Article

Treatment of advanced pancreatic cancer with regional chemotherapy plus hemofiltration

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Abstract

Since 1989, 32 patients with advanced, inoperable pancreatic cancer were treated with regional chemotherapy in combination with ex-tracorporeal hemofiltration. Eleven patients presented to diagnosis with locally advanced, inoperable cancer; and ten, in addition to their primary, had liver metastases. Three patients had recurrent liver metastases following a curative Whipple procedure. One patient had an incomplete resection with local residual disease, and a second had recurred locally following a curative resection. One patient came to diagnosis with an unresectable cystadenocarcinoma. Five patients had failed prior chemoradiotherapy and/or immunotherapy. The patients underwent 83 cycles of regional chemotherapy plus hemofiltration, an average of 2.6 treatments per patient. Amongst 21 patients treated primarily with regional chemotherapy plus hemofiltration, two patients had complete responses (9%) and eight had partial responses (38%)—an overall total response rate of 47%. The average survival for patients with Stage II / III localized, inoperable disease is 13 months and that for Stage IV disease with only liver metastases is 9 months. Patients with recurrent disease following a curative procedure or having failed prior systemic therapies had little response from regional chemotherapy plus hemofiltration.

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Chapter
Pancreatic cancer (PC) is the fifth most common cause of cancer death among males and females in the United States. In 1999, the American Cancer Society estimated that there would be 29,000 new cases of PC (14,100 men and 14,900 women). Even though 20% of patients elsewhere in the United States may live up to 2 yr, in Louisiana, essentially every patient will die within 2 yr. The longest survival time from the Charity Hospital of Louisiana in New Orleans is only 21 mo (1–3).
Chapter
Regional chemotherapy developed in the 1950s continues to play an integral part in the development of newer therapies for advanced solid malignancies. Regional therapies have evolved in complexity, but are still based on the pharmacokinetics of drug delivery to solid malignancies. The quest remains on how to deliver a greater amount of antineoplastic agent to the tumor-bearing region with less side effects and toxicity. Hemodialysis, hemofiltration, and hemoperfusion are used to improve systemic and regional drug clearance. These techniques using drug removal systems demonstrate that the combination of regional therapies plus surgery can be essential in promoting improved patient outcomes. However, recent reports suggest that regional chemotherapy used in a neoadjuvant setting followed by curative surgery yield the best long-term results. Sequentially, the addition of adjuvant chemotherapy further improves patient outcomes.
Chapter
Seit Beginn der chemotherapeutischen Behandlung von Krebs Anfang der 1940er Jahre [1–3] wurden zahlreiche Wirkstoffe, Vorrichtungen und Methoden zur Behandlung fortgeschrittener solider Tumore entwickelt. Diese hatten eine Verbesserung der Wirkstoffzufuhr zum Ziel, wobei gleichzeitig sowohl die lokale/regionale als auch die systemische Toxizität in vertretbaren Grenzen gehalten werden sollte. Die Toxizität als dosisbeschränkender Faktor bei den meisten Chemotherapeutika ist nicht das einzige Hindernis für bessere Tumoransprechraten und klinische Ergebnisse. Die Wirkstoffzufuhr in die Tumorzellen stellt jedoch weiterhin einen der Hauptfaktoren dar, der eine komplette Remission bei fortgeschrittenen malignen Erkrankungen verhindert.
Article
Objective: The very limited efficacy of current chemotherapeutic strategies in advanced pancreatic cancer (APC) and the pattern of metastastic spread, largely confined to the upper abdominal organs within the arterial supply of celiac axis, induced us to design this phase-II study of locoregional intra-arterial chemotherapy. The aim of the present study was to evaluate the feasibility, the toxicity, the response rate and survival of a new combination of drugs administered intra-arterially in the treatment of APC. Methods: From January 1994 to August 1995, thirty-six consecutive patients with APC were given intra-arterial cycles of chemotherapy every 3 weeks through a catheter in the celiac axis introduced via the femoral artery. Seventeen patients were classified as UICC stage III and 19 as stage IV. Nineteen had liver metastases and 1 patient also had lung metastases. The schedule was: 5-fluorouracil 1,000 mg/m2; folinic acid 100mg/m2; epirubicin 60 mg/m2 and carboplatin 300 mg/m2. Each drug was infused over a period of 10 min and only 1 day of hospitalization was necessary for each cycle. After 3 cycles, when a response or stable disease had been obtained, another 2 cycles were planned, health conditions permitting. Results: A total of 114 courses of chemotherapy were administered with a mean of 3 for each patient (range 1-5). 33 patients were evaluable for response by CT scan: 7 of 33 (21%) had a partial response; 16 of 33 (49%) had stable disease; 10 of 33 (30%) had a progressive disease, and 23 of 36 (64%) had a decrease in Ca 19-9. A reduction in pain was reached in 16 of 26 patients (62%) and particularly 9 of 26 patients (35%) showed complete regression for 8 weeks or more. Weight increase was obtained in 13 of 28 patients (46%). Grade-3-4 hematological toxicity was observed in 9 of 36 (25%), and ematemesis in 2 of 36 patients (6%). Grade-3 gastrointestinal toxicity was observed in 4 of 36 (11%); alopecia in 3 of 36 (8%). One sudden death was observed in a patient on day 23 after the third cycle. No complication related to the angiographic procedure was noted. At a median follow-up of 7 months (range 1-17), the median survival was 6.2 months and, according to stage, 4.9 and 13.4 months for stages IV and III, respectively. The median time to progression was 4 months (range 2-11). Conclusions: This study shows that this drug combination, given through a celiac axis infusion, is well tolerated and active, requires only 1 day of hospitalization and might become an interesting form of integrated strategy in a palliative setting. Stage-111 patients are probably the group that might profit most with prolonged survival.
Article
Purpose: To evaluate the effects of transcatheter arterial infusion (TAI) therapy in 18 patients with advanced pancreatic cancer. Methods: The drugs infused were epirubicin 60 mg, mitomycin C 20 mg, and 5-fluorouracil 500 mg. The efficacy of TAI was evaluated by a tumor marker (CA19-9), computed tomography (CT) findings, and postoperative histopathological specimens. Results: In 10 of 15 cases, the tumor marker level was decreased after TAI therapy. In 6 of 14 cases, CT showed a decrease in the tumor size, and in 1 case, the tumor disappeared completely. In 6 cases the tumor could be resected. Necrosis, fibrosis, and degeneration of cancer cells were seen in 3 of 4 cases for whom a histopathological evaluation was done. The median survival was 11 months. In 17 patients back pain was the chief complaint, and was reduced to a self-controlled level in 10 patients following TAI therapy. No major complications were encountered. Conclusion: TAI appears to be an effective palliative treatment for advanced pancreatic cancer.
Article
Regional chemotherapy was developed in the 1950s and continues to play an integral part in the development of newer therapies for advanced solid malignancies. Regional therapies have evolved in complexity but are still based on the pharmacokinetics of drug delivery to solid malignancies. Newer techniques demonstrate that the combination of regional therapies, hyperthermia, and surgery is essential in promoting improved patient outcomes.
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Survival for adenocarcinoma of the pancreatic remains unchanged over the last two decades. The majority of patients (85%) are diagnosed with an inoperable tumor. Patterns of failure reveal that pancreatic cancer involves three compartments: the pancreatic bed and regional lymph nodes, the liver and the peritoneal surfaces. Twelve patients with advanced, unresectable pancreatic cancer, Stage II/III, were treated with regional intra-arterial chemotherapy and extracorporeal hemofiltration directed towards the pancreatic tumor-bearing area and the liver. Five patients had an arterial catheter/port system placed within the celiac axis; the rest had an angiographically placed arterial catheter. All patients had a 16 Fr PFM filtration catheter inserted in the vena cava positioning the tip at the level of the diaphragm and then connected to a hemofiltration unit. Mitomycin C was infused over 25 minutes followed by 5-FU over 10 minutes. The hemofiltration was begun before the drug infusion and continued for 70 minutes. The twelve patients underwent 33 cycles of regional chemotherapy plus hemofiltration. Five patients had a partial response (45.5%), five had stable disease (45.5%), and one had progression (9%). Four patients were re-explored with one patient undergoing a curative resection. The average survival for patients with unresectable pancreatic adenocarcinoma is 13 months. Tumor implantation and progression on the peritoneal surfaces remains the major site of treatment failure. Regional chemotherapy plus hemofiltration with MMC and 5-FU appears to improve the response of Stage II/III inoperable pancreatic cancer and can convert some patients to resectability without significant complications and with no mortality.
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Regional chemotherapy plus hemofiltration (chemofiltration) may be indicated in selected patients with advanced pancreatic, hepatic, or pelvic malignancies as either induction therapy prior to surgery or for the palliation of pain.
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Considerable controversy surrounds the management of gastric cancer and this has largely overshadowed recent progress in our understanding of the epidemiology and molecular pathogenesis of the disease, and improvements in diagnostic and staging techniques. Differences identifiable in the molecular pathogenesis of the ‘intestinal’ and ‘diffuse’ types of gastric cancer may help to unravel the biological behaviour of variants and ultimately influence therapeutic strategies. Endoscopic ultrasound is well established as being accurate for T staging and the introduction of laparoscopy, with or without ultrasound, is obviating unnecessary laparotomy in non-bleeding, non-obstructed patients. Controversies in surgery encompass the role of laparoscopic surgery in early gastric cancer, the extent of lymphadenectomy including para-aortic nodal dissection, resection of en bloc contiguous organ involvement, pancreatosplenectomy, left upper abdominal evisceration, and modes of reconstruction (pylorus-preserving gastrectomy, pouch formation) to enhance quality of life. Whereas adjuvant chemotherapy does not impact favourably on survival, emphasis has now shifted to neoadjuvant (induction) chemotherapy to downstage the disease. Preoperative regional chemotherapy and intra-operative hyperthermic chemotherapy or irradiation may prove to be of benefit in patients with resectable disease, but some scepticism still exists as to the usefulness of biological response modifiers (e.g. OK432, PSK) for adjuvant treatment. Ethical issues relating to cultural differences in Asia sometimes mitigate against adequate trial design (e.g. a surgery-alone control group or a no adjuvant therapy treatment group may be considered inappropriate) and this has understandably hindered acceptance in Western countries of the value of current management practices in Asia. These issues and the need for ongoing well-conducted randomized trials with prospective subset analysis are now being addressed.
Article
The treatment of pancreatic cancer is still problematic for physicians. Only 15% of patients present with resectable tumours, and systemic chemotherapy is of limited effectiveness. In order to achieve higher local drug concentrations in the tumour without causing the side-effects of a comparable level of systemic treatment, regional chemotherapy has been introduced as an alternative treatment. Several techniques have been developed over recent years, these include: celiac axis infusion (CAI), CAI with microspheres or haemofiltration, aortic stop flow (ASF) and isolated hypoxic perfusion (IHP). Whilst several authors have reported improved response rates and a prolongation of median survival time, these results have not been confirmed by others. In addition, the incidence of side-effects and the rate of technical complications have been reported to be high during regional chemotherapy. Except for a single trial containing 14 patients, no randomised trial comparing systemic and regional chemotherapy has been conducted. For these reasons, none of the reported treatment regimens can be considered to be standard treatment and in order to evaluate, if regional chemotherapy is indeed superior to systemic chemotherapy, randomised trials must be conducted.
Article
Regional chemotherapy is an interesting treatment option in patients with advanced pancreatic cancer but cannot be considered standard treatment, and it should not be performed outside controlled clinical trials. The real value of regional chemotherapy must be evaluated in larger, randomized trials. New drug combinations may reduce the observed side effects and improve tumor response. Gene therapy with p53 and K-ras modulated herpesviruses may become a palliative treatment option and can be administered easily by regional chemotherapy techniques [23].
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Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.
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Despite a paucity of data, cystadenocarcinoma of the pancreas has been considered to be resistant to chemoradiation, with a limited effect similar to that of the more common pancreatic adenocarcinoma. We describe a case of a partially excised cystadenocarcinoma with a positive surgical margin that was treated by neoadjuvant chemoradiation. No epithelial elements were found on histologic examination after reresection. Three previous cases of dramatic response of pancreatic cystadenocarcinoma to chemoradiation have been described in the literature. The current dogma alleging poor response of pancreatic cystadenocarcinoma to chemoradiation may be in error.
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To evaluate the effects of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in patients with advanced pancreatic carcinoma. CTAI was performed in 17 patients with stage IV pancreatic cancer with (n = 11) or without (n = 6) liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The inferior pancreatic artery (IPA) was embolized to achieve delivery of the pancreatic blood supply through only the celiac artery. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. Treatment effects were evaluated based on the primary tumor size, liver metastasis, and survival time and factors such as tumor size, tumor location, and stage of pancreatic carcinoma; the embolized arteries were analyzed with respect to treatment effects and prognosis. A catheter was fixed in the gastroduodenal artery and splenic artery in 10 and 7 patients, respectively. Complete peripancreatic arterial occlusion was successful in 10 patients. CT showed a decrease in tumor size in 6 of 17 (35%) patients and a decrease in liver metastases in 6 of 11 (55%) patients. The survival time ranged from 4 to 18 months (mean +/- SD, 8.8 +/- 1.5 months). Complete embolization of arteries surrounding the pancreas was achieved in 10 patients; they manifested superior treatment effects and prognoses (p < 0.05). In patients with advanced pancreatic cancer, long-term CTAI with systemic chemotherapy appeared to be effective not only against the primary tumor but also against liver metastases. Patients with successfully occluded peripancreatic arteries tended to survive longer.
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Full-text available
The final results of a new regimen given intra-arterially for unresectable pancreatic cancer (UPC) are presented. From January 1994 to January 2006, 5-fluorouracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2 and carboplatin 300 mg/m2 were administered every 3 weeks into the celiac axis (CA) angiografically (FLEC regimen) to 211 patients with UPC. Seven hundred and sixty-four cycles were administered. Grade 3-4 hematological toxicity was observed in 24%; ematemesis in 4%; grade 3 gastrointestinal toxicity in 3%; grade 3 alopecia in 15%. One sudden death, a pre-infarction angina and a transitory ischemic attack were observed. No complications related to the angiographic procedure took place, but three tunica intima dissections of the iliac artery occurred; 7.6% of patients with partial responses and 50.7% with stable disease were observed. Two hundred and one patients have died; median overall survival was 9.2 months: 10.5 and 6.6 for stage III and IV, respectively. The FLEC regimen given intra-arterially is well-tolerated and effective in patients with UPC.
Article
The purpose of this study was to compare intrahepatic and pancreatic perfusion on fusion images using a combined single-photon emission computed tomography (SPECT)/CT system and to evaluate the efficacy of combined continuous transcatheter arterial infusion (CTAI) and systemic chemotherapy in the treatment of advanced pancreatic carcinoma. CTAI was performed in 33 patients (22 men, 11 women; age range, 35-77 years; mean age, 60 years) with stage IV pancreatic cancer with liver metastasis. The reservoir was transcutaneously implanted with the help of angiography. The systemic administration of gemcitabine was combined with the infusion of 5-fluorouracil via the reservoir. In all patients we obtained fusion images using a combined SPECT/CT system. Pancreatic perfusion on fusion images was classified as perfusion presence or as perfusion absent in the pancreatic cancer. Using WHO criteria we recorded the tumor response after 3 months on multislice helical CT scans. Treatment effects were evaluated based on the pancreatic cancer, liver metastasis, and factors such as intrahepatic and pancreatic perfusion on fusion images. For statistical analysis we used the chi-square test; survival was evaluated by the Kaplan Meier method (log-rank test). On fusion images, pancreatic and intrahepatic perfusion was recorded as hot spot and as homogeneous distribution, respectively, in 18 patients (55%) and as cold spot and heterogeneous distribution, respectively, in 15 (45%). Patients with hot spot in the pancreatic tumor and homogeneous distribution in the liver manifested better treatment results (p < 0.05 and p < 0.01, respectively). Patients with hot spot both in the pancreatic cancer and in the liver survived longer than those with cold spot in the pancreatic cancer and heterogeneous distribution in the liver (median +/- SD, 16.0 +/- 3.7 vs. 8.0 +/- 1.4 months; p < 0.05). We conclude that in patients with advanced pancreatic cancer, CTAI with systemic chemotherapy appeared to be effective and may prolong their survival. The development of a reservoir port system allowing for the homogeneous distribution of anticancer drugs is necessary to improve the prognosis of patients with advanced pancreatic cancer.
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The frequency of point mutations at codons 12 and 13 of the c-K-ras gene has been determined in a panel of more than 400 human tumors. Mutant c-K-ras genes were detected in about 75% of adenocarcinomas of the pancreas (n = 84); 40% of adenomas (n = 72) and carcinomas (n = 244) of the colon end rectum; 30% of carcinomas of the bile duct (n = 19); 25% of carcinomas of the lung (n = 92), and in lower frequency in other carcinomas, including liver, stomach, and kidney. No mutations were found in carcinomas of the breast, prostate, esophagus, and gall bladder, among others. Comparative analysis of the spectrum of mutations show that while G to A transitions were the most frequent mutations in pancreatic and colo-rectal tumors, G to T transversions were more prevalent in lung carcinomas. The aspartic acid mutation at codon 13 (GGC----GAC) was relatively frequent in colo-rectal tumors but rare in pancreatic and lung carcinomas. The differences in the mutation spectrum of the c-K-ras gene in cancers of the gastrointestinal and respiratory tracts are suggestive of differential exposure to genotoxic agents. Images FIGURE 1.
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Clinical response of liver metastases treated by high-dose intraarterial chemotherapy (HDIAC) delivered via the hepatic artery was predicted by a modification of the human tumor colony-forming assay (HTCFA) originally described by Hamburger and Salmon [Science (Wash. DC), 197:461-463, 1977. In a first set of experiments, the immediate clinical response to HDIAC was determined in 12 patients with colorectal liver metastases. Biopsies were taken immediately before and after HDIAC, and cells were plated in the HTCFA. Three patients received intraoperative 4-epidoxorubicin and another 9 received mitomycin C by 15-min intraarterial infusions. Sensitivity in the HTCFA was defined as 50% inhibition of colony formation in tumors exposed to the chemotherapeutic agent, compared to the untreated controls. Clinical response was accurately predicted by the HTCFA in 11 of 12 cases. Eight patients had a regression of disease following HDIAC treatment with mitomycin C, as evidenced by either greater than 50% reduction in carcinoembryonic antigen serum level (7 patients) or regression of tumor by computed tomography scan (1 patient). Three patients had no evidence of clinical response to epidoxorubicin, and their tumors were resistant to epidoxorubicin in the HTCFA. One tumor was sensitive to mitomycin C in the HTCFA, but serum carcinoembryonic antigen in the patient continued to increase following HDIAC. The HTCFA was also performed on untreated biopsies following incubation in vitro with the drug used for HDIAC. Results correlated with clinical response in all 12 cases. In a second set of experiments, the HTCFA was used to predict the long-term clinical response to HDIAC of 30 patients with liver metastases. One patient had breast cancer metastases, one patient had carcinoid liver metastases, 4 had liver metastases of malignant melanoma, and 24 patients had colorectal liver metastases. All 21 of the patients whose tumors were sensitive in vitro had clinical response, while 6 of 9 patients predicted by the HTCFA to be resistant had no clinical response. Our results demonstrate a high correlation between the HTCFA and clinical response.
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Thirty-four pancreatic adenocarcinomas were studied for the presence of p53 gene mutations by the single-strand conformation polymorphism method and by direct sequencing of PCR-amplified fragments. p53 protein expression was immunohistochemically evaluated using monoclonal PAb1801 and polyclonal CM1 antibodies. Mutations were detected in 14 cases. The transitions were six G to A and two A to G; the transversions were one C to G and two A to C; the remaining three were frameshift mutations. Immunostaining results were identical with both antibodies. Nuclear immunohistochemical p53-positive cells were found in nine p53 mutated cases and in 12 cases in which no mutation was detected. In most of these latter cases only a minority of cancer cells showed immunohistochemical positivity. Twenty-nine cases, including all p53 mutated cancers, were known to contain codon 12 Ki-ras gene mutations. Also in the light of the demonstrated cooperation of ras and p53 gene alterations in the transformation of cultured cells, our data suggest that p53 mutation is one of the genetic defects that may have a role in the pathogenesis of a proportion of pancreatic cancers.
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Advanced intra-abdominal malignancies and hepatic metastases are treated with a new technique using regional high-dose intra-arterial chemotherapy delivering up to four times the systemic dose to a tumor-bearing region. Using a modified hemofiltration unit, 85% of the serum drug concentration can be rapidly cleared from the venous systemic compartment of patients within 60 min. Ten patients underwent 15 treatments with high-dose intra-arterial chemotherapy with concomitant hemofiltration. Five patients with liver metastases had hepatic arterial catheters placed angiographically or a hepatic arterial port placed. Three patients with pelvic metastases and one with advanced bladder adenocarcinoma had aortic catheters placed intraoperatively retrograde from the common femoral artery. A double-lumen filtration catheter was placed in the vena cava at the diaphragm via the saphenous or femoral vein and connected to a modified hemofiltration unit. Mitomycin C, 5-fluorouracil, Adriamycin, or cisplatin was infused over 20-30 min. The hemofiltration continued for another 30 min. One of the ten patients had a complete response, six had a reduction in tumor size, two had stable disease, and two had progression.
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• The efficacy of combined radiation and fluorouracil as adjuvant therapy for pancreatic cancer is suggested by a prospective randomized study conducted by the Gastrointestinal Tumor Study Group (GITSG). Twenty-two patients randomized to no adjuvant treatment and 21 to combined therapy were analyzed. Neither life-threatening toxic reaction nor death due to toxic effect was encountered. The study was terminated prematurely because of an unacceptably low rate of accrual combined with the observation of increasingly large survival differences between the study arms. Median survival for the treatment group (20 months) was significantly longer than that observed for the control group (11 months). Four patients, three in the treated and one in the control group, have survived five years or longer following surgery. The extent of the tumor and initial performance status were significantly and independently related to survival. (Arch Surg 1985;120:899-903)
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• The regional delivery of high-dose chemotherapy for malignant neoplasms of the limb with the isolated regional perfusion technique was first described in the late 1950s. Recently, the use of concomitant hemofiltration for rapid systemic drug removal permits the use of higher regional drug levels in treating patients with advanced abdominal malignant neoplasms without complete vascular isolation. Twenty-five patients successfully underwent 42 treatments of high-dose intra-arterial chemotherapy with concomitant hemofiltration at Tulane University Medical Center Hospital, New Orleans, La, from 1989 through 1990. One patient (4%) achieved a complete response. Two patients (8%) had partial responses following high-dose intra-arterial chemotherapy with concomitant hemofiltration and their residual disease was resected for cure. Seven patients (28%) achieved a partial response, 11 (44%) had stable disease, and four (16%) had progression of disease. (Arch Surg. 1991;126:1390-1396)
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One hundred eighty-seven patients with histologically proven advanced pancreatic adenocarcinoma were randomly assigned to therapy with 5-fluorouracil (5-FU) alone, to the Mallinson regimen (combined and sequential 5-FU, cyclophosphamide, methotrexate, vincristine, and mitomycin C), or to combined 5-FU, doxorubicin, and cisplatin (FAP). Patients with both measurable and nonmeasurable disease were included and the primary study end point was survival. Among 41 patients with measurable disease, objective response rates were 7% for 5-FU alone, 21% for the Mallinson regimen, and 15% for FAP. The median interval to progression for each of the three regimens was 2.5 months. Survival curves intertwined with the median survival times for 5-FU alone and the Mallinson regimen at 4.5 months and for FAP at 3.5 months. Compared with 5-FU alone, both the Mallinson regimen and FAP produced significantly more toxicity. Neither the Mallinson regimen nor FAP can be recommended as therapy for advanced pancreatic carcinoma. Any chemotherapy for this disease should remain an experimental endeavor.
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Thirty-six patients underwent curative resection of a primary pancreatic carcinoma from January 1977 to September 1987; 26 had Whipple resections, seven had total pancreatectomies, and three had distal pancreatectomies. Twenty-six patients manifested recurrent disease, four died of intercurrent disease, and six were apparently cured. Median survival was 11.5 months with actuarial survival at 2 and 5 years of 32% and 17%, respectively. of the eventual recurrences, 19% were local only (pancreatic bed, regional nodes, adjacent organs, and immediately adjacent peritoneum) and 73% had a component of local failure. All patients failing did so with a component in the intraabdominal cavity. Peritoneal (42%) and hepatic failures (62%) were common. Extraabdominal metastases were documented in only 27%, but never as a sole site. Fourteen patient and tumor characteristics were evaluated for any relationships with failure or survival. No single variable independently predicted for local failure. However, a group of three (age > 60 years, T2 or T3 stage, and location of tumor in the body or tail) was associated with a substantial local failure risk (85% of all patients with local failure). Multivariate analysis showed that low tumor grade (P = 0.002), female sex (P = 0.002), and adjuvant radiation (P = 0.02) were all independent predictors of prolonged survival. Ten patients were treated in an adjacent setting. Those given 55 Gy or greater had improved local control (50% versus 25%) and cure (33% versus none) when compared with patients treated to lower doses. The authors conclude that local failure after curative resection remains a significant problem and further efforts to improve local control are warranted. However, peritoneal and hepatic relapses occur frequently. Thus, adjuvant treatment strategies using wide-field radiation techniques or intraperitoneal therapy, in combination with local tumor bed irradiation and chemotherapy, should be explored.
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A high-performance liquid chromatographic method for the determination of the antitumor drug mitomycin C in blood plasma samples of cancer patients is described. The drug is extracted from the plasma with chloroform–2-propanol (1+1, ) and chromatographed on a reversed-phase column with u.v. detection at 365 nm. The detection limit of the determination is 1 ng ml-1 for 0.2–1.0 ml plasma samples. Preliminary results of a pharmacokinetic study show that the sensitivity and selectivity of the assay are adequate for drug monitoring in clinical practice. The results obtained from multiwavelength detection suggest the existence of metabolites.
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A prospective study to determine the lymph node involvement in 33 pancreatectomy specimens (regional pancreatectomy 18, total pancreatectomy 7, Whipple partial pancreatectomy 8) was undertaken. There were 22 patients with pancreas duct adenocarcinoma, 6 with ampullary carcinoma, 3 with duodenal adenocarcinoma, 1 bile duct carcinoma and 1 of undetermined site of origin. Peripancreatic lymph nodes were divided into 5 main groups with subgroups. They are 1) Superior, Superior Head, Superior Body and Gastric; 2) Inferior: Inferior Head and Inferior Body, 3) Anterior: Anterior Pancreaticoduodenal, Pyloric and Mesenteric, 4) Posterior: Posterior Pancreaticoduodenal, Common Bile Duct, and 5) Splenic: lymph nodes at hilum of spleen and at the tail of pancreas. The average number of lymph nodes found in different types of surgical specimens was: regional pancreatectomy 70, total pancreatectomy 41, and Whipple procedure 33. The average number of lymph nodes involved with metastatic tumor in these specimens was, respectively, 5, 3 and 1. The most common sites of metastasis were in the Superior Head and in the Posterior Pancreaticoduodenal groups. Pancreatic duct adenocarcinoma tended to me-tastasize to multiple lymph nodes of the Superior Head, Superior Body and Posterior Pancreaticoduodenal lymph nodes (88% of patients). Ampullary adenocarcinoma metastasized less often (33%), usually to fewer nodes and to one adjacent periampullary group. Since in 33% of patients nodal metastases of duct adenocarcinoma of the head of the pancreas were present in groups not usually removed in the Whipple procedure, it would appear that this operation is inadequate for surgical eradication of pancreas duct adenocarcinoma of the head of the pancreas.
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To elucidate the clinical significance of perineural invasion on bile duct cancer, a clinicopathologic study was performed on 70 resected patients with bile duct carcinoma. The overall incidence of perineural invasion in the resected specimen was 81.4%. There seemed to be no correlation between perineural invasion and site, size of the tumor, and lymph node metastasis. A significant correlation was observed, however, between macroscopic type, microscopic type, depth of invasion, and perineural invasion. Perineural invasion index (PNI) was defined as the ratio between the number of nerve fibers invaded by cancer and the total number of nerve fibers with and without cancer invasion. Perineural invasion index was significantly higher at the center compared with the proximal and distal part of the tumor (p less than 0.001). The 5-year survival rate for patients with perineural invasion was significantly lower (p less than 0.05) than that for those without perineural invasion (67% versus 32%).
Article
The regional delivery of high-dose chemotherapy for malignant neoplasms of the limb with the isolated regional perfusion technique was first described in the late 1950s. Recently, the use of concomitant hemofiltration for rapid systemic drug removal permits the use of higher regional drug levels in treating patients with advanced abdominal malignant neoplasms without complete vascular isolation. Twenty-five patients successfully underwent 42 treatments of high-dose intra-arterial chemotherapy with concomitant hemofiltration at Tulane University Medical Center Hospital, New Orleans, La, from 1989 through 1990. One patient (4%) achieved a complete response. Two patients (8%) had partial responses following high-dose intra-arterial chemotherapy with concomitant hemofiltration and their residual disease was resected for cure. Seven patients (28%) achieved a partial response, 11 (44%) had stable disease, and four (16%) had progression of disease.
Article
Cytologic examination of peritoneal washings was performed in 40 patients with pancreatic ductal adenocarcinoma (35 head, 5 body) whose tumors had been selected as potentially resectable by computed tomographic (CT) findings. Saline (100 mL) was instilled and aspirated at laparoscopy in 27 patients and at laparotomy in 13. Malignant cells were found in the peritoneal washings in 12 of 40 patients (30%): 29% in cancers of the pancreatic head versus 40% in the body; 33% at laparoscopy versus 23% at laparotomy; and in 4 of 8 patients with ascites versus 8 of 32 without ascites. The cytology was positive in 6 of 8 patients (75%) who had a prior percutaneous needle biopsy versus 6 of 32 (19%) of those who did not (p less than 0.01). Liver metastases were found in six patients, all with negative cytology. One of 10 pancreatic head cancers with positive cytology was resectable versus 13 of 25 with negative cytology (p less than 0.05). Survival was significantly longer in patients with negative cytology. We conclude that (1) pancreatic cancer sheds malignant cells into the peritoneum early and commonly; (2) laparoscopic lavage is an effective means of cytologic study; (3) ascites is not a precondition for cytologic study, nor does its presence necessarily imply carcinomatosis; (4) intraperitoneal spread of cancer cells may be promoted by tumor biopsy; (5) cytologic findings provide an additional index of resectability; and (6) cytologic findings appear to correlate with duration of survival. This study shows that even "localized" pancreatic cancer is often not contained and suggests caution with biopsy of potentially curable lesions.
Article
The National Cancer Data Base, a joint effort of the American Cancer Society and the Commission on Cancer of the American College of Surgeons, was created one year ago as an ongoing national network for evaluation of patient care. The goal is to assist physicians and hospitals in making more efficient treatment decisions. The preliminary findings of the project are presented in this report.
Article
Forty-two previously untreated patients with advanced, measurable adenocarcinoma of the pancreas were treated with weekly fluorouracil (5-FU; 600 mg/m2 intravenous [IV]) and leucovorin 500 mg/m2 IV for 6 weeks followed by a 2-week rest. A median of 11 (range, one to 76) doses were given. There were three partial responses (three of 42 [7%]; exact 95% confidence interval, 1% to 19%) and no complete responses. Median survival was 6.2 months, with seven patients surviving longer than 12 months. The most common toxicity was diarrhea; there was one treatment-related death. Despite promising results in patients with advanced colorectal cancer, this dose schedule of 5-FU and leucovorin does not appear to be superior to 5-FU alone for the treatment of advanced pancreatic cancer. Alternative investigative approaches are needed.
Article
Eighty-nine patients with carcinoma of the head of the pancreas underwent pancreaticoduodenectomies. The actuarial 5-year survival for all 89 patients was 19%, with a median survival of 11.9 months. The 81 hospital survivors were analyzed in an effort to determine factors influencing long-term survival. Negative lymph nodes and the absence of blood vessel invasion both favored long-term survival. The strongest predictive factor was negative lymph node status with a median survival of 55.8 months, compared with 11 months with lymph nodes involved with tumor (p less than 0.05). Blood transfusions were also predictive, with patients receiving two or fewer units having a median survival of 24.7 months, compared with 10.2 months for those receiving three or more units (p less than 0.05). The most important determinant of long-term survival after pancreaticoduodenectomy for pancreatic cancer is biology of the tumor (lymph node status, blood vessel invasion). However, performance of the resection (units of blood transfused) also appears to be an important factor influencing survival.
Article
Twenty-one years ago, Howard published a paper entitled "Forty-one Consecutive Whipple Resections Without an Operative Mortality." That paper stimulated the present analysis of the last 118 consecutive pancreatoduodenectomies (107 Whipple and 11 total resections) performed at the Surgical University Clinic Mannheim from November 1985 to the present day with no deaths. Ninety-one resections were performed for neoplasms and 27 were for complicated chronic pancreatitis. The preoperative evaluation, operative technique, and postoperative care of these cases is discussed in detail and compared to the experience of Howard. While there was general agreement on operative technique, there were differences concerning preoperative evaluation (modern imaging methods) and postoperative care (simplification). In this series 21 postoperative complications required seven relaparotomies. Long-term survival after resection for carcinoma was analyzed for 133 consecutive patients who were shown to have true ductal adenocarcinoma. In 76 patients, who had radical (R0-) resections, the actuarial 5-year-survival rate was 36%. In 44 patients, whose R0-resections for pancreatic cancer occurred more than 5 years ago, the actual survival rate was 25%.
Article
The 5-fluorouracil content of serum, bile, pancreatic juice, liver, pancreas and muscle was measured by reversed-phase high-performance liquid chromatography using a mobile phase of 5 mM 1-heptanesulfonic acid in 5 mM acetic acid. Free or unmetabolized 5-fluorouracil was extracted from samples with a mixture of light petroleum-n-propanol (40:60). The active metabolites of 5-fluorouracil were hydrolyzed with hot perchloric acid to free 5-fluorouracil and the combined 5-fluorouracil content was extracted. The active metabolite fraction was calculated from the difference between the combined and the free fractions. A straight line plot of the peak areas against concentration was achieved and the detection limit was 50 ng/ml. Five minutes after stopping an intravenous infusion of 15 mg/kg of 5-fluorouracil in a dog, the serum contained only the free form, but other body fluids and tissues contained both free and metabolite fractions. The method may be useful to determine the amount of total drug in patient samples.
Article
Using in vitro gene amplification by the polymerase chain reaction (PCR) and mutation detection by the RNAase A mismatch cleavage method, we have examined c-K-ras genes in human pancreatic carcinomas. We used frozen tumor specimens and single 5 micron sections from formalin-fixed, paraffin-embedded tumor tissue surgically removed or obtained at autopsy. Twenty-one out of 22 carcinomas of the exocrine pancreas contained c-K-ras genes with mutations at codon 12. In seven cases tested, the mutation was present in both primary tumors and their corresponding metastases. No mutations were detected in normal tissue from the same cancer patients or in five gall bladder carcinomas. We conclude from these results that c-K-ras somatic mutational activation is a critical event in the oncogenesis of most, if not all, human cancers of the exocrine pancreas.
Article
Forty-eight patients with ductal cell carcinoma of the pancreas underwent total pancreatectomy. During 1970-1976, there were four deaths (a mortality of 18%). During the last twenty-eight operations (1977-1986), there were no hospital deaths. Seventeen per cent of the patients suffered intraoperative complications involving the mesenteric vessels. Twenty-seven per cent suffered postoperative complications. Twenty-five per cent of the patients left the hospital within 2 weeks, 50% left within 4 weeks, and another 25% remained in the hospital for longer than 4 weeks. Thirty-five per cent of the patients have returned to their preoperative job or similar life activity. Another 35% were able to lead an active life but did not return to regular work, and 30% were to some degree incapacitated by their operative procedure and disease. Twenty-one per cent of the patients lived for 4 years, and 14% survived for 5 years.
Article
Pancreatic cancer is the fifth leading cause of cancer death, second only to cancer of the colon among neoplasms of the gastrointestinal tract. It is estimated that 27000 new cases and 24500 deaths attributed to pancreatic cancer will occur in the United States in 1988. Death rates have risen steadily in the U.S. since approximately 1930 with a recent leveling off, and this trend also has been observed in similarly developed countries. The time trends for pancreatic cancer in both males and females have been examined in relation to cigarette use in the U.S. Although the correlation is not as dramatic as that for lung cancer, pancreatic cancer mortality rates for both males and females have paralleled the prevalence rates of cigarette smoking with the expected latency lag of several decades. Although ecologic correlations such as this have been used to support meaningless associations, the temporal relation between cigarette usage and pancreatic cancer supports the validity of cigarette smoking as a risk factor for pancreatic cancer established in analytic epidemiologic studies.
Article
Among 1001 patients with carcinoma of the pancreas, 23 of 912 patients with exocrine carcinomas, 10 of 46 with ampullary carcinomas, and 21 of 43 with malignant islet cell tumors survived 3 years. Of the survivors with exocrine cancers, there were nine of 97 patients who had curative operation, two had had palliative resections only, and one was an incidental microfocal carcinoma; in the remaining 11 patients a histologic origin in the pancreas was not established. Preoperatively suspected and histologically proven 3-year survivors included six patients with ductal adenocarcinomas, three patients with mucinous cystadenocarcinomas, one patient with acinic cell carcinoma, and one patient with microadenocarcinoma. Only two patients can be considered cured. Tumor size and lymph node status did not correlate with survival. Cystadenocarcinomas comprised 1% of cases but one third of 3-year survivors. Long-term survival in histologically confirmed pancreatic carcinoma is a rare event that cannot be predicted in the individual case.
Article
In a group of 76 patients with various gastrointestinal malignant lesions, we found that peritoneal washings contained tumor cells in 43% of patients with gastric cancer, 22% of those with pancreatic cancer, and 3% of those with colonic cancer. Aside from tumor site, we were unable to identify any criteria that would help to predict the presence of malignant cells in peritoneal fluid specimens. We found no malignant cells on cytology in patients with early localized cancer. The ease of obtaining such data, coupled with the fact that the test is inexpensive, makes cytologic assessment attractive. Furthermore, the results of cytology have been shown to bear a direct relationship to prognosis in some cancers and may serve as an indication for more intensive therapy. The results of sequential cytology tend to support the theory that tumor manipulation may be a source of intraperitoneal spread in certain tumors.
Article
The pharmacokinetic theory of intra-arterial drug administration has been clearly articulated. It provides a useful guide to the development and interpretation of preclinical studies and clinical trials. Despite the clarity and usefulness of the theory, there are misunderstandings of its implications and technical problems associated with its implementation. Few studies have been properly designed to validate the theory experimentally. Independence of steady-state pharmacokinetic advantage on intraregion blood flow differences predicted for a nonextracted drug is counterintuitive. Extrapolation from laboratory animals to humans raises some important questions of allometry, particularly for the brain, which does not follow the scaling rules applicable to other organs. Finally, drug streaming from the site of infusion has been observed in vitro and in vivo. The extent of the resulting clinical problem has not been adequately characterized, but it may be severe under some circumstances.
Article
The course of 196 patients with proven carcinoma of the pancreas seen at Yale New Haven Hospital from 1972 to 1982 was analyzed. Only 73% of the patients were preoperatively expected to have cancer of the pancreas. The patients who underwent resection had the longest mean survival but also the longest total hospital stay. Twenty-seven patients survived 1 year or more, but nonresected patients constituted 81.5% of this group. The only 5-year survivor did not undergo resection. Forty-seven percent of patients who survived 1 year and had not undergone gastroduodenal bypass, developed duodenal obstruction. It was not possible to identify a subset of patients with a favorable prognosis. A review totaling approximately 37000 patients, of whom 4100 had undergone resections, revealed only 156 survivors, 12 of whom had not been resected, for an overall survival rate of only 0.4%. No author had more than 3.4% of the total number of patients as 5-year survivors.
Article
Between 1969 and 1986, 88 patients had a Whipple resection for adenocarcinoma of the pancreas (N = 50), ampulla (N = 19), distal bile duct (N = 10), and duodenum (N = 9). Forty-nine patients were men, 39 were women, and the mean age was 58 years (range: 34-84 years). The patients were divided into two groups on the basis of two different time periods: those operated on from 1969 to 1980 (N = 41) and those operated on from 1981 to 1986 (N = 47). There were no significant differences between the two groups in terms of mean age, sex distribution, duration of symptoms before presentation, or mean weight loss. Likewise, preoperative laboratory data were similar for both groups of patients. In addition, mean tumor size for patients with pancreatic cancer (3.5 cm vs. 3.2 cm) and patients with nonpancreatic periampullary cancer (1.9 cm vs. 2.2 cm) was similar in both groups, as was the incidence of positive lymph nodes. Among the 41 patients operated on during the first period, hospital morbidity and mortality rates were 59% and 24%, respectively. In contrast, hospital morbidity and mortality rates were 36% and 2%, respectively, among the 47 patients operated on during the recent period. During the recent period, more Whipple procedures were performed each year (7.8 vs. 3.4) and by fewer surgeons (3.4 operations/surgeon vs. 1.9 operations/surgeon). In addition, between 1981 and 1986, there were fewer total pancreatectomies (9% vs. 39%), fewer vagotomies (26% vs. 76%), and more pyloric-preserving procedures (30% vs. 0) performed compared with the earlier period. During the recent period, mean operative time (7.8 vs. 9.0 hours), mean estimated blood loss (1694 vs. 3271 mL), and mean intraoperative blood replacement (3.6 vs. 6.3 units) were all significantly less than in the earlier period. These findings suggest that the recent decline in operative morbidity and mortality may be due to fewer surgeons performing more Whipple resections in less time and with less blood loss. The actuarial 5-year survival rate for the 38 patients with nonpancreatic periampullary cancer was 34%. Surprisingly, the actuarial 5-year survival rate among the 50 patients with pancreatic cancer was 18%. Moreover, in the absence of positive lymph node involvement, the 5-year actuarial survival rate among patients with pancreatic cancer was 48%. No explanation is obvious for the improvement in survival among patients with pancreatic cancer.
Article
In two 5 year periods (1975 to 1979 and 1980 to 1984), 96 patients underwent pancreatoduodenal resection, which included 74 partial pancreatic resections and 22 total pancreatectomies. Thirty-seven of these patients had resections with preservation of the pylorus. Substantial reductions in perioperative mortality (2 percent versus 10 percent) and morbidity (26 percent versus 49 percent) (p less than 0.05) were achieved in the latter period. Pylorus preservation, with a mortality and morbidity of 3 percent and 27 percent, respectively, did not increase operative risk or compromise long-term survival in patients with malignant disease. In comparison, relatively high mortality and morbidity rates (14 percent and 59 percent) accompanied total pancreatectomy without improved long-term survival. Five year actuarial survival for nonpancreatic periampullary adenocarcinomas was 58 percent. Thus, we recommend pancreatoduodenectomy with preservation of the pylorus for resection of periampullary tumors. These patients, whose only possibility for cure is a major pancreatic resection, should not be denied this opportunity on the basis of reports from a previous era.
Article
Evaluation of diagnosis and treatment modalities in pancreas cancer is hampered by the lack of a suitable staging system. The current staging protocol of the American Joint Committee is arranged as follows: intrapancreatic disease (stage I), localized invasion (stage II), positive regional lymph nodes (stage III), and distant metastases (stage IV). Primary size is not taken into account and may represent an important determinant of survival, as it does in other malignancies. Primary size as a criterion of operability may assume increasing importance, given the demonstrated accuracy of sonography and computed tomography. Chart review was undertaken of the 119 consecutive patients with pancreas cancer presenting at Grady Hospital between 1976 and 1981. Ninety-one per cent were histologically confirmed. The presence or absence of metastases continues to be the most important factor predicting survival (P less than 0.001). It was demonstrated, however, that patients with primary lesions less than 5 cm lived significantly longer than those with primaries greater than or equal to 5 cm (P less than 0.02). Using the currently recommended American Joint Committee protocol, there was no difference in survival curves among stages, I, II, and III. The median survival times were 7.5 months, 5 months, and 5 months, respectively. Between combined stages I, II, and III and stage IV (median survival, 1.0 month), there was a significant difference (P less than 0.001) in survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Resection was carried out in 118 patients for periampullary lesions. Ninety-eight of these were adenocarcinomas and were treated by the Whipple operation, total pancreatectomy, or local resection (87 patients, 7 patients, and 4 patients, respectively). Diagnosis of pancreatic head carcinoma before resection was falsely positive in 27 percent of the patients. Mortality for radical resection was 4 percent. Five year survival for ampullary carcinoma was 32 percent, and for pancreatic head carcinoma it was 7 percent. Resection of all periampullary tumors is recommended, with the Whipple operation being the standard in most cases.
Article
The techniques now exist to deliver drug infusions reliably through the hepatic artery to infuse the entire liver and tumor within the liver. Drug selection for use in these systems should be rational and include agents with short half-lives (high total body clearance) and some evidence of activity against the tumor type in question. Hepatic extraction and metabolism of the drug will in turn decrease systemic exposure or allow more drug to be given per set amount of systemic exposure. The dose-limiting toxicity of appropriate drug programs may well be regional and not systemic. Further pharmacokinetic studies and controlled clinical trials are needed to evaluate existing regimens and to design new regimens. Future advances are likely to involve the combination of effective drugs and the use of therapeutic microspheres to improve selectivity based on tumor microcirculation.
Article
The pharmacological advantage of mitomycin C (MMC) given by intraarterial infusion as compared to i.v. infusion was studied in seven patients with cancer metastatic to the liver. Hepatic artery, hepatic vein, and peripheral vein catheters were placed, and then each patient received constant infusions of MMC via the intraarterial and peripheral i.v. routes at 0.4, 1.2, and 4.0 mg/sq m/hr. MMC concentrations were measured in the hepatic artery, hepatic vein, and a peripheral vein by high-pressure liquid chromatography after steady state had been reached at 2 hr. Mean plasma clearance increased significantly with infusion rate from 0.6 liter/min at 0.4 mg/sq m/hr to 1.1 liters/min at 4.0 mg/sq m/hr. The calculated relative advantage of treating hepatic tumors via the intraarterial route (Rt) was found to be 2.5- to 3.6-fold at a plasma flow rate of 0.4 liter/sq m and MMC infusion rates of 0.4 to 4.0 mg/sq m/hr. The hepatic vein MMC concentration averaged 30% higher during intraarterial than during i.v. infusion. Hepatic extraction of MMC averaged only 23%, so that the intraarterial route offered little advantage with respect to reduced systemic toxicity. These data suggest a limited pharmacological rationale for the selection of the intraarterial route for the treatment of hepatic tumors with MMC.
Article
Since December, 1976, intraoperative irradiation combined with resection for cancer of the head of the pancreas has been used in our clinic to prevent local recurrence. Thirty Gy of the electron beam from a linear accelerator were administered to the operative field including the celiac axis and mesenteric artery following pancreaticoduodenectomy. Results of the combined therapy in 12 patients were compared to results in 12 patients who underwent pancreaticoduodenectomy alone. The combined therapy group compared to pancreaticoduodenectomy alone showed improvement in the 1-year survival rate, but not in the 2-year survival rate. Autopsy of 3 paients who underwent the combined therapy did not reveal any involvement of the lymph nodes in the irradiation field. However, there was involvement of the lymph nodes around the aorta from the diaphragm above to the inferior mesenteric artery below (except in the irradiation field). Additionally, there were metastases to the liver in all autopsied patients and recurrence in the pancreatic remnant in 1 patient. In spite of the local effect of irradiation therapy, there was no prolongation of survival. These results suggest that treatment for carcinoma of the head of the pancreas should be intensified toward liver metastases and the lymph nodes around the aorta from the diaphragm above to the inferior mesenteric artery below.
Article
The results of treatment with intraoperative and external beam radiation for patients with carcinoma of the pancreas are presented. Among patients treated with125I implants for localized unresectable disease, local control rates ranged from 67% to 93% and median survival ranged from 7 to 12 months. In a series using intraoperative electron beam boosts, a 59% local control rate with a median survival of 16 months was achieved. Good palliation rates were achieved, although a high proportion of fatal complications occurred in one125I series. Less promising results were seen in patients receiving intraoperative radiation following resections, with a local control rate of 50% and a median survival of 7 months in a series of 10 patients.Se presentan los resultados del tratamiento con irradiacin intraoperatoria y con irradiacin externa para carcinoma de pncreas.Entre los pacientes tratados con implantes de yodo-125 para enfermedad localizada no resecable, las tasas de control local oscilaron entre 67% y 93% y la supervivencia media vari entre 7 y 12 meses. En una serie en la cual se utiliz una sobredosis intraoperatoria con haz de electrones, se logr una tasa de control local de 59% con una supervivencia media de 16 meses. En una de las series con I-125 se obtuvieron buenas tasas de paliacin, an cuando hubo una elevada proporcin de complicaciones fatales. Resultados menos promisorios fueron observados en una serie de 10 pacientes que recibieron irradiacin intraoperatoria despus de la reseccin, con una tasa de control local de 50% y una supervivencia media de 7 meses.
One of the most common cancers in Europe and North America is that originating in the exocrine pancreas. In Sweden it constitutes 4% of all cancers and approximately 6% of all deaths from cancer. The incidence in Sweden has increased more than 100% during the last 15 years. In the United States today, pancreatic cancer is exceeded only by bronchial, colorectal, and mammary cancer as a cause of death. The increase in number of cases is only higher for bronchial cancer — a similar development can be expected in Sweden and the rest of Western Europe.
Article
Regional cancer chemotherapy is a means of exploiting dose-response effects by delivering more drug to regionally confined tumors. Regional chemotherapy can be divided into two major categories, third-space (cerebrospinal, peritoneal, pleural, and pericardial fluid) and intra-arterial treatments. Interest in regional chemotherapy has risen recently for a variety of reasons, including evidence for significantly higher response rates compared to systemic therapies. The applicable pharmacokinetic principles for drug selection have been defined and indicate that regional drug exposure advantage is directly proportional to total-body drug clearance and is inversely proportional to rate of egress from a third-space or to regional blood flow. Reliable drug delivery to the entire region in question is important. The recently introduced totally implanted devices (pumps and ports) make regional therapy more reliable, safe, and convenient. In addition, nuclear medicine scanning techniques have proven useful in assessing drug distribution with regional delivery. Regional therapy may control regional tumor, but extraregional failure may ensue. However, when regional therapy is regionally selective in its toxic effects, systemic therapy may be combined in full doses. Future efforts will need to focus on the development of more potent regional therapies, alone and in combination with systemic therapies, as well as on the validation of such treatments through controlled clinical trials.
Article
The pharmacokinetic advantage of intra-arterial drug administration can be improved if blood from the infused region is perfused through a suitable extracorporeal device. The extent of improvement depends on the blood flow to the device, the fraction of the vascular drainage that can be obtained, and the drug extraction by the device. A relatively simple equation is derived to assess the pharmacokinetic advantage and to define the governing parameters. Application of the theory to the treatment of brain tumors includes a discussion of the selection of an experimental animal and interpretation of results. It is suggested that tumor exposure to carmustine comparable to that associated with very high tumor cell kill in vitro may be feasible with little or no systemic toxicity.
Article
During the period 1972–1980, regional pancreatectomy has been performed in 40 patients: 36 had periampullary or pancreatic cancer, and 4 patients had benign disease. The 30-day postoperative mortality rate is 15% (6/40) overall, being 7% for the regional total pancreatectomy Type I, 29% for Type II, and 50% for regional subtotal Type I. Of the 30 patients with cancer who survived the operation, 33% are currently alive and 27% have died of other causes with no evidence of recurrent disease. An analysis of treatment failures in the remaining 12 patients (40%) who died of disease is presented.
Article
Between 1940 and 1978, 150 major pancreatic resections--92 pancreatoduodenal resections (PDRs) and 58 total pancreatectomies (TPs)--were performed for benign and malignant disease. The majority of resections were for pancreatic cancer (70 patients) and ampullary cancer (40 patients). The overall operative mortality rate for PDR was 14%; it was 26% for TP. After resection for adenocarcinoma of the head of the pancreas, the operative mortality rate was 28% for TP and 15% for PDR. The number of 5-year survivors after resection for cancer of the head of the pancreas was four (5.7%). Three survived after PDR and one after TP. Of the 42 adenocarcinomas resected by TP, one of the patients had multicentric cancer and two others had carcinoma in situ. TP appears to have no advantage over PDR for cancers of the head of the pancreas from a theoretical or practical standpoint.
Article
This study used data from the population-based Connecticut Tumor Registry, a unique resource for examining secular trends in cancer incidence rates since 1935. Trends in average annual age-standardized incidence rates (ASRs) for invasive cancers in Connecticut residents were examined from 1935-1939 to 1990-1991. Trends in ASRs were complex, with some sites showing large increases but others only small changes since 1935-1939. Declines were evident for stomach and cervical since 1935-1939 and for colorectal cancer after 1980-1984. Since 1965-1969, when 2% or less of cancers were ascertained only by death certificates, exclusion of cancers of the breast and prostate (strongly affected by increased screening), smoking-related cancers, and cancers of other sites with identified causes (melanoma and human immunodeficiency virus-related cancers), resulted in little or no increase in the ASRs for all other sites combined. For young (20-44-year-old) adults, unexplained increases since 1965-1969 were limited to testicular cancer and Hodgkin's disease. Reducing cancer incidence rates will require expanded primary prevention efforts (mainly involving behavioral changes) and more etiologic research on common cancers whose causes are poorly understood (e.g., breast and prostate cancer) and rarer cancers showing unexplained recent increases (i.e., testicular cancer and Hodgkin's disease).
Article
A retrospective review of the pathology and clinical course of 72 patients undergoing resection of carcinoma of the head of the pancreas was undertaken to identify the frequency of tumor involvement at standard surgical transection margins (stomach, duodenum, pancreas, and bile duct) as well as the peripancreatic soft tissue margin and the potential clinical significance of these findings. Of 72 patients undergoing resection, 37 patients (51%) were found to have tumor extension to the surgical margins. The most commonly involved margin was peripancreatic soft tissue (27 patients) followed by pancreatic transection line (14 patients) and bile duct transection line (4 patients). For 37 patients with tumor present at a resection margin, there were no survivors beyond 41 months. No difference in survival or local control was seen between 14 patients receiving postoperative radiation therapy and 5-fluorouracil (5-FU) compared with 23 patients not receiving additional treatment. In contrast, the 5-year actuarial survival and local control of 35 patients undergoing resection without tumor invasion to a resection margin was 22% and 43%, respectively. The 5-year survival and local control of 16 patients receiving adjuvant radiation therapy and 5-FU was 29% and 42%, respectively, whereas these figures were 18% and 31% for 19 patients not receiving adjuvant therapy (p > 0.10). Because residual local tumor after resection is common, preoperative radiation therapy may be beneficial in this disease. It should minimize the risk of dissemination during operative manipulation and facilitate a curative resection by promoting tumor regression. Because local failure rates approach 60% after resection and adjuvant therapy even in cases having clear resection margins, intraoperative radiation therapy to the tumor bed at the time of resection also might be considered. Protocols evaluating the feasibility and efficacy of preoperative radiation therapy and resection with intraoperative radiation therapy for patients with pancreatic cancer are underway.
Article
At Kanazawa University, the authors have been developing an appropriate radical operation for the treatment of cancer of the head of the pancreas. As a result of previous research, it was believed that lymphatic metastasis of carcinoma of the head of the pancreas should be investigated more thoroughly to improve the surgical results. Forty-two cases of carcinoma of the head of the pancreas were investigated to determine the distribution of lymphatic metastases. From among these cases, the authors injected activated carbon particles in 10 patients with pancreatic cancer and 111In colloid in seven patients with pancreatoduodenal cancer to investigate the lymphatic spread from the head of the pancreas to the paraaortic lymph nodes (area 16). The main lymphatic route from the head of the pancrease to lymphatic area 16 was found to pass through the nodes in the posterior part of the head of the pancrease (area 13) and around the superior mesenteric artery (area 14). Lymphatic metastases in area 16 were seen mainly in the lower segment of the middle region from the celiac artery to the inferior mesenteric artery (subarea 16b2). The carbon and 111In colloid flowed mostly to the same area 16 lymph nodes and toward the dorsal side of the renal artery rather than spreading superficially along the abdominal aorta. These results indicate that area 16 lymph node dissection should be extended toward the dorsal side of the renal artery rather than be performed widely along the abdominal aorta to make the radical operation for pancreatic cancer more extensive.
Article
Regional chemotherapy plus hemofiltration (chemofiltration) may be indicated in selected patients with advanced pancreatic, hepatic, or pelvic malignancies as either induction therapy prior to surgery or for the palliation of pain.
Basics concepts for the application of mitomycin C in regional cancer treatment
  • Link
Link KH: Basics concepts for the application of mitomycin C in regional cancer treatment. In Taguchi T, Aigner KR (eds):
Chemosensitivity testing of human colorectal carcinoma cell lines using a tet-razolium-based colorimetric assay
  • Park J Bs Kramer
  • Steinberg
  • Sm
Park J, Kramer BS, Steinberg SM, et al: Chemosensitivity testing of human colorectal carcinoma cell lines using a tet-razolium-based colorimetric assay. Cancer Res 47:5875-5879, 1987. SUTg 215134-349, 1992. 2207-2212, 1990. 142: 1534-1543, 1993. 86:13-14, 1983.
A phase I11 trial on the therapy of advanced pancreatic carcinoma
  • Culliman S Cg
  • Wieand
  • Hs
Culliman S, Moertel CG, Wieand HS, et al: A phase I11 trial on the therapy of advanced pancreatic carcinoma. Cancer 65: