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Treatment Options for Recurrent Glioblastoma: Pitfalls and Future Tren...

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Authors and Disclosures Enrico Franceschi,1 Alicia Tosoni,1 Stefania Bartolini,1 Valeria Mazzocchi,1 Antonio Fioravanti 2 and Alba A. Brandes 1 1

Department of Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL of Bologna, Bologna, Italy Department of Neurosurgery, Bellaria-Maggiore Hospital, Azienda USL of Bologna, Bologna, Italy

2

Disclosure: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

From Expert Review of Anticancer Therapy

Treatment Options for Recurrent Glioblastoma: Pitfalls and Future Trends Enrico Franceschi; Alicia Tosoni; Stefania Bartolini; Valeria Mazzocchi; Antonio Fioravanti; Alba A. Brandes Posted: 05/29/2009; Expert Rev Anticancer Ther. 2009;9(5):613-619. © 2009 Expert Reviews Ltd.

Abstract and Introduction Abstract

Standard treatment with temozolomide and radiotherapy for patients with newly diagnosed glioblastoma has increased the median overall survival and, more importantly, the 2-year survival rate of patients. However, as yet, no investigations have been conducted to define effective strategies against recurrence, which occurs in most patients following combined radiotherapy/temozolomide treatment. Furthermore, in recent years, new issues have emerged regarding the evaluation of disease response, and also with the identification of patterns such as pseudoprogression, frequently indistinguishable from real disease progression. New therapeutic strategies, such as targeted therapies and anti-angiogenic treatments that appear promising with regard to improving the results at the time of recurrence are discussed. Introduction

It is widely accepted that treatment with the oral alkylating agent temozolomide (TMZ) administered concurrently with and adjuvant to radiation therapy (RT) is standard care for patients with newly diagnosed glioblastoma (GBM); and it is widely agreed that this approach increases overall survival.[1] During the course of treatment, however, deterioration in the patient’s neuroradiological picture with an increase in, or the appearance of, contrast-enhancing lesions can suggest tumor progression or recurrence, and these radiological findings are not necessarily accompanied by any clinical decline. The clinical and radiological patterns that may be caused by RT usually occur within 2-3 months following treatment. In 1979, Hoffman et al. described these alterations in a group of patients treated with RT and carmustine (BCNU).[2] Within 18 weeks following RT, approximately a third of patients had a deterioration that suggested tumor progression; spontaneous improvement occurred without therapy being changed. This pattern, indistinguishable from that of tumor recurrence, usually improves within a few weeks or months; at a thorough neuroradiological follow-up, a regression in these signs may be observed within 4-8 weeks. The clinical features observed following RT have been defined as 'early-delayed reactions'.[3] Conventional neuroradiological techniques do not always enable a differentiation to be made between early-delayed reactions and recurrence,[4,5] the former appearing as postradiotherapy radiological deterioration, with an increase in contrast-enhancement, a worsening in cerebral edema and the picture of a mass, with signs similar to those of recurrence.[6] These difficulties in discriminating between tumor progression and the effect of treatment can profoundly compromise the quality of any subsequent patient management. Magnetic resonance spectroscopy can improve the distinction between residual or recurrent tumors from pure treatment-related necrosis, but not from mixed necrosis and tumor tissue.[7] Moreover, metabolic imaging, such as PET examination with amino acid tracers (e.g., 11C-methionine and 18 F-fluoroethyltyrosine), seems to be a promising approach in discriminating between treatment-induced necrosis and disease recurrence.[8,9]

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The risk of mistaking early-delayed reactions (recently redefined as 'pseudoprogressions' [psPDs]) for early disease progression following radiotherapy has been investigated by de Wit et al. who, in a series of 32 glioma patients, found that the first post-RT MRI (within 3 months) showed progressive enhancement in nine cases;[10] in three out of nine patients, the MRI picture improved or stabilized for 6 months without additional treatment being given. Chamberlain et al. evaluated 65 GBM patients treated with concurrent RT and TMZ and reported that seven out of 15 (46%) of those who underwent surgical resection for suspected recurrence had histologically confirmed psPD with patterns of radiation-induced necrosis.[11] Recent studies have evaluated the incidence of psPD in patients treated with concurrent RT and TMZ. Taal et al. showed that, in a cohort of 85 high-grade gliomas, the psPD rate was 21%.[12] Furthermore, data from a large study on 103 GBM patients showed that the psPD rate was 31%.[13] Interestingly, in this study, a correlation was found between MGMT methylation status and the psPD rate, the probability of psPDs being 91% in patients with suspect images at the first post-RT/TMZ investigation and methylated MGMTpromoter tumors, and the probability of early progression being 59% in those with unmethylated MGMTpromoter tumors. The results reported in studies on psPD are listed in Table 1 , and the issue of psPD has recently been reviewed.[14,15] Table 1. Studies on Pseudoprogression in Glioblastoma Patients Treated With Concurrent Chemoradiation.

Author

Patients (n) Pseudoprogression (%) Ref. *

Chamberlain et al.

65

46.7

Jefferies et al.

15

20

Taal et al.

85

21

Brandes et al.

103

31

[11] [55] [12] [13]

*Calculated in patients undergoing resection for images suggesting tumor enlargement.

Owing to the potential risk of including progression-free patients in clinical trials on recurrent disease, psPDs have extremely important implications in neuro-oncology. Clearly, a more reliable approach is required for the identification of psPD in patients with GBM treated with TMZ concomitant with and adjuvant to RT, as this would allow the identification of patients for whom there is no need to switch from effective adjuvant treatment to a potentially less-effective and more-toxic regimen. Further information is required to better understand the nature of psPD in order to distinguish it from true early progression, thus obviating biases in the evaluation of results from clinical trials and sparing patients inappropriate treatment. Therefore, in many clinical trials evaluating the role of new drugs at recurrence after RT/TMZ treatment, patients are enrolled at least 3 months after RT completion.

Second Surgery Repeat resection is the best available method for prolonging the survival of selected patients with recurrent GBM, especially those with a mass effect. However, prognostic factors, such as age, performance status and presumed maximal extent of resection, which must always be considered, may indicate that repeat resection is unfeasible. Surgery may also be performed to confirm the diagnosis and provide symptomatic relief from mass effect or cerebral edema. Removal of the tumor bulk may enhance the efficacy of postsurgical therapy, and the longer period of survival gained may also allow more time for benefit from sequential treatments. At repeat resection, any chemoresistant hypoxic tissue found to be present may also be removed. Although survival generally appears to be longer in patients who undergo repeat resection, a lack of randomized trials and the bias in the selection of patients for this procedure makes it difficult to objectively assess its benefit. The major advantages of repeat resection are that it provides rapid palliation of symptoms and allows a histological diagnosis to be made. Few studies have provided data on repeat resection as a sole treatment modality. However, a randomized study has been conducted to compare the effects of BCNU-impregnated polymer implantation with placebo polymer implantation after repeat resection;[16] the median survival obtained (31 and 23 weeks, respectively) demonstrated that the outcome was significantly better in the BCNU group. In a smaller study on 24 GBM patients who underwent repeat resection alone, the median survival was 14 weeks.[17] In most other trials conducted, postoperative RT and/or chemotherapy were administered and, therefore, the impact of repeat resection alone is not entirely clear. In their study on outcome following repeat resection plus additional tailored

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treatment (chemotherapy in 85% of cases) for GBM, Barker et al. reported a median survival of 36 weeks.[18] This suggests that the improvement achieved was moderate with respect to that of 23 weeks, achieved in a group of 130 patients who received comparable first-line treatment and chemotherapy without repeat resection. However, a number of selection factors might have influenced the decision not to perform surgery in the latter group.

Repeat Irradiation Patients with recurrent GBM almost invariably have undergone a previous full course of external-beam RT, making repeated irradiation more complex, and potentially much more toxic. Given the difficulty and risk incurred by administering repeated irradiation to the brain, this option is offered to a relatively small minority of patients with recurrent GBM: a highly selected group of patients with focal disease and a good performance status. The great variety of radiation techniques used to treat recurrent GBM in the clinical setting include: conventional RT; intensity-modulated RT; temporary or permanent brachytherapy; single- or multi-fraction stereotactic radiosurgery; and photodynamic therapy. It has been shown that the median survival time for GBM patients who undergo repeated irradiation using techniques other than conventional RT is 26-47 weeks and the radionecrosis rate is 6–8%.[19] Salvage therapy should be highly tailored to patients with a good performance status, young age and a prolonged time interval following previous RT. However, as with repeated resection, a lack of prospective randomized trials, and bias in selecting patients for single-arm trials, prevent any reliable conclusions from being made regarding the benefit provided by repeated irradiation in patients with recurrent malignant glioma.

Chemotherapy at Recurrence/progression Macdonald et al. have attempted to standardize response criteria on the basis of CT/MRI imaging, neurological status and steroid usage.[20] Currently, however, time to progression (TTP) and/or progression-free survival at 6 months (PFS-6) are believed to be more reliable and objective end points in evaluating the efficacy of medical treatment. Indeed, TTP measurement is straightforward and, unlike survival, is not influenced by further treatment.[21] Recently, the prognostic role of PFS-6 in patients with GBM recurrence was confirmed by Ballmann et al., whose findings showed that PFS-6 was correlated with overall survival at 12 months.[22] Chemotherapy, in association with corticosteroids, may often palliate symptoms and improve the quality of life.[23] This is an undeniable, although less objectively measurable, end point of efficacy for medical treatments, and should be assessed in state-of-the-art clinical trials. Chemotherapy is extensively administered to patients with recurrent GBM, although objective response rates remain unsatisfactory and TTP is short (3-6 months).[24] A retrospective analysis of eight Phase II chemotherapy trials conducted on 225 patients with GBM (partly pretreated with one or more chemotherapy regimens) reported a PFS-6 of 15% and a median progression-free survival of 9 weeks,[25] thus representing the benchmark for drug activity in the pre-RT/TMZ era. Before the European Organisation for the Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) Phase III trial,[1] nitrosoureas, BCNU and lomustine, liposoluble alkylating drugs, were the gold standard for first-line chemotherapy for recurrent GBM after surgery and RT, with a response rate of approximately 30%. However, this may have been an overestimation, with findings being based on criteria that were essentially clinical. Data reported in subsequent studies on chemonaive patients indicated that BCNU treatment was followed by a response rate of 15% and a PFS-6 of 17.5%.[26] Furthermore, many other Phase II trials, conducted before the era of combined RT/TMZ for newly diagnosed GBM, reported PFS-6 rates of up to 39% in patients with recurrent disease receiving TMZ in combination with other agents (i.e., marimastat,[27] cisplatin[28] and 13-cis-retinoic acid[29]). However, it has not yet been proven that multiagent chemotherapy is more effective than single nitrosourea administration.[24,30] Nor has it been demonstrated that TMZ has advantages over a BCNU or procarbazine, lomustine and vincristine regimen, despite the fact that an indirect comparison made between studies suggests that TMZ has a better, noncumulative toxicity profile than other regimens used. Following the introduction of the current standard of care for newly diagnosed GBM patients with RT and concomitant/adjuvant TMZ, novel first- and second-line treatments are under evaluation. Therefore, even though clear data are not yet available, nitrosourea-based chemotherapy should be considered a reasonable option,[26] as well as a TMZ rechallenge for patients without disease progression during TMZ treatment.[31] Temozolomide rechallenge was recently investigated also by Perry et al. In their retrospective analysis, the authors showed that TMZ rechallenge with a continuous 50 mg/m2 daily schedule is an intriguing approach, especially for patients with recurrence after completion of TMZ administration concurrent with and adjuvant to RT: GBM patients failing during the first 3-6 months of adjuvant therapy (B1); GBM patients failing after more than 6 months of therapy (B2); and GBM patients

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who recurred after stopping treatment (B3). The PFS-6 rates were 28.6 (B1), 9.5 (B2) and 30.4% (B3).[32] Repeat surgery and implantation of chemotherapy (BCNU)-impregnated polymers (Gliadel®) may also prolong survival in selected patients.[16] Recently, a Phase II trial using a thirdgeneration nitrosourea, fotemustine, investigated treatment efficacy in a population treated exclusively with TMZ and RT; MGMT methylation status was also assessed. A PFS-6 of 20.9% was obtained, and the authors suggested that their study findings represented a benchmark of activity at the time of recurrence.[33] The same approach has also been investigated by other groups.[34,35]

Targeted Therapies Recent advances in the understanding of molecular and cytogenetic pathways that influence tumor growth, invasion, angiogenesis and apoptosis have led to the direct targeting of the aberrant pathways found in cancer. The high specificity provided by targeted therapies may allow malignancies to be treated without incurring the adverse effects of toxicity from systemic chemotherapy. Many of the molecular therapeutic agents targeting these pathways, administered either alone or with commercially available agents, are under evaluation in ongoing clinical trials. Treatments against specific molecular targets, in particular the EGF receptor (EGFR), have been investigated in brain tumor patients. However, as yet, no specific trials investigating outcome after concurrent RT/TMZ have appeared in the literature. EGFR amplification and overexpression, present in approximately 50% of GBM patients, are associated with a poor prognosis. In recent years, small-molecule inhibitors targeting tyrosine kinases, such as erlotinib (Tarceva®) and gefitinib (Iressa®), which bind to the intracellular part of the receptor, have been introduced in clinical practice and have been widely evaluated in neuro-oncology. In a Phase II gefitinib trial on a series of 53 patients with recurrent GBM, no objective responses were found.[36] The PFS-6 (13%) was the same as in historical controls, with other agents considered inactive. In this trial, EGFR protein expression and gene status, and EGFRvIII protein expression, were not significantly correlated with PFS-6 and survival, and gefitinib as a single agent was considered inactive in this setting. Likewise, 28 patients with recurrent or progressive high-grade glioma were prospectively treated with gefitinib within the Gruppo Italiano Cooperativo di Neuro-Oncologia network. No objective responses were observed and a PFS-6 of 14% was reported.[37] On analyzing phospho-Akt, EGFR gene copy number and protein expression, no significant correlations with survival and response parameters were found. However, findings made in two retrospective series suggest that there are molecular biomarkers that are correlated with response and/or survival. Haas-Kogan et al. observed that the response to erlotinib treatment was greater in GBM patients with high EGFR expression and low phospho-Akt levels than in those with low EGFR expression and high phospho-Akt levels. The authors found no correlation between EGFRvIII expression and response.[38] In their study on 49 GBM patients treated with erlotinib or gefitinib, Mellinghoff et al. found that EGFRvIII and PTEN protein co-expression was correlated with response to treatment.[39] More recently, a large and well-conducted randomized Phase II study by the EORTC 26034 trial compared first-line erlotinib with either TMZ or BCNU as standard treatments [40] and found that results were disappointing when the EGFR inhibitor was given as a single agent for recurrent disease: PFS-6 was 12% in the erlotinib arm and 24% in the control arm. No responses were observed following erlotinib administration, and no correlations were found between treatment effect and EGFR expression or amplification and EGFRvIII expression. Furthermore, a Phase II trial with erlotinib in combination with carboplatin showed that the activity of this regimen was modest, with the PFS-6 being 14%. Moreover, no correlation was observed between EGFR, Akt or PTEN expression and PFS or overall survival (OS).[41] Other targeted therapies have been investigated in the neuro-oncological setting Table 2 . In particular, anti-angiogenic treatments appear promising when given for GBM characterized by florid angiogenesis. Several molecular mechanisms contribute to tumor angiogenesis, but the VEGF pathway seems to play a particularly important role and has been a prominent target in cancer treatment. Findings reported from a recent Phase II clinical trial showed that patients with malignant glioma benefited from treatment with a VEGF-neutralizing antibody, bevacizumab (Avastin®), administered in combination with a topoisomerase-I inhibitor, irinotecan;[42] the radiographic response rate was 63%, the PFS-6 was 30% for GBM and 56% for recurrent WHO grade 3 gliomas. In another Phase II trial on recurrent GBM patients, bevacizumab and irinotecan showed a response rate of 57% and a PFS-6 of 46%.[43] A similar response rate, but a PFS-6 of 25% and a median survival of 7 months, was demonstrated by Bokstein et al.[44] Interestingly, in a randomized Phase II trial on bevacizumab, administered alone or combined with irinotecan for recurrent GBM, a PFS-6 of 35.1 and 50.2%, respectively, were reported, and there was no significant difference in terms of OS (9.7 and 8.9 months, respectively).[45] Recently, another Phase II trial on single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression showed a PFS-6 of 29%.[46] The authors suggested that the Levin criteria for response evaluation, which consider extent of gadolinium enhancement, edema and mass effect in an overall assessment,[47] were more predictive of longer PFS than the Macdonald[20] criteria. Moreover, no response was obtained with the addition of

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irinotecan at time of disease progression after bevacizumab had been used as a single agent, and the median TTP was 30 days.[46] Since VEGF (also known as the vascular permeability factor) regulates vascular permeability, targeting VEGF with bevacizumab may reduce contrast leakage into the tumor, thus maximizing the radiographic response. However, the following radiological changes may not reflect the real state of tumor response and, therefore, common end points for Phase II studies, such as response rate and PFS-6, could not be appropriate in evaluating anti-angiogenic agents, as suggested by Norden et al.[48] Moreover, a small exploratory study on 18F-fluorothymidine PET in malignant glioma patients treated with bevacizumab and irinotecan showed that metabolic response was predictive of OS while MRI radiological response showed only a trend, and that metabolic responders did not clearly correlate with PFS, confirming that classical neuroradiological imaging should not provide conclusive information about the activity of these regimens.[49] Response rates, PFS-6 and OS of bevacizumab-based regimens are listed in Table 3 . Table 2. Results of Phase II Trials on Small Molecule-targeted Therapies.

Patients (n)

6-month progression-free survival (%)

Response rate (%)

Overall survival (months)

Gefitinib

53

13

0

9.9

Gefitinib

28

14

0

6.2

Cediranib

30

25.8

56

7.4

Erlotinib

54

11.4

4

7.7

Temsirolimus

65

8

0

4.4

Cilengitide

81

16

9

7.2

Agent

Ref. [36] [37] [50] [40] [56] [53]

Table 3. Results of Studies on Bevacizumab-based Treatments in Glioblastoma. Carmustine/temozolomide evaluated in the European Organisation for the Research and Treatment of Cancer 26034 study was also included as a historical control.

Patients (n)

6-month progression-free survival (%)

Response rate (%)

Overall survival (months)

Bevacizumabirinotecan

23

30

61

9.3


35

46

57

9.8


20*

25

47

7


82

50

33

8.9

Bevacizumab

85

35

20

9.7

Bevacizumab

48

29

35

7

Carmustine/ temozolomide

56

24

10

7

Regimen

Ref. [42]

[43]

[44]

[45]

[45] [46] [40]

*In high-grade gliomas (17 glioblastoma).

Other anti-angiogenic drugs, such as AZD2171 (cediranib), an oral tyrosine kinase inhibitor of VEGF receptors, have been evaluated in a Phase II trial in patients with recurrent GBM. Cediranib was found to provide a significant clinical benefit by alleviating edema, and a PFS-6 of 25.6% was recorded. In this study, however, no data were provided on timing and type of previous treatments (i.e., RT with or without TMZ).[50] Moreover, the use of bevacizumab and other anti-angiogenetic agents shifted the spectrum of toxicities from hematological to nonhematological, with toxic effects that were rare but, in some cases, severe (i.e., bowel perforation)[51] and that were previously almost unknown in neuro-oncology. Thrombotic events and intracranial hemorrhages have been described across the aforementioned studies. Taken together, these data

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on anti-VEGF treatments, in terms of response rate and PFS-6, attracted considerable interest. However, because these regimens have been investigated only in Phase II studies on relatively small populations of patients, no definitive conclusions can be drawn, and cross-comparisons with historical data are challenging. Moreover, different end points to evaluate activity of these compounds in Phase II trials should be taken into consideration. Angiogenesis is also regulated by integrin-mediated signaling. Integrins, cell-surface adhesion molecules that are often overexpressed in gliomas, mediate cell adhesion, migration and invasion into the surrounding tissue. Agents that target integrins, such as EMD121974 (cilengitide), found to be active when combined with TMZ and RT in newly diagnosed GBM patients,[52] were evaluated as a single agent in a Phase IIa trial on patients with recurrent GBM; the toxicity profile was manageable, no cases of grade 4 toxicity occurred and the PFS-6 was 15%.[53] Interestingly, in the Phase II trial on the administration of cilengitide combined with RT and TMZ, MGMT-methylated status appeared to enhance the efficacy of the drug combination; it has been suggested that this may be due to the blood flow within the tumor being regulated by cilengitide, which should increase the delivery of TMZ to cells more sensitive to alkylating agents. This possibility is being evaluated in a large, ongoing randomized Phase III trial on MGMT-methylated patients given cilengitide combined with TMZ and radiation (CENTRIC trial). A significant percentage of GBMs have PTEN gene suppression alterations, resulting in the increased activation of the downstream PI3K/Akt/mTOR pathway, which regulates cell survival and proliferation; the deregulation of this pathway is thought to play a role in tumor pathogenesis. Thus, another target for new compounds is mTOR, a serine/threonine kinase that acts as a central component of the PI3K/Akt signaling pathway that mediates cell growth and proliferation. Efforts to downregulate this pathway have been pursued through inhibitors of mTOR, such as rapamycin (sirolimus), RAD-001 (everolimus) and CCI-779 (temsirolimus). Two recently completed trials on temsirolimus in patients with recurrent GBM report a PFS-6 of 2.5 and 7.8%, respectively. Finally, imatinib mesylate, a small-molecule inhibitor of KIT, Bcr/Abl and PDGF receptor (PDGFR), has been evaluated in recurrent gliomas in a multicenter EORTC Phase II trial. In patients with recurrent GBM, PFS-6 was 16% and overall PFS was not correlated with PDGFR-a single nucleotide polymorphisms.[54]

Expert Commentary The majority of GBMs recur regardless of initial treatment and despite RT/TMZ treatment. The reliability of any radiological assessment of recurrence is compromised by the possibility of psPD after RT; findings must therefore be evaluated in conjunction with a clinical appraisal, molecular biology information and a radiological investigation and/or biopsy if diagnosis of progression is not clear. Progressive disease can be treated with secondary therapeutic approaches (surgery, radiosurgery, chemotherapy and novel agents), although there is no clear evidence that they prolong survival. However, the final decision regarding treatment for recurrent GBM must take into account the specific characteristics of each patient and tumor and, whenever possible, patients should be given the opportunity to participate in experimental trials.

Five-year View The treatment of recurrent GBM is still a challenge and the real value of approaches that were used at the time of first recurrence in the pre-RT/TMZ era is still unknown. However, the development of novel therapeutic options for patients with recurrent GBM remains a priority. The results to date for anti-angiogenic treatments appear promising but definitive results are needed. Other agents currently in clinical development for recurrent GBM include new molecular targeted therapies (i.e., SRC inhibitors).

Key Issues Pseudoprogressions are clinically relevant entities after concurrent radiotherapy (RT)/temozolomide (TMZ). The onset of pseudoprogressions is correlated with O6-methylguanine-DNA methyltransferase methylation status. After RT/TMZ combined treatment no standard of care has currently been developed. As yet, targeted therapies have failed to provide effective results in recurrent glioblastoma patients. Anti-angiogenic treatments have demonstrated intriguing results in terms of response rate and 6-month progression-free survival. Further studies with new drugs and regimens on different molecular targets, and with new mechanisms of action

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are needed for recurrent glioblastomas. References

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Disclaimer No writing assistance was utilized in the production of this manuscript. Reprint Address Enrico Franceschi, Department of Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL of Bologna, Bologna, Italy. [email protected] Expert Rev Anticancer Ther. 2009;9(5):613-619. © 2009 Expert Reviews Ltd.

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