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Year : 2017  |  Volume : 54  |  Issue : 2  |  Page : 415--420

Retrospective analysis of patients with relapsed or refractory testicular nonseminous germ cell tumors treated with autologous stem cell transplantation

F Yilmaz1, N Soyer2, R Uslu3, AP Erdogan3, B Karaca3, G Saydam2, F Sahin2, F Vural2,  
1 Department of Hematology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey
2 Department of Hematology, Ege University Hospital, Izmir, Turkey
3 Department of Medical Oncology, Ege University Hospital, Izmir, Turkey

Correspondence Address:
Dr. F Yilmaz
Department of Hematology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir
Turkey

Abstract

BACKGROUND AND AIM: About 20-25% of the testicular germ cell tumors (TGCT) are relapsed or refractory after first line therapy and optimal treatment for this group is poorly defined. We aimed to analyze the efficacy and safety of autologous stem cell transplantation (ASCT) in this patient group.Material and METHODS: 19 patients with 28 ASCT were retrospectively analyzed. All the patients were treated with BEP (Bleomycin, etoposide, cisplatin) as first line therapy and TIP(paclitexalifosfamide, cisplatin) was given as salvage chemotherapy. Stem cell collection was performed with TIP and granulocyte stimulating factor. ASCT was performed with carboplatin(700mg/m2) and etoposite(750mg /m 2). The results were provided as median(min-max). P<0.05 was accepted as statistical significant level. RESULTS: After ASCT, complete(CR) and partial remission (PR) rates were 47.3% and 31 .5% respectively. The median overall survival(OS) and progression free survival (PFS) were 18(0-37.4 months) and 7(0-15months) months respectively. Estimated 2-year OS was 47.4% and PFS was 35.3%. Grade 3/4 toxicities including diarrhea, mucositis, and toxic hepatitis were observed in 5 patients. Only one patient died due to complication of transplantation. CONCLUSION: Although the number of the patients in this study is limited, ASCT seems to be a safe and effective treatment modality in relapsed refractory non-seminomatousTGCT with an acceptable OS, PFS and mortality rates.



How to cite this article:
Yilmaz F, Soyer N, Uslu R, Erdogan A P, Karaca B, Saydam G, Sahin F, Vural F. Retrospective analysis of patients with relapsed or refractory testicular nonseminous germ cell tumors treated with autologous stem cell transplantation.Indian J Cancer 2017;54:415-420


How to cite this URL:
Yilmaz F, Soyer N, Uslu R, Erdogan A P, Karaca B, Saydam G, Sahin F, Vural F. Retrospective analysis of patients with relapsed or refractory testicular nonseminous germ cell tumors treated with autologous stem cell transplantation. Indian J Cancer [serial online] 2017 [cited 2019 Dec 10 ];54:415-420
Available from: http://www.indianjcancer.com/text.asp?2017/54/2/415/225805


Full Text



 Introduction



Testicular cancer is one of the most common solid tumors affecting males between the ages of 15 and 40. Testicular germ cell tumors (TGCT) consisted of 95% of all testicular cancers.[1] They may be classified according to histologic types of the cells, seminomatous, and nonseminomatous. They are highly chemotherapy-sensitive tumors. Especially after introduction of cisplatin-based chemotherapies, the disease can be cured even if it presents as advanced disease with poor prognostic risk factors according to the International Germ Cell Consensus Classification (IGCCC).[2],[3] More than 80% of patients with good risk and 50%–60% of poor risk have long-term remissions after treated with the first-line chemotherapy. Furthermore, as high as 70% of metastatic testicular cancer can be cured with the first-line cisplatin-based chemotherapy protocols.[4] Salvage therapy alternatives became important in this 20%–30% of patients who are refractory or relapsed after the first-line chemotherapy. High-dose chemotherapy with autologous stem cell transplantation (ASCT) mostly performed as tandem transplantation is an alternative in relapsed or refractory cases. Report from the Swedish-Norwegian Testicular Cancer Group evaluated the effect of ASCT in 55 patients with metastatic nonseminomatous testicular cancer who were refractory to the first-line treatment. In this analysis, it was concluded that ASCT was a feasible alternative in patients who had an inadequate response to the first-line therapy.[5] Although ASCT is a promising therapy in relapsed or refractory patients, it is associated with hematologic or nonhematologic toxicities and treatment-related mortalities.[6],[7],[8] Einhorn et al. reported that ASCT was a good option in patients who were relapsed or refractory to first-line cisplatin-based chemotherapies. It had also favorable results when used as third-line or later therapy.[7] The high-dose chemotherapy was mainly based on carboplatin and etoposide as high as 1500 mg/m 2 and 1500 mg/m 2, respectively.[8]

Other conventional-dose combination chemotherapies may also be used as salvage therapies. These are mostly based on ifosfamide and cisplatin with addition of a third agent. Third agent can be vinblastine, etoposide, or paclitaxel. A combination chemotherapy with gemcitabine etoposide and ifosfamide is another alternative for salvage therapy.[8] There is conflicting data in the literature about the superiority of ASCT over other salvage chemotherapies. While Pico et al.[9] could not demonstrate a survival benefit of addition of ASCT to VIP (etoposide, cisplatin, ifosfamide)/VeIP (vinblastine, ifosfamide, cisplatin) chemotherapies; Lorch et al.[10] reported an improvement in overall survival (OS) when ASCT was performed.

In this study, we aimed to evaluate the data of ASCT in nonseminomatous testicular stem cell patients who were relapsed or refractory.

 Subjects and Methods



Patients

Patients diagnosed as nonseminomatous TGCT between January 2006 and January 2015 were retrospectively scanned from the database of Oncology and Hematology Clinics in Ege University Hospital. Patients ≥18 years of age at the time of ASCT were enrolled in the study. The study was approved by the Institutional Ethics Committee. The characteristics of the patients and laboratory findings including beta-human chorionic gonadotropin (β-HCG), lactate dehydrogenase (LDH), and alpha-fetoprotein (AFP) were documented. Clinical data were retrieved from clinical records of the patients. All the patients had metastatic disease and they were classified as poor or intermediate risk group according to the IGCCC.[11]

Treatment protocol

All the patients were treated with BEP (bleomycin 30 mg/day at D1, 8, 15, etoposide 100 mg/m 2/day D1-D5, cisplatin 20 mg/m 2/day D1-D5, every 21 days) as first-line therapy for three cycles. TIP (paclitexal 175 mg/m 2/day D1, ifosfamide 1000 mg/m 2/day D1, 2, 3, mesna 1000 D1, 2, 3, cisplatin 60 mg/m 2/day D1, every 12 days) regimen was given as salvage chemotherapy for at least three cycles in all patients. Stem cell collection was performed with TIP chemotherapy in conjunction with subcutaneous injection of granulocyte colony-stimulating factor (G-CSF) of 10 microgram/kg/day started at 5th day of the therapy. We preferred treatment with three cycles of TIP before harvesting CD 34+ stem cells in eligible patients for the benefit of in vivo purging effect of the therapy. ASCT consisted of 700 mg/m 2 of carboplatin in combination with 750 mg/m 2 etoposite in days 1–3.[7] Patients were treated with G-CSF after 5th day of transplantation. Prophylactic antibiotic treatment with acyclovir, fluconazole, and ciprofloxacin was initiated at day 1. Prophylactic antiemetics were also added to the standard therapy in all patients. Platelet and red blood cells were transfused to maintain 20 × 109/l and 8 g/dl, respectively. Patients were treated according to neutropenic fever guidelines. Thrombocyte engraftment was defined as thrombocytes more than 20 × 109/l on 3 consecutive days and neutrophil engraftment was defined as neutrophil number ≥500 × 109/l.

Response evaluation

All the patients were evaluated after three cycles of BEP, before, and approximately after 1 month after ASCT and whenever a progressive disease (PD) was expected. The radiologic response to treatment was evaluated with thorax, abdomen, and cervical computed tomography (CT) or positron emission tomography/CT. Biochemical evaluation was performed with tumor markers, LDH, β-HCG, and AFP which were measured after each course of chemotherapy and after approximately 1 month after ASCT. Responses were classified as complete and partial response (PR). Complete response (CR) was defined as disappearance of all radiologic evidence of disease together with tumor markers within normal range. PR was defined as radiologic persistence of disease with an evidence of response. PR was divided into PR with negative tumor markers when tumor markers were within normal range and PR with positive tumor markers when radiologic PR was documented with high tumor marker levels.[12] PD was accepted as more than 25% increase in radiologically measurable mass or more than 10% increase of elevated tumor markers. Stable disease (SD) was classified as a response which did not fit the criteria of PR or PD.[13]

Progression-free survival (PFS) was defined as the time between the transplantation and disease progression or death. OS was defined as time between transplantation and death.[12] Toxicities were evaluated according to the World Health Organization criteria.

Statistical analysis

Statistical analyses were performed using SPSS version 16.0 (Statistical Package for Social Sciences Inc., Chicago, IL, USA). The variables were first assessed by Kolmogorov–Smirnov/Shapiro–Wilk testing in terms of normal distribution. The results were provided as mean ± SD for normally distributed variables and as median (min-max) for abnormally distributed parameters. All P values were two-tailed and statistical significance was set at the level of P Characteristic of patients and therapy

We retrospectively analyzed 28 ASCT in 19 patients with refractory or relapsed nonseminomatous TGCT. The median age at diagnosis was 26 years of age (range, 18–43). In nine patients, tandem transplantation was performed. In ten of the patients, one cycle of ASCT was performed due to unwillingness of the patients, refractory disease, Grade 4 hematologic or nonhematologic toxicities. According to the IGCCC, 10 and 9 of the patients were classified as intermediate and poor risk group, respectively. LDH levels were above the normal limit in all of the patients at diagnosis. AFP and beta-HCG were high in all patients except 3 and 2 of the patients, respectively. All the patients were advanced stage with lymph node metastasis in all and organ metastasis including lung, brain, liver, and bone was documented in 14 (73.6%) patients. Twelve patients (63%) got remission, PR, or CR after three cycles of BEP. The characteristics were shown in [Table 1]. TIP regimen was administered as first-line salvage to all patients before ASCT. Five refractory patients to TIP chemotherapy were treated with VeIP or gemcitabine and oxaliplatin was administered at least three cycles before ASCT. The median line of chemotherapy before ASCT was two (range, 2–4). Thirteen of the patients were transplanted as first salvage therapy and five of the patients were treated with ASCT as second or third line. Only two of the patients were treated with radiotherapy before ASCT. Radiotherapy was performed due to pulmonary and bone metastasis in these patients.{Table 1}

Time to ASCT was median 14 months (range, 4–50 months). In 10 (52.6%) patients, remission (PR or CR) was achieved before ASCT. In the PR group, all the patients had normal levels of AFP and beta-HCG (PR negative).

The median number of stem cells collected per patient was 4.5 × 106/ kg (range, 2.5–9 × 106/ kg). The median number of stem cell delivered per patient per transplantation was 4.3 × 106/kg (range, 3–5.3 × 106/ kg). In only one patient who was refractory and got four lines of therapy before ASCT, 3.5 × 106/ kg CD 34+ cell was collected which was safe for only one ASCT.

Safety

Neutropenic fever attacks were observed in 18 of the transplantation procedures. Neutropenic fever attacks were treated according to neutropenic fever guidelines. Only one patient experienced Grade 4 mucositis required total parenteral nutrition. Two patients needed oral nutrition solution during period with mucositis. Only one patient had Grade 1 hearing loss and neuropathy. [Table 2] summarizes the toxicities. Transplantation-related mortality was observed in one patient. He died due to uncontrolled infection, sepsis, and multiorgan failure during neutropenic period. He had a PD. The median number of apheresis thrombocyte and red blood cell transfused were 4 (range, 0–12) and 3 (0–6), respectively. Thrombocyte and neutrophil engraftments were observed at a median of 14th day (range, 8–16) and 14th day (range, 10–22), respectively. No engraftment failure was documented. During the median of 18-month (0–37.4) follow-up period, we did not observe any secondary malignancy.{Table 2}

Efficacy

After ASCT, CR and PR rates were 47.3% and 31.5%, respectively. Three patients (15.6%) had PD. The median OS and PFS were 18 (0–37.4 months) and 7 (0–15 months), respectively. Estimated 2-year OS and PFS were 47.4% and 35.3%, respectively [Figure 1] and [Figure 2].{Figure 1}{Figure 2}

Factors possibly effecting PFS and OS including IGCCC classification, lymph node metastasis, organ metastasis, response to first-line treatment, LDH/AFP/beta HCG levels before salvage therapy and before ASCT, number of line of chemotherapy, response before and after ASCT, presence or absence of radiotherapy were evaluated. In the univariate analysis, high beta HCG levels (P = 0.008) before salvage therapy, progressive or stable disease before ASCT (P = 0.02), and after ASCT (P = 0.005), high LDH levels before ASCT (P = 0.004) were negatively affect PFS. OS was negatively affected by high beta HCG levels before salvage therapy (P = 0.007), progressive or stable disease before ASCT (P = 0.02) or after ASCT (P = 0.000), high LDH levels before ASCT (P = 0.000), high beta HCG levels before ASCT (P = 0.009) in univariate analysis.

In multivariate analysis, while no independent prognostic factor could be determined for PFS, high LDH levels before ASCT was observed as an independent prognostic factor for OS [Figure 3] and [Table 3].{Figure 3}{Table 3}

 Discussion



As far as we know, this is the first Turkish report of ASCT in patients with relapsed or refractory nonseminomatous TGCT. In the literature, most of the studies consisted of heterogeneous group of patients with poor or good prognostic factors or including both seminoma and nonseminoma.[5],[12],[13],[14],[15] In this regard, our study group is relatively homogenous consisted of only relapsed or refractory primary nonseminomatous TGCT tumors. We aimed to analyze the efficacy and safety of ASCT in this group of patients only with poor prognosis without interfering with good prognostic factors such diagnosed as seminoma or having good prognostic factors according to IGCCC.

ASCT could be accepted as a relatively safe procedure with only one death related to transplantation (5.2%). The most common nonhematologic side effects were mucositis and diarrhea. Since prophylactic antiemetic therapy was given in all patients, Grade 3-4 nausea or vomiting was not documented. Among hematologic adverse events, the most common one was neutropenia. In a study consisted of 364 relapsed metastatic GCT patients treated with ASCT, the treatment-related mortality found to be 9 (2.4%) patients. Infection was the most common cause of treatment-related mortality.[14] In another prospective study, the treatment-related mortality was 5.5% in primarily treated patients and 8.3% in relapsed group.[5] The vast majority of patients had mucositis and infections as nonhematologic toxicities similar to our results.[5]

At long-term follow-up, one of the most important adverse events was secondary malignancies. In the literature, there was conflicting data about secondary malignancies including acute leukemia. Although Adra et al.[14] reported that five patients developed secondary leukemia with a range of 17–120 months after transplantation, no acute leukemia was reported in another study.[5] Solid tumors were also reported in the literature after ASCT.[14] In our study with a median follow-up of 18 months, no secondary malignancy including leukemia was observed.

Since nonhomogeneous group of patients were enrolled in most of the studies, different efficacy results can be observed. In a retrospective analysis of patients with poor or intermediate prognostic factors according to the IGCCC including seminoma and nonseminoma subtypes CR, PR, and refractory disease was 50%, 36%, and 14%, respectively, which were compatible with our results (CR 47.3%, PR 31.5%, and refractory disease 15.6%).[12] In another previous analysis at the early 2000s, lower response rates were reported with a higher mortality rates.[4]

In our analysis of relapsed or refractory patient group, estimated 2-year OS was 47.4% and 2-year PFS was 35.3%. A wide range of OS (30%–66%) and PFS (25%–50%) rates was reported [16],[17],[18] in the literature. In a study by Rick et al., TIP chemotherapy followed by one cycle of high-dose carboplatin and etoposide with stem cell rescue was evaluated. Survival probabilities at 3 years were 30% for overall and 25% for event-free survival.[16] Our survival rates estimated at 2 years were seemed to be similar to survival rates estimated at 3 years in this analysis. We could perform only one cycle of ASCT in ten patients due to several reasons including PD, unwilling patient, Grade 4 toxicities. In a retrospective analysis of 364 patients, 2-year PFS and OS were 60% and 66%, respectively. These rates were higher than calculated in our study. This difference might be related to several factors. First, most of the patients (n = 303) in this study were transplanted as a first salvage therapy. Only 6/364 (1.6%) patients were heavily treated. However, in our series, 5/19 (26.3%) patients were heavily treated with equal or more than three lines of chemotherapy. Second, the cohort of 364 patients consisted of both seminoma and nonseminoma patients although we only enrolled patients diagnosed as nonseminomas. Third, 151/364 patients were classified as good prognosis according to the IGCCCG. In our study, we only included patients with intermediate and poor prognostic factors.[14]

Many factors were investigated as possible risk factors effecting PFS and OS. We found that high beta HCG levels before salvage therapy, response of the patient before and after ASCT, LDH levels before ASCT were negatively affected OS and PFS in univariate analysis. However, in the multivariate analysis, only high LDH levels were associated with poor OS rates. High serum beta HCG levels and AFP levels, initial IGCCCG risk, and the time of ASCT (second vs. third or later) were possible demonstrated variables,[14] but these data could not be confirmed by others.[15] We could not demonstrate the statistical differences of variables in multivariate analysis possible due to small sample size.

There is also conflicting data in the literature about the exact time of the ASCT in GCT. It would be performed as a first-line, second-line therapy or it would be an alternative therapy in heavily treated refractory patients. Although high-survival rates (more than 70%) were documented in the literature when ASCT was performed as first-line therapy in patients with poor prognostic factors,[12] in a phase 3 randomized trial, improvement in treatment outcomes could not be demonstrated.[19] Hence, the role of ASCT as a first-line treatment in patients with poor prognostic markers remained obscure. The International Prognostic Factors Study Group analyzed data of 1594 patients with GCT, who have progressed after at least three cycles of cisplatin-based chemotherapy. Patients were treated with standard dose or ASCT as first salvage therapy. Two-year PFS (49.6% vs. 27.8%; P P < 0.001) were significantly longer in the ASCT group than standard-dose group.[20] Hence, the exact time and exact effective number of ASCT should be determined with phase 3 large cohort prospective studies.

Our study also had limitations. First, we analyzed the data of limited number of patients. Second, it was a retrospective study. It was not a randomized study and there was not a control group.

 Conclusion



ASCT is a safe and effective treatment modality in relapsed refractory nonseminomatous TGCT with an acceptable OS, PFS, and mortality rates. Although the number of the patients in this study is limited, the survival rates seem to be increased when ASCT is performed as a first-line salvage. Beside this, large cohort prospective studies with homogeneous groups will better document the role of ASCT.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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