# Radiation Oncology/Pancreas/Unresectable

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Unresectable Pancreatic Cancer

## Epidemiology

* 30-40% are locally advanced, unresectable (30-40% are metastatic, 15-20% resectable)

## Treatment Overview

Gem alone dose is 1000mg/m2. Gem dose is reduced to 300-600mg/m2 concurrently with RT. 5FU dose is 250mg/m2.
Capecitabine dose is 825mg/m2 bid M - F concurrent with RT (rtog 0848).
* Median survival for untreated patients is ~4 months, and ~7 months with palliative bypass
* EBRT alone had survival ~6 months in 1960's.
* A randomized trial from Mayo Clinic in unresectable GI tumors (Moertel, 1969) showed that combined chemo-RT is superior to RT alone
* GITSG 9273 confirmed that chemo-RT is superior over RT alone. The outcome of chemo-RT 40/20 split-course was comparable to chemo-RT 60/30 split-course
* GITSG 9283 then compared RT + 5-FU to SMF chemotherapy alone and determined chemoRT was superior to chemo alone.
* Conversely, ECOG trial published around the same time compared 5-FU alone to 5-FU + RT and found no benefit for addition of RT, with more toxicity
* In the US, concurrent 5-FU and RT became standard of care
* Gemcitabine became treatment of choice in metastatic pancreatic cancer, and efforts are made to evaluate its role in unresectable locally advanced disease
* A Taiwan trial showed that gemcitabine + RT is superior to 5-FU + RT, with comparable toxicity
* A French trial was closed prematurely, after 5-FU + RT arm had significantly worse survival compared with gemcitabine alone. Median OS of the chemo-RT arm was comparable to the original GITSG data, despite modern RT and infusional 5-FU
* An ECOG trial (published thus far as abstract), showed that gemcitabine + RT may be superior to gemcitabine alone; however, the trial closed early due to nonaccrual
* At the moment (12/2008), it is not entirely clear what the best strategy is for unresectable patients
* A reasonable strategy may be that proposed by MDACC (see below) of using induction chemotherapy to exclude patients with rapid distant progression, and select patients who benefit from local consolidative chemo-RT

## Palliative bypass

Median survival is 4 months for untreated patient, 7 months with palliative bypass (gastric or biliary), and 16 months with a Whipple procedure.

## RT +/- Chemotherapy

* ECOG E8282 -- RT alone vs. RT + 5-FU + Mitomycin-C
** Randomized. 114 patients with locally advanced adenocarcinoma of the pancreas. Arm 1) EBRT 59.4 Gy vs. Arm 2) Same EBRT + concurrent 5-FU (1,000 mg/m$^2$/day by continuous infusion on Days 2-5 and 28-31) and MMC (10 mg/m$^2$ on Day 2)
** 2005 PMID 16029791 -- "A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282." (Cohen SJ, Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1345-50.)
*** Outcome: Response rate RT alone 6% vs. chemo-RT 9%; DFS 5 months vs. 5.1 months (p=0.19); OS 7.1 months vs 8.4 months (p=0.16)
*** Conclusion: Addition of 5-FU and MMC increased toxicity without improving DFS or OS. Alternative drugs for radiosensitization may improve outcome.
* GITSG 9273 (1970's) -- RT 60 Gy vs. RT 40 Gy + 5-FU vs. RT 60 Gy + 5-FU
** Randomized, 3 arms. 194 patients with locally unresectable pancreatic CA. Arm 1) RT alone 60/30 Gy split course (On interim analysis found inferior and was discontinued) vs. Arm 2) RT 40/20 Gy split course + concurrent 5-FU vs. Arm 3) RT 60/30 Gy split course + concurrent 5-FU. Concurrent 5-FU 500 mg/m2, followed by maintenance 5-FU 500 mg/m2 x2 years
** 1981 PMID 7284971 "Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group," Moertel CG et al. Cancer. 1981 Oct 15;48(8):1705-10.
*** Outcome: DFS RT-60 2.9 months vs. C-RT-40 7.0 months vs. C-RT 60 7.6 months (SS); median OS 5.3 months vs. 9.7 months vs. 9.3 months (SS); 1-year OS 10% vs. 35% vs. 46%
*** Toxicity: No severe GI toxicity >10%
*** Conclusion: Concurrent chemo-RT superior to RT alone; C-RT 40 Gy comparable to C-RT 60 Gy
* Mayo Clinic (1960's) -- RT alone vs. RT + 5-FU
** Randomized. 64 patients with unresectable cancers of the stomach, pancreas, and large bowel. Arm 1) EBRT 35-37.5 Gy vs. Arm 2) Same EBRT + concurrent 5-FU bolus 45 mg/kg
** 1969 PMID 4186452 -- "Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer." (Moertel CG, Lancet. 1969 Oct 25;2(7626):865-7.)
*** Outcome: median OS RT alone 6.3 months vs. chemo-RT 10.4 months (SS); 1-year OS 6% vs. 22%
*** Conclusion: Concurrent chemo-RT significantly augments RT alone

## Choice of Concurrent Chemotherapy

Randomized Trials
* PACT -- 5-FU + RT +/- TNFerade
** Randomized. 330 patients with locally advanced pancreatic CA. Treated with 1) TNFerade (adenoviral vector carrying TNF-a regulated by radiation-inducible promoter Egr-1) + C.I. 5-FU 200 mg/m2/d + RT 50.4 Gy vs 2) 5-FU + RT, randomized 2:1
** 2007 ASCO Abstract -- "Multi-center phase II/III randomized controlled clinical trial using TNFerade combined with chemoradiation in patients with locally advanced pancreatic cancer (LAPC)." (Posner M, Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4518)
*** First 50 patients assessed for response. 1-year OS (primary endpoint): 71% vs. 28%; median OS 1.4 years vs. 0.9 years
*** Conclusion: Preliminary data encouraging
** 2010 -- "GenVec Press Release - GenVec discontinues Phase 3 Clinical Trial Of TNFerade"
*** Interim analysis indicated that PACT trial did not provide sufficient evidence of the clinical effectiveness of TNFerade to warrant completion of the trial.
* Taipei (1998-2001) -- 5-FU + RT vs. GEM + RT
** Randomized. 34 patients. Unresectable pancreatic CA. Arm 1) 5-FU 500 mg/m2 + RT vs. Arm 2) Gemcitabine 600 mg/m2 + RT. RT 50.4 - 61.2 Gy @ 1.8 Gy/fx. All patients received maintenance GEM 1000 mg/m2 thereafter
** 2003 PMID 12909221 "Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study." (Li CP, Int J Radiat Oncol Biol Phys. 2003 Sep 1;57(1):98-104.)
*** Outcome: median OS 5-FU 7 months vs. GEM 14 months (SS). 1-year OS 31% vs. 56%. 2-year OS 0% vs. 15%. Also improvement in pain control, performance status, and QoL
*** Toxicity: No difference
*** Conclusion: Gemcitabine + RT more effective than 5-FU + RT, comparable tolerability
** Comment: Small size, poor outcome in control group
* GITSG 9277 (1980's) -- RT + 5-FU vs. RT + adriamycin
** Randomized. 143 patients with locally unresectable pancreatic CA, surgically staged. Arm 1) RT 60/30 split course + concurrent 5-FU bolus 500 mg/m2 + maintenance 5-FU vs Arm 2) RT 40/20 continuous course + concurrent adriamycin 10 mg/m2 + maintenance adriamycin x5 courses + maintenance 5-FU
** 1985 PMID 2864997 "Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group," ([No Authors Listed], Cancer. 1985 Dec 1;56(11):2563-8.)
*** Outcome: Median OS 5-FU 8.5 months vs. adriamycin 7.6 months (NS). Initial recurrence LRR 5-FU 58% vs. adriamycin 51%
*** Toxicity: 5-FU 36% vs. adriamycin 53% (SS)
*** Conclusion: No difference in outcome, but adriamycin significantly more toxic
Non-Randomized
* RTOG 98-12 PMID 14758134 - "Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12." Rich T, Am J Clin Oncol. 2004 Feb;27(1):51-6.
** 122 patients w/ unresectable pancreatic CA by imaging criteria tx'd w/ weekly Taxol + XRT (50.4 Gy) for unresectable pancreatic cancer.
** 26% PR, 6% CR, 43% 1yr OS, 13% 2yr OS. 40% grade 3 toxicity, 5% grade 4
** Conclusion: tolerable regimen w/ outcomes that appear better than historical data w/ concurrent 5FU
* Michigan; 2001 - PMID 11709563 "Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer." McGinn CJ et al. J Clin Oncol. 2001 Nov 15;19(22):4202-8.
** 37 pts w/ unresectable or incompletely resected pancreatic CA tx'd w/ full dose gemcitabine and xrt.
** Dose escalation of fraction size, keeping duration of xrt at 3 wks. 2/6 pts experienced dose limiting toxicity at 42 Gy (2.8 Gy fractions) (grade 4 vomiting and grade 4 gastric/duodenal ulceration)
* M.D. Anderson; 2000 (1996-2000) - PMID 11955742 — "Is the therapeutic index better with gemcitabine-based chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer?" Crane CH et al. Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1293-302.
** Retrospective. 114 pts with localized unresectable dz. Treated with chemo/RT (median RT dose 30 Gy in 10 fx). Compared pts treated with weekly gemcitabine vs C.I. 5-FU.
** No difference in OS, LR, or DM. Higher toxicity rate with gemcitabine.

## Chemo-RT vs. Chemo Alone

* LAP07 -- 1) Randomize: induction chemo (4 mo) gemcitabine vs. gemcitabine + erlotinib. 2) 2nd randomization: 2 additional months of the same chemo vs chemo/RT (54 Gy, capecitabine)
** 449 pts. Locally advanced. 4 mo induction chemo. 2nd randomization for non-progressing pts: 2 months of same chemo vs chemo/RT (54 Gy plus capecitabine).
** 2016 PMID 27139057 -- "Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib. The LAP07 Randomized Clinical Trial" (Hammel P, JAMA. 2016 May 3;315(17):1844-53.)
*** Conclusion: "There was no significant difference in overall survival with chemoradiotherapy compared with chemotherapy alone and there was no significant difference in overall survival with gemcitabine compared with gemcitabine plus erlotinib used as maintenance therapy."
* ECOG E4201 (2003-2005) -- gemcitabine vs. gemcitabine + RT
** Randomized. Closed early due to slow accrual. 69 of planned 316 patients with unresectable disease. Arm 1) Gemcitabine alone 1000 mg/m2 x7 cycles vs. Arm 2) RT 50.4/28 + gemcitabine 600 mg/m2, then gemcitabine alone 1000 mg/m2 x5 cycles
** 2011 PMID 21969502 --"Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial." (Loehrer PJ, J Clin Oncol 29:4105-4112, 2011)
*** Outcome: PFS GEM 6.7 months vs. GEM/RT 6.0 months (NS). Median OS 9.2 months vs. 11.1 months (SS)
*** Toxicity: Grade 4 or 5 GEM 9% vs. GEM/RT 41% (SS) (1 grade 5 toxicity in each arm)
*** Conclusion: Gem+RT had increased but generally manageable toxicity, with improved OS
** Editorial PMID 21969514 (Philip PA, JCO 29:4066-4068, 2011) Moderate OS benefit with small patient number (wide CI) and no PFS benefit. In future, need consensus on clinical trial priorities and better systemic therapy.
* FFCD-SFRO (2000-2005) -- RT + 5-FU vs. gemcitabine alone
** Randomized. Stopped prematurely due to worse survival in Chemo-RT arm. 119 patients with unresectable pancreatic CA. Arm 1) 3D-RT 60/30 + concurrent 5-FU C.I. 300 mg/m2 + cisplatin 20 mg/m2 vs Arm 2) Gemcitabine 1000 mg/m2 alone x7 weeks. Both arms then maintenance Gemcitabine 1000 mg/m2 until disease progression/toxicity. RT technique: GTV = tumor + probably involved LNs. CTV = tumor + peripancreatic, celiac, and hepatic hilar LNs. PTV = CTV + 2cm. Only 42% of Chemo-RT group received at least 75% of planned RT and CT (though 83% received at least 75% of RT); 73% of GEM group received at least 75% of CT
** 2008 PMID 18467316 -- "Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study." (Chauffert B, Ann Oncol. 2008 May 7. [Epub ahead of print])
*** Outcome: median OS Chemo-RT 8.6 months vs. GEM 13 months (SS); 1-year OS 32% vs. 53%. Median OS in Chemo-RT patients who received >75% of planned dose still only 9.5 months
*** Toxicity: higher in Chemo-RT arm 36% vs. GEM 22% (SS)
*** Conclusion: RT/5-FU is more toxic and less effective than Gemcitabine alone. May be due to dose intensity
* GITSG 9283 (1980's) -- Chemo-RT vs. SMF (Streptozocin, mytomycin, 5-FU)
** Randomized. 43 patients with locally unresectable pancreatic CA. Arm 1) Streptozocin + mitomycin + 5FU (SMF) vs Arm 2) RT 54 Gy + concurrent 5FU, followed by SMF.
** 1988 PMID 2898536 "Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group," ([No Authors Listed], J Natl Cancer Inst. 1988 Jul 20;80(10):751-5.)
*** Outcome: median OS Chemo-RT 9.7 months vs. SMF alone 7.4 months (SS); 1-year OS 41% vs. 19% (SS)
*** Conclusion: Combined chemo-RT superior to SMF chemotherapy alone
* ECOG (1980's) -- 5-FU alone vs. 5-FU + concurrent RT
** Randomized. 148/191 patients with locally unresectable adenoCA of stomach (n=57) or pancreas (n=91). Arm 1) 5-FU 600 mg/m2 alone vs. Arm 2) RT 40/20 + concurrent 5-FU bolus 600 mg/m2 + adjuvant 5-FU 600 gm/m2
** 1985 PMID 3973648 -- "Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study." (Klaassen DJ, J Clin Oncol. 1985 Mar;3(3):373-8.)
*** Outcome: median OS 5-FU 6.5 months vs. chemo-RT 5.1 months (NS); pancreas subgroup 8.2 months vs. 8.3 months (NS)
*** Toxicity: 5-FU alone 27% vs. chemo-RT 51% (SS)
*** Conclusion: Adding RT to 5-FU didn't improve survival, and was more toxic

## Induction Chemotherapy + Chemo-RT

* MD Anderson; 2007 (1993-2005) PMID 17538975 -- "Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy." (Krishnan S, Cancer. 2007 Jul 1;110(1):47-55.)
** Retrospective. 323 patients locally advanced. 247 patients with initial chemo-RT (concurrent 5-FU or GEM), 76 patients induction GEM followed by RT 30/10 concurrent with chemo (5-FU, GEM, or capecitabine). RT 4 field; originally ENI (69%) but since 2001 primary tumor only (31%) to reduce toxicity. Median F/U 5 months
** Outcome: Median OS CRT group 8 months vs. induction-CRT group 12 months (SS). Median time to local progression 6 months vs. 9 months (SS). No difference in patterns of failure
** Conclusion: Induction chemo (2-3 months) may select patients who may optimally benefit from consolidative chemo-RT, by identifying patients who already have micrometastatic disease

## RT Technique
### Dose
#### Hypofractionated RT

With Concurrent Chemotherapy:
* UT-San Antonio; 2005 (1993-2001) PMID 15923793 -- "Radiation dose considerations in the palliative treatment of locally advanced adenocarcinoma of the pancreas." (Wong AA, Am J Clin Oncol. 2005 Jun;28(3):227-33.)
** Retrospective. 107 pts with locally advanced dz.
** Concurrent C.I. 5-FU.
** Low dose group (30 Gy in 10 fractions): 86 pts
** High dose group (50.4 Gy): total of 21 pts. 18 pts received 50.4. 3 others received: 33 Gy, 36 Gy, 52.2 Gy.
** MS: 8 months (30 Gy) vs 9 months (standard dose), NS. 6-mo local disease progression rate: 45% vs 50%, NS; distant metastasis: 54% vs 50%
** Conclusion: "Compared with higher doses given over 5 to 6 weeks, chemoradiation (30 Gy in 10 fractions in 2 weeks with concurrent infusional 5-FU) results in a similar median survival, and local disease progression rates in patients with locally advanced pancreatic cancer apparently do not substantially improve local disease control or median survival time. Because higher doses of radiotherapy can lead to increased acute treatment-related morbidity, we recommend using 30 Gy in 10 fractions unless the patient is part of a prospective study evaluating novel biologic or cytotoxic radiosensitizers."
* Germany; 2005 PMID 15783041 -- "Dose escalation of concurrent hypofractionated radiotherapy and continuous infusion 5-FU-chemotherapy in advanced adenocarcinoma of the pancreas." (Zimmermann FB, Hepatogastroenterology. 2005 Jan-Feb;52(61):246-50.)
** 26 pts. Locally advanced (20 pts) or metastatic (6).
** Concurrent C.I. 5-FU. RT Dose-escalation (all at 4 fractions per week): 1) 24 Gy in 8 fractions (3 Gy/fx); 2) 30 Gy in 10; 3) 36 Gy in 12.
** Toxicity: gr 3 mucositis - 1 pt. gr 2 nausea - 12 pts (46%). gr 2 weakness - 1. No treatment interruption or dose reduction.
** Pain improved in 70% of pts. MS: 8 months (all pts); 9 months (loc adv); 5 mos (metastatic).
** Conclusion: "Dose escalation to 36 Gy in a hypofractionated manner proved to be feasible with low toxicity in patients with locally advanced and metastatic adenocarcinoma of the pancreas and warrants further investigation aiming at optimal tailoring in these two subgroups of patients."

### IMRT/IGRT

* San Antonio; 2007 PMID 19262697 "Image-Guided Intensity-Modulated Radiotherapy for Pancreatic Carcinoma" (Fuss M, Gastrointestinal Cancer Research,1 (1), p. 2)
** Retrospective. 41 patients treated with ultrasound IGRT, doses of 55 Gy (range, 45-64 Gy).
** Acute upper GI toxicity was grade 0–1 in 22 patients (53.7%), grade 2 in 16 patients (39%), and grade 3 in 3 patients (7.3%). Lower GI grade 0–1 in 32 patients (78%), grade 2 in 7 patients (17.1%), and grade 4 in 2 patients (4.9%). Treatment was stopped early in 4 patients.
** Conclusion: Daily image-guidance during delivery of IMRT for pancreatic carcinoma is clinically feasible. Safety margin reduction and moderate dose escalation yields preliminary outcomes at least comparable with published survival data.
* Washington University; 2005 ASTRO Abstract "4D CT for Hepatobiliary Malignancies: Organs at Risk and Implications for Gating" (Ma D, ASTRO 2005, Abstract 2550)
** 11 patients (1 CCA, 1 ampullary, 9 pancreas) reviewed for end-expiration, mid-inspiration, end inspiration, and mid-expiration respiratory phases. Estimated V18 for RT and LT kidney and V20/V30 for liver
** Liver received more dose during inspiration, max (V20 10%, V30 9%), mean (6% V20, 5% V30); Kidney dose varied
** Conclusion: Individualized patient protocols using gating treatment during inspiration or expiration could potentially reduce dose to liver and kidneys, allowing dose escalation or increased chemotherapy during radiation.
* Wayne State; 2004 PMID 15145162 — "Intensity-modulated radiotherapy (IMRT) and concurrent capecitabine for pancreatic cancer." Ben-Josef E et al. Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):454-9.
** Retrospective. 15 pts (7 post-surgical, 8 unresectable). IMRT in 25 fx - 45 Gy to lymph nodes, and 45-54 Gy (post-op) or 54 Gy (unresectable) to tumor bed or tumor.
** Well tolerated.

### SBRT boost

* Stanford, 2005 - PMID 16168826 "Phase II study to assess the efficacy of conventionally fractionated radiotherapy followed by a stereotactic radiosurgery boost in patients with locally advanced pancreatic cancer," Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):320-3.
** 16 pts tx'd w/ 45 Gy IMRT + concurrent 5FU + 25 Gy SRS boost.
** 2 pts had grade 3 toxicity, none had grade 4 toxicity.
** 15/16 pts free of local progression until death.

### Primary SBRT

* Stanford
** Retrospective; 2009 (2002-2007) PMID 19117351 -- "Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas." (Chang DT, Cancer. 2009 Feb 1;115(3):665-72.)
*** Retrospective. 77 patients, no surgery (58% locally advanced, 14% medically inoperable, 19% metastatic, 8% locally recurrent), <7.5 cm diameter. GEM-based regimens in 96%. SBRT 25/1. Prior EBRT 45-54 Gy in 16%. Median F/U 6 months (12 months among surviving patients).
*** Outcome: LC 6-months 91%, 12-months 84%. Isolated local failure 5%, 5%. Regional failure 12%, but 8/9 concurrent distant failure. PFS 26%, 9%. OS 56%, 21%.
*** Toxicity: Acute Grade 2+ in 5%; Late Grade 3+ 9% (3/10 in patients with prior EBRT). 12-month actuarial late toxicity 25%
*** Conclusion: SBRT effective for local control; efforts to reduce complications warranted. Distant mets vast majority of disease-related mortality
** Phase II; 2008 (2004-2006) PMID 18395362 -- "Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer." (Schellenberg D, Int J Radiat Oncol Biol Phys. 2008 Nov 1;72(3):678-86. Epub 2008 Apr 18.)
*** Phase II. 16 patients, locally advanced. GEM 1000 mg/m2 x1 cycle, SBRT 25/1, GEM 1000 mg/m2 until disease progression (median 4 cycles). SBRT to ITV (respiratory expanded GTV) + 2-3 mm margin using fiducial markers. Median F/U 9 months (22 months for living patients)
*** Outcome: LC 81%. Median OS 11 months
*** Toxicity: Acute GI toxicity mild; Late GI toxicity Grade 2 (ulcers) 5/16, Grade 3 (duodenal stenosis) 1/16, Grade 4 (duodenal perforation) 1/16
*** Conclusion: SBRT with GEM resulted in comparable survival to conventional CRT. However, late toxicity was significant
** Phase I; 2004 PMID 15001240 -- "Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer." (Koong AC, Int J Radiat Oncol Biol Phys. 2004 Mar 15;58(4):1017-21.)
*** Dose-escalation study. Locally advanced pancreas. Single fractions 15 Gy (3 patients) -> 20 Gy (5 patients) -> 25 Gy (7 patients). Trial stopped early prior to reaching MTD due to 100% local control at 25 Gy
*** Toxicity: No Grade 3+
*** Conclusion: SRS is feasible; recommend 25 Gy in single fraction
* Aarhus, Denmark; 2005 (2000-2001) PMID 15990186 -- "Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma." (Hoyer M, Radiother Oncol. 2005 Jul;76(1):48-53.)
** Phase II. 22 patients, unresectable. SBRT Dmax 45/3
** Outcome: LF 27%, but only 5% isolated LF. Median OS 6 months; 1-year OS 5%
** Toxicity: Acute toxicity: severe mucositis, ulceration, or perforation 22%
** Conclusion: SBRT poor outcome, unacceptable toxicity, and questionable palliative effect

### Brachytherapy

* Rome 1988-91 PMID 7538501 -- Intraluminal brachytherapy in the treatment of pancreas and bile duct carcinoma. (1995 Montemaggi P, Int J Radiat Oncol Biol Phys. 1995 May 15;32(2):437-43.)
** Retrospective. 12 patients with billiary or pancreatic CA with obstructive jaundice treated with ILRT (20-50 Gy @ 1cm) +/- 5-FU
** Median OS 14 months. 3 patients developed GI toxicity
** Conclusion: "Further experience is necessary to determine whether ILBT in the common bile duct and/or in the duct of Wirsung may be, in pancreatic head patients, an alternative boost technique to Interstitial Brachy-therapy (IBT) or Intraoperative Electron Beam Radiation Therapy (IOEBRT)."

### P-32

* South Florida; 2008 PMID 18266048 -- "(32)P as an Adjunct to Standard Therapy for Locally Advanced Unresectable Pancreatic Cancer: A Randomized Trial." (Rosemurgy A, J Gastrointest Surg. 2008 Feb 12 [Epub ahead of print])
** Randomized. Stopped early. 30 patients out of expected 80, biopsy proven unresectable adenoCA. Treated with 5-FU + RT (45 Gy nodal basin, pancreatic boost to 59.4 Gy), followed by Arm 1) intratumoral injection of colloidal chromic P-32 0.5 mCi/g tumor vs. Arm 2) observation. Both arms were followed by gemcitabine.
** Outcome: median OS P-32 7 months vs. control 11 months (NS)
** Severe toxicity: P-32 4% vs. control 2% (SS)
** Conclusion: Intratumoral P-32 did not improve survival, and was associated with more serious adverse events

## Advanced Stage

* 5-FU alone was historically the main treatment; no combination of 5-FU based regimens has shown a benefit
* Gemcitabine became standard treatment in 1997, after showing better symptom control and a modest survival benefit over 5-FU
* Multiple trials evaluating combinations of agents with gemcitabine have not resulted in improved survival
* NCI Canada trial with gemcitabine + erlotinib (Tarceva) suggests a modest survival benefit over gemcitabine alone
* Swiss, 2007 (2001-2004) -- Gemcitabine +/- capecitabine
** Randomized. 319 patients with advanced/metastatic Ca. Gemcitabine 1000 mg/m2 + Capecitabine 650 mg/m2 vs. Gemcitabine alone
** 2007 PMID 17538165 -- "Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group." (Herrmann R, J Clin Oncol. 2007 Jun 1;25(16):2212-7.)
** Median OS: 8.4 months vs. 7.2 months (NS). Subgroup KPS 90-100 10.1 months vs. 7.4 months (SS). Toxicity comparable
** Conclusion: No overall benefit to GemCap; subgroup survival benefit with good KPS
* NCI Canada CTG PA.3 -- Gemcitabine +/- erlotinib
** Randomized. 569 patients with unresectable, locally advanced, or metastatic pancreatic CA. Gemcitabine 1000 mg/m2, erlotinib 100 or 150 mg/d
** 2007 PMID 17452677 -- "Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group." (Moore MJ, J Clin Oncol. 2007 May 20;25(15):1960-6.)
** Outcome: Median OS: Gem alone 5.9 months vs. Gem + Tarceva 6.2 months (SS); 1-year OS: 17% vs. 23% (SS); PFS also longer
** Toxicity: higher incidence, but most Grade 1-2
** Conclusion: Significantly improved survival
* Multi-institutional -- 5-FU vs. Gemcitabine
** Randomized. 126 patients, advanced symptomatic pancreatic CA. Treated with Gemcitabine 1000 mg/m2 vs. 5-FU 600 mg/m2
** 1997 PMID 9196156 -- "Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial." (Burris HA, J Clin Oncol. 1997 Jun;15(6):2403-13.)
** Outcome: Clinical benefit: Gem 24% vs. 5-FU 5% (SS); Median OS: Gem 5.6 months vs. 5-FU 4.4 months (SS); 1-year OS: Gem 18% vs. 5-FU 2%
** Toxicity: well tolerated
** Conclusion: Gemcitabine more effective than 5-FU

## Patterns of care

* National Patterns of Care Study
** PMID 8604906 Full text, 1996 — "National patterns of care for pancreatic cancer. Results of a survey by the Commission on Cancer." Janes RH Jr et al. Ann Surg. 1996 Mar;223(3):261-72.
** Two study periods: 1983-85 and 1990. 16,942 total case reports.

## Ongoing Trials

* RTOG PA 00-20 (Closed) — Phase II, weekly gemcitabine + paclitaxel + XRT followed by farnesyl transferase inhibitor R115777 for locally advanced pancreatic cancer
* RTOG P04-11 — Phase II, Bevacizumab + Capecitabine + RT, followed by maintenance Gemcitabine + Bevacizumab for locally advanced pancreatic cancer