ESMO 2011 Report – Shaping the future: from principle to practice

by Dr Sunil Upadhyay – One of the most important advances in cancer research over the last decade or so has been the appearance of targeted therapies. It has been possible following identification of genomic and epigenomic alterations and validation of candidate oncogenic drivers, metabolic changes and cancer cell signalling. Angiogenesis, immunotherapy and cancer stem cell biology are the other areas of intense research. Though cytotoxic chemotherapy remains one the major pillars of the management for the majority of tumours, during recent times, chemotherapeutic agents have become less favourable topics of investigation.

Angiogenesis is defined as the growth of new blood vessels and was actually first described by the British surgeon John Hunter in 1787. It is a natural phenomenon in the body during the growth of the organism, reproductive function and wound healing. However, pathological angiogenesis is an essential feature of rheumatoid arthritis, diabetic retinopathy, macular degeneration and development of tumours. In 1971 Dr Judah Folkman from Boston, USA hypothesized that angiogenesis was essential for tumour growth and survival. Initially he was ridiculed by many but today his hypothesis is widely accepted and extensively researched.

Currently, many angiogenetic and anti-angiogenetic molecules are being developed all over the world. In 1989, Dr Napolene Ferra and colleagues discovered the vascular endothelial growth factor (VEGF) protein molecule which plays a crucial role in new blood vessel formation. Similarly, though the EGFR was first identified in mice in 1962, the human EGFR (ErbB1) was only discovered in 1980.

Over time, clinical characteristics of the patient followed by histology and more recently molecular profile have become important for choosing the most appropriate therapy in large variety of cancers. During The European Multidisciplinary Cancer Congress 2011 at a symposium hosted by Boehringer Ingelheim, eminent clinicians from Europe and the USA addressed the issue of the molecular pathways and the role of monoclonal antibodies, TKI and anti-angiogenesis agents in the management of cancer. At the start Martin Reck from Germany reviewed the evidence and discussed the approach in inhibiting angiogenesis in non small cell lung cancer. He reminded the audience that chemotherapy using platinum doublets has reached a plateau in its efficacy.

Treatment of metastatic NSCLC

Angiogenesis is a complex process with a delicate balance between pro and anti-angiogenetic factors. Several tumours produce a high quantity of VEGF, which stimulates proliferation and migration of endothelial cells. It can also be of prognostic value. Tumours with low VEGF carry better probability of survival compared with high VEGF. Recently, VEGF expression has been shown to significantly affect the prognosis of different cancers. Fontanini G et al reported that VEGF expression was an independent prognostic factor in patients with NSCLC for overall survival and disease free survival. High VEGF expression was found to be strongly associated with poor prognosis.¹ These observations clearly support the role of VEGF inhibitors in tumours with high VEGF expression.

Two Phase III trials on the role of bevacizumab with platinum doublets in advanced stage or recurrent non-squamous NSCLC have been reported to show superiority over no bevacizumab (E4599 & AVAiL).^2,3  Hypertension, bleeding, headache and proteinuria are well known toxicities from anti-angiogenetic agents like bevacizumab.

Though the bevacizumab based therapy was the first regimen to extend OS beyond the historical bench mark of 1 year survival in advanced NSCLC, the amount of benefit was limited. aflibercept and vadimezan (ASA 404) were the other two anti-angiogenesis agents studied but unfortunately the results, including subgroup analysis, have been disappointing. We do need to have potential biomarkers. Rash and hypertension may be predictive factors but are not really reliable markers for patient selection. Similarly, ‘though the predictive imaging markers have undergone investigation, they have never been confirmed to be of any practical value.

Inhibiting angiogenesis in ovarian cancer: VEGF blockade and beyond

Angiogenesis is a normal function of ovary and anti-VEGFR agents are known to inhibit corpus luteum formation in the ovary. VEGF increases the permeability of tumour vasculature thus inducing the formation of malignant ascites. It also stimulates the ovarian cancer cell proliferation and evasion from apoptosis. Not only the expression of VEGF and VEGFR is higher in ovarian cancer than in normal ovarian tissue, but approximately 97% of ovarian tumours are known to over express the VEGF ligand, which correlates with poor prognosis and reduced survival.

Two well publicised trials using bevacizumab in first-line treatment have been reported. The US trial GOG – 0218 (n=1873) showed that the concomitant as well as maintenance use of bevacizumab with carboplatin + paclitaxel was beneficial in advanced ovarian cancer.⁴ Maximum beneficial effect was seen whilst the bevacizumab was administered.  Soon after the treatment with bevacizumab was stopped, the three curves started coming together indicating that the duration of treatment with bevacizumab may be of critical importance.

In the European trial ICON7, patients with better prognosis were also included but unfortunately, the total duration of bevacizumab was only 12 months unlike 15 months in GOG. Although, the PFS benefit was only 2.4 months (17.4 vs 19.8 months; HR 0.87, p 0.039), the subgroup analysis showed the median OS of 36.6 months vs 28.8 months (HR 0.64) in favour of bevacizumab which is similar to GOG outcome.

The results from three trials on the use of bevacizumab in relapsed ovarian cancer were positive hence it was approved in Europe.

TRIAL	PATIENT SELECTION	REGIMENS
OCEANS	Platinum sensitive	Bevacizumab + carboplatin/gemcitabine followed by bevacizumab monotherapy ________________________________ Placebo + carboplatin/gemcitabine followed by placebo monotherapy
GOG 213	Platinum sensitive	Bevacizumab + carboplatin/paclitaxel followed by bevacizumab monotherapy ________________________________ Placebo + carboplatin/paclitaxel followed by placebo monotherapy
AURELIA	Platinum resistant	Bevacizumab + single non-platinum agent (liposomal doxorubicin or paclitaxel or topotecan) followed by bevacizumab monotherapy   Single non-platinum agent (liposomal doxorubicin or paclitaxel or topotecan)

EMCC 2011

Management of ovarian cancer still remains complex. Advanced stage and relapsed patients eventually progress and die. Several studies are currently looking at the activity of multi-targeted agents either alone or in combination like pazopanib, BIBF1120, cediranib, aflibercept and many others. These agents have potential to block multiple compensatory pathway sites hence reduced rate of resistance, but they may also increase the risk of off-target effects and toxicity. The long-term safety needs to be established. The main challenge is the selection of patient who is most likely going to benefit from the specific agent, optimum duration of therapy and how to overcome resistance. Reliable biomarkers need to be identified for desirable clinical outcome. Functional imaging could be the other area of investigation. There could be a subgroup of patients who may drive benefit from PARP inhibitors.

Spotlight on Squamous Cell Carcinoma of the Head and Neck

The majority of head and neck cancers are of squamous cell histological subtype (SCCHN). EGFR is over-expressed and/or up-regulated in most which is known to have more aggressive behaviour and poor prognosis. Moreover, their biological behaviour is different to other primary anatomical site tumours of similar histology particularly squamous cell carcinoma of the lung. Cetuximab, a chimeric antibody is approved for the treatment of locally advanced SCCHN with radiotherapy with significantly better loco-regional control and overall survival in Phase III trial.⁵ Similarly, for relapsed/metastatic SCCHN, cetuximab in combination with platinum/5-Fu based chemotherapy (EXTREME) is known to significantly improve the overall survival compared to chemotherapy alone with minimal negative impact on quality of life.⁶ Ongoing trials are exploring other molecular agents like bevacizumab, zalutumumab, afatinib, lapatinib and gefitinib. Predictive markers remain elusive hence carefully conducted trials are needed for selection of patients and future success.

 

References:

1. Fontanini G, Vignati S, Boldrini L  et al. Clinical Cancer Research 1997 June; 3: 861-865
2. Sandler A, Grey R, Perry M et al. NEJM 2006; 355: 2542-2550
3. Reck M, von Pawel J, Zatloukal P et al. JCO 2009 March; 27(8): 1227-1234
4. Burger RA, Brady MF, Bookman JL et al. JCO 2010 June 22; 28(suppl.18, ASCO meeting abstracts): LBA1
5. Bonner JA, Harari PM, Giralt J et al. NEJM 2006; 354: 567-578
6. Vermorken JB, Mesia R, Rivera F et al. NEJM 2008; 359: 1116-1127