*9.5.1 Baseline vascular perfusion on imaging*

Several studies have examined pre-treatment levels of tumour perfusion and whether they can predict outcome. For example, enhanced levels of vessel perfusion at baseline (measured by contrast-assisted tumour enhancement) in mRCC patients treated with VEGF TKIs has been shown to predict for response and survival [103].

#### *9.5.2 Changes in vascular characteristics on imaging*

Early alterations in features of the tumour vasculature on imaging after a short period of therapy have also been shown to be associated with response and outcome. For example, in studies of mRCC patients treated with anti-angiogenic TKIs, response criteria that measured both a significant reduction in tumour vascular perfusion and a significant reduction in tumour size were more predictive of outcome compared to change in lesion size alone [104].

Although the use of the above radiological criteria may seem promising as predictors of response and outcome, there are associated challenges that need to be considered before incorporating them into clinical practice. These include, (a) diversity in the methodologies used to assess potential surrogate radiological biomarkers of response between studies and across centres, and (b) insufficient comprehension of how certain radiological features correlate with the underlying tumour biology.

## **10. Measuring the clinical response to anti-angiogenic agents**

Currently, the efficacy of any anti-neoplastic therapy is assessed by several outcome measures, which include (a) effective downsizing of tumours on clinical imaging (to facilitate curative surgery or consolidative radiotherapy for localised disease and to reduce the symptomatic burden of disease in the metastatic setting), (b) prolongation of the interval where a patient is either disease-free or progression-free, and (c) prolongation of survival.

Conventional assessment of residual tumour volume after cytotoxic chemotherapy has traditionally been performed with the use of size-based criteria (overall response rate, ORR, by RECIST). This was based on evidence that there is good correlation between radiological information and residual viable tumour (pathological response) and good correlation with progression-free (PFS) and overall survival (OS) in patients treated with cytotoxic chemotherapy [105]. However, with the advent of biological therapies, such as bevacizumab, the value of utilising RECIST on its own as a surrogate for outcome has been questioned and new imaging criteria have been proposed [102].

#### **10.1 RECIST criteria**

For anti-angiogenic therapy employed in advanced malignant disease, retrospective clinical meta-analyses have (a) highlighted the pitfalls and limitations of using RECIST alone in the assessment of response and progression, and (b) highlighted a disassociation of RECIST from time-related endpoints of PFS and OS [105].

This curiosity was provoked by several large randomised clinical trials investigating the effect of adding bevacizumab to conventional chemotherapy in different tumour types. These have consistently demonstrated that significant improvements in PFS and OS were incongruent with modest increases in ORRs [25, 28, 40]. In their CRC metaanalysis, Grothey and colleagues specifically examined the impact of tumour response to bevacizumab (ORR) on treatment benefit (PFS, OS) and concluded that patients who did not attain a positive response according to RECIST (i.e. stable disease) in fact

**53**

*DOI: http://dx.doi.org/10.5772/intechopen.89667*

**10.2 Morphological response criteria**

chemotherapy [110].

**10.3 Pathological response criteria**

survival (DFS) and OS [112].

methods may be superior.

responding patients (i.e. complete or partial response) [105].

*Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

showed significant benefit from bevacizumab, which was of the same magnitude as

Moreover, similar concepts have consistently featured in several Phase I and II clinical trials employing antiangiogenic agents, and other molecular targeted therapies. These studies corroborate that there is little value in utilising ORR alone, particularly in predicting whether an agent will ultimately have truly meaningful effects on pathological response or in prolonging survival [106]. The underlying reason for these incongruent observations with bevacizumab and other molecular targeted therapies may be because such agents are cytostatic rather than cytotoxic [107].

There has been growing interest in how the appearance of lesions on clinical imaging can be utilised to accurately assess the effect of bevacizumab on tumour volume and how this appearance may correlate with other clinical end-points. In a small retrospective colorectal liver only metastasis (CRLM) patient cohort treated with bevacizumab and chemotherapy, Chun and colleagues demonstrated that novel morphological response criteria predicted more accurately for OS and pathological response than RECIST (**Figure 2**) [108]. This was subsequently validated in a larger patient population which included patients who were treated with and without bevacizumab [109]. Not only were the morphological response criteria superior to RECIST in predicting major pathological response and OS, further analyses confirmed that the morphological response criteria did not correlate with responses measured according to RECIST. Moreover, there was a significantly higher incidence of optimal responses (measured by morphological response criteria) in the patient cohort receiving bevacizumab with chemotherapy compared to the chemotherapy alone cohort [109]. These data suggest that (a) morphological response criteria and RECIST measure different biological parameters, and (b) the use of morphological response criteria represents a more sensitive tool for measuring tumour response and time-related endpoints of survival for bevacizumab. Similar findings were reported in a retrospective study of non-small cell lung cancer patients treated with bevacizumab and concomitant

Radiological assessment alone may not accurately reflect response to therapy because simple, unidimensional imaging parameters may overestimate or underestimate downstaging of tumour burden [111]. Furthermore, in the case of adding anti-angiogenic therapy to chemotherapy, although it has been suggested that proposed morphological imaging characteristics can accurately predict tumour response and clinical outcome, such scoring methods have not yet been validated for conventional use in clinical practice and may also be too subjective. Scoring of pathological response may therefore be a better alternative or perhaps an adjunct in assessing residual viable tumour. Moreover, in the case of preoperative chemotherapy or radiotherapy in settings such as rectal cancer and oesophageal cancer, pathological response has also been shown to correlate significantly to disease-free

Several methodologies incorporating various parameters for scoring pathological response in resected CRLMs, treated with and without bevacizumab, have been proposed. It is still not clear from the current literature which of these classification

#### *DOI: http://dx.doi.org/10.5772/intechopen.89667 Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

showed significant benefit from bevacizumab, which was of the same magnitude as responding patients (i.e. complete or partial response) [105].

Moreover, similar concepts have consistently featured in several Phase I and II clinical trials employing antiangiogenic agents, and other molecular targeted therapies. These studies corroborate that there is little value in utilising ORR alone, particularly in predicting whether an agent will ultimately have truly meaningful effects on pathological response or in prolonging survival [106]. The underlying reason for these incongruent observations with bevacizumab and other molecular targeted therapies may be because such agents are cytostatic rather than cytotoxic [107].

### **10.2 Morphological response criteria**

*Current Cancer Treatment*

tumour biology.

*9.5.2 Changes in vascular characteristics on imaging*

compared to change in lesion size alone [104].

sion-free, and (c) prolongation of survival.

have been proposed [102].

**10.1 RECIST criteria**

OS [105].

at baseline (measured by contrast-assisted tumour enhancement) in mRCC patients treated with VEGF TKIs has been shown to predict for response and survival [103].

Early alterations in features of the tumour vasculature on imaging after a short period of therapy have also been shown to be associated with response and outcome. For example, in studies of mRCC patients treated with anti-angiogenic TKIs, response criteria that measured both a significant reduction in tumour vascular perfusion and a significant reduction in tumour size were more predictive of outcome

Although the use of the above radiological criteria may seem promising as predictors of response and outcome, there are associated challenges that need to be considered before incorporating them into clinical practice. These include, (a) diversity in the methodologies used to assess potential surrogate radiological biomarkers of response between studies and across centres, and (b) insufficient comprehension of how certain radiological features correlate with the underlying

Currently, the efficacy of any anti-neoplastic therapy is assessed by several outcome measures, which include (a) effective downsizing of tumours on clinical imaging (to facilitate curative surgery or consolidative radiotherapy for localised disease and to reduce the symptomatic burden of disease in the metastatic setting), (b) prolongation of the interval where a patient is either disease-free or progres-

Conventional assessment of residual tumour volume after cytotoxic chemotherapy has traditionally been performed with the use of size-based criteria (overall response rate, ORR, by RECIST). This was based on evidence that there is good correlation between radiological information and residual viable tumour (pathological response) and good correlation with progression-free (PFS) and overall survival (OS) in patients treated with cytotoxic chemotherapy [105]. However, with the advent of biological therapies, such as bevacizumab, the value of utilising RECIST on its own as a surrogate for outcome has been questioned and new imaging criteria

For anti-angiogenic therapy employed in advanced malignant disease, retrospective clinical meta-analyses have (a) highlighted the pitfalls and limitations of using RECIST alone in the assessment of response and progression, and (b) highlighted a disassociation of RECIST from time-related endpoints of PFS and

This curiosity was provoked by several large randomised clinical trials investigating the effect of adding bevacizumab to conventional chemotherapy in different tumour types. These have consistently demonstrated that significant improvements in PFS and OS were incongruent with modest increases in ORRs [25, 28, 40]. In their CRC metaanalysis, Grothey and colleagues specifically examined the impact of tumour response to bevacizumab (ORR) on treatment benefit (PFS, OS) and concluded that patients who did not attain a positive response according to RECIST (i.e. stable disease) in fact

**10. Measuring the clinical response to anti-angiogenic agents**

**52**

There has been growing interest in how the appearance of lesions on clinical imaging can be utilised to accurately assess the effect of bevacizumab on tumour volume and how this appearance may correlate with other clinical end-points. In a small retrospective colorectal liver only metastasis (CRLM) patient cohort treated with bevacizumab and chemotherapy, Chun and colleagues demonstrated that novel morphological response criteria predicted more accurately for OS and pathological response than RECIST (**Figure 2**) [108]. This was subsequently validated in a larger patient population which included patients who were treated with and without bevacizumab [109]. Not only were the morphological response criteria superior to RECIST in predicting major pathological response and OS, further analyses confirmed that the morphological response criteria did not correlate with responses measured according to RECIST. Moreover, there was a significantly higher incidence of optimal responses (measured by morphological response criteria) in the patient cohort receiving bevacizumab with chemotherapy compared to the chemotherapy alone cohort [109]. These data suggest that (a) morphological response criteria and RECIST measure different biological parameters, and (b) the use of morphological response criteria represents a more sensitive tool for measuring tumour response and time-related endpoints of survival for bevacizumab. Similar findings were reported in a retrospective study of non-small cell lung cancer patients treated with bevacizumab and concomitant chemotherapy [110].
