**5. Novel strategies to overcome TRAIL resistance**

During the last decades, a better understanding of cancer biology has led to the development of new promising therapeutic approaches, based on "molecular targeted" drugs, directed against specific "target" molecules playing a key role in tumour maintenance (Urruticoechea et al., 2010). Based on the principle that inhibiting as many targets as possible reduces the emergence of drug resistance, the use of combined therapies or multi-target inhibitors is gaining field in the design of new treatments. A number of chemical and physical anticancer strategies have been developed to bypass TRAIL resistance, based on the combination of rTRAIL or agonistic antibodies with chemotherapeutic agents, irradiation, or targeted small molecules, like proteasome, histone deacetylase or NF-B inhibitors (Testa, 2010; Russo et al., 2010). The agents used in combination with TRAIL either enhance TRAIL-R1/-R2 expression or decrease expression of anti-apoptotic proteins (c-FLIP, X-IAP, Bcl-2) (Mellier et al., 2010) (Fig. 2). Many of these combinatorial therapies hold promise for future developments in the treatment of haematological malignancies since they may reduce excessive systemic toxicity toward normal cells and resistance of tumour cells after recurrent treatments. We and other authors have demonstrated that TRAIL-mediated cytotoxicity is increased by ionizing radiation and chemotherapy in both myeloid and erythroid leukaemia cell lines as well as in T lymphoma cell lines (Gong & Almasan, 2000; Di Pietro et al., 2001; Sabatini et al., 2004; Zauli et al., 2005; Caravatta et al., 2008; Impicciatore et al., 2010; Signore et al., 2011). Although an increasing number of drugs warrant further investigation as potential new strategies for the treatment of solid tumours or AML in combination with soluble rTRAIL (Suh et al., 2003), only in few cases the efficacy of the combined treatments has been proved *in vivo* and a general consensus on how chemotherapy and radiotherapy may synergize with TRAIL therapy is far to be reached (Russo et al., 2010).

#### **5.1 TRAIL-death receptor-targeted treatment**

A number of receptor-specific TRAIL-variants and agonistic antibodies have been recently developed. Some of these soluble rTRAIL and MoAbs targeting TRAIL-R1 and/or TRAIL-R2 (TRAIL receptor agonists, TRAs) are progressing to phase I/II clinical trials (Mahmood &

clones. Interestingly, also thalidomide, which holds great promise as a new anti-neoplastic agent for the treatment of refractory MM, triggers activation of caspase-8 and downregulates NF-B activity and c-FLIP (Mitsiades et al, 2002). These studies form the basis for clinical trials of these agents, alone and coupled with conventional and novel therapies, to improve outcome in MM. It is worth underlining that while the potential therapeutic use of rTRAIL or TRAs in most myeloid and lymphoid malignancies is still to be evaluated, rTRAIL appears to be a very promising candidate for the therapy of MM, either alone or in combination with valproic acid, a histone deacetylase inhibitor, arsenic trioxide, IFN, or with the low-molecular-weight Smac mimetic LBW242 (Secchiero & Zauli, 2008). Moreover, the use of specific anti-TRAIL-R1 or anti-TRAIL-R2 agonistic antibodies, more than the treatment with TRAIL itself (Locklin et al., 2007), has proved an effective strategy to counteract OPG-mediated effects and increase TRAIL-induced apoptosis of MM cells (Secchiero & Zauli, 2008). Of note, other preclinical studies aimed at targeting the RANK/RANKL/OPG pathway have paved the way to clinical experimentation likely to

During the last decades, a better understanding of cancer biology has led to the development of new promising therapeutic approaches, based on "molecular targeted" drugs, directed against specific "target" molecules playing a key role in tumour maintenance (Urruticoechea et al., 2010). Based on the principle that inhibiting as many targets as possible reduces the emergence of drug resistance, the use of combined therapies or multi-target inhibitors is gaining field in the design of new treatments. A number of chemical and physical anticancer strategies have been developed to bypass TRAIL resistance, based on the combination of rTRAIL or agonistic antibodies with chemotherapeutic agents, irradiation, or targeted small molecules, like proteasome, histone deacetylase or NF-B inhibitors (Testa, 2010; Russo et al., 2010). The agents used in combination with TRAIL either enhance TRAIL-R1/-R2 expression or decrease expression of anti-apoptotic proteins (c-FLIP, X-IAP, Bcl-2) (Mellier et al., 2010) (Fig. 2). Many of these combinatorial therapies hold promise for future developments in the treatment of haematological malignancies since they may reduce excessive systemic toxicity toward normal cells and resistance of tumour cells after recurrent treatments. We and other authors have demonstrated that TRAIL-mediated cytotoxicity is increased by ionizing radiation and chemotherapy in both myeloid and erythroid leukaemia cell lines as well as in T lymphoma cell lines (Gong & Almasan, 2000; Di Pietro et al., 2001; Sabatini et al., 2004; Zauli et al., 2005; Caravatta et al., 2008; Impicciatore et al., 2010; Signore et al., 2011). Although an increasing number of drugs warrant further investigation as potential new strategies for the treatment of solid tumours or AML in combination with soluble rTRAIL (Suh et al., 2003), only in few cases the efficacy of the combined treatments has been proved *in vivo* and a general consensus on how chemotherapy and radiotherapy may synergize with TRAIL therapy is

A number of receptor-specific TRAIL-variants and agonistic antibodies have been recently developed. Some of these soluble rTRAIL and MoAbs targeting TRAIL-R1 and/or TRAIL-R2 (TRAIL receptor agonists, TRAs) are progressing to phase I/II clinical trials (Mahmood &

lead to new therapeutic approaches (Buckle et al., 2010).

far to be reached (Russo et al., 2010).

**5.1 TRAIL-death receptor-targeted treatment** 

**5. Novel strategies to overcome TRAIL resistance** 

Shukla, 2010). The clinical use of TRAs is a very promising and innovative approach to increase selectivity and reduce undesired toxicity of cancer treatments in comparison with modern anticancer drugs (protein kinase inhibitors or MoAb agonists for growth receptors) (Russo et al., 2010). These compounds were generated to selectively bind and activate their respective DRs without affecting decoy receptors or OPG. DRs engagement, using recombinant death ligands or agonistic antibodies, leads to the activation of both extrinsic and intrinsic apoptosis pathways, while, generally, chemotherapy or radiotherapy triggers the mitochondrial/intrinsic pathway (Fig. 2). Therefore, the conventional therapeutic approach could be implemented by DR-induced apoptosis when DRs are expressed and functional on tumour cells. As already mentioned, although soluble rTRAIL as well as TRAs are not completely free from toxicity, both reagents elicit a significant lower hepatotoxicity when administered systemically compared to CD95 receptor agonists (Lawrence et al., 2001). Besides the advantage of an improved specificity and a lower toxicity of TRAs over TRAIL ligand, pharmacokinetic studies performed in primates and humans have shown that these agents have a longer half-life (around 15 days) than soluble TRAIL (30 min) that makes them easier to dose and administer (Duiker et al., 2006). Preclinical studies performed *in vitro* in cultured human cell lines and *in vivo* in murine xenograft cancer models (Cretney et al., 2007) showed favourable results when TRAs were used as single agents and enhanced cytotoxicity when they were combined with chemotherapy or radiotherapy (Marini et al., 2006). In particular, HGS-ETR1 (anti-TRAIL-R1, mapatumumab) as well as HGS-ETR2 (anti-TRAIL-R2, lexatumumab) was able to induce apoptosis in primary and cultured lymphoma cells increasing cell death when associated either with conventional chemotherapy (doxorubicin) or novel drugs like proteasome inhibitors (bortezomib) (Georgakis et al., 2005). As well, multiple solid tumours including lung, colon and renal carcinoma were found responsive to TRAs treatment used alone or in combination with chemotherapy (Pukac et al., 2005). To date, the fully humanized MoAbs HGS-ETR1, HGS-ETR2 and HGS-TR2J (anti-TRAIL-R2) (all three from Human Genome Sciences, Rockville, MD) are used in ongoing trials for the treatment of advanced solid tumours, lymphoma or MM (Mahmood & Shukla, 2010). A number of excellent reviews on different therapeutic approaches to specifically target TRAIL and DR pathways have been recently published (Ashkenazi et al., 2008; Papenfuss et al., 2008; Mahmood & Shukla, 2010; Russo et al., 2010).

Of particular interest is the current use of rTRAIL and TRAs for the treatment of B cell malignancies (Mahmood & Shuka, 2010). As shown by other authors, the DR pathway is intact and functional in various types of cancers, including B-cell lymphomas (Snell et al., 1997; Georgakis et al., 2005). B-cell sensitivity to TRAs is a fundamental requirement for therapeutic efficacy, since TRAIL-R1 and TRAIL–R2 mutations, observed in NHL as well as in other human tumours (Lee et al., 2001), make neoplastic B cells insensitive to TRAIL and, presumably, to agonistic antibodies mimicking its action. TRAIL-R1 and TRAIL-R2 map to human chromosome 8p21-22, a site of frequent allelic loss in tumours. This led to the hypothesis that, as potential tumour suppressors, TRAIL-Rs may also harbour somatic mutations in human tumours. The most frequent mutations identified so far concern TRAIL-R2 and affect the intracellular domain of the receptor, i.e. the FADD-binding domain, and, as a consequence, its capability of inducing apoptosis (Bin et al., 2007). Although still poor is the knowledge of how TRAIL-Rs mutations affect signalling events, it is predictable that a patient displaying a TRAIL-R2 mutation would not benefit from treatment with either rTRAIL or an anti-TRAIL-R2 antibody but from treatment with mapatumumab or a

Signalling Pathways Leading to TRAIL Resistance 215

Besides oncogenes over-expression and cell cycle control mechanisms disruption, mutations in apoptotic regulators (namely p53) are very frequent in cancer cells and represent for them a way to escape toxic effects inducible with radio-chemotherapy. As an alternative strategy to restoring transcriptional activation to mutant p53 proteins in solid tumours, small molecule selective inhibitors of p53/MDM2 interaction (Nutlins) are emerging as an innovative tool in the treatment of malignancies expressing wtp53 including haematological disorders (Secchiero et al., 2008; Impicciatore et al., 2010). Nutlins were the first potent and selective small molecules, antagonists of the p53/MDM2 interaction, to be identified 7 years ago (Vassilev et al., 2004). Since then several classes of small-molecule inhibitors with distinct chemical structure have been reported (Shangary & Wang, 2009), although only Nutlin-3 has been extensively evaluated for its therapeutic potential and mechanism of action in human cancer and represents a promising therapeutic candidate for drug development (Shangary & Wang, 2009). Several authors have investigated the effects of Nutlins, used alone or in combination with other therapeutic agents, on primary cells, different cell lines and tumour xenografts (Kojima et al., 2005; Lehmann et al., 2007). In particular, it has been reported that the active enantiomer Nutlin-3a induces i) increased levels of p53, ii) p53- and p21-dependent cell cycle arrest and iii) p53-dependent apoptosis in a number of solid tumours and haematological malignancies including primary AML (Kojima et al., 2005), MM (Stuhmer et al., 2005), B-CLL (Coll-Mulet et al., 2006) and Hodgkin lymphomas (HL) (Drakos et al., 2007). Unlike radiation and conventional chemotherapy, MDM2 inhibitors induce accumulation and activation of p53 in cancer and normal cells without inducing DNA damage or post-translational modifications of p53. Nutlins in fact restore p53 function in wtp53 tumour cells without inducing p53 phosphorylation and with limited effects on primary cells (Vassilev et al., 2004). Interestingly, when used at concentrations higher than 10 mM, Nutlin-3, MI-63 and MI-219 are able to inhibit cell proliferation even in cancer cells lacking wtp53 (Shangary & Wang, 2009). In response to Nutlin-3 treatment TRAIL-R2 is up-regulated in B-CLL cells in a p53-dependent manner (Coll-Mulet et al., 2006). Moreover, Nutlins reduce the MDM2 ability to stimulate p53 degradation and represent a promising approach for improving radiotherapy effects especially for tumours over-expressing MDM2 such as sarcomas, solid tumours (Momand et

Besides the use of a broad range of protein inhibitors, chemotherapeutic agents or irradiation to exert synergistic effects with TRAIL action (Mahalingam et al., 2009), more recently the use of natural compounds, including polyphenols, has gained increasing interest due to their relative safety and anti-tumour efficacy in preclinical models (Jacquemin et al., 2010). Actually, it has been demonstrated that a number of natural compounds are able to enhance TRAIL-induced apoptosis in leukaemia cells (Fas et al., 2006; Russo et al., 2007; Hussain et al., 2008; Sung et al. 2010). In particular, it has been shown that wogonin, derived from a popular Chinese herb, attenuates NF-B activity (Fas et al., 2006), whereas curcumin, responsible for the yellow colour of the spice turmeric, upregulates TRAIL-R2 expression and inactivates NF-B in a ROS-dependent manner in a number of solid tumours including Burkitt's lymphoma (Hussain et al., 2008). Moreover, Russo et al. (2007) reported that leukaemia cell lines were efficiently sensitized by quercetin and TRAIL co-treatment through the inhibition of the Akt pathway, while Sung et al., 2010 observed other survival proteins down-regulation after TRAIL and triterpenoids co-

**5.3 Small molecules and natural compounds** 

al., 1998) and NHL (Finnegan et al., 1994).

modified version of rTRAIL able to target only one death receptor (MacFarlane et al., 2005). Similarly to TRAIL, TRAs (mapatumumab and lexatumumab) are capable of inducing antilymphoma effects both *in vitro* and *in vivo* (Motoki et al., 2005). In particular, it has been recently demonstrated that mapatumumab can trigger apoptosis through caspase-8 activation via the extrinsic apoptotic pathway (Maddiplata et al., 2007). Various groups of investigators have shown that the activation of the TRAIL-Rs by either ligands or MoAbs sensitizes cancer cells to the effects of various chemotherapeutic and/or biological agents (Secchiero et al., 2007), although in a recent report no correlation between the degree of antitumour *in vitro* activity of mapatumumab and TRAIL-R1 antigen density has been shown (Maddiplata et al., 2007). To explain their results these investigators hypothesized differences in the receptor hetero-dimerization between various B-cell lymphoma cells upon TRAIL-R1 binding to mapatumumab. In fact, it has been published that following *in vitro* exposure to TRAIL ligand or TRAIL-R1 agonists, other DRs are recruited via trimerization, leading to signal transduction and apoptosis (Cretney et al., 2007). Depending on the type of DR undergoing trimerization upon TRAIL-R1 binding the intensity and type of response could change. In theory, the same principle could justify the absence of anti-tumour activity of lexatumumab despite ample surface expression of TRAIL-R2 in the cell lines tested *in vitro* (Maddiplata et al., 2007). Further studies are needed to address this issue.

#### **5.2 Proteasome and histone deacetylase inhibitors**

Inhibition of NF-B (e.g. with mutant forms of IB or proteasome inhibitors) has also been shown to increase TRAIL responsiveness (Sayers & Murphy, 2006). In this respect, besides the clinical use of bortezomib (Velcade, PS-341) for the treatment of multiple myeloma (Sayers & Murphy, 2006), it has been recently reported that treatment with the proteasome inhibitors MG-132 and PS-341 is associated with the up-regulation of TRAIL and its death receptors, TRAIL-R1/TRAIL-R2, in primary B-CLL cells and in the Burkitt lymphoma cell line, BJAB (Kabore et al., 2006). Interestingly, the combined treatment with TRAIL or TRAs and proteasome inhibitors leads to a significant apoptosis induction in B-CLL but not in normal B cells (Kabore et al., 2006). DRs up-regulation by PS-341 was attributed to TRAIL-R2 mRNA stabilization and the consequent increased receptor half-life (Kamdasamy & Kraft, 2008). In addition to the proteasome inhibitors, inhibition of histone deacetylase (HDAC) class I sensitizes B-CLL to TRAIL-induced apoptosis (Hamilton et al., 2010). An aberrant regulation of gene expression due to alterations in histone acetyltransferase (HAT) or HDAC recruitment and activity has been constantly found in both solid and haematological tumours (Mai & Altucci, 2009). Therefore HDAC can be considered as potential therapeutic targets of human malignancies. Interestingly, the reduction of TRAIL protein degradation has been recently observed in thyroid cancer cells and proposed as a novel action of HDAC inhibitors (Borbone et al., 2010). It is worth outlining that HDAC inhibitors exert anti-tumour effects at doses that are well tolerated by the patients. Hydroxamic acids, such as SAHA (Vorinostat, Zolinza), were recently approved by the US FDA for the treatment of cutaneous manifestations in patients affected with advanced refractory CTCL. In fact, similarly to what has been seen in B-CLL, CTCL cell lines show pronounced resistance to TRAIL cytotoxicity (Braun et al., 2007). Lastly, a phase I study, currently recruiting participants, will use vorinostat in combination with cytarabine and etoposide for the treatment of patients with relapsed and/or refractory acute leukaemia, MDS or myeloproliferative disorders (see for details http://clinicaltrials.gov).

modified version of rTRAIL able to target only one death receptor (MacFarlane et al., 2005). Similarly to TRAIL, TRAs (mapatumumab and lexatumumab) are capable of inducing antilymphoma effects both *in vitro* and *in vivo* (Motoki et al., 2005). In particular, it has been recently demonstrated that mapatumumab can trigger apoptosis through caspase-8 activation via the extrinsic apoptotic pathway (Maddiplata et al., 2007). Various groups of investigators have shown that the activation of the TRAIL-Rs by either ligands or MoAbs sensitizes cancer cells to the effects of various chemotherapeutic and/or biological agents (Secchiero et al., 2007), although in a recent report no correlation between the degree of antitumour *in vitro* activity of mapatumumab and TRAIL-R1 antigen density has been shown (Maddiplata et al., 2007). To explain their results these investigators hypothesized differences in the receptor hetero-dimerization between various B-cell lymphoma cells upon TRAIL-R1 binding to mapatumumab. In fact, it has been published that following *in vitro* exposure to TRAIL ligand or TRAIL-R1 agonists, other DRs are recruited via trimerization, leading to signal transduction and apoptosis (Cretney et al., 2007). Depending on the type of DR undergoing trimerization upon TRAIL-R1 binding the intensity and type of response could change. In theory, the same principle could justify the absence of anti-tumour activity of lexatumumab despite ample surface expression of TRAIL-R2 in the cell lines tested *in* 

*vitro* (Maddiplata et al., 2007). Further studies are needed to address this issue.

MDS or myeloproliferative disorders (see for details http://clinicaltrials.gov).

Inhibition of NF-B (e.g. with mutant forms of IB or proteasome inhibitors) has also been shown to increase TRAIL responsiveness (Sayers & Murphy, 2006). In this respect, besides the clinical use of bortezomib (Velcade, PS-341) for the treatment of multiple myeloma (Sayers & Murphy, 2006), it has been recently reported that treatment with the proteasome inhibitors MG-132 and PS-341 is associated with the up-regulation of TRAIL and its death receptors, TRAIL-R1/TRAIL-R2, in primary B-CLL cells and in the Burkitt lymphoma cell line, BJAB (Kabore et al., 2006). Interestingly, the combined treatment with TRAIL or TRAs and proteasome inhibitors leads to a significant apoptosis induction in B-CLL but not in normal B cells (Kabore et al., 2006). DRs up-regulation by PS-341 was attributed to TRAIL-R2 mRNA stabilization and the consequent increased receptor half-life (Kamdasamy & Kraft, 2008). In addition to the proteasome inhibitors, inhibition of histone deacetylase (HDAC) class I sensitizes B-CLL to TRAIL-induced apoptosis (Hamilton et al., 2010). An aberrant regulation of gene expression due to alterations in histone acetyltransferase (HAT) or HDAC recruitment and activity has been constantly found in both solid and haematological tumours (Mai & Altucci, 2009). Therefore HDAC can be considered as potential therapeutic targets of human malignancies. Interestingly, the reduction of TRAIL protein degradation has been recently observed in thyroid cancer cells and proposed as a novel action of HDAC inhibitors (Borbone et al., 2010). It is worth outlining that HDAC inhibitors exert anti-tumour effects at doses that are well tolerated by the patients. Hydroxamic acids, such as SAHA (Vorinostat, Zolinza), were recently approved by the US FDA for the treatment of cutaneous manifestations in patients affected with advanced refractory CTCL. In fact, similarly to what has been seen in B-CLL, CTCL cell lines show pronounced resistance to TRAIL cytotoxicity (Braun et al., 2007). Lastly, a phase I study, currently recruiting participants, will use vorinostat in combination with cytarabine and etoposide for the treatment of patients with relapsed and/or refractory acute leukaemia,

**5.2 Proteasome and histone deacetylase inhibitors** 

#### **5.3 Small molecules and natural compounds**

Besides oncogenes over-expression and cell cycle control mechanisms disruption, mutations in apoptotic regulators (namely p53) are very frequent in cancer cells and represent for them a way to escape toxic effects inducible with radio-chemotherapy. As an alternative strategy to restoring transcriptional activation to mutant p53 proteins in solid tumours, small molecule selective inhibitors of p53/MDM2 interaction (Nutlins) are emerging as an innovative tool in the treatment of malignancies expressing wtp53 including haematological disorders (Secchiero et al., 2008; Impicciatore et al., 2010). Nutlins were the first potent and selective small molecules, antagonists of the p53/MDM2 interaction, to be identified 7 years ago (Vassilev et al., 2004). Since then several classes of small-molecule inhibitors with distinct chemical structure have been reported (Shangary & Wang, 2009), although only Nutlin-3 has been extensively evaluated for its therapeutic potential and mechanism of action in human cancer and represents a promising therapeutic candidate for drug development (Shangary & Wang, 2009). Several authors have investigated the effects of Nutlins, used alone or in combination with other therapeutic agents, on primary cells, different cell lines and tumour xenografts (Kojima et al., 2005; Lehmann et al., 2007). In particular, it has been reported that the active enantiomer Nutlin-3a induces i) increased levels of p53, ii) p53- and p21-dependent cell cycle arrest and iii) p53-dependent apoptosis in a number of solid tumours and haematological malignancies including primary AML (Kojima et al., 2005), MM (Stuhmer et al., 2005), B-CLL (Coll-Mulet et al., 2006) and Hodgkin lymphomas (HL) (Drakos et al., 2007). Unlike radiation and conventional chemotherapy, MDM2 inhibitors induce accumulation and activation of p53 in cancer and normal cells without inducing DNA damage or post-translational modifications of p53. Nutlins in fact restore p53 function in wtp53 tumour cells without inducing p53 phosphorylation and with limited effects on primary cells (Vassilev et al., 2004). Interestingly, when used at concentrations higher than 10 mM, Nutlin-3, MI-63 and MI-219 are able to inhibit cell proliferation even in cancer cells lacking wtp53 (Shangary & Wang, 2009). In response to Nutlin-3 treatment TRAIL-R2 is up-regulated in B-CLL cells in a p53-dependent manner (Coll-Mulet et al., 2006). Moreover, Nutlins reduce the MDM2 ability to stimulate p53 degradation and represent a promising approach for improving radiotherapy effects especially for tumours over-expressing MDM2 such as sarcomas, solid tumours (Momand et al., 1998) and NHL (Finnegan et al., 1994).

Besides the use of a broad range of protein inhibitors, chemotherapeutic agents or irradiation to exert synergistic effects with TRAIL action (Mahalingam et al., 2009), more recently the use of natural compounds, including polyphenols, has gained increasing interest due to their relative safety and anti-tumour efficacy in preclinical models (Jacquemin et al., 2010). Actually, it has been demonstrated that a number of natural compounds are able to enhance TRAIL-induced apoptosis in leukaemia cells (Fas et al., 2006; Russo et al., 2007; Hussain et al., 2008; Sung et al. 2010). In particular, it has been shown that wogonin, derived from a popular Chinese herb, attenuates NF-B activity (Fas et al., 2006), whereas curcumin, responsible for the yellow colour of the spice turmeric, upregulates TRAIL-R2 expression and inactivates NF-B in a ROS-dependent manner in a number of solid tumours including Burkitt's lymphoma (Hussain et al., 2008). Moreover, Russo et al. (2007) reported that leukaemia cell lines were efficiently sensitized by quercetin and TRAIL co-treatment through the inhibition of the Akt pathway, while Sung et al., 2010 observed other survival proteins down-regulation after TRAIL and triterpenoids co-

Signalling Pathways Leading to TRAIL Resistance 217

The author wishes to thank Dr. Francesca Gambacorta for helpful assistance in the artwork.

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**8. References** 

treatment. Taken together, these findings demonstrate that nongenotoxic natural molecules or small compounds enhance TRAIL-mediated killing of tumour cells with reduced side effects compared to conventional radio-chemotherapy.

Fig. 2. Schematic representation of molecular mechanisms of novel strategies aimed at restoring TRAIL sensitivity of haematological malignancies. RAD: radiotherapy; CHT: chemotherapy. See text for other abbreviations.
