Case study Strahlenther Onkol 2014 · 190:223–228 DOI 10.1007/s00066-013-0470-7 Received: 11 May 2013 Accepted: 16 September 2013 Published online: 6 December 2013 © Springer-Verlag Berlin Heidelberg 2013
P. Berkovic1 · L. van de Voorde1 · G. De Meerleer1 · L. Delrue2 · B. Speleers1 · S. Van Belle3 · K. Vandecasteele1 1 Department of Radiotherapy, Ghent University Hospital, Ghent 2 Department of Radiology, Ghent University Hospital, Ghent 3 Department of Medical Oncology, Ghent University Hospital, Ghent
Whole abdominopelvic radiotherapy in the palliative treatment of pseudomyxoma peritonei
Pseudomyxoma peritonei (PMP) is a rare clinical syndrome characterized by mucinous tumor on peritoneal surfaces and the omentum producing progressive amounts of mucinous ascites [19]. The primary tumor is currently thought to be of appendiceal mucinous epithelial origin showing varying amounts of invasiveness [20]. There still remains confusion on the definition, origin, pathology, classification and treatment of PMP [13]. Metastatic dissemination, hematogenic or lymphatic, has been reported but is rare [18]. A typical feature of this tumor is the production and secretion of mucus into the appendiceal lumen with progressive growth. At a later stage, PMP will engulf the entire peritoneal cavity involving all bowel surfaces, limiting intestinal movement and eventually resulting in bowel obstruction. Traditional treatment of PMP consists of repetitive surgical debulking with removal of all mucinous ascites. However, cure or prolonged remission is uncommon with this approach [10]. Results improved with an aggressive locoregional, combined modality strategy with cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC). This approach resulted in a 5-year overall survival rate ranging from 52–75% [12]. However, this combined modality treatment is not universally accepted as standard of care due to the lack of randomized trials [20]. The combination of surgery and other treatment modalities have been reported in small retrospective series with inconclu-
sive results [18]. Several authors reported the use of intraoperative and postoperative radiotherapy (PORT) [7, 8, 9]. However, similarly with other adjuvant treatment modalities, lack of randomized trials and small patient numbers makes it difficult to assess its effectiveness. In case of recurrence, and in selected patients, repeated cytoreductive surgery with or without HIPEC might improve outcome. However, each repeated debulking procedure becomes less effective with increased morbidity [22]. Other management options at recurrence include observation, systemic chemotherapy and abdominopelvic radiotherapy [9]. We present a case of recurrent PMP treated by whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT).
Case presentation A 63-year-old Caucasian woman with no significant past medical history was referred to the radiotherapy (RT) department in January 2010. Her oncologic history started in September 2008 when she presented with pain in the lower abdomen. Diagnostic work-up revealed an appendicular gelatinous mass in the peritoneal cavity. The tumor markers CA 125 and CEA were 6.87 U/ml and 8.85 ng/ml, respectively. A CT-guided biopsy was performed and showed mucinous material and strips of atypical epithelial cells consistent with mucinous adenocarcinoma suggestive of appendicial origin. The patient underwent a cytoreductive laparoto-
my followed by HIPEC using mitomycin C. Four months after surgery, she started complaining about recurrent abdominal pains along with a progressive elevation of CA 125. 18FDG PET-CT revealed panabdominal disease recurrence. The patient underwent a second extensive cytoreductive laparotomy followed by HIPEC, this time using oxaliplatin (460 mg/m2). Histopathology revealed an extensive mucinous adenocarcinoma involving the whole peritoneal cavity. Four cycles of adjuvant carboplatin plus paclitaxel combination chemotherapy were administered. Re-evaluation after treatment showed no evidence of disease with a CA 125 of 10 U/ ml, which remained normal during the whole period. Six months later, the patient presented with acute abdominal pain, nausea, lack of stools, poor appetite, and weight loss. Clinical examination revealed a tense distended abdomen with diffuse pain. A CT scan revealed a large mass in the right flank extending towards the whole abdominal cavity leading to a mechanical small bowel obstruction, suggestive of a recurrent pseudomyxoma peritonei (. Fig. 1). The patient was referred for surgery and an explorative laparotomy revealed diffuse retroperitoneal recurrence of PMP involving the whole abdominal cavity together with diffuse adhesions. The adhesions were maximally removed but most of the tumor load was deemed unresectable. After postoperative recovery, the patient was referred to our department. Strahlentherapie und Onkologie 2 · 2014
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Fig. 1 8 Pre-adhesiolysis: contrast-enhanced CT scan in venous phase (in axial, coronal, and sagittal planes) reveals a large gelatinous collection in the right hypochonder in combination with nodular thickening of the peritoneal surface
Fig. 2 9 Transversal (a, d), coronal (b, e), and sagittal (c, f) dose distributions of the patient treated with 18 MV photons using a technique of intensity-modulated arc therapy (IMAT) (a, b, c) or 3D conformal radiotherapy (d, e, f) covering the whole abdominopelvic cavity. A dose of 33 Gy was prescribed and delivered in 22 daily fractions of 1.5 Gy. Using 5 arcs, the IMAT plan delivered a combination of conformal avoidance of both kidneys, while providing sufficient coverage of the planning target volume. Using a 4-field box technique, the total dose for the 3D conformal plan was reached with the use of kidney blocks at a median kidney dose of 18 Gy. This results (among others) in an underdosage of the prerenal tissues (d)
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Abstract · Zusammenfassung At admission, she had a Karnofsky performance score of 80 [17] and complained of abdominal bloating, anorexia, and periodic constipation. Clinical examination revealed hyperperistalsis without abdominal pain or ascites. Patient was accepted for WAPRT performed by IMAT. We prescribed a dose of 33 Gy delivered in 22 daily fractions of 1.5 Gy, using 18 MV photons. At each fraction, a cone beam CT was performed for optimal patient setup and target verification [23].The clinical target volume (CTV) was defined as the whole peritoneal cavity. To create the planning target volume, the CTV was expanded with an isotropic margin of 5 mm. Organs at risk (OAR) including the liver, both kidneys and the spinal cord were delineated (. Fig. 2). The treatment was well tolerated. Acute toxicity, scored using CTCAE toxicity criteria version 3.0 [21], consisted of grade II diarrhea and abdominal cramps along with grade I nausea, fatigue, and lymphocytopenia. A Sandostatin analogue and low dose corticosteroids were prescribed with good tolerance and effect. Eight weeks after radiation treatment all toxicities except grade I fatigue and nausea subsided and a return to normal peristalsis, stools, and food intake was observed. CA-125 remained unchanged. A CT re-evaluation, 6 month after WAPRT showed the absence of any obstructive masses (. Fig. 3). Nine month after completion of radiotherapy the patient was admitted for IV fluids and corticosteroids due to suspected late radiation enteritis which subsided after 2 weeks. Eleven months after completion of WAPRT, disease progression was observed with the diagnosis of lung metastasis, lesions around the liver and a cutaneous lesion at the laparotomy scar. The patient started with weekly chemotherapy with liposomal doxorubicin. Re-evaluation after 6 cycles showed stable disease. Due to the painful cutaneous lesions around the laparotomy scar, RT treatment with 6 MeV electrons at a total dose of 20 Gy was delivered in 5 fractions using a bolus of 0.5 cm. The treatment was repeated due to persistent pain. Both treatments were well tolerated and the pain eventually subsided 6 weeks after completion of the second treatment course. Unfortunately,
Strahlenther Onkol 2014 · 190:223–228 DOI 10.1007/s00066-013-0470-7 © Springer-Verlag Berlin Heidelberg 2013 P. Berkovic · L. van de Voorde · G. De Meerleer · L. Delrue · B. Speleers · S. Van Belle · K. Vandecasteele
Whole abdominopelvic radiotherapy in the palliative treatment of pseudomyxoma peritonei Abstract Background. Pseudomyxoma peritonei (PMP) is a rare clinical syndrome characterized by mucinous peritoneal disease arising from disseminated peritoneal adenomucinosis. Primary treatment involves a combination of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). There is no consensus on the proper treatment of recurrent PMP. In selected patients, repeated cytoreductive surgery with or without HIPEC might improve outcome. However, every repeated debulking procedure becomes less effective with increased morbidity. Case report. We present a case of a patient with intestinal obstruction caused by recurrent pseudomyxoma peritonei. We treated the patient with whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT) to a total dose of 33 Gy,
delivered in 22 daily fractions. The treatment was well tolerated and resulted in resolution of the obstruction for a period of 24 months. Conclusion. To the best of our knowledge, we present the first case report showing the possibility of resolving intestinal obstruction with WAPRT in a patient with recurrent PMP. It is our opinion that WAPRT delivered by IMAT, in analogy with ovarian cancer, should be considered as a palliative treatment option in managing patients with recurrent PMP especially in case of obstruction. Keywords Recurrent pseudomyxoma peritonei · Whole abdominopelvic radiotherapy · WAPRT · Intensity-modulated arc therapy · Abdominal obstruction
Bestrahlung des ganzen Abdomens in der Palliativbehandlung des Pseudomyxoma peritonei Zusammenfassung Hintergrund. Pseudomyxoma peritonei (PMP) ist ein seltenes klinisches Syndrom, das sich durch eine muzinöse peritoneale Läsion kennzeichnet, die wiederum aus disse minierter peritonealer Adenomuzinose hervorgeht. Die Erstbehandlung besteht aus ei ner Kombination von zytoreduktiver Chirurgie mit hyperthermischer, intraperitonealer Chemotherapie (HIPEC). Bei Rezidiv-PMP besteht kein Konsens über die richtige Behandlung. Bei ausgewählten Patienten könnte eine erneute zytoreduktive Chirurgie mit oder ohne HIPEC zu einem besseren Ergebnis führen. Allerdings wird jedes neue Debulking minder effektiv und geht einher mit erhöhter Morbidität. Fallbeschreibung. Wir präsentieren einen Patienten mit Darmverschluss, der durch ein Rezidiv-PMP verursacht wurde. Mit Hilfe der intensitätsmodulierten Arc-Therapie (IMAT) behandelten wir den Patienten mit einer Bestrahlung des ganzen Abdomens (WAPRT)
22 months after WAPRT, the patient was diagnosed with progressive lung metastasis and the patient was referred for palliative care where she died 24 months after WAPRT.
mit einer Gesamtdosis von 33 Gy in 22 täglichen Fraktionen. Die Behandlung wurde gut vertragen und führte zu einer langzeitigen Auflösung des Darmverschlusses für einen Zeitraum von 24 Monaten. Schlussfolgerung. Dies ist unseres Wissens nach der erste Fallbericht, der die Möglichkeit zur Behandlung des Darmverschlusses bei einem Patienten mit Rezidiv-PMP mit Hilfe von WAPRT aufzeigt. WAPRT appliziert mit IMAT sollte unserer Ansicht nach, in Analogie zum Ovariumkarzinom, als palliative Behandlungsmöglichkeit bei Patienten mit Rezidiv-PMP in Erwägung gezogen werden, besonders im Falle eines Darmverschlusses. Schlüsselwörter Rezidiv Pseudomyxoma peritonei · Bestrahlung des ganzen Abdomens · WAPRT · Intensitätsmodulierten Arc-Therapie · Darmverschluss
Discussion There is no consensus on the proper treatment of recurrent PMP. In this setting, repeated cytoreductive surgery with or without HIPEC has been reported in seStrahlentherapie und Onkologie 2 · 2014
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Fig. 3 8 Six months post-WAPRT: contrast-enhanced CT scan in venous phase (in axial, coronal, and sagittal planes) shows the absence of obstructive masses and normal appearance of the intestinal loops
100
frequency (%)
80
60
40 CTV PTV PTVoptim liver left kidney exp. 5 mm right kidney exp. 5 mm spinal axis
20
0
0
5
10
15
20 dose (Gy)
25
30
35
40
Fig. 4 8 Dose–volume histograms (DVH) compiled from the data of both planning techniques. IMAT (solid lines) and 3D conventional (dotted lines) represent the DVH for the contoured volumes. Using a 4-field box technique the total dose for the 3D conventional plan was reached with the use of kidney blocks at a median kidney dose of 18 Gy. This resulted in a significant underdosage of the PTV and less homogeneous dose distributions. PTVoptim = PTV minus expanded kidneys, kidney exp.5 mm = contoured kidney expanded with 5 mm to encompass organ movement. Spinal axis = spinal cord + cauda equina
lected patients showing an improved outcome. However, in case of diffusely spread disease throughout the abdomen, repeated surgery might be less successful with increased morbidity and mortality [18]. There is limited experience on the role of external radiotherapy in the adjuvant and recurrent setting of PMP [9]. Furthermore, data on the radiosensitivity of PMP are scarce. Previous reports on the use of radiotherapy in PMP are dated and based on conventional radiotherapy fields. Long
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et al. [11] found no convincing evidence of response of PORT. Fernandez and Daly [8] suggested that PORT improves survival with a 5-year survival rate of 75% after surgery compared with 44% with adjuvant chemotherapy, but the differences were not statistically significant. El Sayed [7] reported a case with the use of megavoltage radiotherapy with large parallel opposed fields to treat the whole abdomen and pelvis in the adjuvant and salvage setting. The intended dose was 35 Gy
in 20 fractions over 4 weeks. However, the treatment had to be terminated at 14 Gy due to deterioration of the patient’s condition but was continued 13 years later. The Mayo Clinic retrospective series reported on the combination of surgery and intracavitary or external beam radiotherapy. A shorter disease-free survival but no overall survival benefit was observed [9]. We hypothesized that WAPRT could be a valuable treatment option in the setting of recurrent PMP due to the spreading pattern of PMP which resembles the transperitoneal dissemination that is common in ovarian cancer [10, 18]. Mature data have demonstrated the role of WAPRT in the treatment of ovarian cancer [4]. Historically, the whole abdomen was treated with large conventional radiotherapy fields. This induced substantial morbidity, particularly small bowel toxicity and myelosuppression, resulting in frequent treatment interruptions and prolonged overall treatment time which decreases overall survival [5]. In fact, when conventional technology was used, WAPRT was not able to deliver adequate radiation doses to the upper abdomen due to the tolerance limits of the OAR (. Fig. 2). Duthoy et al. [6] described a first clinical experience with IMAT for WAPRT and obtained a more homogeneous dose distribution than with conventional planning. By comparing both planning techniques for our patient we could also observe the superiority of the IMAT plan vs. the conventional plan (3D conformal) with superior target coverage and a decrease of dose in the OAR (especially to
Tab. 1 Summary of the DVH data for the IMAT plan and the 3D conformal plan PTV D02 D50 D98 PTV optim D02 D50 D98 CTV D02 D50 D98 Organs at risk Liver D50 Kidney left (exp.5 mm) D02 D50 Kidney right (exp. 5 mm) D02 D50 Spinal Axis D02
IMAT (Gy)
3D conformal (Gy)
36.0 33.4 26.5
35.77 33.00 18.51
36.0 33.5 29.7
35.81 33.07 18.89
36.0 33.6 30.8
35.93 33.20 18.79
17.3
14.65
30.8 16.5
22.46 18.61
31.9 14.5
22.55 18.59
29.2
31.02
PTVoptim = PTV minus expanded kidneys, kidney (exp. 5 mm) = contoured kidney expanded with 5 mm to encompass organ movement, Spinal axis = spinal cord + cauda equine, DVH = dose–volume histogram, IMAT = intensity-modulated arc therapy, 3D = three dimentional, PTV = planning target volume, Gy = Gray, D02, D50, D98 = Dose given to 2%, 50% and 98% of the volume.
the kidneys; . Tab. 1, . Fig. 2, 4). Helical tomotherapy for fast WAPRT is also feasible and enables excellent coverage of the PTV and effective sparing of the OAR [14] Our patient benefitted from these modern radiotherapy techniques. The whole abdomen was treated in 22 daily fractions of 1.5 Gy without interruptions using IMAT. This might explain the favorable long-term response and low toxicity profile. Also in ovarian cancer, malignant bowel obstruction is an important and devastating clinical condition. Most patients show multiple intestinal levels of obstruction precluding any surgical intent with a mean survival between 20 and 75 days and a 3-month life expectancy lower than 25% [1]. In this setting, WAPRT is able to resolve intestinal obstruction for a median duration of 16 weeks with a response rate of 66% [3]. Similarly, in PMP, the major causes of mortality are related to recurrent locoregional disease causing intestinal and biliary obstruction eventually leading to death by long-term starva-
tion [20]. In this setting, Yan et al. [22] observed a progression-free survival of 55% after a second cytoreduction with HIPEC and an overall survival in patients with mixed histologies of 75% at 10 years. The pattern of recurrence remained focal in 58% of patients. However, the study did not report specifically on intestinal obstruction. To the best of our knowledge, this is the first report demonstrating the possibility of resolving intestinal obstruction with WAPRT in a patient with recurrent PMP for a period of 24 months. This compares favorably with the data on ovarian cancer with an obstruction-free survival of only 16 weeks [3]. Eleven months after WAPRT, our patient was diagnosed with lung metastasis. This could be related to the subtype of the neoplasm. The patient was diagnosed on both occasions with a mucinous adenocarcinoma of appendicial origin. Although different grading systems are proposed and controversy persists over the classification of mucinous
peritoneal lesions, these tumors are generally classified as high grade lesions [18]. This variant, compared to the more indolent mucinous peritoneal lesions, is probably a separate entity with differences in biology and worst prognostic outcome [2, 15]. Parenchymal organ and lymph node involvement is more frequent and distant metastasis occur [16].
Conclusion We present a case of a patient with recurrent pseudomyxoma peritonei with intestinal obstruction. The whole abdomen was treated with IMAT to a total dose of 33 Gy, delivered in 22 daily fractions. The treatment was well tolerated and resulted in an obstruction-free survival period of 24 months. It is therefore our opinion that WAPRT delivered by IMAT could be considered as a palliative treatment option in managing patients with recurrent PMP, especially in case of obstruction.
Corresponding address P. Berkovic, M.D. Department of Radiotherapy, Ghent University Hospital De Pintelaan 185, 9000 Ghent Belgium [email protected]
Acknowledgments. The authors would like to thank Prof. M. Mareel M.D., Ph.D. for his valuable comments and suggestions to improve the quality of the manuscript.
Compliance with ethical guidelines Conflict of interest. P. Berkovic, L. van de Voorde, G. De Meerleer, L. Delrue, B. Speleers, S. Van Belle, and K. Vandecasteele state that there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.
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References 1. Ayhan A, Reed N, Gultekin M et al (2011) Textbook of gynaecologic oncology, 2nd edn. Hünes Publishing, Ankara 2. Chua TC, Moran BJ, Sugarbaker PH et al (2012) Early- and long-term outcome data of patients with pseudomyxoma peritonei from appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. J Clin Oncol 30:2449–2456 3. De Meerleer G, Vandecasteele K, Ost P et al (2011) Whole abdominopelvic radiotherapy using intensity-modulated arc therapy in the palliative treatment of chemotherapy-resistant ovarian cancer with bulky peritoneal disease: a single-institution experience. Int J Radiat Oncol Biol Phys 79:775– 781 4. Dembo AJ (1992) Epithelial ovarian cancer: the role of radiotherapy. Int J Radiat Oncol Biol Phys 22:835–845 5. Dowdy SC, Metzinger DS, Gebhart JB et al (2005) Salvage whole-abdominal radiation therapy after second-look laparotomy or secondary debulking surgery in patients with ovarian cancer. Gynecol Oncol 96:389–394 6. Duthoy W, De Gersem W, Vergote K et al (2003) Whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT): first clinical experience. Int J Radiat Oncol Biol Phys 57:1019–1032 7. El Sayed S (1990) Pseudomyxoma peritonei treated by radiotherapy. Clin Oncol 2:120–122 8. Fernandez RN, Daly JM (1980) Pseudomyxoma peritonei. Arch Surg 115:409–414 9. Gough DB, Donohue JH, Schutt AJ et al (1994) Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach. Ann Surg 219:112–119 10. Hinson FL, Ambrose NS (1998) Pseudomyxoma peritonei. Br J Surg 85:1332–1339 11. Long RT, Spratt JS Jr, Dowling E (1969) Pseudomyxoma peritonei. New concepts in management with a report of seventeen patients. Am J Surg 117:162–169 12. Moran B, Baratti D, Yan TD et al (2008) Consensus statement on the loco-regional treatment of appendiceal mucinous neoplasms with peritoneal dissemination (pseudomyxoma peritonei). J Surg Oncol 98:277–282 13. Nakakura EK (2012) Pseudomyxoma peritonei: more questions than answers. J Clin Oncol 30:2429–2430 14. Rochet N, Sterzing F, Jensen A et al (2008) Helical tomotherapy as a new treatment technique for whole abdominal irradiation. Strahlenther Onkol 184:145–149 15. Ronnett BM, Yan H, Kurman RJ et al (2001) Patients with pseudomyxoma peritonei associated with disseminated peritoneal adenomucinosis have a significantly more favorable prognosis than patients with peritoneal mucinous carcinomatosis. Cancer 92:85–91 16. Ronnett BM, Zahn CM, Kurman RJ et al (1995) Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 19:1390–1408 17. Schag CC, Heinrich RL, Ganz PA (1984) Karnofsky Performance Status revisited: reliability, validity, and guidelines. J Clin Oncol 2:187–193
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18. Smeenk RM, Bruin SC, Van Velthuysen ML et al (2008) Pseudomyxoma peritonei. Curr Probl Surg 45:527–575 19. Smeenk RM, Verwaal VJ, Zoetmulder FA (2007) Pseudomyxoma peritonei. Cancer Treat Rev 33:138–145 20. Sugarbaker PH (2006) New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol 7:69–76 21. Trotti A, Colevas AD, Setser A et al (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176–181 22. Yan TD, Bijelic L, Sugarbaker PH (2007) Critical analysis of treatment failure after complete cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal dissemination from appendiceal mucinous neoplasms. Ann Surg Oncol 14:2289–2299 23. Yoon WS, Yang DS, Lee JA et al (2012) Risk factors related to interfractional variation in whole pelvic irradiation for locally advanced pelvic malignancies. Strahlenther Onkol 188:395–401
P. Berkovic1 · L. van de Voorde1 · G. De Meerleer1 · L. Delrue2 · B. Speleers1 · S. Van Belle3 · K. Vandecasteele1 1 Department of Radiotherapy, Ghent University Hospital, Ghent 2 Department of Radiology, Ghent University Hospital, Ghent 3 Department of Medical Oncology, Ghent University Hospital, Ghent
Whole abdominopelvic radiotherapy in the palliative treatment of pseudomyxoma peritonei
Pseudomyxoma peritonei (PMP) is a rare clinical syndrome characterized by mucinous tumor on peritoneal surfaces and the omentum producing progressive amounts of mucinous ascites [19]. The primary tumor is currently thought to be of appendiceal mucinous epithelial origin showing varying amounts of invasiveness [20]. There still remains confusion on the definition, origin, pathology, classification and treatment of PMP [13]. Metastatic dissemination, hematogenic or lymphatic, has been reported but is rare [18]. A typical feature of this tumor is the production and secretion of mucus into the appendiceal lumen with progressive growth. At a later stage, PMP will engulf the entire peritoneal cavity involving all bowel surfaces, limiting intestinal movement and eventually resulting in bowel obstruction. Traditional treatment of PMP consists of repetitive surgical debulking with removal of all mucinous ascites. However, cure or prolonged remission is uncommon with this approach [10]. Results improved with an aggressive locoregional, combined modality strategy with cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC). This approach resulted in a 5-year overall survival rate ranging from 52–75% [12]. However, this combined modality treatment is not universally accepted as standard of care due to the lack of randomized trials [20]. The combination of surgery and other treatment modalities have been reported in small retrospective series with inconclu-
sive results [18]. Several authors reported the use of intraoperative and postoperative radiotherapy (PORT) [7, 8, 9]. However, similarly with other adjuvant treatment modalities, lack of randomized trials and small patient numbers makes it difficult to assess its effectiveness. In case of recurrence, and in selected patients, repeated cytoreductive surgery with or without HIPEC might improve outcome. However, each repeated debulking procedure becomes less effective with increased morbidity [22]. Other management options at recurrence include observation, systemic chemotherapy and abdominopelvic radiotherapy [9]. We present a case of recurrent PMP treated by whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT).
Case presentation A 63-year-old Caucasian woman with no significant past medical history was referred to the radiotherapy (RT) department in January 2010. Her oncologic history started in September 2008 when she presented with pain in the lower abdomen. Diagnostic work-up revealed an appendicular gelatinous mass in the peritoneal cavity. The tumor markers CA 125 and CEA were 6.87 U/ml and 8.85 ng/ml, respectively. A CT-guided biopsy was performed and showed mucinous material and strips of atypical epithelial cells consistent with mucinous adenocarcinoma suggestive of appendicial origin. The patient underwent a cytoreductive laparoto-
my followed by HIPEC using mitomycin C. Four months after surgery, she started complaining about recurrent abdominal pains along with a progressive elevation of CA 125. 18FDG PET-CT revealed panabdominal disease recurrence. The patient underwent a second extensive cytoreductive laparotomy followed by HIPEC, this time using oxaliplatin (460 mg/m2). Histopathology revealed an extensive mucinous adenocarcinoma involving the whole peritoneal cavity. Four cycles of adjuvant carboplatin plus paclitaxel combination chemotherapy were administered. Re-evaluation after treatment showed no evidence of disease with a CA 125 of 10 U/ ml, which remained normal during the whole period. Six months later, the patient presented with acute abdominal pain, nausea, lack of stools, poor appetite, and weight loss. Clinical examination revealed a tense distended abdomen with diffuse pain. A CT scan revealed a large mass in the right flank extending towards the whole abdominal cavity leading to a mechanical small bowel obstruction, suggestive of a recurrent pseudomyxoma peritonei (. Fig. 1). The patient was referred for surgery and an explorative laparotomy revealed diffuse retroperitoneal recurrence of PMP involving the whole abdominal cavity together with diffuse adhesions. The adhesions were maximally removed but most of the tumor load was deemed unresectable. After postoperative recovery, the patient was referred to our department. Strahlentherapie und Onkologie 2 · 2014
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Fig. 1 8 Pre-adhesiolysis: contrast-enhanced CT scan in venous phase (in axial, coronal, and sagittal planes) reveals a large gelatinous collection in the right hypochonder in combination with nodular thickening of the peritoneal surface
Fig. 2 9 Transversal (a, d), coronal (b, e), and sagittal (c, f) dose distributions of the patient treated with 18 MV photons using a technique of intensity-modulated arc therapy (IMAT) (a, b, c) or 3D conformal radiotherapy (d, e, f) covering the whole abdominopelvic cavity. A dose of 33 Gy was prescribed and delivered in 22 daily fractions of 1.5 Gy. Using 5 arcs, the IMAT plan delivered a combination of conformal avoidance of both kidneys, while providing sufficient coverage of the planning target volume. Using a 4-field box technique, the total dose for the 3D conformal plan was reached with the use of kidney blocks at a median kidney dose of 18 Gy. This results (among others) in an underdosage of the prerenal tissues (d)
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Abstract · Zusammenfassung At admission, she had a Karnofsky performance score of 80 [17] and complained of abdominal bloating, anorexia, and periodic constipation. Clinical examination revealed hyperperistalsis without abdominal pain or ascites. Patient was accepted for WAPRT performed by IMAT. We prescribed a dose of 33 Gy delivered in 22 daily fractions of 1.5 Gy, using 18 MV photons. At each fraction, a cone beam CT was performed for optimal patient setup and target verification [23].The clinical target volume (CTV) was defined as the whole peritoneal cavity. To create the planning target volume, the CTV was expanded with an isotropic margin of 5 mm. Organs at risk (OAR) including the liver, both kidneys and the spinal cord were delineated (. Fig. 2). The treatment was well tolerated. Acute toxicity, scored using CTCAE toxicity criteria version 3.0 [21], consisted of grade II diarrhea and abdominal cramps along with grade I nausea, fatigue, and lymphocytopenia. A Sandostatin analogue and low dose corticosteroids were prescribed with good tolerance and effect. Eight weeks after radiation treatment all toxicities except grade I fatigue and nausea subsided and a return to normal peristalsis, stools, and food intake was observed. CA-125 remained unchanged. A CT re-evaluation, 6 month after WAPRT showed the absence of any obstructive masses (. Fig. 3). Nine month after completion of radiotherapy the patient was admitted for IV fluids and corticosteroids due to suspected late radiation enteritis which subsided after 2 weeks. Eleven months after completion of WAPRT, disease progression was observed with the diagnosis of lung metastasis, lesions around the liver and a cutaneous lesion at the laparotomy scar. The patient started with weekly chemotherapy with liposomal doxorubicin. Re-evaluation after 6 cycles showed stable disease. Due to the painful cutaneous lesions around the laparotomy scar, RT treatment with 6 MeV electrons at a total dose of 20 Gy was delivered in 5 fractions using a bolus of 0.5 cm. The treatment was repeated due to persistent pain. Both treatments were well tolerated and the pain eventually subsided 6 weeks after completion of the second treatment course. Unfortunately,
Strahlenther Onkol 2014 · 190:223–228 DOI 10.1007/s00066-013-0470-7 © Springer-Verlag Berlin Heidelberg 2013 P. Berkovic · L. van de Voorde · G. De Meerleer · L. Delrue · B. Speleers · S. Van Belle · K. Vandecasteele
Whole abdominopelvic radiotherapy in the palliative treatment of pseudomyxoma peritonei Abstract Background. Pseudomyxoma peritonei (PMP) is a rare clinical syndrome characterized by mucinous peritoneal disease arising from disseminated peritoneal adenomucinosis. Primary treatment involves a combination of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). There is no consensus on the proper treatment of recurrent PMP. In selected patients, repeated cytoreductive surgery with or without HIPEC might improve outcome. However, every repeated debulking procedure becomes less effective with increased morbidity. Case report. We present a case of a patient with intestinal obstruction caused by recurrent pseudomyxoma peritonei. We treated the patient with whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT) to a total dose of 33 Gy,
delivered in 22 daily fractions. The treatment was well tolerated and resulted in resolution of the obstruction for a period of 24 months. Conclusion. To the best of our knowledge, we present the first case report showing the possibility of resolving intestinal obstruction with WAPRT in a patient with recurrent PMP. It is our opinion that WAPRT delivered by IMAT, in analogy with ovarian cancer, should be considered as a palliative treatment option in managing patients with recurrent PMP especially in case of obstruction. Keywords Recurrent pseudomyxoma peritonei · Whole abdominopelvic radiotherapy · WAPRT · Intensity-modulated arc therapy · Abdominal obstruction
Bestrahlung des ganzen Abdomens in der Palliativbehandlung des Pseudomyxoma peritonei Zusammenfassung Hintergrund. Pseudomyxoma peritonei (PMP) ist ein seltenes klinisches Syndrom, das sich durch eine muzinöse peritoneale Läsion kennzeichnet, die wiederum aus disse minierter peritonealer Adenomuzinose hervorgeht. Die Erstbehandlung besteht aus ei ner Kombination von zytoreduktiver Chirurgie mit hyperthermischer, intraperitonealer Chemotherapie (HIPEC). Bei Rezidiv-PMP besteht kein Konsens über die richtige Behandlung. Bei ausgewählten Patienten könnte eine erneute zytoreduktive Chirurgie mit oder ohne HIPEC zu einem besseren Ergebnis führen. Allerdings wird jedes neue Debulking minder effektiv und geht einher mit erhöhter Morbidität. Fallbeschreibung. Wir präsentieren einen Patienten mit Darmverschluss, der durch ein Rezidiv-PMP verursacht wurde. Mit Hilfe der intensitätsmodulierten Arc-Therapie (IMAT) behandelten wir den Patienten mit einer Bestrahlung des ganzen Abdomens (WAPRT)
22 months after WAPRT, the patient was diagnosed with progressive lung metastasis and the patient was referred for palliative care where she died 24 months after WAPRT.
mit einer Gesamtdosis von 33 Gy in 22 täglichen Fraktionen. Die Behandlung wurde gut vertragen und führte zu einer langzeitigen Auflösung des Darmverschlusses für einen Zeitraum von 24 Monaten. Schlussfolgerung. Dies ist unseres Wissens nach der erste Fallbericht, der die Möglichkeit zur Behandlung des Darmverschlusses bei einem Patienten mit Rezidiv-PMP mit Hilfe von WAPRT aufzeigt. WAPRT appliziert mit IMAT sollte unserer Ansicht nach, in Analogie zum Ovariumkarzinom, als palliative Behandlungsmöglichkeit bei Patienten mit Rezidiv-PMP in Erwägung gezogen werden, besonders im Falle eines Darmverschlusses. Schlüsselwörter Rezidiv Pseudomyxoma peritonei · Bestrahlung des ganzen Abdomens · WAPRT · Intensitätsmodulierten Arc-Therapie · Darmverschluss
Discussion There is no consensus on the proper treatment of recurrent PMP. In this setting, repeated cytoreductive surgery with or without HIPEC has been reported in seStrahlentherapie und Onkologie 2 · 2014
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Fig. 3 8 Six months post-WAPRT: contrast-enhanced CT scan in venous phase (in axial, coronal, and sagittal planes) shows the absence of obstructive masses and normal appearance of the intestinal loops
100
frequency (%)
80
60
40 CTV PTV PTVoptim liver left kidney exp. 5 mm right kidney exp. 5 mm spinal axis
20
0
0
5
10
15
20 dose (Gy)
25
30
35
40
Fig. 4 8 Dose–volume histograms (DVH) compiled from the data of both planning techniques. IMAT (solid lines) and 3D conventional (dotted lines) represent the DVH for the contoured volumes. Using a 4-field box technique the total dose for the 3D conventional plan was reached with the use of kidney blocks at a median kidney dose of 18 Gy. This resulted in a significant underdosage of the PTV and less homogeneous dose distributions. PTVoptim = PTV minus expanded kidneys, kidney exp.5 mm = contoured kidney expanded with 5 mm to encompass organ movement. Spinal axis = spinal cord + cauda equina
lected patients showing an improved outcome. However, in case of diffusely spread disease throughout the abdomen, repeated surgery might be less successful with increased morbidity and mortality [18]. There is limited experience on the role of external radiotherapy in the adjuvant and recurrent setting of PMP [9]. Furthermore, data on the radiosensitivity of PMP are scarce. Previous reports on the use of radiotherapy in PMP are dated and based on conventional radiotherapy fields. Long
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et al. [11] found no convincing evidence of response of PORT. Fernandez and Daly [8] suggested that PORT improves survival with a 5-year survival rate of 75% after surgery compared with 44% with adjuvant chemotherapy, but the differences were not statistically significant. El Sayed [7] reported a case with the use of megavoltage radiotherapy with large parallel opposed fields to treat the whole abdomen and pelvis in the adjuvant and salvage setting. The intended dose was 35 Gy
in 20 fractions over 4 weeks. However, the treatment had to be terminated at 14 Gy due to deterioration of the patient’s condition but was continued 13 years later. The Mayo Clinic retrospective series reported on the combination of surgery and intracavitary or external beam radiotherapy. A shorter disease-free survival but no overall survival benefit was observed [9]. We hypothesized that WAPRT could be a valuable treatment option in the setting of recurrent PMP due to the spreading pattern of PMP which resembles the transperitoneal dissemination that is common in ovarian cancer [10, 18]. Mature data have demonstrated the role of WAPRT in the treatment of ovarian cancer [4]. Historically, the whole abdomen was treated with large conventional radiotherapy fields. This induced substantial morbidity, particularly small bowel toxicity and myelosuppression, resulting in frequent treatment interruptions and prolonged overall treatment time which decreases overall survival [5]. In fact, when conventional technology was used, WAPRT was not able to deliver adequate radiation doses to the upper abdomen due to the tolerance limits of the OAR (. Fig. 2). Duthoy et al. [6] described a first clinical experience with IMAT for WAPRT and obtained a more homogeneous dose distribution than with conventional planning. By comparing both planning techniques for our patient we could also observe the superiority of the IMAT plan vs. the conventional plan (3D conformal) with superior target coverage and a decrease of dose in the OAR (especially to
Tab. 1 Summary of the DVH data for the IMAT plan and the 3D conformal plan PTV D02 D50 D98 PTV optim D02 D50 D98 CTV D02 D50 D98 Organs at risk Liver D50 Kidney left (exp.5 mm) D02 D50 Kidney right (exp. 5 mm) D02 D50 Spinal Axis D02
IMAT (Gy)
3D conformal (Gy)
36.0 33.4 26.5
35.77 33.00 18.51
36.0 33.5 29.7
35.81 33.07 18.89
36.0 33.6 30.8
35.93 33.20 18.79
17.3
14.65
30.8 16.5
22.46 18.61
31.9 14.5
22.55 18.59
29.2
31.02
PTVoptim = PTV minus expanded kidneys, kidney (exp. 5 mm) = contoured kidney expanded with 5 mm to encompass organ movement, Spinal axis = spinal cord + cauda equine, DVH = dose–volume histogram, IMAT = intensity-modulated arc therapy, 3D = three dimentional, PTV = planning target volume, Gy = Gray, D02, D50, D98 = Dose given to 2%, 50% and 98% of the volume.
the kidneys; . Tab. 1, . Fig. 2, 4). Helical tomotherapy for fast WAPRT is also feasible and enables excellent coverage of the PTV and effective sparing of the OAR [14] Our patient benefitted from these modern radiotherapy techniques. The whole abdomen was treated in 22 daily fractions of 1.5 Gy without interruptions using IMAT. This might explain the favorable long-term response and low toxicity profile. Also in ovarian cancer, malignant bowel obstruction is an important and devastating clinical condition. Most patients show multiple intestinal levels of obstruction precluding any surgical intent with a mean survival between 20 and 75 days and a 3-month life expectancy lower than 25% [1]. In this setting, WAPRT is able to resolve intestinal obstruction for a median duration of 16 weeks with a response rate of 66% [3]. Similarly, in PMP, the major causes of mortality are related to recurrent locoregional disease causing intestinal and biliary obstruction eventually leading to death by long-term starva-
tion [20]. In this setting, Yan et al. [22] observed a progression-free survival of 55% after a second cytoreduction with HIPEC and an overall survival in patients with mixed histologies of 75% at 10 years. The pattern of recurrence remained focal in 58% of patients. However, the study did not report specifically on intestinal obstruction. To the best of our knowledge, this is the first report demonstrating the possibility of resolving intestinal obstruction with WAPRT in a patient with recurrent PMP for a period of 24 months. This compares favorably with the data on ovarian cancer with an obstruction-free survival of only 16 weeks [3]. Eleven months after WAPRT, our patient was diagnosed with lung metastasis. This could be related to the subtype of the neoplasm. The patient was diagnosed on both occasions with a mucinous adenocarcinoma of appendicial origin. Although different grading systems are proposed and controversy persists over the classification of mucinous
peritoneal lesions, these tumors are generally classified as high grade lesions [18]. This variant, compared to the more indolent mucinous peritoneal lesions, is probably a separate entity with differences in biology and worst prognostic outcome [2, 15]. Parenchymal organ and lymph node involvement is more frequent and distant metastasis occur [16].
Conclusion We present a case of a patient with recurrent pseudomyxoma peritonei with intestinal obstruction. The whole abdomen was treated with IMAT to a total dose of 33 Gy, delivered in 22 daily fractions. The treatment was well tolerated and resulted in an obstruction-free survival period of 24 months. It is therefore our opinion that WAPRT delivered by IMAT could be considered as a palliative treatment option in managing patients with recurrent PMP, especially in case of obstruction.
Corresponding address P. Berkovic, M.D. Department of Radiotherapy, Ghent University Hospital De Pintelaan 185, 9000 Ghent Belgium [email protected]
Acknowledgments. The authors would like to thank Prof. M. Mareel M.D., Ph.D. for his valuable comments and suggestions to improve the quality of the manuscript.
Compliance with ethical guidelines Conflict of interest. P. Berkovic, L. van de Voorde, G. De Meerleer, L. Delrue, B. Speleers, S. Van Belle, and K. Vandecasteele state that there are no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.
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