The Oncologist, Vol. 13, No. 5, 526-529, May 2008; doi:10.1634/theoncologist.2007-0253
© 2008 AlphaMed Press
False Tumor Marker Surge Evoked by Peripheral Blood Stem Cell Transplantation
Masaharu Inoue,
Fumitaka Koga,
Satoru Kawakami,
Noboru Numao,
Mizuaki Sakura,
Tsuyoshi Kobayashi,
Kazunori Kihara
Department of Urology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
Key Words. Peripheral blood stem cell transplantation • Tumor marker surges • Testicular cancer • Human chorionic gonadotropin
Correspondence: Fumitaka Koga, M.D., Department of Urology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Telephone and Fax: 81-3-5803-5295; e-mail: f-koga.uro{at}tmd.ac.jp
Received December 24, 2007;
accepted for publication March 24, 2008.
Disclosure: No potential conflicts of interest were reported by the authors.
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ABSTRACT
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Peripheral blood stem cell transplantation (PBSCT) allows multiple intensive chemotherapy treatments and hematopoietic progenitor cell rescues for poor-risk patients with a variety of malignancies. We report false surges of a tumor marker, serum human chorionic gonadotropin (hCG), evoked by PBSCT in the course of chemotherapy for a poor-risk testicular cancer patient. We confirmed that this phenomenon resulted from reinfusion of peripheral blood stem cells (PBSCs) containing hCG at a high concentration, collected when the patient's serum hCG levels were remarkably elevated. This is the first report to demonstrate false tumor marker surges caused by PBSCT. Because a rapid rise in tumor markers may demand an immediate change in the therapeutic strategy, physicians should be aware of the possibility of this phenomenon when treating poor-risk cancer patients whose tumor markers are remarkably elevated at the time of PBSC harvest.
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INTRODUCTION
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Autologous hematopoietic stem cell transplantation allows multiple intensive chemotherapy treatments, which is expected to improve the prognosis of poor-risk patients with a variety of malignancies, including testicular cancer [1–3]. As a source of hematopoietic stem cells, the use of bone marrow was standardized in the late 1950s [4]. In the mid-1980s, the use of peripheral blood stem cells (PBSCs) was started, has rapidly spread, and has almost completely replaced the use of bone marrow [1, 2, 5]. Peripheral blood stem cell transplantation (PBSCT) is considered to be superior to conventional bone marrow transplantation in the following aspects. First, the procedure for PBSC collection is easier than that for bone marrow collection, which requires general anesthesia. Second, PBSCs obtained after mobilization using hematopoietic growth factors contain far more CD34+ cells than steady-state bone marrow, resulting in more rapid engraftment, in particular, of platelets [1, 2, 5]. Third, PBSCT is more cost-effective than bone marrow transplantation [2]. An additional advantage of PBSCs is the lower risk for contamination with tumor cells that may reside in the bone marrow [1, 2, 5].
Patients receiving intensive chemotherapy followed by autologous PBSCT usually present with a high tumor burden at the time of procedure initiation. When the tumor produces specific markers, their levels in serum are remarkably elevated at the time of PBSC harvest. In this context, PBSC preparations could contain tumor markers at high concentrations, and reinfusion of such PBSCs would result in a rapid elevation in tumor markers. To our knowledge, however, tumor marker surges as a consequence of PBSCT have not been recognized, although those as a consequence of chemotherapy have been observed in breast, testicular, and colorectal cancers [6–10]. Here, we report false tumor marker surges evoked by PBSCT, documented in the course of chemotherapy for a poor-risk testicular cancer patient, and briefly discuss the possible prognostic impact of tumor marker surges.
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CASE REPORT
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A 25-year-old man with a left testicular tumor was referred to our hospital in April of 2006. Chest and abdominal computed tomography scans revealed multiple pulmonary masses and an aortocaval lymph node swelling of 1.5 cm. He was classified into a poor prognosis group according to the International Germ Cell Cancer Collaborative Group risk criteria [11] because of an extremely high level of serum human chorionic gonadotropin (hCG), which was 534,000 IU/l. The primary testicular tumor histologically consisted of a yolk sac tumor and immature teratoma. On the first day of systemic chemotherapy, he suddenly became hypotensive, accompanied by acute respiratory insufficiency. Intrathoracic hemorrhage from a 7-cm left pulmonary mass resulting from acute tumor lysis syndrome [12] was highly suspected. Hemorrhagic shock ensued and the patient fell into a coma. An emergent thoracotomy revealed rupture of the 7-cm mass in the lower lobe and another mass in the upper lobe that seemed ready to rupture. In the left lung, a lower lobectomy and partial upper lobectomy were carried out. Histologically, pulmonary metastases were predominantly composed of choriocarcinoma. To prevent rupture of a 4-cm right pulmonary mass, he received external beam radiation of 40 Gy to the mass concomitantly with low-dose cisplatin.
Therapies given to the patient and serum hCG kinetics are summarized in Figure 1. Because of a generally poor condition, in particular, impaired respiratory function, multiple courses of a nonstandard drug combination with a moderate dose intensity, rather than the standard conventional or high-dose chemotherapy, were planned for this patient with highly refractory disease. Following induction chemotherapy, a sufficient number of PBSCs (27 x 106 CD34+ cells/kg) were harvested on days 21–23 of the chemotherapy. The patient's serum hCG levels on days 20 and 24 were 12,552 and 59,343 IU/l, respectively.
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Figure 1. Therapies given to the patient and kinetics of serum hCG. Chemotherapeutic regimens consisted of etoposide and cisplatin (EP) for the first cycle; paclitaxel, ifosfamide, and cisplatin (TIP) for the second to fourth cycles; paclitaxel and cisplatin (TP) for the fifth and sixth cycles; and gemcitabine, etoposide, and cisplatin (GEP) for the seventh to eleventh cycles. The dotted line indicates the upper limit of normal range of serum hCG.
Abbreviations: EBRT, external beam radiation therapy with concurrent low-dose cisplatin to prevent rupture of a residual pulmonary mass; hCG, human chorionic gonadotropin; PBSCH, peripheral blood stem cell harvest; PBSCT, peripheral blood stem cell transplantation; RPLND, retroperitoneal lymph node dissection.
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After five courses of chemotherapy, his serum hCG level had decreased to <10 IU/l. Following the sixth course of chemotherapy, however, his serum hCG rapidly rose from 2.1 IU/l on day 5 to 112 IU/l on day 8. This rapid rise in serum hCG was transient and it attenuated along the theoretical half-life curve of hCG (Fig. 1). Because no other evidence of disease progression was observed clinically, we strongly suspected that this hCG surge was caused by the PBSCT on day 7.
A similar phenomenon was observed again. On day 5 of the seventh course of chemotherapy, his serum hCG level was 16 IU/l before PBSCT. Two hours after the PBSCT, his serum hCG level was elevated to 251 IU/l, followed by a prompt decay along its theoretical half-life curve again (Fig. 1). To confirm that the PBSCT evoked the tumor marker surges, we measured the concentration of hCG in the PBSC preparations reinfused. The hCG concentration was 11,600 IU/l. Because PBSCs were diluted in an equal volume of cryoprotectant solution, the serum hCG level at the time of the PBSC harvest was estimated to be 23,200 IU/l, which falls within the range of serum hCG levels during the PBSC harvest (12,552–59,343 IU/l). Because the volume of the PBSC preparations was 90 ml, the total amount of hCG given to the patient was 1,044 IU. Thus, the theoretical serum hCG level after PBSCT, calculated using formulas A and B listed in Figure 2, was roughly estimated 280 IU/l, which approaches the actual value of 251 IU/l.
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Figure 2. Formulas used to estimate serum human chorionic gonadotropin (hCG) level after peripheral blood stem cell transplantation (PBSCT), whole serum volume, and hCG given to the patient at PBSCT.
aThe body weight of the patient was 74 kg.
bThe patient's hematocrit at the time of the peripheral blood stem cell harvest (PBSCH) was 30%.
cThe dilution ratio of PBSCs to cryoprotectant solution was 2.
dThe volume of PBSC preparations was 90 ml.
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The patient eventually achieved complete remission, with a normalized serum hCG level (<1 IU/l) after the eighth course of chemotherapy, and received three additional courses of consolidation chemotherapy. He was alive without any evidence of disease 15 months after the normalization of his serum hCG.
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DISCUSSION
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In the current report, we clearly demonstrate that reinfusion of PBSC preparations containing a tumor marker at a high concentration evoked false tumor marker surges. The rapid rise in serum hCG following PBSCT promptly diminished along the half-life curve of serum hCG without any clinical evidence of disease progression, indicating that this phenomenon was not a true tumor marker rise yielded by persisting viable tumor cells, but a false tumor marker surge. The fact that the PBSC preparations contained hCG at a concentration equivalent to the serum hCG level at the time of the PBSC harvest confirmed that the false tumor marker surges resulted from reinfusion of PBSCs containing hCG.
A false hCG surge was not observed following the first PBSCT, at which time the patient's serum hCG level was still remarkably elevated (Fig. 1). For the second PBSCT, at which time his serum hCG level was slightly elevated, a false hCG surge was retrospectively realized as a small hump, whereas the elevation was overt for the third and fourth PBSCTs, at which time his serum hCG levels were almost normal (Fig. 1). Assuming various levels of serum hCG at the time of PBSC harvest, the PBSCT-evoked false hCG surges were simulated in a situation identical to the fourth PBSCT in the current case (Fig. 3). When serum hCG levels were 100,000, 10,000, 1,000, and 100 IU/l at PBSC harvest, the increments in serum hCG immediately after PBSCT were roughly estimated at 1,000, 100, 10, and 1 IU/l, respectively (Figs. 2 and 3). Thus, the PBSCT-evoked false hCG surges appear to be clinically overt when serum hCG levels exceed 10,000 IU/l at the time of PBSC harvest and when the serum hCG level regresses nearly to its normal range before PBSCT (Fig. 3).
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Figure 3. Simulation of the peripheral blood stem cell transplantation (PBSCT)-evoked surges of serum human chorionic gonadotropin (hCG) on day 5 of the seventh course of chemotherapy in the present case, assuming variously increased serum hCG levels at the time of peripheral blood stem cell harvest (PBSCH).
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Contamination of PBSCs with tumor cells has been recognized in a variety of solid tumors, including testicular cancer [13–18]. The biggest concern is potential engraftment of contaminating tumor cells after PBSCT and eventual treatment failure. The malignant contamination appears to be associated with an unfavorable prognosis in breast cancer [17, 18], whereas this is not the case in testicular cancer [13] or neuroblastoma [15, 16].
What about contaminating tumor markers in PBSCs? Does reinfusion of PBSCs containing tumor markers at high concentrations compromise the oncological outcome? To date, no answer to this question has been available. Concerning tumor marker surges as a consequence of chemotherapy, Vogelzang et al. [10] first reported an acute rise in alpha fetoprotein (AFP) and hCG during induction chemotherapy in testicular cancer patients. de Wit et al. [7] reported that AFP surges, but not hCG surges, following the initiation of chemotherapy have an adverse prognostic impact. However, it remains unknown why AFP surges are associated with the progression of testicular cancer. In vitro studies showed that the exogenous β-subunit of hCG stimulates cancer cell growth [19, 20]. Despite no clinical evidence of an adverse prognostic impact of hCG surges, these preclinical data suggest that reinfusion of PBSCs containing hCG at extremely high concentrations might potentially promote cancer progression. Further investigations are needed to answer the question.
An acute elevation in tumor markers during the course of therapy is always disturbing both to patients and physicians, and may prompt an immediate change in the therapeutic strategy. Indeed, tumor marker surges as a consequence of chemotherapy have been incorrectly interpreted as disease progression and inappropriate therapeutic changes have been made in breast cancer patients [8]. Physicians should be aware of the possibility of false tumor marker surges evoked by PBSCT when treating poor-risk cancer patients whose tumor markers are elevated at the time of PBSC harvest.
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AUTHOR CONTRIBUTIONS
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Conception/design: Fumitaka Koga, Satoru Kawakami, Masaharu Inoue, Kazunori Kihara
Administrative support: Fumitaka Koga
Provision of study materials or patients: Masaharu Inoue
Collection/assembly of data: Masaharu Inoue, Noboru Numao, Mizuaki Sakura, Tsuyoshi Kobayashi
Data analysis and interpretation: Masaharu Inoue, Fumitaka Koga, Satoru Kawakami, Noboru Numao, Mizuaki Sakura, Tsuyoshi Kobayashi, Kazunori Kihara
Manuscript writing: Fumitaka Koga, Satoru Kawakami, Masaharu Inoue
Final approval of manuscript: Masaharu Inoue, Fumitaka Koga, Satoru Kawakami, Noboru Numao, Mizuaki Sakura, Tsuyoshi Kobayashi, Kazunori Kihara
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Abstract
Introduction
