Pancreatic Cancer by Toby Shutters
Pancreatic cancer is the fourth leading cause of death, amongst cancers, in the United States.
Unfortunately, this is due to the nondescript symptoms that are associated with the disease (6). Due to
the fatal nature of the disease, pancreatic cancers are generally classified as resectable, unresectable, or
metastatic even though the American Joint Committee on Cancer has a TNM staging system (7). As of
now, surgical resection is the only curative option and only 20% or less of all patients are eligible for this
treatment. Even though they are curative candidates, the median survival is 12-20 months (6).
Furthermore, the overall survival is fairly grim for patients with almost all experiencing disease
progression and death. Radiation therapy in patients with pancreatic cancer is normally in combination
with chemotherapy in an attempt to extend survival or ease symptoms for quality of life (6). There are
numerous debates surrounding clinical trials providing differing results as to the efficacy of radiation and
its role in extending survival (5). There are also discussions as to which mode of radiation therapy
provides the best dose configuration while sparing important organs in close proximity.
Reviewing the anatomy of the pancreas and the organs at risk will provide a greater
understanding in determining the optimal radiation treatments. The pancreas is located in the
retroperitoneal space of the upper abdomen at the approximate level of the first two lumbar vertebrae
(7). The pancreatic head is located medially in the "C-loop" of the duodenum and the tail extends
laterally to the splenic hilum. Anteriorly, the pancreas is in contact with the stomach and posteriorly ,
extends to the aorta, splenic vein, and left kidney. The pancreas also has an extensive lymphatic network
(6). Primary drainage is to the super and inferior pancreaticoduodenal , porta hepatis, celiac, and super
mesenteric nodes (7). The pancreas's main functions are to secrete insulin and glucagon to regulate
blood sugar, neutralize gastric acid as it enters the duodenum, and excrete digestive enzymes to
liquidize food (6).
Shutters 2
Tumors of the pancreatic head usually invade or compress the common bile duct as well as the
pancreatic duct causing dilation of the bile ducts and gallbladder. Digestion issues, diarrhea, jaundice,
and sometimes pain are the resulting symptoms ( 6, 7). If the disease is small and the patient is eligible
for surgery, then the Whipple procedure is performed. Pancreatoduodenectomy consists of removing
the pancreas head, a segment of the duodenum, approximately 15cm of jejunum, the gallbladder, the
distal stomach, a part of the common bile duct, and the lymph nodes. Then the remaining pancreas, bile
duct, and stomach are reattached to the small intestine for digestion (6). High local failure rates of 50%80% occur because of invasion into retroperitoneal tissues and inadequate surgical margins. However,
for unresectable or metastatic disease, the tumor blocking the bile duct or hepatic replacement by
metastatic invasion results in fatality (7 ).
In the 1980's, the Gastrointestinal Tumor Study Group demonstrated the efficacy of
chemoradiation in improving median survival in resectable patients from 10.9 months to 21 months.
This was accomplished with a 40 Gy split course over 6 weeks with 5-flourouracil. For unresectable
patients, chemoradiation increased median survival from 5.2 months to 9.6 months on a 10 week
regimen with 60 Gy . Since then, there have been several studies questioning the benefits of
chemoradiation ( 1, 6, 7 ). Therefore, the complex issue at hand is administering an effective radiation
dose to the pancreas or surgical bed while sparing the surrounding structures. The organs that normally
limit the dose are the kidneys, liver, small bowel, stomach and spinal cord. The total dose delivered and
the volume of tissue irradiated are the common parameters for these dose sensitive structures ( 1 , 4) .
When comparing IMRT to 3D-CRT, IMRT provides better dose conformality and increased or
comparable dosage to the pancreas or surgical bed while decreasing critical structure doses. Almost all
radiation treatments are in combination with chemotherapy which makes these structures more
radiosensitive. One of the most critical structures in the area is the small bowel. Acute effects occur
Shutters 3
when epithelial cells are damaged which usually leads to diarrhea. Additionally, serious complications of
the bowel include obstruction, stricture, fistula formation due to small vessel damage and chronic
ischemia, and fibrotic scar tissue in peritoneum (5). IMRT has demonstrated decreased median and
maximum doses to the small bowel. For example, in one study published by Landry et al., IMRT
delivered 45 Gy to the gross tumor and microscopic disease. In the study, the doses to one -third of the
patients' small bowel are 30.2 Gy with IMRT compared to 38.5 Gy of 3D-CRT (1, 8). Milano et al., also did
a study demonstrating that IMRT delivers lower doses to critical structures like the small bowel when
compared to 3D-CRT. The doses range from 50.4 Gy for resectable tumors and 50.4 Gy-59.4 Gy for
unresectable tumors. For IMRT, results showed 20 of 25 patients experienced grade 2 or less acute GI
toxicity (4).
Helical IMRT or TomoTherapy uses a ring gantry and a 6 mm mutlileaf collimator that rotates
around a couch as it is moving. It continuously delivers beam from all angles by using tens of thousands
of beamlets to maximize conformality. In the first published data, it is being compared to IMRT (linear
accelerator) and 3D-CRT for its ability to reduce doses to critical structures. Prescription doses are 54 Gy
for resectable and unresectable tumors. DVH data compared doses to critical organs and found no
difference in dose reduction between HIMRT and IMRT. There are few gains HIMRT has over IMRT
except improved dose homogeneity. However, HIMRT and IMRT both showed lower mean doses to the
small bowel, liver, and stomach with unchanged doses kidney. Again, doses to critical structures are
decreased in comparison to 3D-CRT. Ideal target volumes were met in75% of the IMRT or HIMRT plans
compared to the 13% of 3D-CRT plans (3).
The advantage of IMRT is lower doses to the critical structures while increasing the dose to the
pancreas or surgical bed. Furthermore, a lower dose reduces the side effects which make patients more
comfortable. This is important since most patients present with advanced disease and quality of life
Shutters 4
should seriously be considered (4). Lower doses and equally lower toxicities can also allow the use of
other chemotherapy agents in combination with radiation at a smaller risk. IMRT can also affect dose
escalation by allowing higher and possibly more effective doses of radiation. In a study using IMRT
compared to 3D-CRT, the mean percentage volume at the specifed dose level for normal tissues was
lower in the IMRT plans at 64.8 Gy compared to 54 Gy in the 3D-CRT for all critical stuctures (1). One of
the more important advantages is extending survival, as was seen in the Gastrointestinal Study but not
at risk of losing quality of life (4, 6, 7).
The disadvantage of IMRT for smaller institutions can be found in the amount of available
resources. One resource, the fiscal budget, usually limits an institution's ability to purchase the state of
the art equipment that has IMRT capability (2). A second resource, the personnel, requires more
individuals and technical training to plan and deliver the treatments . Furthermore, IMRT treatments
require longer treatment times making an institution's time management resources important (4).
Another disadvantage is the increased length of time an IMRT patient can be on the table. Additionally,
biological organ movement of the pancreas can affect the treatment margin around the pancreas. Both
patient and organ movement, when administering IMRT, can have radiobiological implications (4).
Overall, pancreatic cancer is a fairly fatal disease with very few options for treatment. These
options are limited due to the usually advanced nature of the disease and the inability to administer
effective doses of radiation because of critical structures. IMRT demonstrates reduction in dose to
critical structures while increasing the dose to the pancreas. This opens the door to the future raising
the possibility of better tolerated and curative regimens.
Shutters 5
References
1. A Dosimetric Analysis of Dose Escalation Using Two Intensity-Modulated Radiation Therapy
Techniques in Locally Advanced Pancreatic Carcinoma
by Michael Brown M.D., Holly Ning Ph.D., Barbra Arora M.S., Paul Albert Ph.D.,
Matthew Poggi M.D., Kevin Camphausen M.D., Deborah Citrin M.D.
Int. J. Radiation Oncology Biol. Phys. ( Vol. 65, No.1 )
2. An Improved Approach to External Beam Radiation Therapy for Intra-Abdominal Cavity
Lesions for Rural Cancer Centers
by Darren M. Gearheart M.S., Peggy Walker R.R.T., Brad S. Collett M.D.,
Raghuram S. Modur M.D.
Medical Dosimetry (Vol.32, Issue 4)
http://www.meddos.org/article/S0958-3947%2807%2900049-0/abstract?source=aemfA
3. Comparison of Helical Intensity-Modulated Radiotherapy, Intensity- Modulated Radiotherapy,
and 3D-Conformal Radiation Therapy for Pancreatic Cancer
by Matthew M. Poppe M.D., Venkat Narra Ph.D., Ning J. Yue Ph.D., Jinghao Zhou Ph.D.,
Carl Nelson M.D., Salma K. Jabbour M.D.
Medical Dosimetry (Vol.36, Issue 4)
http://www.meddos.org/article/S0958-3947%2810%2900130-5/abstract?source=aemf
4. Intensity-Modulated Radiotherapy in Treatment of Pancreatic and Bile Duct Malignancies:
Toxicity and Clinical Outcome
by Michael Milano M.D., Ph.D. , Steven ChmuraM.D., Ph.D. , Michael Garofalo M.D.,
Carla Rash C.M.D. , John Roeske Ph.D., Phillip Connell M.D., Oh-Hoon Kwon M.D.,
Ashesh Jani M.D., Ruth Heimann M.D., Ph.D.
Int. J. Radiation Oncology Biol. Phys. ( Vol.59, No2 )
5. Intensity-Modulated Radiation Therapy Significantly Improves Acute Gastrointestinal
Toxicity in Pancreatic and Ampullary Cancers
by Susannah Yovino M.D., Matthew Poppe M.D., Salma Jabbour M.D., Vera David M.D.,
Michael Garofalo M.D., Naimish Pandya M.D., Richard Alexander M.D., Nader Hanna M.D.,
William Regine M.D.
Int. J. Radiation Oncology Biol. Phys (Vol.79, No.1)
6. Pancreatic Cancer: Current Practice, Future Directions
by Maida Williams Broudo B.A., R.T.(R)(T)
Radiation Therapist ( Vol.19, No.2, Fall 2010 )
7. Radiation Oncology Management Decisions
by K.S. Clifford Chao M.D., Carlos Perez M.D., Luther Brady M.D.
Philadelphia, Lippincott Williams & Wilkins, 2011 pg 427-428
Shutters 6
8. Treatment of pancreatic cancer tumors with intensity-modulated radiation therapy (IMRT)
using the volume at risk approach (VARA): Employing dose-volume histogram (DVH) and
normal tissue complication probability (NTCP) to evaluate small bowel toxicity
by Jerome C Landry M.D., Gary Y Yang M.D., Joseph Y Ting Ph.D., Charles A Staley M.D.,
William Torres M.D., Natia Esiashvili M.D., Lawrence W Davis M.D.
Medical Dosimetry (Vol.27, Issue 2)
http://www.meddos.org/article/S0958-3947%2802%2900094-8/abstract?source=aemf