Metronomic chemotherapy may be active in heavily pre-treated patients with metastatic adreno-cortical carcinoma
A. Ferrero1, P. Sperone1, A. Ardito2, G. Rossi3, S. Del Buono3, A.M. Priola4, S. Bracarda3, E. Taberna1, M. Terzolo2, and A. Berruti1
1Medical Oncology; 2Internal Medicine, Azienda Ospedaliera San Luigi, Department of Clinical and Biological Sciences, University of Turin, Orbassano; 3Medical Oncology, Arezzo Hospital, Arezzo; 4Radiology, Azienda Ospedaliera San Luigi, Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
ABSTRACT. Objective: The potential benefit of further che- motherapy approaches in patients with adrenocortical carci- noma (ACC) showing progressive disease after 2 chemo- therapy lines is actually unknown. This study provides ex- plorative information on the activity of metronomic chemo- therapy in heavily pre-treated ACC patients. Design and methods: We tested the activity of cytotoxic treatments ad- ministered on a metronomic schedule in metastatic ACC pa- tients showing disease progression after treatment with gem- citabine and capecitabine scheme. Results: Eight patients out of 28 consecutively enrolled in that trial were treated with several metronomic cytotoxic regimens. Six of them showed disease progression, but 2 patients obtained a clear bene- fit. The first patient was treated with oral etoposide (50 mg
daily) as the 6th-line therapy and obtained a partial response lasting 24 months, while the second patient obtained a par- tial response lasting 10 months with metronomic oral cyclo- phosphamide (50 mg daily) as the 5th chemotherapy line. Both patients had sex hormone secreting tumors and were bearing a rather indolent ACC. Conclusions: The administra- tion of several chemotherapy lines in advanced ACC patients cannot be routinely recommended outside prospective clin- ical trials. Few patients with indolent tumors, however, may benefit from this approach. According to our experience, oral cyclophosphamide and oral etoposide may be used in this setting.
(J. Endocrinol. Invest. 36: 148-152, 2013) @2013, Editrice Kurtis
INTRODUCTION
Adrenocortical carcinoma (ACC) is a highly malignant disease whose treatment remains challenging. The main- stay of treatment for ACC patients is surgery (1), but most radically resected patients are destined to pro- gress, frequently within the first 2 yr following operation (2, 3). The standard treatment for advanced patients not amenable to surgery is the polychemotherapy with etoposide, doxorubicin, and cisplatin in combination with oral mitotane (EDP-M). The efficacy of the EDP-M regimen, however, is modest and most patients progress after treatment; therefore, new treatment strategies are urgently needed (4).
Metronomic chemotherapy is the administration of anti- neoplastic drugs at low doses, on a frequent or contin- uous schedule, with no extended interruptions (5). Metronomic chemotherapy protocols are characterized by the absence of a dose-escalation up to the maximal tolerated dose (MTD), no need for hematopoietic growth factor support, possibility of oral administration in an outpatient regimen, and low incidence of treat- ment related side effects. Interestingly, metronomic chemotherapy has the potential for delayed resistance to treatment.
We have recently published the results of a Multicenter Italian Trial, aimed to test the activity of gemcitabine as- sociated with fluoropyrimidines such as 5-fluorouracil and capecitabine given on a metronomic schedule in patients with adrenocortical carcinoma (6). This regimen led to a disease response or stabilization lasting 4 months in 46% of the 28 patients consecutively enrolled. In case of disease progression, if the performance status was good and the patients were able to tolerate further treatment, additional chemotherapy regimens with a metronomic schedule were given. In this paper, we re- port on the outcome of these patients, focusing particu- larly on the case history of 2 patients who showed a durable partial response after several chemotherapeutic lines.
PATIENTS AND METHODS
As outlined in Figure 1, 8 of the 28 patients enrolled in the “gemcitabine plus capecitabine” trial, were addressed to fur- ther chemotherapy lines. We detail below the case history of two patients obtaining a clear benefit from oral metronomic chemotherapy with etoposide or cyclophosphamide.
Both drugs were administered at a dose of 50 mg daily without interruption until progression or unacceptable toxicities. Con- comitant mitotane was mantained during chemotherapy treat- ment and plasma levels of mitotane were regularly monitored (every 2-3 months).
A computed tomography (CT) scan was repeated every 3 months. The evaluation of disease response was performed by “Response Evaluation Criteria In Solid Tumors (RECIST) criteria” (7), toxicity was assessed by means of the “National Cancer In- stitute (NCI) criteria”.
Key-words: Adreno-cortical carcinoma, cyclophosphamide, etoposide, mitotane, metronomic chemotherapy.
Correspondence: A. Berruti, MD, Oncologia Medica, Azienda Ospedaliera San Luigi, Regione Gonzole 10, 10043 Orbassano, Italy
E-mail: alfredo.berruti@gmail.com
Accepted March 5, 2012.
First published online April 5, 2012.
28 patients enrolled in the “gem + cape” trial
One patient with complete response still alive and disease-free after 41 months
27 patients with PD
19 patients not addressed to further treatments due to poor clinical condition
8 patients addressed to further chemotherapy lines:
- 2 pts were included in a Prospective Phase II Trial (PAXO trial)
- 1 pt → weekly paclitaxel
- 1 pt → paclitaxel + metronomic cyclophosphamide
- 2 pts → metronomic etoposide
- 2 pts → metronomic cyclophosphamide
RESULTS
The outcome of the 2 patients is summarized in Table 1 (8).
Case 1
A 39-yr-old man underwent radical (R0) surgical resec- tion of an estrogen secreting ACC (15 x 9 x 10 cm at CT scan). Pathologic examination revealed the subsequent characteristics: spleen infiltration; Ki-67 positivity in 22% of neoplastic cells, Weiss score 4, and a mitotic count of 5 x 50 HPF. One month later, bilateral lung metastases become evident, and chemotherapy with EDP-M was in- troduced. At disease progression, there was not evidence of hormonal hypersecretion and circulating adrenal cor- tical hormones (estrogen, testosterone, androstenedione, DHEAS, 17OH-progesterone) were not elevated.
A stable disease was documented after 3 cycles, but af- ter 6 cycles disease progression was observed. From September 2003 to April 2004, the patient received a second-line chemotherapy with weekly paclitaxel (60 mg/m2) with a partial response. In May 2004, the patient underwent surgical removal of lung lesions and became disease free. In July 2006, a CT scan revealed disease progression in the lung, therefore he was treated with a 3rd-line treatment with streptozotocin plus mitotane, but the regimen was not active and a disease progression was observed after 4 cycles of therapy.
The patient was then enrolled in the previously men- tioned Multicenter Clinical Italian Trial of metronomic oral capecitabine and gemcitabine plus mitotane. A stable disease was obtained that lasted 6 months. On May 2007, radiological examination proved an increase in size and number of the pulmonary lesions.
The clinical general conditions of patients were good, so a 5th-line treatment with metronomic oral cyclophos- phamide (50 mg/daily) was prescribed. The disease re- mained stable till February 2008, when a further pro- gression was detected. The patient discontinued any
systemic treatment and the disease remained stable till December 2008, when further progression of lung metastases was observed at the CT scan. The patient started a 6th-line therapy with oral metronomic etopo- side (50 mg daily) associated with oral mitotane. A CT scan, performed after 3 months, showed a partial dis- ease response (Fig. 2). The disease response further im- proved in the subsequent CT scans till December 2010. Treatment was continued till January 2011, when dis- ease progression was observed. Mitotane serum levels during etoposide treatment ranged between 6 and 9 mg/l. Oral etoposide treatment was rather well tolerat- ed and was only temporarily interrupted due to asthenia lasting for 15 days.
Case 2
A 59-yr-old woman presented in December 2007 with a metastatic ACC involving liver, lymph nodes, and lung (bilateral metastases). The disease was androgen secret- ing, causing severe testosterone excess (6 ng/ml; normal values in women: 0.11-0.78 ng/ml) and androstenedione excess (>10 ng/ml; normal values: 0.30-3.30 ng/ml). ACTH and serum cortisol were normal.
A fine needle aspiration of the adrenal mass was per- formed and the histology revealed a malignant tumor with Ki-67 positivity in 20% of cancer cells and presence of atypical mitoses (Weiss score was not calculated).
She was in good clinical conditions, her performance sta- tus was 1 according to the Eastern Cooperative Oncolo- gy Group (ECOG) scale, the physical examination showed a clear hirsutism on face and chest. On the basis of the histology and the disease stage, the patient started a first-line chemotherapy regimen with EDP-M. From Jan- uary 2008 to March 2008, she received 3 cycles with ev- idence of pulmonary and hepatic disease progression ac- cording to RECIST criteria (7) on image restaging. Mi- totane serum levels achieved after 3 months of treatment
| Pt | Stage at diagnosis | Ki-67 | Hormone secretion | 1 st line CT | Best R | CT lines before GMC-C | Best R | Best R to GMC-C | 1 st line therapy after GMC-C | Best R | 2nd line therapy after GMC-C | Best R | 3rd line therapy after GMC-C | Best R |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| FG | Locally advanced | 22% | estrogen | EDP+M | SD | Weekly PXT Strepto + M | PR lasting 7 months | SD lasting 6 months | CTX | SD lasting 8 months | VP-16 | PR lasting 24 months | - | - |
| CP | Metastatic | 20% | androgens | EDP+M | PD | none | - | MR lasting 10 months | Weekly PXT+ | PD | VP-16 | PD | CTX | PR lasting 10 months |
sorafenib (PAXO trial)
Pt: patient; CT: chemotherapy; EDP: etoposide, doxorubicin, cisplatin; M: mitotane; R: response; SD: stable disease; PD: progression disease; GMC: gemcitabine; C: capecitabine; PXT: paclitaxel; Strepto: streptozotocine; PR: partial response; MR: minimal response; CTX: cycloposphamide on metronomiuc schedule; VP-16: etoposide on metronomic schedule; PAXO trial: weekly paclitaxel + sorafenib (8).
case #1.
3 months of metronomic chemotherapy with etoposide in the Fig. 2 - Disease response at computed tomography scan after
B
A
A
B
were 16.9 mg/l (therapeutic range: 14-20 mg/l).
The patient was then treated with gemcitabine plus metronomic capecitabine. At the planned first restaging after 3 months, there was evidence of minimal response at CT scan (mild regression of pulmonary and mediasti- nal lymph nodes). This regimen was continued till a total of 8 cycles. At the end of the 8th cycle, in October 2008, the CT showed a further reduction in the size of pul- monary and lymphnodal metastases. On January 2009, a new disease progression both in liver and lung was de- tected. She was included in a prospective clinical trial (PAXO trial NCT 00786110) and treated with the associa- tion of weekly paclitaxel (60 mg/m2) and daily sorafenib (800 mg). Unfortunately, after two cycles, the CT scan doc- umented a clear progressive liver disease. This experi- mental therapy was therefore discontinued, but the pa- tient, whose conditions still remained good, asked for fur- ther treatment. A 4th-line treatment with etoposide ad- ministered with metronomic schedule at the dosage of 50 mg orally was given for three months, in association with oral mitotane. After 3 cycles (July 2009) a CT scan showed a disease progression both in lung and liver. Mitotane serum levels were 6.4 mg/l. A moderate dyspnea that ham- pered significantly her quality of life become apparent. Since the patient strongly requested a further treatment, metronomic chemotherapy with cyclophosphamide (50 mg once daily) was instituted. Mitotane therapy was not interrupted. Radiological examination performed after two months showed an objective response (regression of pulmonary and mediastinal lymphnodes, with no change of abdominal lesions). A complete remission of dyspnea was observed while the patient reported only a mild asthenia. Mitotane serum levels were 15.6 mg/l. The disease response lasted 10 months and afterwards a fur- ther progression become evident, leading to death on January 2011. The patient also obtained a transient re- duction of hormone hypersecretion (testosterone serum levels dosed after 3 months of metronomic cyclophos- phamide were 2.8 ng/ml; and androstenedione serum le- vels were 4.7 ng/ml) lasting 6 months.
DISCUSSION
It is held that ACC is poorly responsive to chemotherapy. The EDP-M regimen is considered one of the standard first-line therapies in the management of metastatic ACC (9) and the combination of gemcitabine and capecitabine (6) represents a second-line option, although the benefit is limited. There is sparse demonstration of efficacy of other cytotoxic drugs beyond these 2 chemotherapy lines (4). A number of patients, however, are still in good gen- eral condition despite ACC progression to systemic ther- apy and frequently ask for further treatment.
The metronomic schedule, targeting the tumor micro- environment and not directly the tumor cells, has the po- tential for efficacy. In addition, the relatively low toxicity profile makes this approach feasible in such patients, in whom the tolerability to cytoxic agents may be reduced because they have been often heavily pre-treated (10, 11).
Among the 28 patients enrolled in the gemcitabine + capecitabine study, eight were eligible for further thera-
pies, and 6 of them received cytotoxic drugs outside a clinical trial. A disease progression was observed in 6 of these patients; however, two patients obtained a sub- stantial benefit. In the first patient, oral cyclophosphamide administered as the 5th-line led to a stable disease lasting 7 months, but more importantly, the 6th-line therapy with metronomic etoposide that was subsequently done led to partial response lasting 24 months. In the second patient, oral cyclophosphamide, administered as the 5th-line ther- apy, led to a significant partial response of lung lesions, which was associated to a temporarily resolution of the clinical symptoms.
As clearly shown in Table 1, both cases obtained the best results in terms of tumor shrinkage with the last treatment received and this is in contrast with the common expe- rience of a progressive reduction in the treatment effica- cy while increasing the number of chemotherapy lines. In addition, since both patients were previously treated with aggressive cytotoxic regimens without success, this observation suggests that aggressive polychemothera- py may be not the best option in all patients and, in a se- lected patient population, it may be worth trying se- quentially several single chemotherapeutic agents given on a metronomic schedule. Of course, it may be argued that patients who become eligible to several chemother- apy lines are bearing indolent, less aggressive tumors, and this may imply a selection bias in an uncontrolled study. Long disease-free survival is frequently considered a marker of good prognosis, but it is not applicable to our cases, since one of them was metastatic ab initio, and the second showed metastatic disease within few months following radical surgery. However, the clinical observa- tion of a long disease history is compatible with the con- cept of a slow-progressing ACC.
The major target of metronomic chemotherapy is not the tumor itself but the blood vessels, so it remains un- clear whether the specific drug or the treatment sched- ule is more important for therapeutic efficacy. It should be noted that endothelial cells within tumor tissues can harbor cytogenetic and chromosomal abnormalities sim- ilar to those observed in cancer cells (12). Accordingly, it is unlikely that a single drug administered on a metro- nomic schedule may have a universal efficacy (13). The patients included in the present study received either metronomic cyclophosphamide or metronomic etopo- side, but their tumors showed a different sensitivity to the drugs administered. These data suggest that some tumors may be sensitive to specific drugs, and tumors that acquire resistance to a given drug may retain sensi- tivity to a cross-resistant agent administered also on a metronomic schedule.
The role of maintaining mitotane in patients showing disease progression to previous mitotane-containing schemes is controversial. In our cases, mitotane treat- ment was maintained, but in the first patient serum mi- totane levels were below the therapeutic range (14), making unlikely that mitotane contributed to tumor re- sponse.
In conclusion, this paper suggests that some patients with a clinical history of slow-progressing ACC could benefit from a metronomic approach. According to our prelimi- nary results, oral cyclophosphamide and oral etoposide
could be well suitable to be used in this setting due to the good tolerability and low costs of such drugs. These data therefore deserve confirmation.
ACKNOWLEDGMENTS
Declaration of interest
The authors declare that there is no conflict of interest that would preju- dice their impartiality.
Funding
This paper was supported in part by Regione Piemonte, Progetto Ricer- ca Sanitaria Finalizzata 2008, and from the Italian Ministry of University and Scientific and Technological Research (PRIN, grant nº 20085P5S49).
Author contribution
Drafting of the manuscript: A. Ferrero, A. Berruti, P. Sperone and M. Terzolo. Radiological revision: A.M. Priola performed the centralized revision of CT imagines.
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