Personalised therapy in pancreatic carcinoma - a forthcoming opportunity?

There are indications of the possible effects of sex hormones on pancreatic carcinoma. Estrogen receptor (ER) has been demonstrated in pancreatic tumors in experimental animals and in humans and it has been suggested that endocrine manipulation may be effective in the treatment of pancreatic carcinoma. However, it is still controversial whether this lethal cancer can potentially benefit from endocrine therapy. One explanation for the conflicting data on the benefit of hormonal manipulation in the treatment of pancreatic carcinoma may stem from the fact that there is no adequate marker to assess estrogen dependency of the pancreatic tumors. In this article, we review our work on tissue plasminogen activator as a prognostic guide to evaluate the efficacy of hormonal therapy in human pancreatic carcinoma, and also suggest that a selected subgroup of patients with this lethal cancer may have a potential clinical benefit from endocrine therapy, especially medroxyprogesterone acetate treatment.

4086 Background: Progress in the management of PC is desperately needed. Non-gemcitabine based regimens are understudied. IXA has demonstrated activity in preclinical PC models including synergistic activity in combination with C. In a phase II cooperative group study in chemo-naïve PC patients (pts) IXA showed promising efficacy. Here we present the results of a phase II, open label trial of IXA plus C as first line therapy for metastatic PC. Methods: Previously untreated pts (KPS 70–100) witheither locallyadvanced (LA) or metastatic (M) PC, were treated with IXA (32 mg/m2) IV over 3h on day 1 every 3 weeks and C, 400 mg/m2 IV (day 1) followed by weekly 250 mg/m2 doses. Pts were treated to progression or unacceptable toxicity. The primary endpoint was six month survival rate. The study tested the null hypothesis that the true 6-month rate ≤ 50% versus the alternative that the true rate > 70%. Results: Fifty-four pts (male/female 35/19; median age 63, range 47–84; LA/M 4/50) were enrolled in the study. A median of 4 cycles (range 1–21) were administered. All enrolled pts were evaluable for toxicity and survival endpoints and 31 pts were evaluable for response. The primary endpoint of 6-month survival rate was 62% (95% CI 49–75). The 95% CI for this 6 month rate did not exclude a prespecified hurdle of 50%. Median overall survival was 7.6 months (95% CI 5.5–12.2) and the 12-month survival rate was 40% (95% CI 26.91–53.75). Objective response rate was 13% (4 PRs), 77% SD, and 6% PD. Median progression free survival was 3.9 months (95% CI 2.6–4.4). Severe neutropenia was observed in 34% of treated patients (grade 3 in 20%; grade 4 in 16%). grade 3/4 febrile neutropenia occurred in 2 (4%) patients. The most frequent nonhematologic grade 3/4 toxicities were fatigue (19%), hypomagnesemia (8%), diarrhea (6%), hypersensitivity reactions (6%), peripheral neuropathy (6%) and acneiform rash (2%). Conclusions: IXA plus C is a feasible and active regimen with an acceptable toxicity profile in chemotherapy naïve PC pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb

Pancreatic carcinoma causes more than 20,000 deaths every year in Japan. The role of (neo-) adjuvant chemotherapy for pancreatic carcinoma is still controversial. At the 34th Annual Meeting of the Japanese Society of Pancreatic Surgery in 2007, questionnaires were distributed regarding the use of (neo-) adjuvant chemo(radio)therapy for pancreatic carcinoma between 2001 and 2005. Sixty of the 146 member institutions responded to the questionnaires. There were a total of 1,846 cases of resected pancreatic carcinoma between 2001 and 2005. The study population had a greater proportion of males, and a mean age of 65.3 years (range 34-90 years). The lesion was located in the head of the pancreas in 1,204 cases (71.7%), in the body in 353 cases (21.0%), and in the tail in 111 cases (6.6%). Overall survival rates were 67.3% at 1 year, 36.0% at 2 years, and 23.9% at 3 years, respectively. Adjuvant chemotherapy (usually involving gemcitabine) was used in 66.0% of cases. The use of adjuvant chemotherapy was found to improve the overall survival rate. Interestingly, adjuvant chemotherapy only improved survival in late-stage (UICC stages IIB, III, and IV) but not early stage (IA, IB, and IIA) patients. Survival was treatment duration-dependent, with patients who received more than 12 months of therapy having a 3-year survival rate of 51.2%. This high volume retrospective data indicated the promising effect of gemcitabine-based adjuvant chemotherapy and the rational duration of adjuvant chemotherapy should be determined in the future prospective studies.

Pancreatic carcinoma (PC) has one of the highest rates of cancer-related death worldwide. Except for surgery, adjuvant chemotherapy, chemoradiotherapy, and immunotherapy have shown various efficacies depending on the stage of the patient. We read the review “Current and emerging therapeutic strategies in pancreatic cancer: Challenges and opportunities” and offer some opinions that may improve its precision and completeness. This review presents a map of appropriate therapies for PC at different stages. Based on the clinical trial outcomes mentioned in the review, we evaluated the potential therapeutic options for PC and helped explain the contradictory efficacy between different programmed cell death protein 1/programmed cell death ligand 1 clinical trials, which may have resulted from the unique features of PC. Although R0 resection and adjuvant chemotherapy are still the gold standards for PC, new modalities, with or without clinical validation, are needed to establish more specific and precise treatments for PC.

Novel therapeutic approaches in the treatment of advanced pancreatic carcinoma

Pathological assessment of tumour regression following neoadjuvant therapy in pancreatic carcinoma

BACKGROUND Recent studies have demonstrated that various tumors express enhanced levels of the radical scavenger glutathione (GSH). Moreover, there are grounds for claiming that GSH plays a crucial role in cell proliferation and tumor resistance. In the current study, we investigated the relation between cell growth and GSH levels in the pancreatic adenocarcinoma cell line, AsPC-1, and the significance of GSH in tumor resistance to chemotherapy. METHODS Cell growth in AsPC-1 was initiated through transforming growth factor-alpha (TGF-α) or fetal calf serum (FCS). Then, cell cycle, cell proliferation, and cellular GSH content were analyzed at different times in the presence or absence of buthionine sulfoximine (BSO). The impact of GSH on chemotherapy-induced apoptosis was studied using 5-fluorouracil or melphalan in the presence or absence of BSO. Finally, we compared the GSH content of 15 pancreatic tumor specimens with 10 normal pancreatic tissue specimens. RESULTS Analysis of GSH in pancreatic tissues demonstrated increased GSH levels in cancerous compared with normal tissue (17.5 ± 2.3 vs. 8.8 ± 1.4 nmol/mg protein; P < 0.004). Incubation of AsPC-1 with TGF-α or FCS resulted in cell proliferation and cell cycle activity, whereas GSH content was not altered. Incubation of GSH-depleted cells with TGF-α did not stimulate cell growth. In addition, GSH-depletion resulted in an increased rate of apoptosis after melphalan (6.3 ± 0.3 % vs. 11.2 ± 0.3 %; P < 0.001), but not after 5-fluorouracil treatment. CONCLUSIONS Taken together, our results show enhanced GSH levels in pancreatic carcinoma and an essential role of GSH in cell proliferation and in resistance of AsPC-1 cells. Therefore, GSH-depletion may improve the effectivity of adjuvant therapy in pancreatic carcinoma. Cancer 2000;89:1440–7. © 2000 American Cancer Society.

Pancreatic carcinoma is clearly a disease that “gives cancer a bad name.” In general, it is refractory to single modality therapy using surgery radiation therapy, or chemotherapy. While only 10-15% of patients present with resectable disease, approximately 50% of patients with pancreatic carcinoma have only locoregional disease (non-resectable) at diagnosis. For these patients without distant metastases, some recent studies employing combined modality therapy show some promise for improving local control and possibly survival in this devastating disease.

Recent studies have demonstrated that various tumors express enhanced levels of the radical scavenger glutathione (GSH). Moreover, there are grounds for claiming that GSH plays a crucial role in cell proliferation and tumor resistance. In the current study, we investigated the relation between cell growth and GSH levels in the pancreatic adenocarcinoma cell line, AsPC-1, and the significance of GSH in tumor resistance to chemotherapy. Cell growth in AsPC-1 was initiated through transforming growth factor-alpha (TGF-alpha) or fetal calf serum (FCS). Then, cell cycle, cell proliferation, and cellular GSH content were analyzed at different times in the presence or absence of buthionine sulfoximine (BSO). The impact of GSH on chemotherapy-induced apoptosis was studied using 5-fluorouracil or melphalan in the presence or absence of BSO. Finally, we compared the GSH content of 15 pancreatic tumor specimens with 10 normal pancreatic tissue specimens. Analysis of GSH in pancreatic tissues demonstrated increased GSH levels in cancerous compared with normal tissue (17.5 +/- 2.3 vs. 8. 8 +/- 1.4 nmol/mg protein; P < 0.004). Incubation of AsPC-1 with TGF-alpha or FCS resulted in cell proliferation and cell cycle activity, whereas GSH content was not altered. Incubation of GSH-depleted cells with TGF-alpha did not stimulate cell growth. In addition, GSH-depletion resulted in an increased rate of apoptosis after melphalan (6.3 +/- 0.3 % vs. 11.2 +/- 0.3 %; P < 0.001), but not after 5-fluorouracil treatment. Taken together, our results show enhanced GSH levels in pancreatic carcinoma and an essential role of GSH in cell proliferation and in resistance of AsPC-1 cells. Therefore, GSH-depletion may improve the efficacy of adjuvant therapy in pancreatic carcinoma.

14150 Background: A literature search shows only one published case report utilizing the combination of thalidomide and capecitabine as second-line therapy in adenocarcinoma of the pancreas. We report two patients with pancreatic carcinoma treated as second-line therapy with this combination. Methods: CASE #1: Fifty five-year-old female with metastatic pancreatic carcinoma demonstrated clear evidence of progression after 8 months of treatment with gemcitabine At this time, she was started on thalidomide 50 mg at bedtime every other night with capecitabine 1500 mg p.o. b.i.d. for two weeks with one week off. After eight weeks of this regimen, the patient had clinical response with a decrease in abdominal pain, improvement in performance status, and a decrease in her CA 19–9 from 1154 units/mL to 101 units/mL. With this treatment the patient was fully ambulatory and without symptoms for 7 months. CASE #2: The patient is 55-year-old male treated with adjuvant radiation therapy and chemotherapy after surgical resection of his adenocarcinoma of the pancreas. Eight months later, he developed hepatic metastasis and was treated with gemcitabine with progression of disease on that agent. Palliative treatment with capecitabine 1500 mg p.o. b.i.d. for two weeks and one week off was instituted with thalidomide 50 mg at bedtime every other day. After four months of this regimen, the patient had a clinical response with no abdominal pain and decrease in his CA 19–9 from 4647 units/mL to 55 units/mL. Ten months after initiation this regimen patient is asymptomatic, working full time and continues to take thalidomide and capecitabine. Conclusions: Response to second line therapy in adenocarcionoma of pancreas is rare. We are reporting two cases of second-line therapy of adenocarcinoma of the pancreas treated with the combination of thalidomide and capecitabine. Decline in CA 19–9, duration of response, and improvement in functional patient status were unexpected findings. Use of combination of capecitabine and thalidomide in the treatment of the pancreatic adenocarcinoma should be evaluated further in clinical trials. No significant financial relationships to disclose.

PurposeTo appraise the ability of a radiomics signature to predict clinical outcome after stereotactic body radiation therapy (SBRT) for pancreas carcinoma.MethodsA cohort of 100 patients was included in this retrospective, single institution analysis. Radiomics texture features were extracted from computed tomography (CT) images obtained for the clinical target volume. The cohort of patients was randomly divided into two separate groups for the training (60 patients) and validation (40 patients). Cox regression models were built to predict overall survival and local control. The significant predictors at univariate analysis were included in a multivariate model. The quality of the models was appraised by means of area under the curve and concordance index.ResultsA clinical-radiomic signature associated with Overall Survival (OS) was found significant in both training and validation sets (p = 0.01 and 0.05 and concordance index 0.73 and 0.75 respectively). Similarly, a signature was found for Local Control (LC) with p = 0.007 and 0.004 and concordance index 0.69 and 0.75. In the low risk group, the median OS and LC in the validation group were 14.4 and 28.6 months while in the high-risk group were 9.0 and 17.5 months respectively.ConclusionA CT based radiomic signature was identified which correlate with OS and LC after SBRT and allowed to identify low and high-risk groups of patients.

To compare the radiogenic effects on microcirculation in healthy and malignant pancreatic tissue. Vascular injury is an important effect of radiotherapy, which has been suggested for antiangiogenic tumor therapy. An established model of duct-like pancreatic cancer (DSL6A) was used. Investigation was performed in 12 healthy and 24 tumor-bearing Lewis rats. The tumors were locally irradiated with 15 Gy in 12 animals 4 weeks after intraperitoneal inoculation. Additionally, local radiation of the normal pancreas was performed in six healthy animals. Intravital microscopy of tumor and normal pancreatic microcirculation was performed 5 days after radiation. Relevant parameters were erythrocyte velocity and functional vessel density. Tumor apoptosis and the fraction of vital tumor cells were estimated histologically 5 and 12 days after radiation. Local radiation with 15 Gy caused a pronounced impairment of blood flow and functional capillary density in the normal pancreas 5 days after radiation, while the tumor blood flow was not significantly changed. A significant reduction in the fraction of vital tumor cells and a significant increase in tumor apoptosis were observed 12 days after radiation. Local radiation impairs blood flow in healthy pancreas but not in pancreatic cancer tissue. Tumor cell death is the leading consequence of radiation injury in malignant pancreatic tissue without affecting the vascular system of the tumor. The authors conclude that external beam radiation does not appear to be a useful adjunct for a vascular-targeted therapy in pancreatic carcinoma but causes distinct hypoperfusion in the healthy pancreas.

Improved treatment of pancreatic cancer by IL-12 and B7.1 costimulation: antitumor efficacy and immunoregulation in a nonimmunogenic tumor model.

Immunotherapy and antineoplastic therapy in pancreatic carcinoma

Therapeutic modalities for incompletely resected pancreatic carcinoma are rare. Effective treatment must not only prolong the period of palliation but also limit the adverse sequelae of the Whipple procedure so as not to compromise the quality of the remaining life span. New treatments include the use of gemcitabine and type I interferons. We treated a patient with incomplete resection of a pancreatic tumor with two cycles of gemcitabine (1000 mg/m2) and cisplatinum (50 mg/m2) followed by radiotherapy (45 Gy/5 weeks) combined with interferon-beta (three times a week/5 x 10(6) IU). Two small liver metastases occurred subsequently. In all, four cycles of gemcitabine/cisplatinum were delivered. The patient lived at least 9 months with stable metastatic liver disease and local control. He had no acute toxic reactions except for a decrease in the leukocyte count, no long-term side effects, and a satisfactory quality of life. A regimen of sequential gemcitabine/cisplatinum and radiotherapy in combination with interferon-beta deserves further consideration as therapy for pancreatic carcinoma.