Splenic Dose with Abdominal Radiation Therapy: A Quantitative Dosimetric Study

Matthew S. Katz, MD1,2; Andrea B. McKee, MD1,2; Brennan A. MacDonald, PhD2; Luc Sirois, MSc2; Faby M. Gagne, PhD3; Brian R. Knab, MD1,2

1Radiation Oncology Associates, PA, Manchester, NH2Elliot Regional Cancer Center, Manchester, NH

3Research and Statistical Strategies, LLC, Amherst, NH

Contact Information:

Matthew S. Katz, MDRadiation Oncology Associates, PA

One Elliot WayManchester, NH 03103

Email: matt@roa-ne.com

ABSTRACT

Purpose: To quantify splenic radiation dose with abdominal radiation therapy to assess the potential benefit of pneumococcal vaccination prior to treatment.

Methods and Materials: Non-contrast computed tomographic (CT) images were retrospectively reviewed for ten patients undergoing CT simulation treatment between June 2007 and October 2008. The spleen was contoured every 2-3 mm axial image. Using the patients’ original treatment plan, spleen volume and splenic dose-volume relationships were calculated. Specific parameters evaluated include minimum and mean (Dmin and Dmean) as well as V20 Gy and V25 Gy.

Results: Seven patients had gastroesophageal junction/distal esophageal (GEJ/DE) cancer while three had pancreatic or ampullary cancer. Median prescribed dose to the PTV was 50.4 Gy (range: 45-50.4 Gy). For all patients, median splenic volume was 252 cc (86-386). The median Dmean was 23.4 Gy (range: 8.2 - 32.4 Gy). Among the seven GEJ/DE patients, median Dmean was 24.4 Gy (range: 9.6 - 32.4 Gy). Median V20 Gy and V25 Gy were 82% (range: 28-100%) and 72% (range: 17-100%), respectively. In one esophageal cancer patient, the Dmin was 25.5 Gy.

Conclusion: Splenic dose with abdominal radiation therapy appears to be in a clinically relevant range for organ dysfunction. Clinical correlational research is warranted to determine if gastric and esophageal cancer patients have an elevated risk of pneumonia or sepsis after radiation therapy.

Key words: Spleen, esophageal cancer, gastric cancer, chemoradiation, hyposplenism, sepsis, pneumonia, vaccination

INTRODUCTION

For localized esophageal, stomach and pancreatic cancers, the use of concurrent chemoradiation has become standard treatment option, either combined with surgery or as definitive treatment (1-5). Using radiation therapy for any of these diseases comes with the risk of side effects, and treatment planning for three dimensional or intensity modulated radiation therapy plays an important role in minimizing injury to organs at risk within or near the target volume (6-9). Current treatment planning evaluates dose to the heart, lung, liver, spinal cord, small bowel, and kidneys. However, to our knowledge there are no reports on the radiation dose received by the spleen or the potential sequelae for upper abdominal malignancies.

The spleen plays an important role in innate and adaptive immunity. (10) Antigens can be identified, antibodies can be produced in the red pulp and splenic macrophages compete with bacteria for iron. Hyposplenism or splenectomy generally increases future risk of infection or sepsis (11,12), and gastric and esophageal cancer patients with undergoing splenectomy at the time of curative surgery also appear to be a very high risk of postoperative complications. (13-15)

Because no studies quantify splenic radiation dose in the treatment of upper abdominal malignancies, no guidelines exist on the use of pneumococcal vaccination for patients receiving chemoradiation. In this dosimetric study, our aim was to determine radiation dose in curative treatment for upper abdominal malignancies to determine if a risk of radiation-induced hyposplenism may exist in chemoradiation patients without splenectomy.

METHODS AND MATERIALS

PatientsAfter obtaining IRB exemption, we searched for patients undergoing computed tomography (CT) simulation at the Elliot Regional Cancer Center between June 2007 and October 2008 with one of the primary diagnoses: esophageal cancer, gastric cancer, pancreatic cancer, or ampullary carcinoma. During the study period, 35 patients underwent simulation and treatment planning. We retrospectively reviewed electronic records and excluded 16 patients treated palliatively. For 11 patients with esophageal cancer, we included only the seven patients with distal primary tumors or those at the gastro-esophageal junction (GEJ). Our final study cohort consisted of ten patients: seven with esophageal/GEJ cancer, two with pancreatic cancer and one with an ampullary carcinoma.

Spleen contouring and dosimetry At the time of simulation, all patients were supine and immobilized. Using a Siemens Sensation Open 40 CT simulator, noncontrast axial CT images were obtained at 2-3 mm intervals through the thorax and abdomen. No oral or IV contrast was administered. After the isocenter was established, the CT images were transferred to the Pinnacle 8.0m workstation for treatment planning prior to treatment. For each patient, we used the final archived treatment plan and one physician (MSK) contoured the spleen on each axial slice with abdominal window settings. Once the spleen was contoured, we recorded its volume and then included it in the final treatment plan to determine splenic radiation dose. For each patient, we recorded the minimum, mean and maximum splenic dose (Dmin, Dmean, Dmax). Because no previously published data were available to estimate dose-volume relationships to correlate with clinical hyposplenism, we quantified dose-volume at 5 Gy intervals.

RESULTS

Patients and Treatment

Clinical data for the cohort is presented in Table 1. The median age at time of simulation was 68 (range: 39-78). Eight (80%) were men, and the histology for all tumors was adenocarcinoma. All received concurrent chemotherapy. The median RT dose was 50.4 Gy (range: 45 – 50.4 Gy). Six patients (60%) were treated with a 3D conformal technique, two treated with intensity-modulated (IMRT) technique and two with 3D initially and an IMRT boost.

Dosimetric and volumetric analyses of splenic dose The median splenic volume was 252 cc (range: 86–386). For all ten patients the median Dmin was 1.9 Gy (range: 0.2 – 25.5 Gy). The median Dmean was 19.6 Gy (range: 8.2 – 32.4 Gy) (Table 2). Because the radiation dose distribution was higher for the esophageal/GEJ patients, we further looked at the Dmin and Dmean for these seven patients. The median Dmean was 24.4 Gy (range: 9.6 – 32.4 Gy). One of the patients with a distal esophageal cancer had a Dmin of 25.5 Gy. For these patients, the Dmax was a median 50.3 Gy (range: 38.2 – 53.2 Gy). For the three pancreatic/ampullary cancer patients, the median Dmin was 1.9 Gy (range: 0.6 – 2.2 Gy). The median Dmean was 14.8 Gy (range: 8.2 –15.1 Gy). In analyzing dose-volume relationships for the seven esophageal/GEJ patients, the median V20 Gy was 82% (range: 28 – 100%) and median V25 Gy was 72% (range: 17 – 100%). The median esophageal patient’s dose-volume histogram and sample axial and coronal images are shown in Figure 1 and Figure 2. In comparison, for the three pancreatic/ampullary patients the median V20 Gy and V25 Gy were 20% (range:20-35%) and 5% (range:5-20%), respectively. No statistically significant correlation was seen between patient, tumor or RT variables with either Dmin or Dmean .

DISCUSSION

Despite concurrent chemoradiation being an established treatment option for upper abdominal malignancies,4,16-18 little is known about its potential to interfere with spleen function. To our knowledge, this is the first dosimetric study to describe and quantify splenic radiation dose during abdominal radiation therapy for gastrointestinal malignancies. Given the small, heterogeneous cohort of patients in this study, we did not try to determine whether the splenic radiation had any adverse effect. However, splenic irradiation may contribute acutely to thrombocytopenia or pancytopenia in patients receiving concurrent chemoradiation, and chronic splenic dysfunction may increase the risk of sepsis or pneumococcal pneumonia.

Further study is warranted to determine whether cancer patients receiving abdominal radiation therapy are at higher risk of sepsis or pneumococcal pneumonia. Because the radiation dose in this small sample size study suggests that splenic dose is highest for distal esophageal cancer patients, we hypothesize that the benefit would be most readily observed in a cohort of distal esophageal and proximal gastric cancer patients.

Should a higher risk of toxicity exist, it may be worthwhile to consider pneumococcal vaccination prior to chemoradiation. In Hodgkin’s disease, pneumococcal vaccination is increasingly routine for patients after splenectomy to avoid infection or sepsis.19-21 For gastrointestinal malignancies, we do not recommend routine vaccination but our data suggest it is worth further investigation to determine whether the spleen should be considered an organ at risk in patients receiving upper abdominal radiation therapy.

In conclusion, our dosimetric study demonstrates that splenic radiation may be within a clinically relevant range that could lead to organ dysfunction. Future clinical correlational studies are needed to significantly determine if gastric and esophageal cancer patients have an elevated risk of pneumonia or sepsis after radiation therapy.

REFERENCES

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12. Hansen K, Singer DB. Asplenic-hyposplenic overwhelming sepsis: postsplenectomy sepsis revisited. Pediatr Dev Pathol 2001;4:105-121.

13. Viste A, Haùgstvedt T, Eide GE, et al. Postoperative complications and mortality after surgery for gastric cancer. 1988;20:7-13.

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15. Kyriazanos ID, Tachibana M, Yoshimura H, et al. Impact of splenectomy on the early outcome after oesophagectomy for squamous cell carcinoma of the oesophagus. Eur J Surg Oncol 2002;28:113-119.

16. Moertel CG, Childs DS Jr, Reitelmeier RJ, et al. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 1969;2:865-867.

17. Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. New Engl J Med 1992;326:1593-1598.

18. Moertel CG, Frytak S, Hahn RG, et al. 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. Cancer 1981;48:1705-1710.

19. Jockovich M, Mendenhall NP, Sombeck MD, et al. Long-term complications of laparotomy in Hodgkin’s disease. Ann Surg 1994;219:615-621.

20. Omlin AG, Mühlemann K, Fey MF, et al. Pneumococcal vaccination in splenectomised cancer patients. Eur J Cancer 2005;41:1731-1734.

21. Foss Abrahamsen A, Høiby EA, Hannisdal E, et al. Systemic pneumococcal disease after staging splenectomy for Hodgkin’s disease 1969-1980 without pneumococcal vaccine protection: a follow-up study 1994. Eur J Haematol 1997;58:73-77.

Table 1. Characteristics of ten patients undergoing CT simulation for abdominal radiation therapy

Patient Characteristics No. (%)Age (years) Median (range) 68 (39-78)Gender Male 8 (80%) Female 2 (20%)Primary Site Distal esophagus/GE Junction 7 (70%) Pancreas/Ampulla of Vater 3 (30%)Histology Adenocarcinoma 10 (100%)Concurrent chemotherapy Yes 10 (100%)Radiation Dose (Gy) Median (range) 50.4 Gy (45 – 50.4)Radiation Technique 3D-Conformal 6 (60%) Intensity modulated 2 (20%) Both 2 (20%)Spleen volume (cc) Median (range) 252 (86-386)

* Pancreatic/ampullary carcinom

a

Median

10

9

8

7*

6*

5

4

3

2*

1

Patien

t

Tab

le 2. Splenic D

ose-Volum

e data for ten patients treated with abdom

inal radiation therapy

50.4

50.4

50.4

50.4

50.4

50.4

50.4

50.4

50.4

50.4

45

RT

Dose

(Gy)

3D+IM

RT

3D

3D+IM

RT

IMR

T

IMR

T

3D 3D 3D 3D 3D

RT

T

echn

iqu

e

252

155

332

296

305

386

86

199

207

199

351

Spleen

V

olum

e (cc)

1.9

0.8

2.7

4.2

0.5

2.2

25.5

1.7

1.9

1.9

0.2

Dm

in (G

y)

9.6

15.8

28.2

32.4

8.2

15.1

31.3

24.4

23.4

14.8

9.6

Dm

ean

(Gy)

83%

59%

95%

96%

34%

77%

100%

89%

89%

59%

34%

V 1

0 G

y

77%

53%

92%

92%

27%

69%

100%

85%

84%

43%

32%

V 1

5 G

y

63%

46%

88%

87%

20%

20%

100%

82%

80%

35%

28%

V 2

0 G

y

42%

17%

83%

79%

5% 5%

100%

72%

60%

20%

23%

V 2

5 G

y

8%

11%

40%

69%

1% 1%

33%

12%

5% 4% 2%

V 3

0 G

y

Figure 1. Dose-Volume Histogram (DVH) from a patient with distal esophageal cancer

Figure 2. Axial and coronal images with dose distribution and digitallyreconstructed radiograph in the same patient with distal esophageal cancer