Metronomic Therapy Concepts in the Management of Adrenocortical Carcinoma
Alfredo Berruti · Paola Sperone · Elisa Bellini · Fulvia Daffara · Paola Perotti · Arianna Ardito . Andrea Saini · Massimo Terzolo
Published online: 5 October 2011 C Springer Science+Business Media, LLC 2011
Abstract Metronomic chemotherapy is the administration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This treatment approach can target tumor cells indirectly since it can affect the endothelium of the growing tumor vasculature and stimulates the anticancer immune response. Both the antiangiogenetic and the immunomodulatory roles of metronomic chemotherapy favor a tumor dormancy, a condition that may improve the patient outcome. Prospec- tive clinical trials conducted in several malignancies have shown that metronomic chemotherapy can obtain disease stabilization or responses in tumors that had been made resistant in vivo to conventional chemotherapeutic regi- mens. Three prospective phase II trials have been con- ducted in patients with adrenocortical carcinoma (ACC). In all of them, patients heavily pretreated with conventional chemotherapy and mitotane have been enrolled. One trial tested the activity of the association of gemcitabine and fluoropyrimidines administered on a metronomic schedule.
In this trial, 40% of patients attained a disease stabilization or disease response that was long lasting in some of them. In the remaining two trials, metronomic chemotherapy was administered in association with antiangiogenetic drugs, and the results were disappointing since no response or stable disease was obtained. In conclusion, metronomic chemotherapy can delay tumor progression in advanced ACC and deserves to be further tested. The concomitant administration of antiangiogenetic drugs may be detrimen- tal. Several important questions remain to be addressed such as the optimal dose and most effective dosing interval, when to use the metronomic approach in the natural history of the disease, the choice of cytotoxic drugs, and the most efficacious way to integrate metronomic chemotherapy with standard therapy protocols.
Keywords Adrenocortical carcinoma · Metronomic chemotherapy · Angiogenesis · Immune response
A. Berruti . P. Sperone . E. Bellini . F. Daffara . P. Perotti ·
A. Ardito · A. Saini · M. Terzolo Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Turin, Italy
F. Daffara · A. Ardito · M. Terzolo Medicina Interna, Azienda Ospedaliero Universitaria San Luigi di Orbassano, Orbassano, Italy
A. Berruti () · P. Sperone · E. Bellini · P. Perotti . A. Saini Oncologia Medica, Azienda Ospedaliero Universitaria San Luigi di Orbassano, Regione Gonzole 10, 10043 Orbassano, Italy e-mail: alfredo.berruti@gmail.com
Introduction
Adrenocortical carcinoma (ACC) is a highly malignant disease that is often difficult to treat. The mainstay of treatment for ACC patients is surgery [1], but many patients radically resected are destined to relapse [1, 2]. Patients with stage IV disease at diagnosis or with recurrent disease have a poor prognosis when surgical removal of local relapse and distant metastases, or both, is not feasible [1-3].
For these patients, the standard of treatment has been recently suggested by the results of the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment, a multicenter, multina- tional phase III trial that was recently conducted and preliminary results presented as meeting abstract only [4].
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The efficacy of any first-line chemotherapy regimen in ACC patients, however, is modest, and most patients are destined to relapse [4]. There is therefore an urgent need of new treatment strategies [5]. Metronomic chemotherapy is the administration of antineoplastic drugs at low doses, on a frequent or continuous schedule, with no extended inter- ruptions [6]. As summarized by Kerbel and Kamen [6], metronomic chemotherapy protocols are generally character- ized by: absence of a dose escalation up to the maximal tolerated dose (MTD), absence of the need for hematopoietic growth factor support, preference for oral, outpatient regimens, low incidence or absence of treatment-related side effects, and potential for delayed emergence of resistance. Metronomic chemotherapy can be advantageous with respect to the conventional MTD regimens not only in terms of reducing certain toxicities, but even improving antitumor effects [6]. Many preclinical studies have shown striking antitumor activity of low-dose metronomic chemotherapy regimens, which often equal or exceed the antitumor efficacy of chemotherapeutic drugs administered in the conventional MTD schedule [7-9]. Interestingly, this treatment modality seems also to be effective in treating tumors in which the cancer cells have developed resistance to chemotherapeutics [6]. This paper will review the rationale, initial results, and perspectives of the use of metronomic chemotherapy in the management of ACC patients.
Mechanism of Antineoplastic Activity of Metronomic Chemotherapy
The finding that metronomic chemotherapy can induce disease stabilization or responses in tumors that had been made resistant in vivo to a conventional chemotherapeutic regimen suggests that mechanisms other than direct anti- tumor effects are the basis of the efficacy seen with metronomic protocols [10]. Classically, metronomic che- motherapy is thought to exert its anticancer activity mainly by inhibiting tumor angiogenesis (Fig. 1).
Metronomic chemotherapy
Inhibition of active proliferating tumor endothelial cells. Inhibition of bone marrow derived circulating progenitor of endothelial cells
Inhibition of T regulatory cells
Tumor dormancy
According to the paradigm initially proposed by Folk- man and coworkers [11], by targeting tumor endothelial cells, metronomic chemotherapy should be able to indirect- ly destroy drug-naive and drug-resistant cancer cells by induction of hypoxia and starvation of nutrients. However, additional mechanisms of action have been identified; these include selective inhibition of proliferation and/or induction of apoptosis of activated endothelial cells, selective inhibi- tion of endothelial cell migration, and increase in the expression level of the endogenous angiogenesis inhibitor thrombospondin-1 [12]. We have recently observed that oral cyclophosphamide administered in neoadjuvant ap- proach in breast cancer patients is able to significantly reduce the tumor expression of vascular endothelial growth factor (VEGF) [13], confirming previous data in patients with advanced breast cancer showing a significant reduc- tion of circulating VEGF [9].
In addition to angiogenesis mediated by rapidly dividing endothelial cells from preexisting capillaries, the tumor vasculature also depends on vasculogenesis mediated by circulating endothelial precursor cells (CEPs) originating from the bone marrow [12, 14]. The metronomic adminis- tration of cytotoxic drugs may inhibit the CEP release from the bone marrow, and this is another mechanism of antiangiogenic effects of such approach [14]. It has been observed that CEPs together with other mediators of inflammation are involved in the formation of the so- called premetastatic niche in future host organs [15]; therefore, with this mechanism, metronomic chemotherapy can also counteract the tumor spread in the body.
Angiogenesis, however, is not the only target of metronomic chemotherapy since this treatment modality has also an immunomodulatory role [12]. In particular, it may inhibit a specific subpopulation of CD4+CD25+ regulatory T cells (Treg) [16], whose function is to protect against autoimmunity. Treg cells downregulate the activa- tion and expansion of self-reactive lymphocytes and are crucial for the repression of autoimmune disorders and transplant rejection. These cells are likely to be responsible for maintaining the self-tolerance that may hinder the generation and activity of antitumor-reactive T cells by suppressing the activity of both tumor-specific (CD8+ cytotoxic T lymphocytes and CD4+ T helper cells) and tumor-unspecific effector cells (natural killer [nK] and nK T cells) [16].
Interestingly, Treg cells have been shown to be frequent- ly increased in human cancers [17], and tumor infiltration by FOXP3+ regulatory T cells (Treg) is associated with increased relapse and lower survival in cancer patients [18]. Several studies performed in tumor-bearing animals have shown that low dose of alkylating agents such as cyclophosphamide and temozolomide can increase antitu- mor immune response by decreasing numbers and inhibit-
ing the suppressive functions of Treg cells [19, 20]. We have recently observed that the administration of metro- nomic oral cyclophosphamide in association with letrozole as neoadjuvant approach in elderly breast cancer patients significantly reduced the intratumor expression of Treg [21]. Treg number at residual histology was inversely related with response (P<0.03), and a greater Treg reduction was observed in responding patients (P<0.03). This suggests that metronomic chemotherapy plus aroma- tase inhibitors may have an indirect antitumor mechanism of action through reducing Treg in breast tumors.
Tumor dormancy is a phenomenon that occurs as a result of cell-cycle arrest or from a dynamic equilibrium state in which cell proliferation is balanced by apoptosis induction. By inhibiting tumor angiogenesis and favoring anticancer immunity, metronomic chemotherapy can indirectly induce cellular dormancy in cancer cells (Fig. 1) [12]. The induction of tumor dormancy is a reasonable goal in the management of patients with advanced cancer to whom the tumor eradication cannot be obtained by currently available anticancer treatment. Therefore, one could postulate that one important goal of metronomic chemotherapy is the long-term control of the disease.
Rationale of Combining Metronomic Chemotherapy Plus Antiangiogenic Molecular Target Agents
VEGF-receptor tyrosine kinases are expressed preferential- ly by endothelial cells of the growing neovasculature, and VEGF is a key survival factor for the endothelial cells of newly formed vessels. High local concentrations of VEGF in the tumor microenvironment might therefore induce or promote chemotherapy resistance [6]. On these bases, there is a strong rationale for combining metronomic chemother- apy with antiangiogenic drugs.
Prior preclinical metronomic chemotherapy studies have shown that the combination of antiangiogenic drugs with metronomic chemotherapy can increase the antitumor efficacy compared to either agent alone [22, 23]. As a result of these preclinical studies, two nonrandomized phase II trials have been conducted testing the association of metronomic chemotherapy plus bevacizumab in ad- vanced ovarian and breast cancer, respectively. In one of them, the association of cyclophosphamide and bevacizu- mab administered as second-line approach in 70 platinum pretreated advanced ovarian cancer led to a partial response rate of 24% with a median of time to progression and overall survival of 7.2 and 16.9 months, respectively [24].
In the second paper, bevacizumab was administered in association with oral capecitabine and oral cyclophospha- mide, both administered on a metronomic schedule as second third line in advanced breast cancer patients. In 46
assessable patients, one complete response (2%) and 21 partial responses (46%) were obtained. Median time to progression was 42 weeks [25]. In both studies, a control group is lacking, and this is an important limitation; nevertheless, the results obtained are interesting and deserve confirmation.
Activity of Metronomic Chemotherapy in the Management of Patients with Adrenocortical Carcinoma
ACC is poorly responsive to systemic antineoplastic treat- ments; therefore, treatments targeting the tumor microenvi- ronment and not directly the tumor cells can potentially overcome the intrinsic tumor resistance. Few studies have attempted the metronomic approach in ACC patients (Table 1). In all of them, metronomic chemotherapy was tested as salvage treatment after progression to first-/ second-line chemotherapy schemes.
One study, coordinated by our institution, assessed the combination of gemcitabine administered on days 1 and 8 in association with fluoropyrimidines such as 5- fluorouracil and capecitabine administered on a metronomic schedule [26]. Gemcitabine was chosen due to the demonstration of some activity as second-line approach in reference centers in Europe. At the Consensus Conference held in Ann Arbor in 2003 [27], gemcitabine was considered among the most promising agents. Fluoropyr- imidines were added because the combination of gemcita- bine and fluoropyrimidines was repeatedly found to be synergistic and efficacious in the management of advanced pancreatic cancer and renal cancer which are notoriously considered as chemoresistant diseases. Since the main goal of metronomic approach is to induce a tumor dormancy, not only tumor shrinkage but also disease stabilization, partic- ularly of long duration, were considered clinically mean- ingful. Among the 28 patients that entered the study, 13 (46.4%) obtained a clinical benefit (i.e., disease response or stabilization) lasting 4 months at least. Two patients attained a tumor response according to RECIST criteria, one of them complete. These results are interesting, although in the absence of a control arm, it may be difficult to discriminate whether a stable disease is attributable to the treatment efficacy or an indolent behavior of the disease. It should be noted that all patients enrolled in this trial had a documented disease progression to previous treatment regimens before being registered. In addition, three patients with hormone-secreting ACC who had a stable disease at CT scan obtained a partial hormone response while experiencing a significant clinical improvement. Interest- ingly, the patient who attained a complete response is actually still alive and free from progression after
| First author (year) | Setting | Drug tested | Type of study | Number of patients | Main results |
|---|---|---|---|---|---|
| Sperone et al. (2010) [26] | Second/third line | Gemcitabine, capecitabine, mitotane | Prospective phase II study | 28 | 1 complete response, 1 partial response, 11 durable disease stabilization (4 months at least) |
| Wortmann et al. (2010) [29] | Second/third line | Capecitabine, bevacizumab | Case series | 10 | 10 disease progression |
| Berruti (submitted) | Second/third line | Weekly paclitaxel, sorafenib | Prospective phase II study | 25 | Early interruption |
38 months, the partial response obtained in one patient lasted 10 months, while three patients obtained a long-term disease stabilization lasting 8, 12, and 16 months, respec- tively. Taken together, these data are in favor of the efficacy of this combination regimen at least in a subset of patients. Since all patients had progression to platinum-containing regimens plus mitotane, gemcitabine plus capecitabine could be potentially considered non-cross-resistant to cisplatin-containing regimens.
Noteworthy, despite all patients included in the present trial had shown disease progression while they were on mitotane, this drug was not interrupted. Stratifying patients according to serum mitotane level attained, patients who had serum mitotane above the therapeutic threshold had a better TTP than those who did not. These data suggest a possible synergism between mitotane and metronomic chemotherapy in mitotane refractory cases.
It has recently been observed that mitotane is a potent inducer of CYP3A4, a hepatic enzyme that is one of the most important drug-metabolizing micro- somal monooxygenases involved in the metabolism of many drugs including several cytotoxic agents [28]. On this basis, we cannot recommend mitotane in association with chemotherapy as second- or further line approach outside of clinical trials and, as correctly pointed out [28], future prospective trials testing the efficacy of mitotane plus chemotherapy will require detailed pharmacokinetic investigation.
Two trials have tested the activity of metronomic chemotherapy plus antiangiogenic drugs in ACC patients. The first of them was a multicenter phase II trial conducted in Germany. In this trial, ten patients received a combina- tion of bevacizumab and capecitabine administered on a metronomic schedule. All of them have been heavily pretreated with three or more therapeutic lines. In this poor prognosis series, none obtained a disease response or stabilization [29].
A second study, conducted in Italy and France, explored the activity of the combination of weekly paclitaxel with sorafenib as second-/third-line approach in advanced ACC
patients. The study was planned to include 25 consecutive patients, but unfortunately, it was early interrupted after the observation of disease progression in the first ten patients consecutively enrolled (study submitted for publication).
On the basis of these disappointing results, the associ- ation of metronomic chemotherapy with an antiangiogenic drug in ACC patients did not confirm the promising results obtained with this approach in ovarian and breast cancer, so how to explain these discrepancies? It is interesting to note that tumors are heterogeneous, and treatment response may vary according to the type of cancer.
Noteworthy, the association of metronomic chemother- apy with potent antiangiogenic agents may cause increased tumor hypoxia with respect to metronomic chemotherapy alone, and this may be detrimental since it may eventually cause accelerated tumor growth or increases in invasion and metastasis (as discussed above) [30, 31].
Tumor hypoxia, in fact, is notoriously associated with a more aggressive malignant phenotype in cancers. This occurs by stimulation of the HIF-1 transcription factor, which in turn stimulates a number of genes that are involved either in angiogenesis, such as VEGF and PlGF, or in tumor cell motility and invasion [32].
The finding of a U-shaped dose-response of antiangio- genic drugs provides support to this hypothesis [33]. ACC could have acquired phenotypic characteristics that make tumor cells resistant to severe hypoxia.
Future Perspectives of Metronomic Chemotherapy in ACC Patients
The rationale and the encouraging results initially obtained with the administration of metronomic chemotherapy without the concomitant association of antiangiogenic drugs in ACC patients suggest to further test this treatment approach in the management of this rare disease. Several open questions still remain unanswered. Many cytotoxic drugs have been administered on a metronomic schedule, such as cyclophosphamide, capecitabine, 5-fluorouracil,
etoposide, paclitaxel, and anthracyclines. Since the major target of metronomic chemotherapy is not the tumor itself but the microenvironment including blood vessels and immune cells, it remains unclear whether the specific drug or the treatment schedule is more important for therapeutic efficacy [34]. It should be noted that endothelial cells within tumor tissues can harbor cytogenetic and chromo- somal abnormalities similarly to those observed in cancer cells. Accordingly, it is unlikely that a single drug administered on a metronomic schedule has a universal efficacy. Some tumors may be sensitive to specific drugs and resistant to others, and tumors that acquire resistance to a certain metronomic chemotherapy can be sensitive to a cross-resistant agent administered on a metronomic schedule.
A further issue is the optimal biologic “low” dose for any given metronomic chemotherapy regimen [35]. This question has no clear-cut answer actually since all authors employed empiric doses in clinical trials. This empiricism, however, may have increased the probability of obtaining negative results.
Another important question is when in the natural history of ACC metronomic chemotherapy should be introduced. We have conducted some prospective trials in breast cancer patients either in advanced disease or in neoadjuvant setting. The first trial tested the combination of vinorelbine plus 5-fluorouracil continuous infusion in heavily pretreated patients (three lines or more) with metastatic disease. The scheme was extremely active in this setting [36]. On the basis of these encouraging results, we tested this combination in association with weekly epirubicin as first-line approach in a phase II study including patients with anthracycline-naïve metastatic patients [37] and in association to weekly paclitaxel as first-line approach in a further phase II study enrolling metastatic breast cancer patients pretreated with anthracy- clines [38]. These two schemes were active, but the
response rates and response durations did not seem to be superior than those currently obtained with anthracycline and taxane regimens administered on a conventional MTD. Although the absence of randomization suggests caution in interpreting these data, it seems that the introduction of a metronomic schedule up front did not result in a clearly improved efficacy. How can we explain these data? One hypothesis is that patients who receive more than three chemotherapy lines are likely to represent a selected patient population with a relative indolent disease, so metronomic chemotherapy can be more active in the treatment of less aggressive tumors. As a matter of fact, we have observed that metronomic cyclophosphamide plus letrozole is more efficacious than letrozole alone as a neoadjuvant approach in elderly breast cancer patients with endocrine-sensitive disease, a subset of patients bearing relatively indolent tumors [13]. In addition, continuous infusion of 5-FU seems to potentiate the efficacy of somatostatin analogs in patients with advanced well-differentiated neuroendocrine carcinomas [39]. Alternatively, the introduction of metro- nomic schedule can be more efficacious in heavily pre- treated patients with chemotherapy-resistant disease than in patients with chemo-naïve disease. On these grounds, the interesting results obtained with gemcitabine and capecita- bine as second-/third-line approach in advanced ACC patients cannot imply that this regimen can be efficacious as first-line approach. So, the current strategy is to adopt metronomic chemotherapy upon progression to standard first-line regimens.
Another important controversial point is the role of mitotane. Should mitotane be interrupted in case of progression or it may have a potentiating effect to further chemotherapeutic agents? In the phase II trial we have recently conducted, serum mitotane levels were prognostic, suggesting a possible interference with the activity of gemcitabine and capecitabine. In our opinion, this is an interesting issue that deserves confirmation; however, as
Induction
Maintenance
MTD chemotherapy
Metronomic chemotherapy
rest
rest
rest
rest
rest
Tumor shrinkage
Disease response or stabilization
CPE cells
CPE cells
mentioned before, the administration of mitotane with chemotherapy may lead to a negative interaction in terms of bioavailability of the cytotoxic drug. So, pharmacoki- netic studies are needed to test these interactions.
One interesting future approach is to search the best combination of metronomic chemotherapy with the MTD approach. Bertolini et al. [40] demonstrated that shortly after the administration of an intensive MTD course of chemotherapy, levels of CEPs were substantially reduced for the first few days, followed by a marked rebound during the drug-free break period. This rebound and its timing reflect the process of hematopoietic recovery after myelosuppressive therapy [40]. In contrast, when chemotherapy was administered in a metronomic regimen, levels of CEPs gradually declined and remained suppressed during the entire treatment period. These data form a rationale for administering MTD chemotherapy and metronomic therapy on a sequential way (Fig. 2). Metronomic chemotherapy leading to tumor dormancy can delay and in some cases prevent the disease progression and ultimately may prolong the overall survival of advanced ACC patients. This is an interesting hypothesis for a future prospective trial. The role of maintenance chemotherapy in patients with advanced solid tumors has obtained controversial results in the past. It should be noted that initially the chemotherapeutic drugs adopted in the maintenance regimens were chosen among those included in the induction regimen. More recently, several trials conducted in advanced lung cancer patients have demonstrated that if the maintenance regimen adopts different drugs from those included in the induction therapy, a survival advantage can be obtained [41].
Conclusion
Metronomic chemotherapy is an interesting approach in the management of ACC patients that deserves further studies. Several important questions remain to be addressed such as the optimal dose and the most effective dosing interval, when to use the metronomic approach in the natural history of the disease, and the most efficacious way to integrate metronomic chemo- therapy with standard therapy protocols.
Acknowledgment This paper was supported in part by Regione Piemonte, Progetto Ricerca Sanitaria Finalizzata 2008.
Conflict of interest Alfredo Berruti has received a research grant from Bayer. Massimo Terzolo has received a research grant from HRA. Paola Sperone, Elisa Bellini, Fulvia Daffara, Paola Perotti, Arianna Ardito, and Andrea Saini have no conflicts of interest to disclose.
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