**Sequential Use of Targeted Therapies (TT) in Metastatic Renal Cell Cancer (mRCC): Overall Results of a Large Experience**

G. Procopio, E. Verzoni, R. Iacovelli, F. Gelsomino, M. Catanzaro and L. Mariani *'IRCCS 'Istituto Nazionale dei Tumori', Medical Oncology, Milan Italy* 

#### **1. Introduction**

406 Emerging Research and Treatments in Renal Cell Carcinoma

Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P,

the Birt-Hogg-Dube syndrome. *Cancer Epidemiol Biomarkers Prev* 11: 393-400

Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM (2002) Risk of renal and colonic neoplasms and spontaneous pneumothorax in

> Renal cell carcinoma accounts for 80% of all kidney cancers -worldwide; the tumor staging at diagnosis ranges from small, low-stage tumors to more advanced neoplasms [1-5]. The survival rate has increased in recent years: nowadays, patients with localized disease have a 5-year survival >80% but in those with distant metastatic RCC, 5-year survival is <10% [6-8]. The increase in overall survival was due, at least in part, to improved surgical techniques [9,10]. Until recently cytokines (interleukin-2 or interferon-alpha), were the mainstay of systemic treatment despite low response rates and significant toxicity [11,12].

> Since 2005, six targeted therapies for advanced/metastatic RCC were approved by both the FDA and EMA: three are multitargeted tyrosine kinase inhibitors (TKIs), sorafenib (SO), sunitinib (SU) and pazopanib (PZ), two are oral mTOR inhibitors, temsirolimus (TS) and everolimus (EV) and one is the anti-VEGF monoclonal antibody bevacizumab (BV), administered in combination with IFN-alpha [13]. These new agents improved the progression free survival (PFS) and the overall survival (OS) in several subgroups of patients; however, expert opinion on the optimal therapeutic strategy is divided.

> Two main therapeutic approaches—use of these new agents in combination or sequentially—have been studied to increase efficacy and tolerability. Sequential therapy is the current standard of care in the treatment of advanced RCC as existing combination regimens have a high incidence of adverse events without a substantial increase in efficacy. The use of sequential therapy provides a number of important advantages: patients who are refractory to one or more targeted agent(s) may benefit from treatment with a different agent; there is no/limited cross-resistance between agents and patients experiencing disease progression with one anti-angiogenic agent can subsequently benefit from treatment with another [14,15].

> The results of recent phase III randomized controlled trials (RCTs) prompted the National Comprehensive Cancer Network (NCCN) and the European Association of Urology (EAU) to update their clinical practice guidelines for the treatment of metastatic RCC [16,17]. The EAU recommended SU as a first-line therapy in low- and intermediate-risk patients and

Sequential Use of Targeted Therapies (TT) in Metastatic

Patients included in database 310

Previous nephrectomy, % 273 (88.1%)

**5. Statistical analyses** 

significant.

**6. Results** 

Range

Male Female

0 1 2

ECOG PS

Histology Clear-cell Papillary Bellini

Chromophobe Oncocytoma UNK

Fuhrman grade, %

Motzer criteria

Intermediate

Targeted therapies %

High Low

Median age (years)

Renal Cell Cancer (mRCC): Overall Results of a Large Experience 409

All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum, and maximum values for continuous variables, and absolute and relative frequencies for categorical variables. Curves relevant to OS (overall, Motzer and according to therapy option) were estimated by the Kaplan–Meier method and compared by means of the log-rank test. Reports of AEs were categorized according to type, severity, and outcome. A p value <0.05 was considered statistically

A total of 310 patients with metastatic RCC were observed, and followed-up for a median of 37 months (range 21–49 months). Patient characteristics at baseline are shown in **Table 1**.

> 62 55–69

81

41

229 (74%)

168 (54%) 123 (40%) 19 (6%)

268 (86.4%) 27 (8.7%) 7 (2.2%) 6 (1.9%) 1 (0.3%) 1 (0.3%)

15 (5.58%) 93 (34.57%) 118 (43.87%) 43 (15.99%)

64 (20.6%) 100 (32.3%) 146 (47.10%)

163 (52.6%) 113 (36.5%) 30 (9.7%) 4 (1.29%)

concluded that SO is effective as second-line treatment after failure of cytokine therapy or in patients unfit for cytokines [18]. Clinical evidence supports the efficacy of sequential treatment with SU/SO [19]; however, the optimal sequence for SO and SU is still under debate, and additional evidence on the optimal use of sequential targeted therapies is advocated.

In this retrospective study – the preliminary results of which have been previously presented [20] - the safety and efficacy of different sequential schemes of targeted therapies, in patients with advanced/metastatic RCC were studied.

#### **2. Methods**

#### **2.1 Patients**

This retrospective study was conducted at the 'Istituto Nazionale Tumori of Milan' (National Institute of Tumors, Milan, Italy) – one of the most important Italian institutions for cancer diagnosis and treatment - between January 2004 and July 2010. Patients were patients aged ≥18 years with advanced/metastatic RCC and a life expectancy of >3 months who had been treated with antiangiogenic therapy (one or more) were eligible for enrollment in this retrospective study. Patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2 were included. A number of patients enrolled in this study had previously taken part in a range of prospective trials including TARGET , the EU-ARCCS , RECORD-1 , AXIS , AVOREN and ROSORC at our centre.

#### **3. Treatment**

Patients received a range of different systemic agents – SO, SU, BV, EV, TS and axitinib (AX) alone or in combination, and could have received a previous treatment with cytokines. SO was administered orally at a dose of 400 mg twice daily and SU at a daily dose of 50 mg orally with a 4 weeks on 2 weeks off schedule. BV was administered iv at 10 mg/Kg every 2 weeks in combination with Interferon-a subcutaneously, EV was administered orally at 10 mg daily continuously, TS iv weekly at 25 mg/dose and AX at 10 mg/daily orally continuously. Patients received systemic therapy until disease progression or the presence of serious adverse events.

#### **4. Study assessments**

Study assessments were conducted at baseline and once a month thereafter. Baseline characteristics were taken ≤28 days after the start of treatment. Drug safety and tolerability were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCTCA version 3). Efficacy was assessed by progression-free survival (PFS) and overall survival (OS) according to the Motzer classification [21]. PFS was defined as the time from start of systemic treatment to death or disease progression whichever occurred first. Disease progression was evaluated using the Response Evaluation criteria in Solid Tumours (RECIST, version 1.0) by the treating physician. Assessments were performed monthly (every 3 weeks for patients on sunitinib, due to the schedule of administration for this drug). Patients with Bellini duct RCC were excluded from the efficacy analysis, due to the different histology of the tumor.

#### **5. Statistical analyses**

All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum, and maximum values for continuous variables, and absolute and relative frequencies for categorical variables. Curves relevant to OS (overall, Motzer and according to therapy option) were estimated by the Kaplan–Meier method and compared by means of the log-rank test. Reports of AEs were categorized according to type, severity, and outcome. A p value <0.05 was considered statistically significant.

#### **6. Results**

408 Emerging Research and Treatments in Renal Cell Carcinoma

concluded that SO is effective as second-line treatment after failure of cytokine therapy or in patients unfit for cytokines [18]. Clinical evidence supports the efficacy of sequential treatment with SU/SO [19]; however, the optimal sequence for SO and SU is still under debate, and additional evidence on the optimal use of sequential targeted therapies is

In this retrospective study – the preliminary results of which have been previously presented [20] - the safety and efficacy of different sequential schemes of targeted therapies,

This retrospective study was conducted at the 'Istituto Nazionale Tumori of Milan' (National Institute of Tumors, Milan, Italy) – one of the most important Italian institutions for cancer diagnosis and treatment - between January 2004 and July 2010. Patients were patients aged ≥18 years with advanced/metastatic RCC and a life expectancy of >3 months who had been treated with antiangiogenic therapy (one or more) were eligible for enrollment in this retrospective study. Patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2 were included. A number of patients enrolled in this study had previously taken part in a range of prospective trials including TARGET , the

Patients received a range of different systemic agents – SO, SU, BV, EV, TS and axitinib (AX) alone or in combination, and could have received a previous treatment with cytokines. SO was administered orally at a dose of 400 mg twice daily and SU at a daily dose of 50 mg orally with a 4 weeks on 2 weeks off schedule. BV was administered iv at 10 mg/Kg every 2 weeks in combination with Interferon-a subcutaneously, EV was administered orally at 10 mg daily continuously, TS iv weekly at 25 mg/dose and AX at 10 mg/daily orally continuously. Patients received systemic therapy until disease progression or the presence

Study assessments were conducted at baseline and once a month thereafter. Baseline characteristics were taken ≤28 days after the start of treatment. Drug safety and tolerability were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCTCA version 3). Efficacy was assessed by progression-free survival (PFS) and overall survival (OS) according to the Motzer classification [21]. PFS was defined as the time from start of systemic treatment to death or disease progression whichever occurred first. Disease progression was evaluated using the Response Evaluation criteria in Solid Tumours (RECIST, version 1.0) by the treating physician. Assessments were performed monthly (every 3 weeks for patients on sunitinib, due to the schedule of administration for this drug). Patients with Bellini duct RCC were excluded from the

EU-ARCCS , RECORD-1 , AXIS , AVOREN and ROSORC at our centre.

efficacy analysis, due to the different histology of the tumor.

in patients with advanced/metastatic RCC were studied.

advocated.

**2. Methods 2.1 Patients** 

**3. Treatment** 

of serious adverse events.

**4. Study assessments** 

A total of 310 patients with metastatic RCC were observed, and followed-up for a median of 37 months (range 21–49 months). Patient characteristics at baseline are shown in **Table 1**.


Sequential Use of Targeted Therapies (TT) in Metastatic

(**Figure 2**).

**Probability**

**0.0**

(**Table 2, 3 and Figure 3**).

**Probability**

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

Fig. 2. Overall survival according to Motzer classification

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

Renal Cell Cancer (mRCC): Overall Results of a Large Experience 411

The Motzer criteria were validated as prognostic factors in both the uni- and multi-variate analysis (p<0.001). The median and 5-year OS was 43 months and 42.8% in low-risk patients, 21 months and 15.9% in intermediate risk patients and 8 months in patients with poor risk

> **High risk Moderate risk Low risk**

**Time (Months) 0 6 12 18 24 30 36 42 48 54 60**

Interestingly in both the multi- and uni-variate analysis there were no significant differences in the hazard ratios when SO+SU are compared with SU+SO and with other therapies

> **Time (months) 0 6 12 18 24 30 36 42 48 54 60**

**Therapeutic choice: sorafenif + sunitinib or sorafenib only Therapeutic choice: sunitinib + sorafenif or sunitinib only**

**Therapeutic choice: other option**

Fig. 3. Overall survival with sorafenib and sunitinib compared with other therapies


Table 1. Patient characteristics at baseline

Overall the majority of patients (163; 53.9%) received one treatment line with systemic agents while 113 (36.5%) received two, 30 (9.7%) received three line and four patients (1.3%) received four. One-sided analysis of variance showed that the Motzer classification/score was predictive regarding the number of therapy lines (Fisher 8.49, p<0.01) with the mean number of treatments significantly lower in the high-risk group (p<0.05) than in the low/intermediate risk groups (t-tests). Overall the majority of patients 196/310 received SO as first line followed by SU in 96 cases or SU, in 63 cases followed by SO in 13 cases). The remaining 51/310 received other systemic agents in sequence (BV, TS, AX alone or in sequence/combination with SO and SU).

Median OS was 22 months and the 5-year OS was 23.4% (95% CI 16.7, 30.0%) (**Figure 1**).

Fig. 1. Overall survival

Overall the majority of patients (163; 53.9%) received one treatment line with systemic agents while 113 (36.5%) received two, 30 (9.7%) received three line and four patients (1.3%) received four. One-sided analysis of variance showed that the Motzer classification/score was predictive regarding the number of therapy lines (Fisher 8.49, p<0.01) with the mean number of treatments significantly lower in the high-risk group (p<0.05) than in the low/intermediate risk groups (t-tests). Overall the majority of patients 196/310 received SO as first line followed by SU in 96 cases or SU, in 63 cases followed by SO in 13 cases). The remaining 51/310 received other systemic agents in sequence (BV, TS, AX alone or in

Median OS was 22 months and the 5-year OS was 23.4% (95% CI 16.7, 30.0%) (**Figure 1**).

303 251 185 136 100 73 50 32 17 17 17 17

121 (39.0%) 107 (34.5%) 67 (21.2%) 12 (3.9%) 3 (0.9%)

88 (28.39%) 16 (5.16%) 59 (19.03%) 204 (65.81%) 119 (38.39%) 15 (4.84%) 4 (1.29%) 94 (30.32%)

Number of disease sites

Sites of disease (n=599)

Table 1. Patient characteristics at baseline

sequence/combination with SO and SU).

Fig. 1. Overall survival

Bone Brain Liver Lung

Lymph nodes Pancreas Thyroid Other

The Motzer criteria were validated as prognostic factors in both the uni- and multi-variate analysis (p<0.001). The median and 5-year OS was 43 months and 42.8% in low-risk patients, 21 months and 15.9% in intermediate risk patients and 8 months in patients with poor risk (**Figure 2**).

Fig. 2. Overall survival according to Motzer classification

Interestingly in both the multi- and uni-variate analysis there were no significant differences in the hazard ratios when SO+SU are compared with SU+SO and with other therapies (**Table 2, 3 and Figure 3**).

Fig. 3. Overall survival with sorafenib and sunitinib compared with other therapies

Sequential Use of Targeted Therapies (TT) in Metastatic

Intermediate vs. low risk 2.15 (1.44; 3.21)

ECOG PS = Eastern Cooperative Group Performance Score Table 3. Multivariable overall survival analysis

**Age** 

**Sex** 

**ECOG PS** 

**Cytokine** 

**Histology** 

**Nephrectomy** 

**Motzer criteria** 

**Therapeutic choice** 

Other options vs. sorafenib+sunitinib

Sorafenib+sunitinib

Renal Cell Cancer (mRCC): Overall Results of a Large Experience 413

p Hazard ratio (95% CI)

**Not adjusted for Motzer criteria** 

p

**Adjusted for Motzer** 

10 years increasing 0.98 (0.85; 1.12) 0.767 0.91 (0.80; 1.04) 0.180

Males vs. females 0.91 (0.62; 1.32) 0.611 1.09 (0.76; 1.59) 0.631

1 vs. 0 1.09 (0.78; 1.54) 0.838 1.53 (1.11; 2.12) **0.003** 2 vs. 0 0.95 (0.48; 1.89) 2.42 (1.27; 4.59)

Yes vs. no 1.26 (0.91; 1.75) 0.169 1.41 (1.03; 1.94) **0.033** 

Yes vs. no 0.59 (0.35; 0.98) **0.041** 0.40 (0.24; 0.67) **0.001** 

**<0.001** 

0.388

0.70 (0.40; 1.23) 0.85 (0.49; 1.47)



0.85 (0.56; 1.30)

Papillary vs. clear cell 1.35 (0.81; 2.24) 0.478 1.42 (0.86; 2.35) 0.285 Non clear cell vs. clear cell 1.19 (0.60; 2.39) 1.38 (0.69; 2.74)

High vs. low risk 7.23 (4.42; -

0.675 Sunitinib+sorafenib vs.

**Adverse event N % (N/310)** Asthenia 36 11.61 Hand-foot syndrome 13 4.19 Anemia 4 1.29 Cardiac failure 2 0.65 Hypertension 2 0.65 Mucositis 2 0.65 Abdominal pain 1 0.32 Cardiac stroke 1 0.32 Fever 1 0.32 Macroematuria 1 0.32 Nausea 1 0.32 Rash 1 0.32 Table 4. Adverse events Grade ≥3 (patients may have experienced one or more events)

11.83)

0.84 (0.55; 1.29)

**criteria** 

Hazard ratio (95% CI)

In detail, the PFS was 17 months with the specific sequence of SO+SU (9 months + 8 months) and 16 months with SU+SO (12 months + 4 months). The median PFS of first line treatment with either SO or SU was 10.5 months.

Furthermore in the multivariate overall survival analysis un-adjusted for the Motzer classification (**Table 3**) the risk was nearly 1.5 times higher in those patients who had previously been treated with cytokines compared with those who had not received cytokines (p<0.033).


ECOG PS = Eastern Cooperative Group Performance Score

Table 2. Univariable overall survival analysis

#### **7. Adverse events**

The most commonly reported treatment-related all grade adverse events (AEs) were typical of those reported with TKIs including asthenia, hand-foot syndrome, hypertension, diarrhea, mucositis, hypothyroidism and most of these were mild or moderate in intensity (Grade 1 or 2). Overall, 61 (19.68%) patients experienced AEs Grade ≥3 (**Table 4**) and there were a total of 65 Grade ≥3 AEs, and three patients experienced a Grade 4 event (two patients receiving SU+SO had cardiac failure and one receiving SO+SU had a cardiac stroke). The percentage of patients experiencing adverse events Grade ≥3 was similar in patients treated when SO was given as in those treated first with SU then SO (18.88 and 17.46%). In those treated with other systemic therapies there was a tendency to a higher incidence of AEs (25.5%). Furthermore the nature and severity of AEs groups did not differ if SO or SU was given first.

In detail, the PFS was 17 months with the specific sequence of SO+SU (9 months + 8 months) and 16 months with SU+SO (12 months + 4 months). The median PFS of first line treatment

Furthermore in the multivariate overall survival analysis un-adjusted for the Motzer classification (**Table 3**) the risk was nearly 1.5 times higher in those patients who had previously been treated with cytokines compared with those who had not received

10 years increasing 0.98 (0.86; 1.11) 0.735

Male vs. female 1.09 (0.77; 1.55) 0.635

1 vs. 0 1.69 (1.25; 2.29) **<0.001** 2 vs. 0 2.62 (1.39; 4.95)

Yes vs. no 1.28 (0.95 ; 1.72) 0.101

Yes vs. no 0.41 (0.26; 0.65) **<0.001** 

Papillary vs. clear cell 1.39 (0.85; 2.27) 0.247 Non clear cell vs. Clear cell 1.47 (0.75; 2.89)

Intermediate vs. low risk 2.30 (1.57; 3.35) **<0.001** High vs. low risk 7.90 (5.07;12.31)

The most commonly reported treatment-related all grade adverse events (AEs) were typical of those reported with TKIs including asthenia, hand-foot syndrome, hypertension, diarrhea, mucositis, hypothyroidism and most of these were mild or moderate in intensity (Grade 1 or 2). Overall, 61 (19.68%) patients experienced AEs Grade ≥3 (**Table 4**) and there were a total of 65 Grade ≥3 AEs, and three patients experienced a Grade 4 event (two patients receiving SU+SO had cardiac failure and one receiving SO+SU had a cardiac stroke). The percentage of patients experiencing adverse events Grade ≥3 was similar in patients treated when SO was given as in those treated first with SU then SO (18.88 and 17.46%). In those treated with other systemic therapies there was a tendency to a higher incidence of AEs (25.5%). Furthermore the nature and severity of AEs groups did not differ

Other option vs. Sorafenib+sunitinib 0.77 (0.51;1.17) 0.212 Sunitinib+sorafenib vs. sorafenib+sunitinib 0.69 (0.41;1.16)

ECOG PS = Eastern Cooperative Group Performance Score

Table 2. Univariable overall survival analysis

**Hazard ratio (95% CI) p** 

with either SO or SU was 10.5 months.

cytokines (p<0.033).

**Age** 

**Sex** 

**ECOG PS** 

**Cytokine** 

**Histology** 

**Nephrectomy** 

**Motzer criteria** 

**Therapeutic choice** 

**7. Adverse events** 

if SO or SU was given first.


ECOG PS = Eastern Cooperative Group Performance Score

Table 3. Multivariable overall survival analysis


Table 4. Adverse events Grade ≥3 (patients may have experienced one or more events)

Sequential Use of Targeted Therapies (TT) in Metastatic

PFS = progression-free survival; TTP = time to progression.

RCTs but also on clinical experience and judgment

**Sorafenib→Sunitinib**

**Sunitinib→Sorafenib**

**VEGFi→Sorafenib**

**9. References** 

Renal Cell Cancer (mRCC): Overall Results of a Large Experience 415

**Source** *n* **1st PFS (months) 2nd PFS (months)**

Eichelberg et al. 30 8.7 10.3 Dudek et al. 29 5.1 18.0 Porta et al. 83 9.8 8.4 Procopio et al. 50 9.5 8.3 Sablin et al. 68 6.0 6.5 Zimmerman et al. 22 11.5 5.0

Dudek et al. 20 5.8 8.5 Porta et al. 87 8.3 3.7 Sablin et al. 22 5.1 3.9

Garcia et al 48 8.7 3.7

Table 5. Summary of sorafenib and sunitinib sequence data (reproduced from ref 24)

practice: in particular, the optimal sequence of TKIs has yet to be established.

In conclusion, despite the major breakthrough introduced by targeted therapies, further research is necessary to shed new lights on the most effective use of these drugs in clinical

Our study supports – however - the importance of TKI treatment in RCC patients to improve OS. In addition, it suggests that factors other than the specific sequence of treatment, like the Motzer classification, influence the OS in a large unselected population from clinical practice collected in a single institution. On the basis of these results and of current evidence reported in literature is now clear that there is not one therapy that will benefit all patients and treatment should be tailored to meet individual circumstances and needs. Physicians should therefore base their treatment decisions not only on data from

[1] Lindblad P. Epidemiology of renal cell carcinoma. *Scand. J. Surg.* 93(2), 88–96 (2004). [2] Chow WH, Devesa SS, Warren JL, Fraumeni Jr JF. Rising incidence of renal cell cancer in

northern part of the Netherlands. *Eur. Urol*. 37 (3), 267–270 (2000).

[3] Bos SD, Mellema CT, Mensink HJ. Increase in incidental renal cell carcinoma in the

[4] Mevorach RA, Segal AJ, Tersegno ME, Frank IN. Renal cell carcinoma: incidental diagnosis and natural history: review of 235 cases. *Urology*, 39 (6), 519–522 (1992). [5] Hock LM, Lynch J, Balaji KC. Increasing incidence of all stages of kidney cancer in the

[6] Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell

[7] Atzpodien J, Royston P, Wandert T, Reitz M. Metastatic renal carcinoma comprehensive

last 2 decades in the United States: an analysis of surveillance, epidemiology and

the United States. *JAMA*. 281(17), 1628–1631 (1999).

end results program data. *J. Urol.* 167 (1), 57–60 (2002).

prognostic system. *Br. J. Cancer* 88 (3), 348–353 (2003).

carcinoma. *J. Urol.*166 (5), 1611–1623 (2001).

#### **8. Discussion**

Despite improvements in therapy, RCC eventually progresses during therapy and other agent(s) need to be administered in an attempt to control the disease.

This large-scale retrospective analysis was carried out to investigate the effects of systemic therapy in general and in particular to compare the efficacy and safety of different sequential approaches with targeted therapies in controlling the disease progression of patients with RCC. Importantly, our results show that treatment with TKIs improves survival. In fact the median OS for patients with advanced RCC has increased from around 13 months before the introduction of TKIs to around 22 months in the last decade and the median OS of 22 months observed in the present study provides further evidence to support the importance of use of TKI in patients with advanced RCC. In addition, to our knowledge most studies have considered PFS, and not OS, as the major determinant of clinical efficacy of any sequential therapy for the treatment of RCC: our study provides new evidence on OS even in a large unselected population from a single institution. Of note, a relevant proportion of patients received sorafenib as a first-line agent, despite current recommendations suggest this molecule as a second-line treatment, and sunitinib at progression of disease. This therapeutic strategy did not result in any worsening of clinical outcomes and in a similar tolerability with respect to the other therapeutic strategies assessed. Even if this study was not designed to evaluate the feasibility of sorafenib as a first-line agent, and therefore we are unable to draw any conclusion, we believe that this finding could be of some interest in the current therapeutic scenario of RCC patients.

In addition, the Motzer criteria resulted significant prognostic factors in both the uni- and multi-variate analysis. On this basis, we suggest that these criteria should – at present - be regarded to as the most useful tool for the definition of prognosis and, as a consequence, for the optimization of therapy for every single patient.

Of note, the findings reported in the present report were obtained in a real-life scenario, on a large population of unselected patients: it has been suggested that observational trials can expand upon outcomes of randomized controlled trials, which are necessarily conducted in highly-selected patients [22].

In most patients with advanced RCC the objective of treatment is to stabilize disease and prolong survival and there is good evidence that this can be achieved with sequencing systemic agents. The use of this therapeutic approach, in fact, may determine a relevant benefit in terms of OS and quality of life, independently from the specific sequence of targeted therapies used.

Our study confirms the suitability of a TKI sequential therapy. This finding is in line with recent evidence, albeit collected in retrospective studies, which seems to support that the use of SO before SU, rather than vice versa may be more effective in extending PFS (**Table 5**). In addition, some studies suggest that SO may be associated with a more favorable safety profile than more potent SU, in terms of incidence of changes in blood counts and anemia [23,24].

The major limitations of the current study was that the sample size was not randomized and the data were collected retrospectively. In addition the study populations were very hoeterogenous with much patients received the sequence TKI followed TKI and only few cases treated with bevacizumab, everolimus, temsirolimus and axitinib.


PFS = progression-free survival; TTP = time to progression.

Table 5. Summary of sorafenib and sunitinib sequence data (reproduced from ref 24)

In conclusion, despite the major breakthrough introduced by targeted therapies, further research is necessary to shed new lights on the most effective use of these drugs in clinical practice: in particular, the optimal sequence of TKIs has yet to be established.

Our study supports – however - the importance of TKI treatment in RCC patients to improve OS. In addition, it suggests that factors other than the specific sequence of treatment, like the Motzer classification, influence the OS in a large unselected population from clinical practice collected in a single institution. On the basis of these results and of current evidence reported in literature is now clear that there is not one therapy that will benefit all patients and treatment should be tailored to meet individual circumstances and needs. Physicians should therefore base their treatment decisions not only on data from RCTs but also on clinical experience and judgment

#### **9. References**

414 Emerging Research and Treatments in Renal Cell Carcinoma

Despite improvements in therapy, RCC eventually progresses during therapy and other

This large-scale retrospective analysis was carried out to investigate the effects of systemic therapy in general and in particular to compare the efficacy and safety of different sequential approaches with targeted therapies in controlling the disease progression of patients with RCC. Importantly, our results show that treatment with TKIs improves survival. In fact the median OS for patients with advanced RCC has increased from around 13 months before the introduction of TKIs to around 22 months in the last decade and the median OS of 22 months observed in the present study provides further evidence to support the importance of use of TKI in patients with advanced RCC. In addition, to our knowledge most studies have considered PFS, and not OS, as the major determinant of clinical efficacy of any sequential therapy for the treatment of RCC: our study provides new evidence on OS even in a large unselected population from a single institution. Of note, a relevant proportion of patients received sorafenib as a first-line agent, despite current recommendations suggest this molecule as a second-line treatment, and sunitinib at progression of disease. This therapeutic strategy did not result in any worsening of clinical outcomes and in a similar tolerability with respect to the other therapeutic strategies assessed. Even if this study was not designed to evaluate the feasibility of sorafenib as a first-line agent, and therefore we are unable to draw any conclusion, we believe that this

finding could be of some interest in the current therapeutic scenario of RCC patients.

the optimization of therapy for every single patient.

highly-selected patients [22].

targeted therapies used.

In addition, the Motzer criteria resulted significant prognostic factors in both the uni- and multi-variate analysis. On this basis, we suggest that these criteria should – at present - be regarded to as the most useful tool for the definition of prognosis and, as a consequence, for

Of note, the findings reported in the present report were obtained in a real-life scenario, on a large population of unselected patients: it has been suggested that observational trials can expand upon outcomes of randomized controlled trials, which are necessarily conducted in

In most patients with advanced RCC the objective of treatment is to stabilize disease and prolong survival and there is good evidence that this can be achieved with sequencing systemic agents. The use of this therapeutic approach, in fact, may determine a relevant benefit in terms of OS and quality of life, independently from the specific sequence of

Our study confirms the suitability of a TKI sequential therapy. This finding is in line with recent evidence, albeit collected in retrospective studies, which seems to support that the use of SO before SU, rather than vice versa may be more effective in extending PFS (**Table 5**). In addition, some studies suggest that SO may be associated with a more favorable safety profile than more potent SU, in terms of incidence of changes in blood counts and anemia [23,24].

The major limitations of the current study was that the sample size was not randomized and the data were collected retrospectively. In addition the study populations were very hoeterogenous with much patients received the sequence TKI followed TKI and only few

cases treated with bevacizumab, everolimus, temsirolimus and axitinib.

agent(s) need to be administered in an attempt to control the disease.

**8. Discussion** 


**20** 

Mirjana Rajer

*Slovenia* 

*Institute of Oncology Ljubljana* 

**Treatment of Renal Cell Carcinoma** 

Renal cell carcinoma (RCC) is the most common cancer of the kidney (Motzer et.al., 1999). In the United States each year 57.000 new patients are being diagnosed with RCC resulting in 12.900 deaths (Linehan et.al., 2011). The median age at diagnosis today is 64 years and even though it represents only 3% of all cancers, the incidence is increasing steadily. With rising prevalence of some known risk factors like hypertension and population ageing, the incidence of RCC is expected to be rising even more in subsequent years. With increasing incidence of renal cell carcinoma (RCC) combined with population ageing, questions about the treatment of elderly and frail patients with RCC are becoming more and more relevant. Many of the patients with newly diagnosed RCC are in advanced age and/or have some major comorbidities which often results in their poor performance status. Elderly or frail patients are frequently excluded from clinical trials, because the results of their treatment are often difficult to interpret. This is also true for patients with heart, lung, liver or other major co-morbidities. Excluding these patients from clinical trials leads to lack of evidence-based guidelines for their treatment and often poses to oncologists a difficult dilemma when they need to decide what treatment options to offer to patients (Scuch et.al., 2008). In the present chapter we would like to present current recommendations for diagnostics and treatment of elderly and frail patients with RCC. In the second part of the chapter results of the analysis of metastatic RCC patients treated in a single institution with emphasis on differences in the treatment between good and

**1. Introduction** 

**2.1 Age** 

poor performance status patients are presented.

**2. Age, performance status, co-morbidities and prognostic models** 

Ageing is a complex process that affects every aspect of life. The US department of Health and Human Services Administration of Ageing estimates that 1 in every 8 Americans is older than 65 years. In 2006 this group represented 12,4% of the population, but by 2030 this number is expected to increase to 20%. With population ageing, incidence of all cancers is supposed to be rising in the next years and RCC is no exception (Neustadt et.al., 2008).

It is well known that the actual age is determined by physiology rather than chronology. Factors of biological aging include changes in the physical structure of the body as well as changes in the performance of motor skills and sensory awareness. These changes can lead

**in Elderly and Frail Patients** 

