or suspected colorectal cancer were studied by radioimmunoconjugate scintigraphy prior to operation. Study subjects received murine monoclonal anticarcinoembryonic antigen labeled with indium 111 (Indacea). Sensitivity of imaging was 76 percent for primary tumors, 44 percent for hepatic metastases, 38 percent for extrahepatic abdominal metastases, and 78 percent for extraabdominal metastases. Seventeen of 46 patients (37 percent) with known or suspected hepatic metastases and no evidence of extrahepatic disease by conventional imaging methods had extrahepatic metastases at exploratory surgery. Nine of the 17 patients had disease accurately predicted by the Indacea scanning. The management of each of these nine patients was, or could have been, modified by the scan findings and unnecessary surgery eliminated. A number of patients without post-operative disease had an unexplained increase in plasma carcinoembryonic antigen level due to production of human antimouse antibody. The addition of excess mouse immunoglobulin to the plasma prior to assay blocked this artifactual increase.

Immunotherapy of colorectal cancer.

Specific and nonspecific stimulation of the host immune system to reject cancer is an attractive concept that is just beginning to mature. Results with crude extracts and nonspecific immune stimulation have been variable. However, the recent observations of improved survival after administration of levamisole plus 5‐fluorouracil in the adjuvant setting have made an impact on the treatment of colorectal cancer. Animal studies consistently show that immune therapies are most effective for disease that is not advanced. Thus, the small benefit seen with levamisole, a low toxicity immunomodulator, suggests that much more impressive results can be anticipated with more potent and specific agents. Postsurgical autologous tumor cell vaccine has been effective in some prospective randomized trials; in others, no benefit was found. The identification and purification of allogeneic tumor‐associated antigens has lead to enhanced antigen‐specific host cell‐mediated immunity; this may result in more consistent antitumor effects. The current development of chemically defined immune adjuvants of low toxicity allows tumor‐specific immune stimulation to be tested in high‐risk apparently healthy patients after resection of colorectal cancer (Stages II and III). The influx of information regarding immune cell populations, cell‐surface markers, and cytokines has fostered extensive exploration of lymphocyte stimulation, in vitro cell growth and expansion, and in vivo evaluation in patients with advanced cancer. Modest tumor response rates have been documented with adoptive transfer of lymphokine‐activated killer cells and interleukin‐2. Improved results are anticipated with the more potent tumor‐infiltrating lymphocytes and specific in vitro sensitization of draining lymph node cells to autologous and allogeneic tumor antigens. Murine monoclonal antibodies specific for cell‐surface markers, such as carcinoembryonic antigen, have been tested for their value in the diagnosis and therapy of colorectal cancer. A small response rate has been seen with single and multiple injections of C017–1A, a monoclonal antibody specific for colonic and pancreatic cancer. The development of antiidiotypic antibodies in these patients may have been important in those that responded to this type of therapy. However, laboratory evidence suggests that monoclonal antibody conjugated to a cytotoxic agent (i.e., radionuclide, drug, or toxin) should be much more effective. Radioimmunotherapy trials in the nude mouse model bearing human colon cancer xenografts showed good tumor incorporation of the radionuclide (yttrium 90 or iodine 131), inhibition of tumor growth, and long‐term survival. A combination of such therapy with (1) cytokines to enhance antigen expression and (2) cytotoxic drugs has lead to improved antitumor effects. The major hazard of radioimmunotherapy is hematologic toxicity. Bone marrow transplantation has permitted investigators to double the dose and augment the efficacy of this type of treatment. Clinical trials of radioimmunotherapy and other cytotoxic agent and monoclonal antibody combinations have been initiated. Immunotherapy for colorectal cancer currently contributes to patient management. As therapeutic specificity and efficacy increase and as toxicity is ameliorated, immunotherapy will play an increasing role in the treatment of patients with colorectal cancer.

The effects of hyperthermia on tumor carcinoembryonic antigen expression

The effects of hyperthermia on carcinoembryonic antigen (CEA) expression were investigated. The human colon adenocarcinoma cell line, LS174T, was heated in vitro for 42 degrees C/1 hr, 43 degrees C/1 hr, or 45 degrees C/30 min. Carcinoembryonic antigen membrane expression was assayed by live cell radioimmunoassay 0-6 days after heating. A heat exposure of 45 degrees C/30 min resulted in an initial decrease in carcinoembryonic antigen membrane expression 1 day post-heating followed by a 2-3 fold increase which peaked 3 days post-heating. Carcinoembryonic antigen expression began returning to normal by the sixth day. Heat exposures of 42 degrees C/1 hr and 43 degrees C/1 hr also resulted in increased carcinoembryonic antigen expression but this increase was of lesser magnitude and of shorter duration. Carcinoembryonic antigen shed into the medium, as measured by enzyme immunoassay, also increased after heating in a temperature-dependent fashion. Flow cytometry analysis demonstrated that cells in all phases of the cell cycle expressed this increase. We conclude that hyperthermia results in significant changes in carcinoembryonic antigen membrane expression and shedding. The implications that these findings have with regards to clinical hyperthermia and radioimmunotherapy are discussed.