Case Report
Mitomycin-based hepatic arterial infusion chemotherapy for solitary ampullary cancer liver metastasis: an unusual treatment for an uncommon disease
J Oncol Pharm Practice 2015, Vol. 21(5) 396–399 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214531512 opp.sagepub.com
Felice V Vitale1, Placido Romeo2, Bruno Luciani2, Mario Raffaele1, Paolo Colina1 and Francesco Ferrau`1
Abstract Ampullary carcinoma is an uncommon gastrointestinal disease. Its natural history is often characterized by the occurrence of liver metastases. Among patients who undergo pancreatoduodenectomy, those presenting with lymph nodes involvement are more prone to early distant disease relapse. In this report, a patient previously diagnosed with ampullary carcinoma had been treated with curative surgery. After subsequent adjuvant gemcitabine, the patient developed significant myelotoxicity and suffered from a single liver metastasis a few months later. A hepatic intra-arterial mitomycin plus fluorouracil-based chemotherapy was administered in order to avoid any serious systemic toxicity. The treatment was well tolerated and no serious side effects occurred. Extra-hepatic cancer relapse, involving intra-thoracic and abdominal lymph nodes, was observed not long after the initial intra-hepatic almost complete response. In conclusion, the locoregional chemotherapy administration was effective in overcoming any systemic toxicities and showed activity against the liver metastasis but it did not prevent extra-hepatic cancer dissemination.
Keywords Mitomycin, ampullary carcinoma, hepatic intra-arterial chemotherapy, liver metastases
Introduction Carcinoma of the ampulla of Vater accounts for 0.2% of all gastrointestinal malignant tumors.1 Pancreatoduodenectomy is the cornerstone of curative treatment of ampullary carcinoma and chemotherapy or chemo-radiotherapy is considered as an adjuvant approach for node-positive patients.2 Also, the involvement of locoregional lymph nodes predicts a high risk of cancer relapse after surgical resection, and the liver is a frequent site of metastatization.3,4 Patients who are not suitable candidates for surgical resection or suffering from metastatic disease, are usually treated like pancreato-biliary tumors. In this regard, platinum analogs, fluoropirimidines, gemcitabine (GEM) and mitomycin (MMC) are the drugs of choice.1,5,6 As to the MMC and fluorouracil (5-FU) combination, some authors have already reported on their hepatic intraarterial infusion when treating biliary tract tumors.7 The two-year survival in metastatic disease ranges
from 5% to 10%.1,8 Here the authors report on a patient, unfit for systemic chemotherapy, suffering from a single ampullary cancer liver metastasis, which occurred shortly after primary surgery (pancreatoduodenectomy). The patient took transient advantage of hepatic intra-arterial chemotherapy administration.
Case report In January 2011, a 75-year-old male patient underwent duodeno-pancreatectomy for a carcinoma of the 1
Division of Medical Oncology, San Vincenzo Hospital, Taormina, Italy Division of Diagnostic and Interventional Radiology, San Vincenzo Hospital, Taormina, Italy 2
Corresponding author: Felice Vito Vitale, Division of Medical Oncology, San Vincenzo Hospital, Contrada Sirina, Taormina 98039, Italy. Email: [email protected]
Downloaded from opp.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on September 10, 2015
Vitale et al.
397
ampulla of Vater. As postoperative histological findings showed locoregional lymph node metastases, the patient was offered adjuvant chemo-radiotherapy. Thus, a so called ‘‘sandwich chemo-radiotherapy’’ strategy was planned: three courses of GEM-based mono-chemotherapy followed by a complementary radiotherapy and three subsequent cycles of the same chemotherapy. The mono-chemotherapy regimen consisted of GEM 1000 mg/m2 for a 30-min infusion period once a week for three weeks followed by two weeks of rest, and repeated every four weeks. After the first three cycles, grade 2 anemia was observed so the GEM dose was reduced by 20% and eritropoietin was administered. After the completion of subsequent radiotherapy delivered to the surgical bed (5040 centi-Gray from June to July 2011), further five sessions of mono-chemotherapy were administered (the last session was carried out in September 2011). The patient
did not undergo the planned post-radiotherapy for nine sessions (namely three cycles) of chemotherapy due to myelotoxicity (grade 3 non-febrile neutropenia and grade 2 thrombocytopenia). In January 2012, 18-fluorodeoxyglucose positron emission tomography (PET) scans showed cancer relapse in the liver (Figure 1(a)) and a magnetic resonance (MR) confirmed the single metastasis (the longest diameter measure was 25 mm) lodged between the eighth and fourth hepatic segments next to the lower side of the diaphragm and in close proximity to a cyst (Figure 2(a) and (b)). Interventional radiologists and surgeons were consulted for additional evaluation. The proximity of the metastasis to the diaphragm on one hand, and the short period since the completion of adjuvant treatments on the other hand, discouraged interventional radiologists and surgeons from acting. As the patient suffered from serious myelotoxicity during systemic adjuvant chemotherapy he
Figure 1. PET scan before (a) and after (b) three cycles of hepatic intra-arterial chemotherapy. The red circle shows the single liver metastasis.
Downloaded from opp.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on September 10, 2015
398
Journal of Oncology Pharmacy Practice 21(5)
was offered hepatic intra-arterial chemotherapy and signed the informed consent in accordance with the institutional regulations. A chemotherapy combination based on intra-arterial 5-FU 500 mg/m2/day continuous infusion on days 1–4 and MMC 5 mg/m2 on day 1 every four weeks was started. After three cycles of intra-arterial chemotherapy, the abdominal MR showed an almost complete response (Figure 2) and the whole body PET (Figure 1) did not find any significant metabolic activity. Furthermore, after a total of six intra-arterial treatments, both whole body PET and abdominal MR still appeared without variation from the previous examinations. However, in December 2012 the whole body PET/ TC scan showed extra-hepatic cancer recurrence (intrathoracic and abdominal lymph nodes). A further treatment with metronomic low-dose oral capecitabine, 500 mg three times daily, continuously, was ineffective and grade 1 thrombocytopenia occurred reflecting the fact that the chemotherapy delivered by locoregional route was the only option to prevent the patient from significant myelotoxicity.9 In September 2013 the patient died of liver and respiratory insufficiency caused by diffuse liver and lung metastases.
Discussion Almost three decades ago, some authors reported nonnegligible results from the administration of hepatic intra-arterial 5-FU and MCC combination in treating biliary tract tumors.7 In general, the literature data show extra-hepatic progression as a major cause of failure when treating liver metastases with hepatic intra-arterial chemotherapy. At present this type of therapeutic tool seems to be almost fallen into disuse. Nevertheless, some authors suggest to add systemic chemotherapy to intra-arterial chemotherapy administration in order to prevent the development of extra-hepatic metastases.10 In addition, in accordance with literature data and recent published papers, intraarterial chemotherapy might still be taken into consideration when used with neo-adjuvant intent in patients suffering from colon cancer and planning to undergo hepatic metastases resection.11 Regarding our report, despite myelotoxity being a well-known MMC-related side-effect and the patient being prone to suffer from it, MMC and fluorouracil combination used by hepatic intra-arterial route was well tolerated.12 In conclusion, the above described locoregional approach based on hepatic intra-arterial MMC administration was an
Figure 2. MR scan before (a, b) and after (c, d) three cycles of hepatic intra-arterial chemotherapy. The white arrows show the single liver metastasis.
Downloaded from opp.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on September 10, 2015
Vitale et al.
399
effective strategy to overcome systemic myelotoxicity and was helpful to this unfit patient. Therefore, the treatment might be occasionally considered in managing liver metastases from ampullary carcinoma in selected patients. Unfortunately, this kind of therapy does not ensure that extra-hepatic metastatic spread will not occur. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of Interest None declared.
References 1. Romiti A, Barucca V, Zullo A, et al. Tumors of ampulla of Vater: a case series and review of chemotherapy options. World J Gastrointest Oncol 2012; 4: 60–67. 2. Narang AK, Miller RC and Hsu CC. Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study. Radiat Oncol 2011; 6: 126. 3. Roland CL, Katz MH, Gonzalez GM, et al. A high positive lymph node ratio is associated with distant recurrence after surgical resection of ampullary carcinoma. J Gastrointest Surg 2012; 16(11): 2056. 4. Woo SM, Ryu JK, Lee SH, et al. Recurrence and prognostic factors of ampullary carcinoma after radical resection: comparison with distal extrahepatic cholangiocarcinoma. Ann Surg Oncol 2007; 14: 3195–3201.
5. Overman MJ, Varadhachary GR, Kopetz S, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 2009; 27(16): 2598–2603. 6. Morganti AG, Macchia G, Trodella L, et al. Complete response after chemoradiation in ampullary carcinoma: a case report. Tumori 2003; 89(1): 82–84. 7. Smith GW, Bukowski RM, Hewlett JS, et al. Hepatic artery infusion of 5-fluorouracil and mitomycin C in cholangiocarcinoma and gallbladder carcinoma. Cancer 1984; 54: 1513–1516. 8. Key C and Meisner A. Cancers of the liver and biliary tract. In Ries LAG, et al. (eds) SEER survival monograph: cancer survival among adults—USSEER program, 1988– 2001, patient and tumor characteristics. Bethesda, MD: National Cancer Institute, SEER Program, 2007. NIH Pub. No. 07-6215. 9. He S, Shen J, Hong L, et al. Capecitabine ‘‘metronomic’’ chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidinebased chemotherapy. Med Oncol 2012; 29: 100–106. 10. Cohen AD and Kemeny NE. An update on hepatic arterial infusion chemotherapy for colorectal cancer. Oncologist 2003; 8: 553–566. 11. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist 2012; 17: 1225–1239. 12. Doll DC, Weiss RB and Issell BF. Mitomycin: ten years after approval for marketing. J Clin Oncol 1985; 3(2): 276–286.
Downloaded from opp.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on September 10, 2015
Mitomycin-based hepatic arterial infusion chemotherapy for solitary ampullary cancer liver metastasis: an unusual treatment for an uncommon disease
J Oncol Pharm Practice 2015, Vol. 21(5) 396–399 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214531512 opp.sagepub.com
Felice V Vitale1, Placido Romeo2, Bruno Luciani2, Mario Raffaele1, Paolo Colina1 and Francesco Ferrau`1
Abstract Ampullary carcinoma is an uncommon gastrointestinal disease. Its natural history is often characterized by the occurrence of liver metastases. Among patients who undergo pancreatoduodenectomy, those presenting with lymph nodes involvement are more prone to early distant disease relapse. In this report, a patient previously diagnosed with ampullary carcinoma had been treated with curative surgery. After subsequent adjuvant gemcitabine, the patient developed significant myelotoxicity and suffered from a single liver metastasis a few months later. A hepatic intra-arterial mitomycin plus fluorouracil-based chemotherapy was administered in order to avoid any serious systemic toxicity. The treatment was well tolerated and no serious side effects occurred. Extra-hepatic cancer relapse, involving intra-thoracic and abdominal lymph nodes, was observed not long after the initial intra-hepatic almost complete response. In conclusion, the locoregional chemotherapy administration was effective in overcoming any systemic toxicities and showed activity against the liver metastasis but it did not prevent extra-hepatic cancer dissemination.
Keywords Mitomycin, ampullary carcinoma, hepatic intra-arterial chemotherapy, liver metastases
Introduction Carcinoma of the ampulla of Vater accounts for 0.2% of all gastrointestinal malignant tumors.1 Pancreatoduodenectomy is the cornerstone of curative treatment of ampullary carcinoma and chemotherapy or chemo-radiotherapy is considered as an adjuvant approach for node-positive patients.2 Also, the involvement of locoregional lymph nodes predicts a high risk of cancer relapse after surgical resection, and the liver is a frequent site of metastatization.3,4 Patients who are not suitable candidates for surgical resection or suffering from metastatic disease, are usually treated like pancreato-biliary tumors. In this regard, platinum analogs, fluoropirimidines, gemcitabine (GEM) and mitomycin (MMC) are the drugs of choice.1,5,6 As to the MMC and fluorouracil (5-FU) combination, some authors have already reported on their hepatic intraarterial infusion when treating biliary tract tumors.7 The two-year survival in metastatic disease ranges
from 5% to 10%.1,8 Here the authors report on a patient, unfit for systemic chemotherapy, suffering from a single ampullary cancer liver metastasis, which occurred shortly after primary surgery (pancreatoduodenectomy). The patient took transient advantage of hepatic intra-arterial chemotherapy administration.
Case report In January 2011, a 75-year-old male patient underwent duodeno-pancreatectomy for a carcinoma of the 1
Division of Medical Oncology, San Vincenzo Hospital, Taormina, Italy Division of Diagnostic and Interventional Radiology, San Vincenzo Hospital, Taormina, Italy 2
Corresponding author: Felice Vito Vitale, Division of Medical Oncology, San Vincenzo Hospital, Contrada Sirina, Taormina 98039, Italy. Email: [email protected]
Downloaded from opp.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on September 10, 2015
Vitale et al.
397
ampulla of Vater. As postoperative histological findings showed locoregional lymph node metastases, the patient was offered adjuvant chemo-radiotherapy. Thus, a so called ‘‘sandwich chemo-radiotherapy’’ strategy was planned: three courses of GEM-based mono-chemotherapy followed by a complementary radiotherapy and three subsequent cycles of the same chemotherapy. The mono-chemotherapy regimen consisted of GEM 1000 mg/m2 for a 30-min infusion period once a week for three weeks followed by two weeks of rest, and repeated every four weeks. After the first three cycles, grade 2 anemia was observed so the GEM dose was reduced by 20% and eritropoietin was administered. After the completion of subsequent radiotherapy delivered to the surgical bed (5040 centi-Gray from June to July 2011), further five sessions of mono-chemotherapy were administered (the last session was carried out in September 2011). The patient
did not undergo the planned post-radiotherapy for nine sessions (namely three cycles) of chemotherapy due to myelotoxicity (grade 3 non-febrile neutropenia and grade 2 thrombocytopenia). In January 2012, 18-fluorodeoxyglucose positron emission tomography (PET) scans showed cancer relapse in the liver (Figure 1(a)) and a magnetic resonance (MR) confirmed the single metastasis (the longest diameter measure was 25 mm) lodged between the eighth and fourth hepatic segments next to the lower side of the diaphragm and in close proximity to a cyst (Figure 2(a) and (b)). Interventional radiologists and surgeons were consulted for additional evaluation. The proximity of the metastasis to the diaphragm on one hand, and the short period since the completion of adjuvant treatments on the other hand, discouraged interventional radiologists and surgeons from acting. As the patient suffered from serious myelotoxicity during systemic adjuvant chemotherapy he
Figure 1. PET scan before (a) and after (b) three cycles of hepatic intra-arterial chemotherapy. The red circle shows the single liver metastasis.
Downloaded from opp.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on September 10, 2015
398
Journal of Oncology Pharmacy Practice 21(5)
was offered hepatic intra-arterial chemotherapy and signed the informed consent in accordance with the institutional regulations. A chemotherapy combination based on intra-arterial 5-FU 500 mg/m2/day continuous infusion on days 1–4 and MMC 5 mg/m2 on day 1 every four weeks was started. After three cycles of intra-arterial chemotherapy, the abdominal MR showed an almost complete response (Figure 2) and the whole body PET (Figure 1) did not find any significant metabolic activity. Furthermore, after a total of six intra-arterial treatments, both whole body PET and abdominal MR still appeared without variation from the previous examinations. However, in December 2012 the whole body PET/ TC scan showed extra-hepatic cancer recurrence (intrathoracic and abdominal lymph nodes). A further treatment with metronomic low-dose oral capecitabine, 500 mg three times daily, continuously, was ineffective and grade 1 thrombocytopenia occurred reflecting the fact that the chemotherapy delivered by locoregional route was the only option to prevent the patient from significant myelotoxicity.9 In September 2013 the patient died of liver and respiratory insufficiency caused by diffuse liver and lung metastases.
Discussion Almost three decades ago, some authors reported nonnegligible results from the administration of hepatic intra-arterial 5-FU and MCC combination in treating biliary tract tumors.7 In general, the literature data show extra-hepatic progression as a major cause of failure when treating liver metastases with hepatic intra-arterial chemotherapy. At present this type of therapeutic tool seems to be almost fallen into disuse. Nevertheless, some authors suggest to add systemic chemotherapy to intra-arterial chemotherapy administration in order to prevent the development of extra-hepatic metastases.10 In addition, in accordance with literature data and recent published papers, intraarterial chemotherapy might still be taken into consideration when used with neo-adjuvant intent in patients suffering from colon cancer and planning to undergo hepatic metastases resection.11 Regarding our report, despite myelotoxity being a well-known MMC-related side-effect and the patient being prone to suffer from it, MMC and fluorouracil combination used by hepatic intra-arterial route was well tolerated.12 In conclusion, the above described locoregional approach based on hepatic intra-arterial MMC administration was an
Figure 2. MR scan before (a, b) and after (c, d) three cycles of hepatic intra-arterial chemotherapy. The white arrows show the single liver metastasis.
Downloaded from opp.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on September 10, 2015
Vitale et al.
399
effective strategy to overcome systemic myelotoxicity and was helpful to this unfit patient. Therefore, the treatment might be occasionally considered in managing liver metastases from ampullary carcinoma in selected patients. Unfortunately, this kind of therapy does not ensure that extra-hepatic metastatic spread will not occur. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of Interest None declared.
References 1. Romiti A, Barucca V, Zullo A, et al. Tumors of ampulla of Vater: a case series and review of chemotherapy options. World J Gastrointest Oncol 2012; 4: 60–67. 2. Narang AK, Miller RC and Hsu CC. Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study. Radiat Oncol 2011; 6: 126. 3. Roland CL, Katz MH, Gonzalez GM, et al. A high positive lymph node ratio is associated with distant recurrence after surgical resection of ampullary carcinoma. J Gastrointest Surg 2012; 16(11): 2056. 4. Woo SM, Ryu JK, Lee SH, et al. Recurrence and prognostic factors of ampullary carcinoma after radical resection: comparison with distal extrahepatic cholangiocarcinoma. Ann Surg Oncol 2007; 14: 3195–3201.
5. Overman MJ, Varadhachary GR, Kopetz S, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol 2009; 27(16): 2598–2603. 6. Morganti AG, Macchia G, Trodella L, et al. Complete response after chemoradiation in ampullary carcinoma: a case report. Tumori 2003; 89(1): 82–84. 7. Smith GW, Bukowski RM, Hewlett JS, et al. Hepatic artery infusion of 5-fluorouracil and mitomycin C in cholangiocarcinoma and gallbladder carcinoma. Cancer 1984; 54: 1513–1516. 8. Key C and Meisner A. Cancers of the liver and biliary tract. In Ries LAG, et al. (eds) SEER survival monograph: cancer survival among adults—USSEER program, 1988– 2001, patient and tumor characteristics. Bethesda, MD: National Cancer Institute, SEER Program, 2007. NIH Pub. No. 07-6215. 9. He S, Shen J, Hong L, et al. Capecitabine ‘‘metronomic’’ chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidinebased chemotherapy. Med Oncol 2012; 29: 100–106. 10. Cohen AD and Kemeny NE. An update on hepatic arterial infusion chemotherapy for colorectal cancer. Oncologist 2003; 8: 553–566. 11. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist 2012; 17: 1225–1239. 12. Doll DC, Weiss RB and Issell BF. Mitomycin: ten years after approval for marketing. J Clin Oncol 1985; 3(2): 276–286.
Downloaded from opp.sagepub.com at Kungl Tekniska Hogskolan / Royal Institute of Technology on September 10, 2015
