Japanese Journal of Clinical Oncology Advance Access originally published online on February 26, 2008
Japanese Journal of Clinical Oncology 2008 38(3):222-226; doi:10.1093/jjco/hyn004
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Dacarbazine-Doxorubicin Therapy Ameliorated an Extremely Aggressive Mesenteric Desmoid Tumor Associated with Familial Adenomatous Polyposis: Report of a Case
Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
For reprints and all correspondence: Hirofumi Yamamoto, Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita-City, Osaka 565-0871, Japan. E-mail: kobunyam{at}surg2.med.osaka-u.ac.jp
Received September 24, 2007; accepted January 7, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONCASE REPORTDISCUSSIONReferences |
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A 30-year-old man with familial adenomatous polyposis (FAP) underwent prophylactic proctocolectomy by laparoscopy-assisted surgery. After 10 months, we found an intra-abdominal tumor, which grew rapidly to 25 cm in diameter. We performed an emergency operation, which revealed that it was a desmoid tumor derived mainly from colorectal mesenterium. The tumor was removed with three short segments of intestine and the left ureter. A computed tomography (CT) scan done 3 months later showed a 10 cm mesenteric desmoid tumor at the beginning of jejunum, approaching the root of the superior mesenteric artery (SMA). Fortunately, we were able to remove the tumor without injuring the SMA. To our distress, however, another recurrent mesenteric desmoid tumor was discovered in the pelvis one month later, which grew rapidly from 5 cm to 16 cm within 4 months. During this period, we gave the patient several regimens, including antiestrogen (tamoxifen), a nonsteroidal anti-inflammtory drug and imatinib mesylate (Gleevec), which had little or no effect. Finally, when the desmoid occupied the pelvic space, we gave the patient dacarbazine (DTIC) and doxorubicin (DOX). After seven courses, the mesenteric tumor showed an almost complete response (CR). The chemotherapy caused grade 3 to 4 leukocytopenia, but without any hazardous events. No evidence of further recurrence of mesenteric desmoid has been seen for 4 years. This combination chemotherapy is a promising strategy, even against an extremely aggressive, life-threatening mesenteric desmoid associated with FAP.
Key Words: mesenteric desmoid • familial adenomatous polyposis • doxorubicin • dacarbazine
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INTRODUCTION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONReferences |
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Desmoid tumors develop about 1000 times more frequently in patients with familial adenomatous polyposis (FAP) than in the general population, among whom they are rare (1). In fact, desmoid tumors develop in 3.6–13% of patients with FAP (2), and account for 10–14% of deaths of FAP patients, making it the second leading cause of death after colorectal carcinoma (1,3). Surgery is usually indicated for extra-abdominal desmoids such as those in the abdominal-wall, but it is not recommended for mesenteric desmoids, which account for the majority of intra-abdominal desmoids, because they are difficult to resect curatively, the surgery carries a high risk of serious complications such as bleeding and short bowel syndrome, and it is associated with a high incidence of recurrence (4,5). Desmoids do not metastasize to other organs, but invade locally and infiltrate into the surrounding organs such as the intestine, ureters and major vessels, causing bowel and ureteric obstruction. Here we report the case of a Japanese man who underwent emergency surgery twice for life-threatening mesenteric desmoid tumors and survived the third rapidly growing desmoid tumor, thanks to the efficacy of combination chemotherapy using dacarbazine (DTIC) and doxorubicin (DOX).
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CASE REPORT |
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A 29-year-old man was found to have multiple polyposis of the colorectum and stomach at a health check, and a diagnosis of familial adenomatous polyposis (FAP) was subsequently confirmed. He underwent a prophylactic proctocolectomy with ileo-anal canal anastomosis and a diverting ileostomy via laparoscopy-assisted surgery 3 months later, at the age of 30. A computed tomography (CT) scan done 10 months later showed a large intra-abdominal tumor, which grew rapidly, reaching 25 cm in diameter within 2 months. An emergent operation, performed 1 year after his initial operation, revealed that the large tumor originated in the mesenterium of the colorectum since the inferior mesenteric artery was involved in the center of tumor. We removed the giant tumor together with three short fragments of the small bowel, each less than 10 cm in length, and the left ureter because of tumor involvement (Fig. 1a). Pathological examination with hematoxylin and eosin (H&E) staining revealed that the tumor was rich in fibroblasts with mild atypia and abundant collagen deposits, consistent with a desmoid tumor (Fig. 1b).
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A CT scan done 3 months later showed a recurrent desmoid tumor, 10 cm in diameter, at the beginning of the jejunal mesenterium, with imminent involvement of the root of the superior mesenteric artery (SMA). Thus, he underwent a third operation 3 months after the second operation. The tumor was successfully removed with 13 cm of jejunum, without injuring the SMA, and a duodenal-jejunal anastomosis was performed. Only 1 month later, a 5 cm desmoid tumor was found at the bifurcation of the abdominal aorta. This tumor grew rapidly, to 10 cm in 2 months and then to 16 cm in another 2 months. We inserted a stent catheter in the right ureter for hydronephrosis of the right kidney and because surgery was no longer an option, he was treated with several reagents, including nonsteroidal anti-inflammtory drugs (NSAIDs) (etodolac, 200–800 mg/day, total 24000 mg), an anti-estrogen receptor (tamoxifen, 20–40 mg/day, total 5400 mg), a c-kit tyrosine kinase inhibitor (imatinib mesylate, 400–500 mg/day, total 37600 mg) and an HMGCoA reductase inhibitor (pravastatin, 30 mg/day, total 2010 mg) in anticipation of an anti-fibrotic action. However, none of these drugs were effective and 2 months later the tumor occupied the intra-pelvic space (Fig. 2a). As a final treatment option, the patient was started on dacarbazine (DTIC) and doxorubicin (DOX) therapy. With intense monitoring of the peripheral blood cells, we administered dacarbazine (DTIC 650–950 mg/m2/cycle) and doxorubicin (DOX, 65–95 mg/m2/cycle) by continuous infusion for 3 days (72 hrs), repeated every 3–5 weeks for the initial 4 cycles (Fig. 3). Each time that Grade 3 to 4 leukocytopenia developed (graded according to common terminology criteria for adverse events (CTCAE) v3.0 by the National Cancer Institute), he responded quickly to granulocyte stimulating factor (GCSF) (Fig. 3). After three courses, the tumor began to shrink and by 7 months, after the initiation of this regimen, the tumor volume was less than one-seventh of the maximum it had reached, when analyzed by CT volumetry (Fig. 2b). During the tumor regression, the patient had a fever of higher than 38°C, which persisted for 2 months (Fig. 3) without any infectious foci, which was probably a physiological response to the tumor necrosis.
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He was given a further three courses later that year when another abdominal-wall desmoid appeared (Fig. 3). Thus, he received a total of 8400 mg DTIC and 840 mg DOX in the seven courses. To monitor for heart dysfunction caused by DOX, electric cardiography and echocardiogram were repeated periodically, but no problems were detected. The abdominal-wall desmoid remained unchanged at 4 cm in diameter for almost 3 years, then it grew to 8 cm within 2 months and was removed by surgery. However, the mesenteric desmoid has not recurred for 4 years and a complete response (CR) was achieved by this treatment regimen.
A piece of the mesenteric desmoid tumor was examined for adenomatous polyposis coli (APC) gene mutation using in vitro-synthesized protein assay (6,7). A protein truncation pattern indicated that the desmoid harbored mutation among codons 1099–1700 of the APC gene. Further mutation analysis revealed that two base pair insertions (AG) at codon 1465 in exon 15 caused generation of the stop codon in the downstream sequence (Fig. 4). This was exactly the same mutation of the APC gene as that found as germ line mutation in his peripheral blood sample (data not shown).
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DISCUSSION |
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TOPAbstractINTRODUCTIONCASE REPORTDISCUSSIONReferences |
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Desmoids are benign fibromatoses, composed histologically of mature fibroblasts. These tumors usually grow slowly; however, we witnessed a ‘desmoid storm’ after prophylactic proctocolectomy in a patient with FAP. As mentioned in Introduction, surgery is not recommended for intra-abdominal desmoid in the usual situation because of its high rate of recurrence and risk of injury of the involved organs. However, the progression of the first desmoid tumor was amazingly fast, and its compression of the abdominal contents, which became more severe each day, left us no option but to perform an ‘emergency’ operation. Thus, we had no time to await effects of any treatments. The second mesenteric desmoid tumor was life-threatening because it was about to invade the root of the SMA, which supplies blood to the whole intestine. Fortunately, we were able to resect the tumor without injuring the SMA. The third recurrence of the mesenteric desmoid developed only 1 month after resection of the second desmoid tumor, and again, it grew very rapidly, and soon occupied the entire intra-pelvic space. This course of events suggests that the patient had multifocal disease and that surgical intervention might have stimulated the growth of the desmoids, as other clinicians have pointed out (8,9). Therefore, if the tumor growth was not very fast, we had administered chemoreagents instead of surgery.
We initially gave the patient NSAIDs and antiestrogen based on reports of their effectiveness in 15–30% of cases (9, 10). We also gave him imatinib mesylate (Gleevec) based on positive staining of the c-kit protein in the desmoid tumor (data not shown). However, these drugs did not achieve a remarkable response, although there are a few recent reports of imatinib mesylate achieving clinical responses in patients with a desmoid tumor (11, 12).
Our survey of the literature indicated that dacarbazine–doxorubicin (DTIC–DOX) therapy (6,13–15) achieved better results against desmoids than other potential treatments such as prednisolone, interferon gamma, vinorelbine and vinblastine and methotrexate (16–20). DOX interferes with the function of topoisomerase II, and DTIC is an N-methyl-type compound that produces alkylating species. It was clearly demonstrated that adding DTIC to DOX to treat sarcoma patients resulted in a better clinical outcome than DOX alone (21). The adverse effects of this protocol are well documented (22) and do not include renal dysfunction, which was fortunate for this patient who lost function of the left kidney at his first operation for the giant desmoid. Based on the protocol proposed by Patel et al. of DTIC (750–1000 mg/m2) and DOX (60–90 mg/m2), our patient was commenced on a relatively low dose of 667 mg/m2 for DTIC and 67 mg/m2 for DOX, which was graded up to 800 and 80 mg/m2, respectively, with careful monitoring for blood toxicity. Eventually, the DTIC–DOX therapy achieved remarkable tumor inhibitory effects without causing any hazardous events or cardiac dysfunction and the patient survived the desmoid storm. According to one report, if the DOX dose exceeds 550 mg/m2 cardiac muscle damage may occur (22). Thus, periodic examinations with electrocardiography and echocardiography are essential. It is also notewothy that giving DOX as a continuous infusion may reduce the risk of cardiac dysfunction (23).
FAP arises from mutations of the APC gene on chromosome 5q21q22 (24). The mutation region in the APC gene, which is responsible for the development of desmoid tumors in patients with FAP appears not to be specified, although data are limited. These include codons 1309, 1445–1578, 1445–1580, 2643–2644 and others (6,9, 25–29). The desmoid tumors in our patient harbored APC mutation at codon 1465 in exon 15. Further cohort data of germ line mutation in FAP patients, as well as mutations in desmoid tumors, may provides clues to the susceptibility and aggressive potential of desmoid tumors.
The combination of DTIC–DOX has generally achieved excellent clinical outcomes with high rates of partial or CR, as shown in Table 1 (6,13–15). We reported this case to provide further evidence of the remarkable efficacy of DTIC–DOX therapy, even against an extremely aggressive and fast growing mesenteric desmoid tumor. It has been reported that approximately 10% of all desmoid tumors show similar aggressive features (30).
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For extra-abdominal desmoid, the therapeutic strategy appears to come to consensus. Local control may be mainly achieved by surgical intervention and may be improved with the addition of radiation therapy, considering functional and cosmetic outcomes. For patients who cannot undergo surgery, the options for local control include radiation and systemic therapies such as hormones, NSAIDs, interferon and chemotherapy. On the other hand, the optimal therapy for patients with symptomatic, progressive disease, i.e. intra-abdominal desmoid remains to be established and further clinical trials are needed. As mentioned in the Introduction, surgery is usually not a therapeutic option because of its high rate of recurrence and risk of injury of the involved organs. It is recommended that such patients should be presented with low-dose or standard antisarcoma chemotherapy. Hormone therapy, NSAIDs, and interferon are used often, with varying success, and should be reserved for minimally symptomatic patients or for patients who do not want or can not tolerate chemotherapy (31).
According to the recommendation, we should have started with DTIC–DOX therapy instead of the use of several reagents that we initially tested. We actually had hesitation to use chemotherapy of DTIC–DOX to the patient with single kidney because of possible side effects such as myelo-suppression and heart failure and it was difficult to choose which antisarcoma chemotherapy was effective to him. However, the patient himself eventually asked for the DTIC–DOX therapy after his consultation to a physician at Texas Anderson Cancer Center. Following this case, we initially administered DTIC–DOX to the two patients with intra-abdominal desmoid and obtained successful outcomes as well without serious adverse effects (data not shown).
In conclusion, DTIC-DOX therapy shows great potential as an effective treatment strategy to halt the progression of life- threatening, unresectable and fast-growing mesenteric desmoid tumors associated with FAP. Considering its high efficacy and controllable adverse effects, DTIC–DOX therapy should be preferentially considered for these patients.
Conflict of interest statement
None declared.
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Footnotes |
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Abbreviations: APC, adenomatous polyposis coli; CT, computed tomography; DOX, doxorubicin; DTIC, dacarbazine; FAP, familial adenomatous polyposis; NSAID, nonsteroidal anti-inflammtory drug; SMA, superior mesenteric artery.
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References |
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