pseudomyxoma peritonei ( pmp ) is a rare syndrome characterized by loculated gelatinous ascites and peritoneal dissemination of tumor implants . patients present with symptoms of increasing abdominal girth , bloating , nausea and occasionally intestinal obstruction . pmp is reported to originate primarily from gastrointestinal tumors , however , pmp has been associated in patients with mucinous ovarian tumors of low malignant potential ( lmp ) and in association with mature cystic teratomas . in addition , because many patients with pmp of intestinal origin can present with ovarian masses and peritoneal disease consistent with ovarian malignancy , many of these patients are treated by gynecologic oncologists . the diagnosis of pmp associated with ovarian invasion versus primary ovarian tumor remains difficult as appendiceal tumors and borderline mucinous ovarian tumors have very similar histological appearances . histopathologically , pmp is sub - classified into high - grade peritoneal mucinous carcinomatosis ( pmca )   or low - grade disseminated peritoneal adenomucinosis ( dpam ) . histologically dpam can be indistinguishable from intestinal type mucinous ovarian lmp tumors . similar to ovarian lmp tumors regardless of the origin of pmp , traditional treatment for pmp has consisted of aggressive , serial surgical debulking and/or stripping procedures . in an attempt to improve results , several groups have studied the addition of hyperthermic intraperitoneal chemotherapy ( hipec ) administered at the time of debulking . however , morbidity can still be significant , many patients are not candidates for surgery or hipec , and hipec is not available at many centers . even after aggressive surgery and hipec , many patients can progress either as a result of technical complications or disease biology . when patients with pmp are not surgical candidates , they ultimately succumb to the underlying cancer . the use of traditional chemotherapy has not demonstrated a survival advantage over surgery alone . bevacizumab ( bevacizumab , genentech ) binds to the vascular endothelial growth factor ( vegf ) and inhibits angiogenesis . we speculated that bevacizumab would be an effective agent against pmp with significant ovarian invasion because : ( 1 ) vegf levels at the time of cytoreductive surgeries for pmp have been inversely correlated with survival , ( 2 ) bevacizumab has activity in other non - chemoresponsive cancers , and ( 3 ) bevacizumab has activity in both gastrointestinal tumors and refractory ovarian cancer . we describe here two patients with unresectable pmp and ovarian mucinous lmp tumors treated with bevacizumab . no gross appendiceal involvement was noted at the time of surgery and an appendectomy was not performed . the patient showed signs of disease progression early after surgery and she was treated with multiple chemotherapy regimens including 7 cycles of carboplatinum - paclitaxel , 3 cycles of topotecan , 5 cycles of liposomal doxorubicin , 32 cycles of gemcitabine , 3 cycles of etoposide and 2 cycles of doxorubicin - cyclophosphamide . with each she demonstrated progressive disease . she underwent an aggressive interval debulking , however , she was deemed not to be a candidate for hipec . bevacizumab was initiated at 10 mg / kg every other week . while on bevacizumab therapy , the patient 's ca19 - 9 steadily declined , and her symptoms of bloating and early satiety dramatically improved . treatment was complicated by hypertension and proteinuria ( 1.8 g urine protein/24 h ) and treatment was temporarily held for two weeks while anti - hypertensives were initiated . the patient 's blood pressure was controlled with amlodipine and captopril . while off therapy there was a modest rise in the ca19 - 9 . with re - initiation of bevacizumab the patient received a total of 11 cycles of bevacizumab therapy over approximately 9 months ( fig . 1ai ) , then once again developed significant proteinuria ( > 2 g urine protein/24 h ) requiring discontinuation of therapy . the patient was monitored off therapy with stable symptoms and ca19 - 9 laboratory values for 6 months . a ct scan demonstrated an increase in ascites and a partial increase in solid tumor burden ( fig . the patient 's blood pressure remained well - controlled on medication and the patient 's proteinuria had nearly resolved ( 168 mg urine protein/24 h ) . bevacizumab was reinitiated . once again , on therapy the patient experienced a complete resolution of symptoms and the ca19 - 9 declined ( fig . ct scan revealed a reduction in ascites and a stable appearance of solid tumor burden ( fig . currently , the patient has received 9 additional months of bevacizumab therapy without adverse side - effects , though there has been a slight worsening of her proteinuria . a 78-year - old female presented with abdominal bloating and was found to have a large pelvic mass . postoperatively , the patient was asymptomatic for 30 months but then presented with progressive disease . at that time she underwent a second surgery . she had a right colectomy , partial small bowel resection , splenectomy and distal pancreatectomy . despite the aggressive surgery the patient had a suboptimal debulking . she was unable to receive hipec secondary to intraoperative complications . within 3 months of surgery she had clinically evident disease on exam , and she presented to our institution for transfer of care . at that time the patient 's ca19 - 9 was 202.5 , and on exam she had palpable diffuse carcinomatosis of her abdomen . the patient 's ca19 - 9 peaked at 234 after the first cycle of therapy . after successive cycles of therapy , the ca19 - 9 decreased to 180 and the patient reported significant symptom improvement ( fig . after 6 cycles , the patient 's physical exam demonstrated increasing tumor burden and the ca19 - 9 began to increase . the response was again observed for an additional 4 months at which point the treatment was discontinued secondary to worsening symptoms . no gross appendiceal involvement was noted at the time of surgery and an appendectomy was not performed . the patient showed signs of disease progression early after surgery and she was treated with multiple chemotherapy regimens including 7 cycles of carboplatinum - paclitaxel , 3 cycles of topotecan , 5 cycles of liposomal doxorubicin , 32 cycles of gemcitabine , 3 cycles of etoposide and 2 cycles of doxorubicin - cyclophosphamide . with each she demonstrated progressive disease . she underwent an aggressive interval debulking , however , she was deemed not to be a candidate for hipec . bevacizumab was initiated at 10 mg / kg every other week . while on bevacizumab therapy , the patient 's ca19 - 9 steadily declined , and her symptoms of bloating and early satiety dramatically improved . treatment was complicated by hypertension and proteinuria ( 1.8 g urine protein/24 h ) and treatment was temporarily held for two weeks while anti - hypertensives were initiated . the patient 's blood pressure was controlled with amlodipine and captopril . while off therapy there was a modest rise in the ca19 - 9 . with re - initiation of bevacizumab the patient received a total of 11 cycles of bevacizumab therapy over approximately 9 months ( fig . 1ai ) , then once again developed significant proteinuria ( > 2 g urine protein/24 h ) requiring discontinuation of therapy . the patient was monitored off therapy with stable symptoms and ca19 - 9 laboratory values for 6 months . a ct scan demonstrated an increase in ascites and a partial increase in solid tumor burden ( fig . the patient 's blood pressure remained well - controlled on medication and the patient 's proteinuria had nearly resolved ( 168 mg urine protein/24 h ) . bevacizumab was reinitiated . once again , on therapy the patient experienced a complete resolution of symptoms and the ca19 - 9 declined ( fig . ct scan revealed a reduction in ascites and a stable appearance of solid tumor burden ( fig . currently , the patient has received 9 additional months of bevacizumab therapy without adverse side - effects , though there has been a slight worsening of her proteinuria . a 78-year - old female presented with abdominal bloating and was found to have a large pelvic mass . postoperatively , the patient was asymptomatic for 30 months but then presented with progressive disease . at that time she underwent a second surgery . she had a right colectomy , partial small bowel resection , splenectomy and distal pancreatectomy . despite the aggressive surgery the patient had a suboptimal debulking . she was unable to receive hipec secondary to intraoperative complications . within 3 months of surgery she had clinically evident disease on exam , and she presented to our institution for transfer of care . at that time the patient 's ca19 - 9 was 202.5 , and on exam she had palpable diffuse carcinomatosis of her abdomen . the patient 's ca19 - 9 peaked at 234 after the first cycle of therapy . after successive cycles of therapy , the ca19 - 9 decreased to 180 and the patient reported significant symptom improvement ( fig . 1aii ) . after 6 cycles , the patient 's physical exam demonstrated increasing tumor burden and the ca19 - 9 began to increase . the response was again observed for an additional 4 months at which point the treatment was discontinued secondary to worsening symptoms . we present here two cases of inoperable , progressive pmp diagnosed in association with mucinous ovarian lmp tumors treated with bevacizumab . however , the quality and duration of the response for each of these patients was rather distinct . patient 1 responded for over 9 months until therapy was held secondary to proteinuria , remained stable for 6 months , and then responded for an additional 9 months with re - initiation of single agent therapy . she then responded for an additional 4 months to combination therapy with bevacizumab and chemotherapy , before once again progressing . the distinct difference in durability of response may relate to several clinical differences which distinguish the two patients . patient 1 had an optimal interval debulking surgery , whereas patient 2 was suboptimally debulked at her interval surgery . patient 1 was relatively young , whereas patient 2 was an octogenarian at the time of bevacizumab therapy . interestingly , lee et al .   reported age as the only prognostic factor in comparing outcomes among groups with ovarian associated pmp , suggesting age plays a significant role in disease biology . surprisingly , patient 1 had progressed through several lines of chemotherapy yet demonstrated response within 2 cycles of therapy with bevacizumab ( fig . 1 ) . in contrast patient 2 was chemo - nave at the time of bevacizumab therapy . thus younger , optimally debulked patients may be excellent candidates for a trial of bevacizumab therapy , regardless of previous chemotherapy exposure . no evidence of significant hemorrhage , deep - venous thrombosis , or gastric perforation was seen . while the majority of pmp is believed to originate from appendiceal / gastrointestinal tumors , rarely it can be associated with tumors from other sites . pmp has been reported in association with ovarian tumors , including mucinous lmp tumors and cystadenocarcinomas arising from mature cystic teratomas . however , recent molecular and immunohistochemical studies suggest that many pmp - associated ovarian tumors are actually gastrointestinal tumors with ovarian invasion . both of our patients had pmp diagnosed in conjunction with mucinous ovarian lmp tumors . patient 1 had her primary surgery at a community center and did not have an appendectomy so may have had appendiceal disease . interestingly , patient 2 had primary surgery , which included appendectomy , at a major academic center . pathology revealed no evidence of appendiceal disease and intra - ovarian disease without surface involvement , more consistent with ovarian primary . regardless of the origin , the long - term prognosis for recurrent pmp is poor secondary to disease progression . one patient with a progressive dpam tumor with neuroendocrine features demonstrated response to therapy with intravenous gemcitabine . a second report suggested activity of folfox chemotherapy delivered adjuvantly to a patient after surgery for an appendiceal pseudomyxoma . the patient was treated with 10 months of chemotherapy and remained without evidence of disease progression at 21 months . more importantly , the first clinical trial suggesting a potential benefit from chemotherapy in this patient population was recently reported . a phase ii trial of mitomycin - c and capecitabine in 40 patients with non - resectable pmp reported response or stable disease in 38% of patients . of the patients with progressive disease , only 14% demonstrated a reduction in disease ( 3 with decreased ascites and 1 with a decrease in tumor burden ) . interestingly , two thirds of eligible patients reported an improvement in their quality of life while on therapy due to a reduction in symptoms . while this phase ii study is encouraging , further management strategies for pmp are clearly necessary ; the majority of patients in this study did not receive a clinical benefit . our experience with bevacizumab suggests a relatively non - toxic therapy with significant activity in ovarian pmp worthy of further study . similar to the patients in the trial with mitomycin - c and capecitabine , our patients demonstrated tumor marker response that correlated with disease response . patient 2 had a clinical and biomarker response to both single agent bevacizumab and bevacizumab in combination with chemotherapy . this report provides an initial rationale for the use of bevacizumab in clinical trials in pmp . given the improved activity observed with bevacizumab in combination with chemotherapy in other solid tumors and the recent report of an active chemotherapeutic regimen for pmp , trials with bevacizumab as a single agent or in combination with chemotherapy for unresectable pmp may be warranted .
pseudomyxoma peritonei ( pmp ) is a rare tumor syndrome that can be diagnosed in association with mucinous ovarian tumors of low malignant potential . 
 surgical debulking is the primary treatment modality as chemotherapy has generally proven ineffective in this slowly progressive tumor . 
 when patients with pmp are not surgical candidates , there is no effective treatment , and patients will die of progressive disease . 
 we report two patients with pmp with associated mucinous ovarian tumor of low malignant potential treated with bevacizumab therapy . 
 both patients demonstrated disease response to single agent bevacizumab therapy . 
 one patient had a prolonged response while on therapy , remained stable for 6 months when treatment was held , and then after progressing responded to a second course of therapy . 
 we discuss here ( 1 ) the clinical features which may predict a better response to bevacizumab therapy , and ( 2 ) evidence for the use of chemotherapy for inoperable pmp . 
 these cases suggest that bevacizumab may represent a rare effective therapy for patients with inoperable pmp with ovarian involvement and should be considered for clinical trials in this patient population .