CASE REPORT
Osamu Imataki · Atsushi Makimoto · Rie Kojima Michiyo Sakiyama · Ako Hosono · Yoichi Takaue
Intensive multimodality therapy including paclitaxel and reduced-intensity allogeneic hematopoietic stem cell transplantation in the treatment of adrenal cancer with multiple metastases
Received: August 8, 2005 / Accepted: December 15, 2005
Abstract Adrenocortical carcinoma is a rare malign- ancy in adolescents and young adults. The prognosis of unresectable/metastatic adrenocortical carcinoma remains very poor because the rarity of the tumor has made it diffi- cult to establish treatment guidelines, and diagnosis and the resultant treatment can be greatly delayed. We treated a 24- year-old woman who was diagnosed with adrenocortical carcinoma of the right adrenal gland which extended to the inferior vena cava. Although she underwent surgical resec- tion of the extensive tumor as the primary treatment, the disease recurred in the lung and liver as multiple metastases shortly after surgery. She received intensive multimo- dality therapy, including chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP regimen), embolization of the feeding arteries, and proton irradiation for the liver mass. Finally, she underwent reduced-intensity allogeneic hematopoietic stem cell transplantation from an HLA 1- locus-mismatched sibling donor. A prolonged survival of 39 months after the onset of the disease was achieved. Al- though this experience is limited, we suggest that TIP che- motherapy was effective for adrenocortical carcinoma, and a graft-versus-tumor effect after reduced-intensity stem cell transplantation may have contributed to the prolonged survival.
Key words Allogeneic stem cell transplantation (allo-SCT) . Reduced-intensity stem cell transplantation (RIST) . Adrenocortical carcinoma (ACC) · Graft-versus-tumor (GVT) reaction · Graft-versus-host disease (GVHD)
Introduction
Adrenocortical carcinoma (ACC) is a rare neoplasm with an incidence of approximately 0.5-2.0 per million per year.1 The sex ratio is 2.5, with greater female involvement. Pa- tients typically present with endocrine symptoms caused by the excessive production of hormones by the tumor, and abdominal symptoms including fullness, tenderness, nausea, and vomiting. It has been reported that tumor reduction contributes to long-term survival, and whenever possible radical surgery is recommended for all patients, including those with recurrent disease. More than three- forth of these patients have a functioning tumor indepen- dent of their clinical manifestations, and this suggests that early resection of the tumor could lead to a better chance of survival. However, in those without these early clinical manifestations, complete surgical resection becomes diffi- cult or impossible since the diagnosis is delayed. The reported median survival time was 14.5 months, with a sig- nificantly lower survival in those aged 40 years or more, or those who had distant metastasis at the time of diagnosis.2 Although it has been reported that chemotherapy with mitotane (o,p’-DDD, 1,1-dichlorodiphenyl-dichloroethane) could contribute to longer survival in an adjuvant setting,2,3 the optimal therapeutic approach for those with systemic disease has not yet been established. Hence, an accumula- tion of experience is urgently required to identify an effec- tive multidisciplinary strategy.
We describe here a patient with advanced ACC who was treated very intensively with radical resection of the pri- mary tumor, followed by a combination of chemotherapy consisting of paclitaxel, ifosfamide, and cisplatin (TIP) for lung metastases, a combination of arterial embolization and proton irradiation therapy for liver metastases, and allogeneic stem cell transplantation (SCT) with a reduced- intensity regimen (RIST).
O. Imataki · A. Makimoto () · R. Kojima · M. Sakiyama ·
A. Hosono . Y. Takaue Hematopoietic Stem Cell Transplantation Unit and Pediatric
Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Tel. +81-3-3542-2511; Fax +81-3-3542-3815
e-mail: amakimot@ncc.go.jp
C37-4.2 30H1
0.
Tumor thrombi
IVC
6/0 55/1
4/ BR 14.20m
FREE IR
Tumor
RV
LV
Tricaspid valve
Case report
A 24-year-old woman developed general fatigue and amen- orrhea in January 2000, and a giant tumor in the right adre- nal gland was disclosed in October 2000 by evaluation, including ultrasound echography and computed tomogra- phy (CT). The liver mass extended into the inferior vena cava (IVC) and caused thrombi and mass lesion in the right atrium (Fig. 1). Cardiac echography revealed direct inva- sion of the cardiac tricuspid valve by the tumor that origi- nated from the abdomen (Fig. 2). A systemic survey using CT scanning disclosed no other distant metastatic lesion. The patient underwent complete surgical resection of the tumor under support with an extracorporeal circulation de- vice. A pathological diagnosis of adrenocortical carcinoma was established, and the production of androgen was con- firmed by an elevated serum level of androgen.
Four months after surgery, the patient had tumor recur- rence with multiple liver and lung metastases detected by a follow-up CT examination. Because the lesions grew rap- idly, in April 2001 she began to receive chemotherapy which consisted of paclitaxel (TXL, 175mg/m2, day 1), ifosphamide (IFM, 1200mg/m2, days 2-6), and cisplatin (CDDP, 20mg/m2, days 2-6), i.e., the “TIP regimen,” every 3-4 weeks. After 3 courses of TIP chemotherapy, lung lesions showed complete remission (CR), while liver metastases remained stable. For liver lesions, the patient underwent a transarterial embolism (TAE) procedure using a mixture of Lipiodol and falmorubicin following transarterial infusion (TAI) of cisplatin (CDDP) and mito- mycin C (MMC). A total of 3 TAE/TAI procedures were performed up to August 2001, when all therapies were suspended owing to the development of severe myelosuppression. In November 2001, when the liver mass started to increase in size, 60 Gy proton-beam irradiation was administered concurrently with each course of TIP che- motherapy and TAE.
In April 2002, the patient decided to participate in a phase I trial of RIST for refractory solid tumors, which was approved by our institutional review board (IRB), in the expectation of a powerful graft-versus-tumor (GVT) effect. Prior to the patient’s registration on the trial, the medical team held a thorough discussion with the patient and her family regarding possible treatment options such as mitotane. Because of the lack of evidence of curability with the mitotane therapy, the patient did not decide to receive mitotane. She therefore chose the option to receive RIST from an HLA 1-locus-mismatched brother under sufficient informed consent (recipient’s HLA typing: A33, A24, B60, B52, DR12, and DR2; donor’s HLA typing: A33, A11, B60, B52, DR12, and DR2). The RIST regimen consisted of fludarabine (30mg/m2 for 6 days), busulfan (4mg/kg/day for 2 days) and antithymocyte globulin (25 mg/m2 for 2 days). At the time of RIST, her disease was CR in the lung, while the liver lesion was not evaluable because of the earlier intensive local treatments. A combination of cyclosporine (3mg/kg) and methotrexate (10mg/m2 on day 1, and 7mg/ m2 on days 3 and 6) was administered for graft-versus-host disease (GVHD) prophylaxis. The early course after RIST was uneventful except for transient neutropenic fever for 4 days, which was successfully treated with antimicrobial therapy. Hematopoietic engraftment was observed on day 13. On day 33 after RIST, the patient developed grade 1, stage II, skin GVHD, which resolved spontaneously in 3 weeks. The dose of cyclosporine was gradually tapered until it was discontinued on day 80, while the serum androgen level decreased remarkably between day 60 and day 150. The relationship between the occurrence of GVHD and tumor response is illustrated in Fig. 3. Although a CT scan examination on day 90 confirmed PD in the lung lesions, the tumors appeared to be slowly progressive. Thereafter, the patient maintained a relatively high performance status with indolent tumors until April 2003, when she suddenly experienced serious hematemesis. A upper gastrointest- inal endoscopy revealed extensive mucosal damage disproportionally located in the lesser curvature, which ap-
WBC, neutro × 102/ µL
Pltx 104/ 1L
CRP mg/dL
12
- - . neutro
-WBC
CRP
Plt
30
10
Testosterone ng/dl
25
Plt
8
20
6
161
246
149
133
116
112
4
AF
skin rash (stage II)
15
WBC
closporin
10
2
neutro
5
0
CRP
0
30
60
90 day after transplant
0
Chimerism
100
100
(% donor type)
pears secondary to proton irradiation. The patient experi- enced a silent perforation of the gastric wall resulting panperitonitis the next day, which led to her death 12 months after transplantation. Necropsy was not approved.
Discussion
The prognosis of localized ACC primarily depends on the histology4 and tumor size,5 and there have been reports on the value of radical tumor resection and the efficacy of mitotane therapy.2 In contrast, no effective therapy has been reported for patients with distant metastases or unresectable tumor, and the reported median survival pe- riod is 8 months.6 Here, we report the case of a patient who had an extended tumor and survived 39 months after the onset of the disease, which was much longer than the re- ported median value. In addition, this patient maintained a high performance status and qualified daily life for 9 months after progression until the day before her death, although the tumor recurred shortly after RIST.
We believe that three factors may have contributed to this patient’s ability to achieve a durable asymptomatic period. First, the TIP regimen, which has been shown to be effective for germ cell tumors and other types of endocrine tumor as a salvage chemotherapy, might also be effective for ACC. Considering the lack of adequate therapeutic op- tions, we feel that even this limited single-patient experi- ence could still be of value for future evaluations. Second, this patient underwent an experimental RIST procedure from a partially HLA-mismatched sibling as a final consoli-
dation therapy, as part of clinical trials in patients with various types of solid tumor. Clinical studies that have been reported to date provide proof-of-principle that allogeneic T cells can induce clinically relevant GVT effects in solid tumors, including renal cell carcinoma (RCC)8 and oth- ers.9,10 It is widely accepted that the GVT effect is closely associated with GVHD. Hence, it is possible that the GVT effect may be enhanced by selecting a mismatched graft. Although this patient had no measurable lesions at the time of RIST, the decrease in the serum level of androgen be- tween day 60 and day 150 when GVHD emerged and the indolent course of tumor progression after RIST might be considered evidence of a GVT effect. Third, this patient received intensive procedures for local tumor control, in- cluding extensive primary tumor resection, TAE/TAI, and proton-beam irradiation, which may have made the tumor more sensitive to a GVT effect, as previously suggested.11
In summary, successful allogeneic SCT requires a highly integrated program of donor selection, preparative regi- men, and management of GVHD. Nevertheless, it is pos- sible that the combination of TIP chemotherapy, intensive local tumor controls, and a GVT effect may have contrib- uted to the prolonged survival of this patient.
References
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2. Luton JP, Cerdas S, Billaud L, et al. (1990) Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322:1195-1201
3. Venkatesh S, Hickey RC, Sellin RV, et al. (1989) Adrenal cortical carcinoma. Cancer 64:765-769
4. Lack EE, Mulvihill JJ, Travis WD, et al. (1992) Adrenal cortical neoplasms in the pediatric and adolescent age group. Clinicopatho- logic study of 30 cases with emphasis on epidemiological and prog- nostic factors. Pathol Annu 27(Pt 1):1-53
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10. Koscielniak E, Gross-Wieltsch U, Treuner J, et al. (2005) Graft- versus-Ewing sarcoma effect and long-term remission induced by haploidentical stem-cell transplantation in a patient with relapse of metastatic disease. J Clin Oncol 23:242-244
11. Kami M, Makimoto A, Heike Y, et al. (2004) Reduced-intensity hematopoietic stem cell transplantation (RIST) for solid malignan- cies. Jpn J Clin Oncol 34:707-716