oa Editorial [Hot Topic: Molecular Targeted Therapy of Gastrointestinal Cancer (Guest Editor: Marcus W. Wiedmann)]

Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells (e.g. with traditional chemotherapy). Targeted cancer therapies may be more effective than current treatments and less harmful to normal cells. The main categories of targeted therapy are small molecules and monoclonal antibodies. Many oncologists believe that targeted therapies are the chemotherapy of the future. As solid tumor cancer continues to be viewed as a chronic condition, methods for long-term treatment, with less side-effects, continue to be investigated. In this special issue current status of molecular targeted therapy for gastrointestinal cancer will be discussed. Molecular Targeted Therapy for Colorectal Cancer Colorectal cancer (CRC) remains the third most common malignancy and the third leading cause of cancer death worldwide. Approximately 25% present with metastases as initial diagnosis and almost 50% of patients with CRC will develop metastases, contributing to the high mortality rates reported for CRC. The backbone of first-line palliative chemotherapy consists of a fluoropyrimidine [intravenous 5-fluorouracil (5-FU) or oral fluoropyrimidines capacitabine (CAP) and uracilftorafur (UFT)] in various combinations and schedules. Combination chemotherapy with 5-FU/LV (leucovorin)/oxaliplatin (FOLFOX) or 5-FU/LV/irinotecan (FOLFIRI) provides higher response rates (RR), longer progression-free survival (PFS) and better overal survival (OS) [1]. The exposure to all three cytotoxics (fluoropyrimidines, oxaliplatin and irinotecan) in various sequences results in the longest survival [2]. The introduction of monoclonal antibodies (mAb) against vascular endothelial growth factor (VEGF) and against the epidermal growth factor receptor (EGFR) into the treatment protocols for advanced CRC has significantly improved the outcomes with median survival now reaching almost 24 months (for review see [3-5]). Adoption of hepatic resection, especially after induction chemotherapy, even in patients with advanced liver metastases has prolonged median survival further up to 29 months [6, 7]. Bevacizumab (BEV, Avastin™), a recombinant, humanized IgG1 mAb against all isoforms of VEGF-A, increases OS, PFS and RR in first-line treatment in combination with 5-FU/LV/irinotecan and in combination with 5-FU/LV or CAP alone. According to a recently presented Greek phase III study XELIRI (CAP/irinotecan)-BEV did not show significant differences in efficacy as compared to FOLFIRI-BEV (median PFS 14.6 mo. vs. 15.8 mo.; median OS 20.0 mo. vs. 26.2 mo.)1. However, the toxicity profile was different (less neutropenia and metabolic disorders but more diarrhea and vomiting with XELIRIBEV). In combination with FOLFOX/XELOX BEV improves PFS in first-line treatment [8] but not OS and RR. However, improvement in PFS, OS and RR has been shown with FOLFOX-BEV in second-line treatment of metastatic CRC [9] (Table 1, for meta-analysis see [10]). The addition of mitomycin to CAP + BEV did not show extra benefit [11]. Other long-term observational cohort studies, such as first BEAT [12] and BRITE [13], have now confirmed BEV study data. Specific class related side-effects of BEV are: hypertension, proteinuria, arterial thrombosis, mucosal bleeding, gastrointestinal perforation and wound healing problems. There are no validated predictive molecular markers available for BEV [14]. In medically fit older patients, BEV provides similar PFS and OS benefits as in younger patients [15]. Downstaging of isolated liver metastases is another interesting aspect currently investigated in the phase II BOXER study (CAPOX + BEV) and phase III CELIM 2 study (FOLFOXIRI ± BEV). In the first study, overall RR was 78% (95% confidence interval 63% to 89%), conversion rate of primary unresectable metastases was 40% (12/30), and primary resection rate was 49% (22/45) [16]. Results of the second study are still pending. Efficacy of FOLFOXIRI-BEV combination is also currently investigated by the Italian GONO group in the TRIBE study (Table 1). One issue that is still debated is length of treatment in the palliative situation. The OPTIMOX1 study has shown that after six cycles of FOLFOX, oxaliplatin may be safely stopped while continuing 5-FU/LV for a further 12 cycles after which oxaliplatin is reintroduced again, without compromising efficacy [17].In contrast, complete discontinuation of chemotherapy had a negative impact on duration of disease control and PFS compared with the maintenance therapy strategy as has been shown in the OPTIMOX2 study [18]. Other studies, such as MRC CRO 6B [19], GISCAD [20], and MRC COIN (Adams T., ESMO 2009) showed only a slight reduction of OS while improving quality of life with intermittent treatment. The MARCO trial tried to answer the question whether BEV alone can be used as maintenance therapy following induction with XELOX-BEV2. As a result, BEV was not inferior to continuation XELOX-BEV (median PFS 10.3 mo. vs. 11.0 mo.; median OS 20.7 mo. vs. 25.3 mo.). The Dutch CAIRO3 study is currently investigating CAP-BEV maintenance therapy in comparison to observation following induction with 6 cycles CAPOX-BEV. The German AIO group investigates CAP-BEV or BEV maintenance therapy in comparison to observation following induction with XELOX/CAPOX/FOLFOX (AIO Trial KRK 0207). Currently, the label of BEV in colorectal cancer prescribes to continue the administration until disease progression (or unacceptable toxicity). Adjuvant treatment is recommended for stage III and “high risk” (lymph nodes sampling < 12; poorly differentiated tumor; vascular or lymphatic or perineural invasion; tumor presentation with obstruction or tumor perforation and pT4 stage) stage II CRC patients. Large prospective adjuvant phase III studies, such as MOSAIC [21, 22], NSABP C-07 [23], X-ACT [24] and NO16968/XELOXA [25] have established FLOX/FOLFOX/XELOX as standard treatment and 5-FU/LV or CAP when oxaliplatin is contraindicated. In contrast, there was no benefit for CPT-11 (irinotecan) based regimens according to the results of CALGB 89803 [26], PETACC-3 [27] and Accord02 [28] studies. Unfortunately, the addition of BEV to mFOLFOX6 does not significantly prolong disease-free survival (DFS) in stages II and III colon cancer, the primary endpoint of the large phase III NSABP C-08 study [29]. In the AVANT study, BEV did not prolong DFS or OS when added to either FOLFOX4 or XELOX in patients with stage III colon cancer3. Given this lack of improvement in DFS and OS, the use of BEV cannot be recommended in the adjuvant treatment of patients with CRC. Results of other studies, such as QUASAR 2 (CAP ± BEV) and ECOG E5202 (FOLFOX ± BEV) are still pending.....