|Year : 2019 | Volume
| Issue : 2 | Page : 85-88
A Patient with refractory metastatic germ cell tumor successful salvaged after treatment with paclitaxel, ifosfamide, and high-dose 5-Fluorouracil infusional therapy
Keng-Man Chiang1, Ann-Lii Cheng2
1 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Oncology; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
|Date of Submission||29-Jul-2018|
|Date of Decision||19-Nov-2018|
|Date of Acceptance||26-Nov-2018|
|Date of Web Publication||31-May-2019|
Dr. Keng-Man Chiang
Department of Oncology, National Taiwan University Hospital, No. 7, Zhongshan South Road, Taipei 10002
Source of Support: None, Conflict of Interest: None
We report a case of a 24-year-old male with a metastatic extragonadal germ cell tumor (GCT) which was refractory to conventional chemotherapy and progressed after high-dose chemotherapy. The addition of a 24-h infusion of high-dose 5-fluorouracil (5-FU) with leucovorin regimen to a salvage regimen of paclitaxel and ifosfamide provided a durable clinical response. We also discuss the potential of repurposing 5-FU for the treatment of a refractory GCT.
Keywords: 5-fluorouracil, germ cell tumor, high-dose chemotherapy, platinum-refractory
|How to cite this article:|
Chiang KM, Cheng AL. A Patient with refractory metastatic germ cell tumor successful salvaged after treatment with paclitaxel, ifosfamide, and high-dose 5-Fluorouracil infusional therapy. J Cancer Res Pract 2019;6:85-8
|How to cite this URL:|
Chiang KM, Cheng AL. A Patient with refractory metastatic germ cell tumor successful salvaged after treatment with paclitaxel, ifosfamide, and high-dose 5-Fluorouracil infusional therapy. J Cancer Res Pract [serial online] 2019 [cited 2021 Apr 22];6:85-8. Available from: https://www.ejcrp.org/text.asp?2019/6/2/85/259488
| Introduction|| |
The prognosis of a metastatic germ cell tumor (GCT) refractory to conventional chemotherapy and salvage high-dose chemotherapy is poor, and there is currently no standard treatment for these patients. Conventional 5-fluorouracil (5-FU) is rarely used in the treatment of a metastatic GCT. However, in recent decades, the modulation of 5-FU infusion by high-dose continuous infusion has led to better efficacy and broader indications.,,,,, We report the case of a patient who failed platinum-based conventional chemotherapy and experienced disease progression after high-dose chemotherapy with an autologous stem cell transplantation. The level of the tumor marker, beta-human chorionic gonadotropin (beta-hCG) (originally >120,000 mIU/mL), normalized after the addition of a 24-h infusion of high-dose 5-FU and leucovorin (HDFL) to a salvage regimen of paclitaxel and ifosfamide. We also discuss the potential efficacy of HDFL for refractory GCTs.
| Case Report|| |
A 24-year-old male complained of intermittent dyspnea for 1 month, and he was referred to our hospital in February 2017. Multiple pulmonary nodules were detected. A physical examination was unremarkable. Laboratory examinations showed an elevated beta-hCG level of >120,000 mIU/mL (reference range: 0–5 mIU/mL) and an elevated level of lactate dehydrogenase of 930 U/L (reference range: 100–460 U/L). The initial white blood cell count, hemoglobin, serum creatinine, and alfa-fetoprotein were 14.29 K/μL, 12.5 g/dL, 0.7 mg/dL, and 10.88 ng/mL (reference range: <20 ng/mL), respectively. Scrotal ultrasonography revealed no abnormal testicular mass lesions. Contrast-enhanced computerized tomography (CT) showed multiple nodules in the bilateral lungs and hypodense lesions over the liver and para-aortic area [Figure 1]a. An ultrasound-guided liver biopsy disclosed metastatic carcinoma with multinucleated syncytiotrophoblast-like tumor cells. Immunohistochemistry staining revealed that the tumor was reactive to HSD3B1 and CD30 and negative to glypican-3 and c-kit. He was diagnosed with extragonadal GCT, choriocarcinoma, with lung, liver, retroperitoneal, and bone metastases.
|Figure 1: Computed tomography scans showed (a) multiple pulmonary nodules, hepatic nodules, and para-aortic masses in February, 2017. (b) Larger hepatic nodules, lesser pulmonary nodules, and smaller para-aortic masses after four cycles of EP. (c) Pulmonary nodules subsided, and cystic hepatic lesions remained after four cycles of TI- high-dose 5-fluorouracil and leucovorin. (d) Stationary cystic hepatic nodules and para-aortic masses after four cycles of maintenance high-dose 5-fluorouracil and leucovorin|
Click here to view
He received the first cycle of etoposide (100 mg/m2 from day 1 to day 5) and cisplatin (20 mg/m2 from day 1 to day 5) (EP as a tri-weekly protocol) in March 2017. After the first course of chemotherapy, dyspnea worsened with respiratory failure, and he received endotracheal intubation. A superimposed pulmonary infection was suspected. The beta-hCG level increased to a peak of 546,712 mIU/mL in April 2017 [Figure 2]. After recovering from the episode, he received the EP protocol and his condition gradually improved. A CT scan disclosed a marked reduction in the size of the lung metastases and the left para-aortic mass; however, the liver nodules increased in size [Figure 1]b. The serum beta-hCG level plateaued at around 160 mIU/ml. Since the first-line treatment failed to achieve complete remission, he was scheduled for high-dose chemotherapy and peripheral blood stem cell salvage. He received two additional cycles of the EP protocol while waiting to be admitted to the transplantation ward. The beta-hCG level increased to 280 mIU/mL and the serum creatinine level slightly increased to 1.1 mg/dL after six cycles of the EP protocol.
|Figure 2: Graphic illustration of the time course of beta-human chorionic gonadotropin level in relation to the treatment|
Click here to view
He underwent one cycle of high-dose chemotherapy with carboplatin (700 mg/m2) and etoposide (750 mg/m2) for 3 days, followed by autologous peripheral blood stem cell infusion in September 2017. The stem cells were collected by granulocyte-colony-stimulating factor (G-CSF) mobilization. Raised levels of beta-hCG (16,502 mIU/mL) and serum creatinine (1.4 mg/dL) were recorded after high-dose chemotherapy. He also complained of mild high-frequency hearing impairment. Due to concerns of the nephrotoxicity and ototoxicity of platinum, he received salvage chemotherapy of paclitaxel (250 mg/m2, 3-h infusion on day 1) combined with ifosfamide (1.5 g/m2 from day 2 to day 5) tri-weekly as the TI protocol from October 2017. He needed G-SCF supplement in each TI protocol because of neutropenia. After three cycles of the TI protocol, the beta-hCG level fluctuated at around 100 mIU/mL, but never became normal.
He was scheduled to receive the fourth cycle of the TI protocol in January 2018. However, as the beta-hCG level increased to 156 mIU/mL, we decided to add a 24-h continuous infusion of high-dose 5-FU (2000 mg/m2 on day 1 and day 8) with leucovorin (200 mg/m2) (HDFL) to the original TI protocol. After the addition of HDFL, the beta-hCG level dropped to 2.68 mIU/mL, and then normalized after four cycles of TI-HDFL. No additional toxicities were noted after adding HDFL. The follow-up CT scan in April 2018 showed smaller liver lesions and para-aortic masses [Figure 1]c. He has received maintenance HDFL since April 2018. The tumor markers have remained normal, although some low-density cyst-like hepatic nodules have remained [Figure 1]d.
| Discussion|| |
5-FU has never been studied in a systematic fashion for metastatic GCTs. Lapis et al. reported that a bolus of 5-FU led to a 47% reduction in tumor growth of GCTs in a mice model. Some retrospective studies have reported that tumor cells expressing high levels of thymidine phosphorylase were more sensitive to 5-FU., The overexpression of thymidine phosphorylase has also been detected in GCT compared with normal testis tissue. In addition, a few anecdotal reports in the 1960s revealed a modest activity of bolus 5-FU to GCT, in which three of the ten patients obtained a partial response, and the cumulative response rate of 5-FU monotherapy was 30%.,,
A phase I trial of bi-weekly flavopiridol (a pan-cyclin-dependent kinase inhibitor) plus FOLFOX (5-FU 1800 mg/m2 over 48 h, oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2) showed clinical activity in platinum-refractory GCTs. Three of nine (33%) evaluable patients showed a partial response on imaging compared with a 19% response rate to oxaliplatin monotherapy. The increased response rate after flavopiridol therapy led to a phase II trial conducted to evaluate the efficacy of flavopiridol plus oxaliplatin or FOLFOX and the necessity of including 5-FU/LV. Importantly, there were no responders in the arm of flavopiridol combined with oxaliplatin, whereas a 50% response rate was found in flavopiridol plus FOLFOX arm. HDFL may increase the response rate in platinum-refractory GCTs. However, whether increased survival benefits or synergic effects can be achieved with HDFL is not clear yet.
The paclitaxel, ifosfamide, and cisplatin (TIP) regimen is a salvage chemotherapy regimen for GCTs. In our case, the patient received paclitaxel and ifosfamide without cisplatin or carboplatin due to concerns of nephrotoxicity and myelosuppression. However, there was an increase in serum beta-hCG level from 67.4 mIU/mL to 156 mIU/mL on day 22 of the third cycle of paclitaxel and ifosfamide (TI), probably due to tumor progression since the median time to peak beta-hCG level was 5 days (range of 1–12 days). Serum beta-hCG usually decreases if the regimen is responsive., HDFL has already been used for many other cancer types, and it has been associated with less myelosuppression and nephrotoxicity.,,,,, In our patient, the addition of HDFL to the TI regimen, which appeared effective but failed to eradicate the tumors, resulted in a dramatic normalization of the beta-hCG level.
We hypothesize that some residual tumors which are refractory to conventional and high-dose chemotherapies might be sensitive to HDFL. Although the level of beta-hCG was normalized in our patient, some low-density cystic hepatic lesions remained. The nature of these tumors was not clear. Several studies have reported that nearly 50% of residual masses contained necrotic tissue after successful chemotherapy, 30%–40% contained mature teratoma, and only 15%–20% contained residual GCT., A single-center study reported that progression-free survival and overall survival were similar comparing surgery to observation after achieving a serological complete remission. Surgical resection of residual hepatic metastases may be associated with a complication rate of 27%–30%., Therefore, considering the cost–benefit balance, we decided to perform conservative treatment with regular follow-up assessments of CT scans and tumor markers.
HDFL-containing protocols have already been expanded to cover many other types of gastrointestinal and nongastrointestinal cancers. Based on our case, we suggest that a 24-h infusion of HDFL combined with paclitaxel and ifosfamide for platinum-refractory GCT s can provide a durable clinical response. HDFL deserves to be further investigated as a component of salvage treatment for refractory GCTs.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Beyer J, Kingreen D, Krause M, Schleicher J, Schwaner I, Schwella N, et al.
Long-term survival of patients with recurrent or refractory germ cell tumors after high dose chemotherapy. Cancer 1997;79:161-8.
Oing C, Seidel C, Bokemeyer C. Therapeutic approaches for refractory germ cell cancer. Expert Rev Anticancer Ther 2018;18:389-97.
Hsu CH, Yeh KH, Chen LT, Liu JM, Jan CM, Lin JT, et al.
Weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin in the treatment of advanced gastric cancers. An effective and low-toxic regimen for patients with poor general condition. Oncology 1997;54:275-80.
Yeh KH, Lu YS, Hsu CH, Lin JF, Chao HJ, Huang TC, et al.
Phase II study of weekly vinorelbine and 24-h infusion of high-dose 5-fluorouracil plus leucovorin as first-line treatment of advanced breast cancer. Br J Cancer 2005;92:1013-8.
Hsu C, Shen YC, Yang CH, Yeh KH, Lu YS, Hsu CH, et al.
Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract. Br J Cancer 2004;90:1715-9.
Lin CC, Yeh KH, Yang CH, Hsu C, Tsai YC, Hsu WL, et al.
Multifractionated paclitaxel and cisplatin combined with 5-fluorouracil and leucovorin in patients with metastatic or recurrent esophageal squamous cell carcinoma. Anticancer Drugs 2007;18:703-8.
Hsu CH, Yeh KH, Cheng AL. Thymic carcinoma with autoimmune syndrome: Successful treatment with weekly infusional high-dose 5-fluorouracil and leucovorin. Anticancer Res 1997;17:1331-4.
Lin CC, Hsu CH, Huang CY, Cheng AL, Vogelzang NJ, Pu YS. Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma. J Urol 2007;177:84-9.
Lapis P, Kopper L, Bodrogi I, Sugár J, Lapis K, Eckhardt S. Characteristics and chemotherapeutic sensitivity of a human testicular cancer grown in artificially immunosuppressed mice. Oncology 1985;42:112-8.
Haraguchi M, Furukawa T, Sumizawa T, Akiyama S. Sensitivity of human KB cells expressing platelet-derived endothelial cell growth factor to pyrimidine antimetabolites. Cancer Res 1993;53:5680-2.
Schwartz EL, Baptiste N, Wadler S, Makower D. Thymidine phosphorylase mediates the sensitivity of human colon carcinoma cells to 5-fluorouracil. J Biol Chem 1995;270:19073-7.
Jones A, Fujiyama C, Turner K, Fuggle S, Cranston D, Turley H, et al.
Angiogenesis and lymphangiogenesis in stage 1 germ cell tumours of the testis. BJU Int 2000;86:80-6.
Allaire FJ, Thieme ET, Korst DR. Cancer chemotherapy with 5-fluorouracil alone and in combination with x-ray therapy. Cancer Chemother Rep 1961;14:59-75.
Hyman GA, Ultmann JE, Habif DV. Factors to be considered in the clinical evaluation of a new chemotherapeutic agent (5-fluorouracil). Cancer Chemother Rep 1962;16:397-9.
Wilson WL. Chemotherapy of human solid tumors with 5-fluorouracil. Cancer 1960;13:1230-9.
Rathkopf D, Dickson MA, Feldman DR, Carvajal RD, Shah MA, Wu N, et al.
Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors. Clin Cancer Res 2009;15:7405-11.
Fizazi K, Culine S, Chen I. Oxaliplatin in non-seminomatous germ-cell tumors. Ann Oncol 2004;15:1295.
Feldman DR, Stadler WM, Appleman LJ, Quinn DI, Costello BA, Schwartz GK, et al
. Multicenter sequential phase II study of flavopiridol plus oxaliplatin (Alvocidib) with or without 5-FU and leucovorin for patients with refractory germ cell tumors including late relapse. J Clin Oncol 2014;32 Suppl 4:abstr364.
Vogelzang NJ, Lange PH, Goldman A, Vessela RH, Fraley EE, Kennedy BJ. Acute changes of alpha-fetoprotein and human chorionic gonadotropin during induction chemotherapy of germ cell tumors. Cancer Res 1982;42:4855-61.
Horwich A, Peckham MJ. Transient tumor marker elevation following chemotherapy for germ cell tumors of the testis. Cancer Treat Rep 1986;70:1329-31.
Steyerberg EW, Keizer HJ, Fosså SD, Sleijfer DT, Toner GC, Schraffordt Koops H, et al.
Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: Multivariate analysis of individual patient data from six study groups. J Clin Oncol 1995;13:1177-87.
Hartmann JT, Schmoll HJ, Kuczyk MA, Candelaria M, Bokemeyer C. Postchemotherapy resections of residual masses from metastatic non-seminomatous testicular germ cell tumors. Ann Oncol 1997;8:531-8.
Napier MP, Naraghi A, Christmas TJ, Rustin GJ. Long-term follow-up of residual masses after chemotherapy in patients with non-seminomatous germ cell tumours. Br J Cancer 2000;83:1274-80.
Hahn TL, Jacobson L, Einhorn LH, Foster R, Goulet RJ Jr. Hepatic resection of metastatic testicular carcinoma: A further update. Ann Surg Oncol 1999;6:640-4.
Rivoire M, Elias D, De Cian F, Kaemmerlen P, Théodore C, Droz JP. Multimodality treatment of patients with liver metastases from germ cell tumors: The role of surgery. Cancer 2001;92:578-87.
[Figure 1], [Figure 2]