Paraneoplastic Thrombocytosis Is a Significant Independent Prognostic Factor for Overall and Progression Free Survival in Locally Advanced Pancreatic Cancer

PurposeEffective treatment strategies for unresectable locally advanced pancreatic cancer (LAPC) patients are eagerly warranted. Recently, convincing oncological outcomes were demonstrated by carbon ion radiotherapy. Nevertheless, there is a lack of evidence for this modern radiation technique due to the limited number of carbon ion facilities worldwide. Here, we analyze feasibility and efficacy of carbon ion radiotherapy in the management of LAPC at Heidelberg Ion Beam Therapy Center (HIT).MethodsBetween 2015 and 2020, 21 LAPC patients were irradiated with carbon ions with a total dose of 48 Gy (RBE) in single doses of 4 Gy (RBE). Three patients (14%) were treated with concomitant chemotherapy with gemcitabine 300 mg/m2 body surface weekly. Toxicity rates were extracted from the charts. Overall survival, progression free survival, local control, and locoregional control were evaluated using Kaplan–Meier estimates.ResultsOne patient developed ascites CTCAE grade III during radiotherapy, which was related to a later histologically confirmed metachronous peritoneal carcinomatosis. No further higher-graded toxicity could be observed. The most common symptoms were nausea and abdominal pain. After a median estimated follow-up time of 19.1 months, the median progression free survival was 3.7 months, and the median overall survival was 11.9 months. The estimated 1-year local control and locoregional control rates were 89 and 84%, respectively.ConclusionCarbon ion radiotherapy of LAPC patients is safely feasible. Local tumor control rates were high. Nevertheless, compared to historical data, an overall survival improvement could not be observed. This could be explained by the poor prognosis of the selected underlying patients that mostly did not respond to prior chemotherapy as well as the early and frequent emergence of distant metastases that demonstrate the necessity of additional chemotherapy in further studies.

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Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer

Journal of Clinical Oncology ◽

10.1200/jco.19.00730 ◽

2019 ◽

Vol 37 (29) ◽

pp. 2643-2650 ◽

Cited By ~ 25

Author(s):

Kyle C. Cuneo ◽

Meredith A. Morgan ◽

Vaibhav Sahai ◽

Matthew J. Schipper ◽

Leslie A. Parsels ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Radiation Therapy ◽

Phase Ii ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Locally Advanced Pancreatic Cancer ◽

Free Survival ◽

Recommended Phase Ii Dose

PURPOSE AZD1775 (adavosertib) is an inhibitor of the Wee1 kinase. In this study, we built on our preclinical studies to evaluate the safety and efficacy of AZD1775 in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer. PATIENTS AND METHODS Thirty-four patients with locally advanced pancreatic cancer were enrolled with the intention to receive four 21-day cycles of gemcitabine (1,000 mg/m2 days 1 and 8) with AZD1775 (once daily on days 1, 2, 8, and 9). Cycles 2 and 3 were administered concurrently with radiation, and cycles 5 to 8 were optional. AZD1775 was dose escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation. Secondary objectives were to estimate overall and progression-free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues. RESULTS The recommended phase II dose of AZD1775 was 150 mg/d. Eight patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue. The median overall survival for all patients was 21.7 months (90% CI, 16.7 to 24.8 months), and the median progression-free survival was 9.4 months (90% CI, 8.0 to 9.9 months). Hair follicle biopsy samples demonstrated evidence of Wee1 inhibition with decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry after AZD1775 administration at the recommended phase II dose. CONCLUSION AZD1775 in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. The overall survival is substantially higher than prior results combining gemcitabine with radiation therapy and warrants additional investigation.

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Chemoradiotherapy (Gemox Plus Helical Tomotherapy) for Unresectable Locally Advanced Pancreatic Cancer: A Phase II Study

Cancers ◽

10.3390/cancers11050663 ◽

2019 ◽

Vol 11 (5) ◽

pp. 663 ◽

Cited By ~ 2

Author(s):

Alessandro Passardi ◽

Emanuela Scarpi ◽

Elisa Neri ◽

Elisabetta Parisi ◽

Giulia Ghigi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Locally Advanced Pancreatic Cancer ◽

R0 Resection ◽

Resection Rate ◽

Free Survival ◽

Moderate Nausea

The aim of the study was to evaluate the safety and efficacy of a new chemo-radiotherapy regimen for patients with locally advanced pancreatic cancer (LAPC). Patients were treated as follows: gemcitabine 1000 mg/m2 on day 1, and oxaliplatin 100 mg/m2 on day 2, every two weeks (GEMOX regimen) for 4 cycles, 15 days off, hypofractionated radiotherapy (35 Gy in 7 fractions in 9 consecutive days), 15 days off, 4 additional cycles of GEMOX, restaging. From April 2011 to August 2016, a total of 42 patients with non resectable LAPC were enrolled. Median age was 67 years (range 41–75). Radiotherapy was well tolerated and the most frequently encountered adverse events were mild to moderate nausea and vomiting, abdominal pain and fatigue. In total, 9 patients underwent surgical laparotomy (5 radical pancreatic resection 1 thermoablation and 3 explorative laparotomy), 1 patient became operable but refused surgery. The overall resectability rate was 25%, while the R0 resection rate was 12.5%. At a median follow-up of 50 months, the median progression-free survival and overall survival were 9.3 (95% CI 6.2–14.9) and 15.8 (95% CI 8.2–23.4) months, respectively. The results demonstrate the feasibility of a new chemo-radiotherapy regimen as a potential treatment for unresectable LAPC.

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Progression-free Survival After MWA Plus Durvalumab and Tremelimumab for Unresectable Locally Advanced Pancreatic Cancer

Case Medical Research ◽

10.31525/ct1-nct04156087 ◽

2019 ◽

Author(s):

Keyword(s):

Pancreatic Cancer ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Locally Advanced Pancreatic Cancer ◽

Free Survival

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The Survival Benefit of Chemoradiotherapy following Induction Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Unresectable Locally Advanced Pancreatic Cancer

Cancers ◽

10.3390/cancers13184733 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4733

Author(s):

Ryoji Takada ◽

Kenji Ikezawa ◽

Kazuma Daiku ◽

Shingo Maeda ◽

Yutaro Abe ◽

...

Keyword(s):

Pancreatic Cancer ◽

Induction Chemotherapy ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Locally Advanced Pancreatic Cancer ◽

R0 Resection ◽

Free Survival ◽

Promising Treatment ◽

Optimal Therapeutic Strategy

An optimal therapeutic strategy for unresectable locally advanced pancreatic cancer (UR-LAPC) has not been established. This study investigated the therapeutic efficacy of chemoradiotherapy (CRT) following induction chemotherapy with gemcitabine plus nab-paclitaxel (GnP) (CRT group) compared with systemic chemotherapy alone (CTx group) in patients with UR-LAPC. This was a retrospective study of 63 consecutive patients with UR-LAPC treated at our department in a Japanese cancer referral center between February 2015 and July 2018. We excluded patients who underwent other regimens and those enrolled in another prospective study. The CRT group (n = 25) exhibited significantly better progression-free survival (PFS) and overall survival (OS) than the CTx group (n = 20, PFS 17.9 vs. 7.6 months, p = 0.044; OS 29.2 vs. 17.4 months, p < 0.001). In the multivariate analyses, CRT following induction chemotherapy was identified as an independent prognostic factor for OS. Seven (15.6%) patients underwent conversion surgery, all of whom were in the CRT group. The R0 resection rate was 85.7% (6/7). In summary, patients with UR-LAPC experienced favorable treatment outcomes after receiving GnP as the first-line chemotherapy, especially when receiving additional CRT. Thus, this treatment strategy represents a promising treatment option for selected patients with UR-LAPC.

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Failure patterns and outcomes of dose escalation of stereotactic body radiotherapy for locally advanced pancreatic cancer: a multicenter cohort study

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920977155 ◽

2020 ◽

Vol 12 ◽

pp. 175883592097715

Author(s):

Xiaofei Zhu ◽

Yangsen Cao ◽

Tingshi Su ◽

Xixu Zhu ◽

Xiaoping Ju ◽

...

Keyword(s):

Pancreatic Cancer ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Locally Advanced Pancreatic Cancer ◽

Multicenter Cohort Study ◽

Failure Patterns ◽

Kaplan Meier ◽

Prescription Dose ◽

Contrast Ct

Objective: This study aims to compare recurrence patterns and outcomes of biologically effective dose (BED10, α/β = 10) of 60–70 Gy with those of a BED10 >70 Gy for locally advanced pancreatic cancer (LAPC). Methods: Patients from three centers with a biopsy and a radiographically proven LAPC were retrospectively included and data were prospectively collected from June 2012 to June 2019. Radiotherapy was delivered by stereotactic body radiation therapy. Recurrences were categorized as in-field, marginal, and outside-the-field recurrence. Patients in two groups were required to receive abdominal enhanced contrast CT or MRI every 2–3 months and CA19-9 examinations every month during follow-up. Treatment-related toxicities were evaluated every month. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Results: After propensity score matching, there were 486 patients in each group. The median prescription dose of the two groups was 37 Gy/5–8 f (range: 36–40.8 Gy/5–8 f) and 42 Gy/5–8 f (range: 40–49.6 Gy/5–8 f), respectively. The median OS of patients with a BED10 >70 Gy and a BED10 60–70 Gy was 20.3 months (95% CI: 19.1–21.5 months) and 18.2 months (95% CI: 17.8–18.6 months) respectively ( p < 0.001). The median PFS of the two cohorts was 15.4 months (95% CI: 14.2–16.6 months) and 13.3 months (95% CI: 12.9–13.7 months) respectively ( p < 0.001). A higher incidence of in-field and marginal recurrence was found in patients with BED10 of 60–70 Gy (in-field: 97/486 versus 72/486, p = 0.034; marginal: 109/486 versus 84/486, p = 0.044). However, more patients with BED10 >70 Gy had grade 2 or 3 acute (87/486 versus 64/486, p = 0.042) and late gastrointestinal toxicities (77/486 versus 55/486, p = 0.039) than those with BED10 of 60–70 Gy. Conclusion: BED10 >70 Gy was found to have the best survival benefits along with a higher incidence of acute and late gastrointestinal toxicities. Therefore, a higher dose may be required in the case of patients’ good tolerance.

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Randomized phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel combination therapy for locally advanced pancreatic cancer (JCOG1407).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4017 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4017-4017

Author(s):

Masato Ozaka ◽

Makoto Ueno ◽

Hiroshi Ishii ◽

Junki Mizusawa ◽

Hiroshi Katayama ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Primary Endpoint ◽

Response Rate ◽

Controlled Trial ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Locally Advanced Pancreatic Cancer ◽

Free Survival ◽

Randomized Phase Ii

4017 Background: FOLFIRINOX, consisting of leucovorin (LV), fluorouracil (FU), irinotecan (IRI) and oxaliplatin (L-OHP), and GnP, consisting of gemcitabine (GEM) plus nab-paclitaxel (nPTX), have shown superior efficacy over GEM in patients (pts) with metastatic pancreatic cancer. Although several studies have reported the efficacy of FOLFIRINOX or GnP for pts with locally advanced pancreatic cancer (LAPC), no randomized controlled trial to compare the two regimens has been conducted in those pts. To select the most promising chemotherapy for LAPC, a randomized phase II selection design trial (JCOG1407) was conducted to compare between modified FOLFIRINOX (FOLFIRINOX with dose reduction of IRI and without bolus FU; Arm A) and GnP (Arm B) for pts with LAPC. Methods: In Arm A, 85 mg/m2 of L-OHP, 200 mg/m2 of l-LV, 150 mg/m2 of IRI, followed by 2,400 mg/m2 of continuous FU over 46 hours are infused every 2 weeks. In Arm B, 125 mg/m2 of nPTX followed by 1,000 mg/m2 of GEM are infused on days 1, 8, and 15 every 4 weeks. The primary endpoint was overall survival (the proportion of 1-year OS), and secondary endpoints included progression-free survival (PFS), distant metastasis-free survival (MFS) and response rate in pts with target lesions. The planned sample size was 124 pts to select more effective regimen in 1-year OS with a probability of at least 0.85 and to test the null hypothesis of 53% in 1-year OS with a one-sided alpha of 5% and 80% Results: From 2015 to 2019, a total of 126 pts was enrolled from 29 Japanese institutions, and were allocated to Arm A (n = 62) or Arm B (n = 64). The median (range) age was 66 (44-75) years and 58.7% were male. At the analysis, after a median (range) follow-up of 1.52 (0.55-3.99) years, 75 (59.5%) pts died. The proportion of 1-year OS was better in Arm B, 77.4% [95% CI 64.9–86.0] vs. 82.5% [95% CI 70.7–89.9], but 2-year OS was better in Arm A, 48.2% [95% CI 33.3–61.7] vs. 39.7% [95% CI 28.6–52.5]. Median OS was 2.0 years [95% CI 1.6-2.7] in Arm A and 1.8 years [95% CI 1.5-2.0] in Arm B. 1-year PFS for Arm A/B was 47.5 % [95% CI 34.5-59.4]/40.2% [95% CI 27.8-52.3], and 1-year MFS was 64.2 % [95% CI 50.9-74.8]/57.3% [95% CI 43.9-68.6]. Arm A was better OS in pts with CA19-9 <1000 U/mL and the opposite trend was observed in pts with CA19-9>1000 U/mL. Response rate was 30.9% [95% CI 19.1-44.8] in Arm A, and 41.4% [95% CI 28.6-55.1]) in Arm B. Incidences of grade 3-4 non-hematological toxicities for Arm A and Arm B were 66.1% and 67.2%, respectively. There was no treatment-related death. Conclusions: This study was the first randomized trial comparing the two regimens. The 1-year OS of the primary endpoint in GnP was better than mFOLFIRINOX, but mFOLFIRINOX achieved longer survival in 2-year OS. It is required to confirm longer OS and safety profiles which regimen should be selected as a standard regimen in LAPC. Clinical trial information: jRCTs031180085.

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Comparison of concurrent chemoradiotherapy and chemotherapy alone for locally advanced pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.351 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 351-351 ◽

Cited By ~ 1

Author(s):

Younak Choi ◽

Tae-Yong Kim ◽

Do-Youn Oh ◽

Kyubo Kim ◽

Eui Kyu Chie ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Outcomes ◽

Palliative Chemotherapy ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Positive Lymph Node ◽

Locally Advanced Pancreatic Cancer ◽

Hematologic Toxicity

351 Background: The optimal treatment strategy for locally advanced pancreatic cancer (LAPC), especially the role of chemoradiotherapy (CCRT), is still in debate. We compared the clinical outcomes of CCRT and palliative chemotherapy alone (CA) in patients with LAPC. Methods: We consecutively enrolled LAPC patients treated between 2003 and 2010. AJCC 7th edition was followed for the diagnostic criteria of LAPC. We retrospectively evaluated the clinical outcomes according to treatment groups (CCRT vs CA). Results: A total of 86 patients were enrolled. Median age was 60 years. ECOG PS was 0-1 in 77 (89.5%) and 2 in 9 (10.5%). Forty five patients (52.3%) were treated with CCRT and 41 patients (47.7%) with CA. Baseline characteristics were not significantly different between CCRT and CA group. In the CCRT group, gemcitabine (n=7, 15.6%), 5-FU (n=10, 22.2%), and capecitabine (n=28, 62.2%) were concurrently used with radiation. Radiation was delivered with 55.8Gy/ 31fraction. All of the CA group patients were treated with gemcitabine-based chemotherapy. Median progression free survival (PFS) and overall survival (OS) of whole patients were 6.9 months [95%CI 4.8-9.0] and 12.7 months [95%CI 11.6-14.3]. PFS and OS of CCRT versus CA was 8.9 months [95%CI 6.8-11.0] vs 3.7 months [95%CI 2.9-4.5] (p<0.001) and 15.8 months [95%CI 13.5-18.1] vs 11.3 months [95%CI 9.3-13.3] (p=0.017). In multivariate analysis, tumor size (≥3cm), positive lymph node, elevated CA 19-9, decreased serum albumin and CCRT was significant for PFS and OS (adjusted hazard ratio of CCRT was 0.424 (p=0.002) in PFS and 0.472 (p=0.014) in OS). Grade 3-4 hematologic toxicity was less frequent during CCRT period (p=0.002). Conclusions: In LAPC, patients who received CCRT show better OS and PFS compared with patients who were treated with palliative chemotherapy alone. It’s worthy to further study the role of CCRT in LAPC.

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Effect of neoantigen reactive T cells combined with chemotherapy and radiation on survival in advanced pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15756 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15756-e15756

Author(s):

Qin Liu ◽

Zhengyun Zou ◽

Baorui Liu ◽

Weiwei Kong ◽

Fangjun Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Cytotoxic T Lymphocyte ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Standard Regimen ◽

Free Survival ◽

Therapeutic Modalities ◽

Lymphocyte Transfer

e15756 Background: Pancreatic cancer (PC) is one of the most aggressive and death-relating malignancy. Gemcitabine (GEM) is the key agent in the first-line standard regimen for advanced PC, which is mostly diagnosed at advanced stage and unsuitable for curative resection. The objective responsive rate (ORR) and medium progression free survival (PFS) of various GEM-based regimens are still unsatisfied. Therefore, development of new therapeutic modalities, including immunotherapy, is needed. This study is to investigate the efficacy, safety and clinical beneficial of combination neoantigen based immunotherapy with GEM and radiotherapy in locally advanced and metastatic PC patients. Methods: Three locally advanced unresectable and seven metastatic PC patients received at least two cycles of GEM (1000mg/m2 on day 1 and day 6), radiotherapy combing with neoantigen induced DC vaccination on day 7 and cytotoxic T lymphocyte transfer from day 12 to 15 (repeated every 21 days). The locally advanced unresectable PC patients received stereotactic body radiotherapy (SBRT) with a total amount of 50-66Gy during the first cycle. For metastatic patients, their partial lesions received a low dose radiation (0.5Gy bid*2days ) on day 10 and 11 in each cycle. Results: Two cases were observed with partial remission (PR), five with stable disease (sd), and three with progressive disease (PD). The disease control rate (DCR) was 70%. Median progression free survival (PFS) was 6.4 months. After the first treatment cycle, the total effectiveness for pain easement and increasing appetite are 100% (8/8)and 66.7%, respectively. Haematotoxicities with a 40% incidence rate were the most common adverse drug reactions. Two patients had grade 1 to 2 neutropenia, two with grade 3 to 4 thrombocytopenia. Three patients suffered grade 1 to 2 gemcitabine-induced skin rash. No treatment-related mortality occurred. Conclusions: Neoantigen reactive T cells combined chemoradiotherapy demonstrated an acceptable response and safety in advanced pancreatic cancer patients.

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