A rationale for expanding the endpoints for clinical trials in advanced pancreatic carcinoma

Rothenberg, Mace L.; Abbruzzese, James L.; Moore, Malcolm A.S.; Portenoy, Russell K.; Robertson, John M.; Wanebo, Harold J.

doi:10.1002/(sici)1097-0142(19960801)78:3<627::aid-cncr43>3.3.co;2-e

Cited by 32 publications

(8 citation statements)

References 2 publications

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“…Moreover, tumor control in these cases is not normally successful with currently available systemic chemotherapy. In fact, a response rate of one-quarter or less can be expected with standard chemotherapy, with a dismal median survival of Ͻ6 months (4,5). With this background, the question is what different approach, besides standard cytotoxic therapy, could be used to attack this aggressive, highly resistant form of cancer.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer

Bruns

Koehl

Guba

et al. 2004

Clinical Cancer Research

101

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Purpose: Despite current chemotherapies, pancreatic cancer remains an uncontrollable, rapidly progressive disease. Here, we tested an approach combining a recently described antiangiogenic drug, rapamycin, with standard gemcitabine cytotoxic therapy on human pancreatic tumor growth.Experimental Design: Tumor growth was assessed in rapamycin and gemcitabine-treated nude mice orthotopically injected with metastatic L3.6pl human pancreatic cancer cells. H&E staining was performed on tumors, along with Ki67 staining for cell proliferation and immunohistochemical terminal deoxynucleotidyl transferase-mediated nick end labeling and CD31 analysis. Rapamycin-treated tumor vessels were also directly examined in dorsal skin-fold chambers for blood flow after thrombosis induction. Cell death in human umbilical vein endothelial cells was assessed by flow cytometry after annexin-V staining.Results: Rapamycin therapy alone inhibited tumor growth and metastasis more than gemcitabine, with remarkable long-term tumor control when the drugs were combined. Mechanistically, H&E analysis revealed tumor vessel endothelium damage and thrombosis with rapamycin treatment. Indeed, dorsal skin-fold chamber analysis of rapamycin-treated tumors showed an increased susceptibility of tumor-specific vessels to thrombosis. Furthermore, terminal deoxynucleotidyl transferase-mediated nick end labeling/ CD31 double staining of orthotopic tumors demonstrated apoptotic endothelial cells with rapamycin treatment, which also occurred with human umbilical vein endothelial cells in vitro. In contrast, gemcitabine was not antiangiogenic and, despite its known cytotoxicity, did not reduce proliferation in orthotopic tumors; nevertheless, rapamycin did reduce tumor proliferation.Conclusions: Our data suggest a novel mechanism whereby rapamycin targets pancreatic tumor endothelium for destruction and thrombosis. We propose that rapamycin-based vascular targeting not only reduces tumor vascularization, it decreases the number of proliferating tumor cells to be destroyed by gemcitabine, thus introducing a new, clinically feasible strategy against pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer

Bruns

Koehl

Guba

et al. 2004

Clinical Cancer Research

101

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“…First of all, the ability to monitor objective responses to systemic therapy in patients with advanced pancreatic cancer, particularly at the primary pancreatic site, can be difficult using conventional methods such as computerised tomography. Measurement of objective response by formal RECIST criteria does not allow one to gauge accurately the true burden of disease due to the extensive desmoplasia and surrounding inflammation associated with pancreatic tumours and the inability to trace clearly defined tumour margins of the primary pancreatic lesion (Rothenberg et al, 1996). Furthermore, promising response rates in early trials do not uniformly translate into significant improvement in patient outcomes when investigated in phase III studies.…”

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confidence: 99%

Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer

et al. 2005

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The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixeddose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (475%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (Po0.001). Using specific thresholds, patients with X25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; Po0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.

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“…Nevertheless, recent studies have shown that chemotherapy can improve overall survival compared with no treatment, without impairing quality of life (AndrŽ et al, 1996;Glimelius et al, 1996;Rothenberg et al, 1996;Burris et al, 1997). Consequently, attempts to devise new chemotherapeutic regimens, with the aim of improving response rates and survival, are justified.…”

Section: Discussionmentioning

confidence: 99%

“…This can be due to the difficulty in properly quantifying objective response in this tumour, as discussed above. This being the case, the assessment of clinical benefit represents a new field of investigation in evaluating the activity and the role of chemotherapy in pancreatic cancer (Rothenberg et al, 1996). There is general acceptance that this new treatment end point needs to be explored in addition to classical end points (objective response and survival) in future chemotherapy trials in this disease.…”

Section: Discussionmentioning

confidence: 99%

Intensive weekly chemotherapy is not effective in advanced pancreatic cancer patients: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

Cascinu¹,

Frontini²,

Comella³

et al. 1999

Br J Cancer

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Twenty-two patients, with locally advanced unresectable and/or metastatic pancreatic carcinoma, received weekly administration of cisplatin 40 mg m −2 , 5-fluorouracil 500 mg m −2 , epidoxorubicin 35 mg m −2 , 6S stereoisomer of leucovorin 250 mg m −2 and glutathione 1.5 mg m −2 , supported by a daily administration of lenograstim at a dose of 5 μg kg −1 . Nineteen patients were men and three were women. Median age was 63 years (range 47–70). At study entry, pain was present in 15 out of 22 patients (68%) with a mean value of Scott–Huskisson scale of 27.6 ± 23.8, whereas a weight loss >10% was present in 15 patients. After eight weekly treatments, three partial responses were achieved for a response rate of 13% (95% CI 0–26%), five patients had stable disease and 14 progressed on therapy. Pain was present in 9 out of 22 patients (40%) with a mean value of Scott–Huskisson scale of 12.3 ± 18.4. Eight patients (36%) (three partial response and five stable disease) had a positive weight change. Toxicity was mild: WHO grade III or IV toxicity was recorded in terms of anaemia in 7 out of 188 cycles (3.7%), of neutropenia in 9 out of 188 cycles (4.7%) and of thrombocytopenia in 3 out of 188 cycles (1.5%). Median survival of all patients was 6 months. The outcome of this intensive chemotherapy regimen does not support its use in pancreatic cancer. © 1999 Cancer Research Campaign

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A rationale for expanding the endpoints for clinical trials in advanced pancreatic carcinoma

Cited by 32 publications

References 2 publications

Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer

Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer

Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer

Intensive weekly chemotherapy is not effective in advanced pancreatic cancer patients: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD)

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