CT imaging features of acinar cell carcinoma and its hepatic metastases.

OBJECTIVE: To evaluate and describe the computed tomography features of pure acinar cell carcinoma (ACC) and its liver metastases. METHODS: Thirty patients were evaluated. Two radiologists evaluated imaging findings for each tumor for size, location, internal density, enhancement, tumor calcifications, pancreatic, and common biliary ductal obstructions and metastases. RESULTS: 70 % were male. Fourteen tumors were located in the pancreatic head, 14 in the tail, one in the neck, and one in the uncinate process. Abdominal pain was the most common presenting symptom (93 %), 20 % had pancreatitis and 17 % had obstructive jaundice. The average tumor size was 7 cm, 97 % of tumors were solid, well circumscribed (73 %); isodense to normal pancreatic parenchyma (40 %) on the non-contrast study, hypodense on the arterial (47 %), and hypodense on the portal venous (37 %) phase. 30 % patients had pancreatic ductal dilation, 10 % had pancreatic ductal ingrowth, 6 % had calcifications, and 20 % had central necrosis, and 31 % (5/16) showed biliary ductal dilation. At presentation, 50 % had metastatic adenopathy and 40 % patients had liver metastases, which typically were well circumscribed, hypoattenuating to the hepatic parenchyma on all the phases of contrast enhancement and had a lobulated margin. CONCLUSION: ACCs of the pancreas often present as large, well circumscribed, solid masses commonly in males. Despite their large size, they may not cause CBD obstruction.

Phase II trial of imatinib mesylate in patients with metastatic melanoma.

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Splenic versus hepatic artery infusion of interleukin-2 in patients with liver metastases.

In an attempt to improve the therapeutic index of recombinant interleukin-2 (rIL-2) by generating or activating lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL) regionally and/or in situ, we randomly assigned 28 patients with liver metastases to receive rIL-2 by continuous infusion for 5 days via either the splenic artery or the hepatic artery. Clinically significant and lasting tumor regression was observed only in two of 28 patients (7%), one in each of the two treatment arms. The maximum-tolerated daily dosage of rIL-2 was 3 x 10(6) U/m2; beyond this dosage, toxicity was excessive. Peripheral LAK cell activity measured in vitro and clinical tumor regression did not correlate. This observation, coupled with the equal distribution of regressions between the two treatment arms, raises the possibility that tumor regression, rare though it may be in response to rIL-2 administration, is largely mediated by TIL activation and not by LAK cell generation.

Technetium 99m-labeled IMMU-4, a monoclonal antibody against carcinoembryonic antigen, for imaging of occult recurrent colorectal cancer in patients with rising serum carcinoembryonic antigen levels.

PURPOSE: We tested whether nuclear imaging with technetium 99m-labeled murine monoclonal antibody (MoAb) against carcinoembryonic antigen (CEA) IMMU-4 will detect recurrent colorectal disease in patients with a rising serum CEA level but negative abdominal and pelvic computed tomographic (CT) scan, chest radiograph, and colonoscopy, or barium enema. PATIENTS AND METHODS: Sixteen patients with completely resected, CEA-producing colorectal cancer were given 1 mg of 99mTc-labeled IMMU-4 intravenously with no toxic side effects. Planar and single-photon emission CT (SPECT) scans were acquired at 6 hours. Fifteen patients underwent an exploratory laparotomy at 24 hours. Results of the scintigraphy were correlated with surgical findings. RESULTS: Twelve of 15 patients (80%) had true-positive (TP) scans when correlated with surgery. Two of 15 (13%) had true-negative (TN) scans inasmuch as exploratory laparotomy failed to detect recurrent disease. A false-positive (FP) scan was obtained in one of 15 (7%). There were no false-negative (FN) scans. Sensitivity, specificity, accuracy, and the positive predictive value (PPV) were 100%, 67%, 93%, and 92%, respectively. Twenty-six histologically confirmed areas of malignancy were found and correlated with areas of increased activity seen on IMMU-4 scintigraphy. Twenty-one were TP; five were not detected by scintigraphy and were thus considered to be FN. There were five FP lesions and 25 TN regions. Sensitivity, specificity, accuracy, and the PPV in these 26 cancer tissues were 81%, 83%, 82%, and 81%, respectively. The median radioactivity ratio of tumorous tissue to normal tissue was 3.33, with a range of 0.89 to 17.16. CONCLUSIONS: These results suggest that 99mTc IMMU-4 scintigraphy is an important addition to the armamentarium available for diagnostic imaging and may help detect occult metastatic cancer missed by abdominal and pelvic CT in patients with rising CEA levels.

Hepatic arterial infusion with floxuridine and cisplatin: overriding importance of antitumor effect versus degree of tumor burden as determinants of survival among patients with colorectal cancer.

Cisplatin (CDDP) was combined with floxuridine (FUDR) and delivered into the hepatic arteries of 29 patients as induction therapy for colorectal cancer metastatic to the liver. Mitomycin C and FUDR combination was substituted after progression or when response had peaked. Chemotherapy was delivered with an Infusaid pump (Infusaid Corp; Norwood, Mass; 14 patients), Medtronic programmable drug administration device (Medtronic, Inc, Minneapolis; two patients), or percutaneously placed catheters (13 patients). Complete disappearance of liver metastases was observed in four patients and 11 additional patients had a partial remission as determined by computed tomography (CT) scan and substantiated at times by angiography, for a total response rate of 52%. Response as determined by imaging techniques coincided with a concurrent decrease in carcinoembryonic antigen (CEA) and improvement in performance status. The severity of tumor burden was correlated with the response to therapy and survival. Among those patients who responded to arterial chemotherapy, differences in disease severity did not significantly influence survival. Median survival among responders with greater than 25% liver replacement by tumor was 14 months (P = .28), compared with 28 months for those patients with less than 25% liver replacement. In contrast, differences in tumor burden significantly affected survival among patients who failed to respond to chemotherapy; median survival among nonresponding patients with greater than 25% liver replacement was 4 months, compared with 8 months for those who had less than 25% liver replacement (P = .01). The presence of minimal extrahepatic disease at the time of initiation of intraarterial treatment did not seem to have a significant detrimental effect on survival. The study suggests that hepatic tumor response to arterial administration of CDDP and FUDR and mitomycin C and FUDR is clinically significant because it overrides the effect of tumor burden on survival among patients who have colorectal cancer with liver metastases and may offer effective palliation.

Hepatic arterial infusion of floxuridine, leucovorin, doxorubicin, and cisplatin for hepatocellular carcinoma: effects of hepatitis B and C viral infection on drug toxicity and patient survival.

PURPOSE: To conduct a pilot trial of hepatic arterial infusion (HAI) of floxuridine (FUDR), leucovorin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (FLAP) in nonresectable hepatocellular cancer (HCC) confined to the liver and assess the effects of hepatitis B (HBV) and hepatitis C (HCV) viral markers on toxicity, response to treatment, and patient survival. PATIENTS AND METHODS: Of 31 HCC patients, 13 were HBV- and HCV-nonreactive, and 18 had evidence of either current or prior HBV and/or HCV infection. Treatment was delivered through percutaneous hepatic arterial catheters, and Infusaid pumps (Shiley Infusaid, Norwood, MA) were placed in responding patients. Cisplatin (100 mg/m2) and Adriamycin (30 to 35 mg/m2) were administered on day 1, followed by a continuous 24-hour HAI of an admixture of floxuridine (60 mg/m2) and leucovorin (15 mg/m2) daily for 4 days. Treatment was repeated every 5 weeks. RESULTS: Twelve (41%) of 29 assessable patients had a partial response (PR), with a median time to disease progression of 13 months. Six (50%) of 12 HBV-negative (HBV-)/HCV-negative (HCV-) and six of 17 (35%) HBV-positive (HCV+) and/or HCV-positive (HCV+) patients achieved a PR. Eight patients have been maintained in remission for a median duration greater than 15.5 months. The median survival duration of all 31 patients was 15 months, 7.5 months among HBV+ and/or HCV+ patients, and significantly longer among hepatitis-non-reactive patients (P = .007). (A median has not yet been reached.) Granulocylopenia (< 0.1 x 10(3)/microL), thrombocytopenia (< 25 x 10(3)/microL), and hospitalizations for infectious complications were significantly more common among HBV-HCV-reactive than -nonreactive patients: 56%, 50%, and 67% versus 15%, 15%, and 8%, respectively (P < .05 for all). CONCLUSION: HAI of FLAP has induced long-term PR and has palliated extensive nonresectable HCC. Positive hepatitis serology appeared to increase bone marrow susceptibility to myelotoxic drugs. Conceivably, one or both viruses may have a direct inhibitory effect on bone marrow progenitors and thereby contribute to the observed myelotoxicity.

Imaging with indium111-labeled anticarcinoembryonic antigen monoclonal antibody ZCE-025 of recurrent colorectal or carcinoembryonic antigen-producing cancer in patients with rising serum carcinoembryonic antigen levels and occult metastases.

We tested whether nuclear imaging with indium111 (111In)-labeled murine monoclonal (MoAb) anticarcinoembryonic antigen (anti-CEA) ZCE-025 antibody could detect recurrent disease in patients with a rising serum CEA level but negative findings for computed tomographic (CT) scans of the abdomen and pelvis, chest radiograph, and colonoscopy or barium enema. Twenty patients with a history of completely resected CEA-producing adenocarcinoma (18 with colon cancer, one with breast cancer, and one with Hodgkin's disease) and a rising serum CEA level were given an intravenous infusion of 2 mg of 111In-labeled ZCE-025 mixed with 38 mg of unlabeled ZCE-025. Planar and single-photon emission CT (SPECT) scans were acquired at 72 and 144 hours, and in 19 of the 20 patients these were positive. Of those 19, 13 underwent exploratory surgery, and cancer was found in 10, and two had a diagnostic biopsy, which confirmed cancer. Three patients who had negative laparotomies and all four patients who did not undergo surgery or biopsy were followed radiologically. In all seven, cancer was subsequently detected at the sites suggested by the ZCE-025 scan. Thus, tumor was confirmed in all 19 patients with positive scans. Five of 13 patients who were explored benefited from the study and the exploratory laparotomy, as disease was entirely resected in four or was subjected to definitive radiation therapy to the pelvis in the fifth. In two additional patients who were not explored, MoAb imaging resulted in definitive therapy to regionally confined recurrent disease. 111In-labeled anti-CEA MoAb ZCE-025 scanning in patients with rising CEA successfully imaged metastatic colorectal cancer that eluded detection by other methods and affected the care given to some. These results suggest an important role for 111In-labeled ZCE-025 scanning among patients with rising CEA and otherwise occult metastatic cancer.

Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer.

PURPOSE: To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree. PATIENTS AND METHODS: Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree. RESULTS: Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients. CONCLUSION: Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.

Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.

PURPOSE: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. RESULTS: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. CONCLUSION: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.

Tumor irradiation enhances the tumor-specific distribution of poly(L-glutamic acid)-conjugated paclitaxel and its antitumor efficacy.

The poly(L-glutamic acid)-paclitaxel (PG-TXL) conjugate has been shown to exhibit significantly greater antitumor activity than conventionally formulated paclitaxel (TXL) against solid tumors (Li et al., Cancer Res., 58: 2404-2409, 1998). Here we report that local tumor irradiation enhanced the distribution of PG-TXL given 24 h later to ovarian OCa-1 carcinoma implanted i.m. in C3Hf/Kam mice. Radiation significantly increased tumor uptake of PG-TXL and tumor vascular permeability, caused elevation of the serum concentration of vascular endothelial growth factor, and arrested OCa-1 cells in the G1 phase of cell cycle. The enhancement factors, as measured by incremental tumor growth delay compared with PG-TXL alone, ranged from 1.36-4.44. Complete tumor regression was also observed at a higher radiation dose (>10 Gy) and a higher PG-TXL dose (>80 mg equivalentTXL/kg). Furthermore, combined radiation and PG-TXL produced a significantly greater tumor growth delay than treatment with radiation and TXL when both drugs were given at the same equivalent TXL dose of 60 mg/kg 24 h after tumor irradiation (enhancement factors, 4.44 versus 1.50). These data suggest that conjugation of TXL to poly(L-glutamic acid) is necessary for improved response and that the supra-additive effect of combined radiation and PG-TXL therapy is due in part to modulation of the enhanced permeability and retention effect of macromolecules by radiation. We propose a treatment strategy combining radiation and macromolecular chemotherapy that may have important clinical implications in terms of scheduling and optimization of the therapeutic ratio.

Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma.

Gemcitabine has modest activity in the treatment of advanced pancreatic cancer and is a potent radiosensitizer. We conducted a Phase I trial to determine the maximum tolerated dose of weekly gemcitabine delivered concurrently with radiation therapy for the treatment of locally advanced adenocarcinoma of the pancreatic head and to assess the treatment-related toxic effects associated with such a regimen. Eighteen patients with pathologically proven, locally advanced adenocarcinoma of the pancreatic head were enrolled in this study. Patients received seven weekly doses of gemcitabine with 3000 cGy of external beam radiation therapy delivered during the first 2 weeks of therapy. Six patients received gemcitabine at 350 mg/m(2)/week, nine at 400 mg/m(2)/week, and three at 500 mg/m(2)/week. Grade 3-4 hematological toxicity was observed in over half the patients treated. Nonhematological toxicities were significant and included fatigue, anorexia, nausea, vomiting, and dehydration. Forty-four % of the patients required admission to the hospital for management of nausea/vomiting and dehydration. The risk of hospitalization appeared to be dose-related; all of the three patients treated at 500 mg/m(2)/week required hospital admission during treatment. Seventeen patients were evaluated for response, and eight patients (47%) had evidence of a local anticancer effect. Four of these eight patients (24%) had a partial response to therapy. The median survival for the entire group was 6 months. The 1-year survival rate for patients with an objective response to therapy was 66%. The clinical responses observed in this group of patients suggest gemcitabine is a clinically relevant radiosensitizer in patients with pancreatic adenocarcinoma. However, the toxic effects are significant, suggesting that until dose and scheduling issues are explored further, concomitant administration of gemcitabine and radiation therapy should still be considered investigational.

Antitumor activity of poly(L-glutamic acid)-paclitaxel on syngeneic and xenografted tumors.

Poly(L-glutamic acid)-paclitaxel (PG-TXL) is a new water-soluble paclitaxel derivative that has shown remarkable antitumor activity against both ovarian and breast tumors. The purpose of this study was to test whether the antitumor efficacy of PG-TXL depends on tumor type, as is the case for paclitaxel, and to test whether paclitaxel-resistant tumors could be responsive to PG-TXL. We evaluated the therapeutic activity of PG-TXL against four syngeneic murine tumors (MCa-4, MCa-35, HCa-1, and FSa-II) inoculated i.m. into C3Hf/Kam mice, a human SKOV3ip1 ovarian tumor injected i.p. into nude mice, and a human MDA-MB-435Lung2 breast tumor grown in the mammary fat pad of nude mice. Two paclitaxel-responsive murine tumors, MCa-4 and MCa-35, showed significant growth delay with PG-TXL given as a single i.v. injection at its maximum tolerated dose of 160 mg of equivalent paclitaxel/kg or even at a lower dose of 120 mg of equivalent paclitaxel/kg. The other two murine tumors, HCa-1 and FSa-II, did not respond particularly well to either of the two agents, although significant growth delay was observed for both tumors with PG-TXL. In mice with SKOV3ip1 tumors, the median survival times for mice treated with PG alone and PG-TXL at doses of 60 or 120 mg of equivalent paclitaxel/kg were 43, 61, and 75 days, respectively; no survival difference was found between paclitaxel-treated and Cremophor vehicle-treated mice. In mice with MDA-MB-435Lung2 tumor, PG-TXL at a dose of 120 mg of equivalent paclitaxel/kg produced regression of the tumor in 50% of the animals, and in the remaining mice, micrometastases in the lung were found only in 25% of the animals. In comparison, treatment with paclitaxel at 60 mg/kg did not result in tumor regression, and the rate of lung metastases was 42%. These results clearly demonstrate that PG-TXL has significant therapeutic activity against breast and ovarian tumors tested in this study. Future studies to elucidate the mechanism of action of PG-TXL and to assess its clinical applications are warranted.

Combining gemcitabine with radiation in pancreatic cancer: understanding important variables influencing the therapeutic index.

We compared and evaluated available laboratory and clinical data on the use of concurrent gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and radiation in pancreatic cancer to provide guidance for subsequent prospective research initiatives. Preclinical data suggest that the timing of administration of gemcitabine with respect to radiotherapy is important, but this issue has not yet been confirmed by clinical data. Phase I clinical data indicate that the amount of acute toxicity from the combination of gemcitabine and radiotherapy is strongly related to the dose and schedule of administration of gemcitabine, as well as to the radiation field size. There also appears to be an inverse linear relationship between the maximum tolerated gemcitabine dose and radiation dose. Also important, but less clear, is the infusion rate of gemcitabine as it relates to the systemic efficacy of the drug. The combination of additional agents with gemcitabine and radiation appears to be feasible. Finally, the addition of radioprotectors may enable chemotherapy dose escalation, but safe escalation of the radiotherapy dose with newer techniques has not been established. Semin Oncol 28 (suppl 10):25-33.

Potentiation of ovarian OCa-1 tumor radioresponse by poly (L-glutamic acid)-paclitaxel conjugate.

PURPOSE: It has been shown that paclitaxel (TXL) can strongly enhance tumor cells' sensitivity to radiation. We examined whether the radiosensitizing effect of paclitaxel can be further enhanced when it is delivered systemically as a polymer-drug conjugate that provides enhanced tumor uptake and prolonged release of TXL in the tumor. METHODS AND MATERIALS: C3Hf/Kam mice bearing 8-mm murine ovarian OCa-1 tumors were treated with i.v.-injected Poly(L-glutamic acid)-paclitaxel (PG-TXL) at an equivalent TXL dose of 80 mg/kg, followed 24 h later by single doses of local radiation ranging from 5 to 15 Gy. To determine how long the radiopotentiation persisted at extended times after PG-TXL administration, mice with OCa-1 tumors were given i.v. PG-TXL and 4, 24, 48, 72, 120, or 168 h later their tumors were irradiated at a dose of 10 Gy. Antitumor activity was determined by delay in tumor growth. Cell cycle distribution was assayed using flow cytometry. Tumor vascular volume was estimated using Tc-99 m-labeled red blood cells. RESULTS: PG-TXL strongly potentiated the radioresponse of the OCa-1 tumor. The enhancement factors ranged from 2.79 to 4.28, depending on radiation dose, when PG-TXL preceded radiation by 24 h. The enhancement factor derived from radiation dose-response curves was as high as 5.13. The radiosensitizing effect of PG-TXL was also dependent on the interval between PG-TXL administration and radiation delivery, with greater enhancement been observed when the interval was decreased. The percentage of G2/M cells was significantly increased to 21.4% 48 h after PG-TXL but declined to a preinjection level of 14.8% 72 h after PG-TXL. PG-TXL only moderately increased the tumor vascular volume by 37% 24 h after PG-TXL administration. CONCLUSION: PG-TXL markedly potentiated response of OCa-1 tumor to radiation. When compared to literature data obtained from the same tumor model used here, PG-TXL exhibited stronger radiosensitization effect than TXL. Although its action is possibly mediated by arrest of cells in G2/M phases of cell cycle and by increased tumor blood supply, PG-TXL may exert its radiopotentiation activity through increased tumor uptake of PG-TXL and sustained release of TXL in the tumor. Our results show that conjugation of TXL to a polymer has the potential to further enhance its radiosensitizing activity and that clinical trials of PG-TXL in combination with radiation is warranted.

Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer?

PURPOSE: To retrospectively compare the toxicity and efficacy of concurrent gemcitabine-based chemoradiation with that of concurrent 5-fluorouracil (5-FU)-based chemoradiation in patients with unresectable pancreatic cancer. PATIENTS AND METHODS: Between September 1996 and May 2000, 114 patients with localized unresectable adenocarcinoma of the pancreas were treated with concurrent chemoradiation. Locally advanced unresectable disease was defined as low-density tumor in contact with the superior mesenteric artery (SMA) or celiac artery, or occlusion of the superior mesenteric-portal venous confluence. Fifty-three patients were selected to receive gemcitabine in 7 weekly cycles (250-500 mg/m(2)) with concurrent radiotherapy (median dose 30 Gy, range 30-33 Gy in 10-11 fractions). The remaining 61 patients received continuous-infusion 5-FU (200-300 mg/m(2)) with concurrent radiotherapy (30 Gy in 10 fractions). Radiotherapy was delivered to the primary tumor and regional lymphatics. Patients receiving gemcitabine and those receiving 5-FU had a similar mean Karnofsky performance status (KPS, 89% vs. 86%), distribution of tumor grade (43% vs. 33% poorly differentiated), and percent weight loss (all p = NS). However, patients treated with gemcitabine had a significantly larger median maximum cross-sectional tumor area (TA, 8.8 cm(2) vs. 5.7 cm(2), p = 0.046) and were significantly younger (median age 60 vs. 68 years, p <0.001). Severe acute toxicity (ST) was defined as toxicity requiring a hospital stay of more than 5 days, mucosal ulceration with bleeding, more than 3 dose deletions of gemcitabine or discontinuation of 5-FU, or toxicity resulting in surgical intervention or death. Kaplan-Meier analysis was used to calculate the actuarial rate of local progression on imaging (LP), the rate of distant metastasis (DM), and the overall survival (OS) rate. The imaging was reviewed in resected patients. RESULTS: Patients receiving gemcitabine developed significantly more ST during treatment (23% vs. 2%, p < 0.0001) than did those receiving 5-FU. Patients treated with gemcitabine had a similar 10-month LP rate (62% vs. 61%), 10-month DM rate (55% vs. 47%), 1-year OS rate (42% vs. 28%), and median OS duration (11 months vs. 9 months) to patients treated with 5 FU (all p = NS). Five patients who received gemcitabine and 1 patient who received 5-FU underwent margin-negative pancreaticoduodenectomy after chemoradiation. Three patients had a short segment (10 cm(2) (p = 0.03) and poor differentiation (p = 0.07) were associated with a worse survival duration; however, other factors, such as KPS and weight loss >10% and age did not influence OS. CONCLUSION: Despite the selection of healthier patients to receive gemcitabine, there was a significantly higher severe toxicity rate than with 5-FU. The median and 1-year survivals were not significantly different with the use of concurrent gemcitabine; however, the tumors treated were significantly larger. Additionally, a small number of patients with minimal arterial involvement whose disease met our radiographic definition of unresectable disease had margin-negative resections after treatment with gemcitabine-based chemoradiation. These possible benefits and the high rate of severe toxicity define a very narrow therapeutic index for concurrent gemcitabine-based chemoradiation given by this schedule of administration.

Variable patterns of technetium-99m MAA perfusion in the therapeutically embolized liver.

Hepatic perfusion studies using 99mTc macroaggregate albumin (MAA) particles have been utilized to document arterial catheter position and flow distribution in patients who are to undergo hepatic arterial chemotherapy infusion (HAI). We have recently been treating nonresectable hepatic neoplasms with transcatheter hepatic arterial chemoembolization (HAE) followed by HAI. The MAA perfusion studies in these patients show variable patterns. For this reason, we have reviewed our recent experience with 15 patients who underwent 21 HAEs and HAIs. The arteriograms and the MAA perfusion studies were reviewed and correlated. Early (within 4 hr of embolization) perfusion studies revealed flow reversal, or MAA reflux into an undesirable location in 11 cases. Two selected follow-up scans in 24 hr revealed restoration of flow to the embolized lobe, confirming the proper position of the catheter for HAI. Knowledge of both the hepatic arterial anatomy, and of the specific embolization procedure will allow accurate interpretation of the MAA perfusion study. Initial flow reversal, or MAA reflux, should not be interpretated as a malpositioned catheter, but prompt reevaluation after a period of 24 hr to document restoration of antegrade flow is suggested.

Conjugation with (111)In-DTPA-poly(ethylene glycol) improves imaging of anti-EGF receptor antibody C225.

UNLABELLED: Significant liver uptake often limits the clinical application of radiolabeled antibodies in radioimmunodetection. The purpose of this study was to evaluate the gamma-imaging properties of an antiepidermal growth factor receptor (EGFR) antibody, C225, conjugated with heterofunctional poly(ethylene glycol) (PEG) with 1 terminus of the polymer attached to a radiometal chelator, diethylenetriaminepentaacetic acid (DTPA). METHODS: Two preparations of PEG-modified C225, one with 20% and the other with 60% amine substitution, were labeled with (111)In. The conjugates, (111)In-DTPA-PEG-C225, were injected intravenously into nude mice with EGFR-positive A431 tumors. For comparison, C225 directly labeled with (111)In was also injected. In a competitive study, mice with A431 tumors were pretreated intravenously with 100-fold excess of native C225, followed by an injection of (111)In-DTPA-PEG-C225 30 min or 20 h later. In addition, (111)In-DTPA-PEG-C225 was injected into mice with EGFR-positive MDA-MB-468 tumors and EGFR-negative MDA-MB-435 tumors. Images were acquired at 5 min and at 2, 6, 24, and 48 h after injection of the radiotracers. Regions of interest (ROIs) were drawn on the computer images around the whole body, liver, muscle, and tumor. The counts per pixel in the tumor and normal tissues were calculated. At 48 h, the mice were killed and dissected. Blood, liver, muscle, and tumor samples were removed and the radioactivity of each sample was measured. RESULTS: In A431 tumor xenografts, the tumor uptake of C225 modified with PEG was not significantly different than the uptake of unmodified (111)In-DTPA-C225. Uptake in the liver, however, was reduced by 38%-45%, and the reduction increased with increasing degree of PEG substitution. Tumors of A431 and MDA-MB-468 xenografts were clearly visualized with (111)In-DTPA-PEG-C225, whereas tumors of the MDA-MB-435 xenograft, which expresses low levels of EGFR, were not as readily visible. The tumor-to-blood ratios of (111)In-DTPA-PEG-C225 in A431 and MDA-MB-468 xenografts were about 3 fold higher than in MDA-MB-435 xenografts. Blocking EGFR by pretreatment with native C225 significantly reduced the uptake of (111)In-DTPA-PEG-C225 in the liver. The tumor-to-blood ratios in mice with A431 tumors were decreased 2.5-2.7 fold after pretreatment with a large excess of C225. Similar results were obtained with MDA-MB-468 tumor xenografts. In contrast, the tumor-to-blood ratios in mice with MDA-MB-435 tumor xenografts were not significantly different in C225-pretreated mice than in nonpretreated mice. CONCLUSION: These findings indicate that (111)In-DTPA-PEG-C225 selectively localized to the tumors expressing high levels of EGFR. PEG-modification of C225 significantly reduced its liver uptake, resulting in improved visualization of EGFR-positive tumors. Using PEG as a linker between the monoclonal antibody and metal chelator is a useful strategy to optimize the imaging characteristics of antibody-based scintigraphic agents.

Effectiveness of water soluble poly(L-glutamic acid)-camptothecin conjugate against resistant human lung cancer xenografted in nude mice.

A camptothecin (CPT) formulation that can be easily administered, is less toxic, and has greater antitumor effect is needed. In this study, a water-soluble CPT derivative was obtained by direct coupling of CPT to poly(L-glutamic acid) (PG) through the C20(S)-hydroxyl group. CPT was released from the resulting conjugate, PG-CPT, in phosphate-buffered saline with a zero-order kinetics in the initial 50 days. The release rates were 0.623% per day, 1.081% per day, and 1.396% per day at pH 5.3, 7.4, and 9.0, respectively. In vitro, PG-CPT was less potent in inhibiting cell growth than was free CPT in all human tumor cell lines tested. However, PG-CPT showed better antitumor activity and tolerability than did CPT in vivo. When H322 human lung tumor cells were inoculated subcutaneously in nude mice, PG-CPT delayed the growth of these well-established tumors with an absolute growth delay of 32 days when given as 4 doses with 4-day intervals between injections at an equivalent CPT dose of 40 mg/kg. When H322 cells were inoculated intratracheally in nude mice, 5 doses of intravenous injection of PG-CPT at an equivalent CPT dose of 10 mg/kg on days 4, 8, 12, 16, and 20 after inoculation significantly prolonged the median survival of treated mice, averaging 1.8-fold that of untreated mice (p=0.01). Increasing the dose of PG-CPT to an equivalent CPT dose of 40 mg/kg per injection administered in 4 doses on days 4, 8, 12, and 16 prolonged the median survival of treated mice by 4-fold (p=0.0008). Significantly, mice with intratracheally inoculated H322 tumors were resistant to both CPT and cisplatin treatments. These studies demonstrated that PG may be used as an effective solubilizing carrier for CPT and that PG-CPT may have potential application in the treatment of lung cancer.

Significance of peritoneal cytology in patients with potentially resectable adenocarcinoma of the pancreatic head.

BACKGROUND: Recurrence in the peritoneum occurs in up to 50% of patients after a potentially curative pancreaticoduodenectomy. Previous authors have implicated preoperative fine-needle aspiration (FNA) as a cause of intraperitoneal tumor dissemination, although prior studies of peritoneal cytology findings have largely involved patients with locally advanced disease. METHODS: A consecutive series of patients referred to our institution between 1991 and 1993 with suspected or biopsy-proven adenocarcinoma of the pancreatic head was studied prospectively. All patients fulfilled criteria for resectability as assessed by computed tomography: no metastatic disease, no encasement of the superior mesenteric or hepatic arteries, and a patent superior mesenteric-portal venous confluence. Peritoneal washings were obtained at the time of staging laparoscopy and/or at subsequent laparotomy. Data regarding peritoneal cytology results, previous FNA, preoperative chemoradiation, eventual resection, pattern of disease recurrence, and survival were collected. RESULTS: A total of 80 peritoneal washings from 60 consecutive patients were prospectively examined. Forty-nine (82%) of 60 patients underwent FNA before peritoneal washings were obtained. A total of four patients (7%) had positive peritoneal cytology findings: three (6%) of 49 who underwent prior FNA and one (9%) of 11 with no prior FNA. Similarly, no differences in eventual peritoneal failure or short-term survival were observed for patients who underwent prior FNA compared with patients who did not. All four patients with positive peritoneal cytology findings had metastatic disease (liver, three; peritoneum, one) at a median of 4.8 months after diagnosis; three of the four died of disease at a median of 8 months. CONCLUSIONS: Positive peritoneal cytology findings are rare in patients with radiologically resectable adenocarcinoma of the pancreas. When found, positive peritoneal washings are an indicator of advanced disease characterized by unresectability, early metastasis, and short survival. Computed tomographic-guided FNA does not appear to increase the risk for positive peritoneal washings and represents a valid approach to the pretreatment diagnosis of patients with suspected pancreatic malignancy.

Primary pancreatic lymphoma.

BACKGROUND: Primary pancreatic lymphoma is a rare neoplasm that may be confused with pancreatic adenocarcinoma. We reviewed retrospectively our contemporary experience with this disease to define more clearly the clinical presentation of this disease and the proper role for percutaneous fine-needle aspiration biopsy and surgery. METHODS: From 1980 to 1995, 11 patients with primary pancreatic lymphoma were treated at The University of Texas M. D. Anderson Cancer Center. Patient demographics, radiographic studies, fine-needle aspiration biopsy findings, operative procedures, and other treatment data were reviewed. RESULTS: The median age of the 11 patients was 64 years (range, 37 to 74 years). Abdominal pain was the most common symptom at presentation. Five patients had an elevated lactate dehydrogenase level, and only two patients had hyperbilirubinemia. Computed tomography scan demonstrated encasement of the superior mesenteric artery or superior mesenteric-portal vein confluence in six patients. Seven patients underwent computed tomography-guided fine-needle aspiration; five had findings of lymphoma. Two patients underwent distal pancreatectomy and splenectomy, and one underwent pancreaticoduodenectomy. All patients were treated with combination chemotherapy, and seven received radiotherapy. Only two patients have died of disease (12 and 16 months after diagnosis) at a median follow-up time of 67 months. CONCLUSIONS: In the majority of patients, pancreatic lymphoma can be distinguished from pancreatic adenocarcinoma on the basis of symptoms, laboratory and radiographic findings, and fine-needle aspiration biopsy results. Once the diagnosis is established, all patients should undergo systemic chemotherapy followed by involved-field radiotherapy if the tumor has not been resected.