In Malaysia, stomach cancer is the 8th most common cancer.
Most stomach cancers were detected at late stage; III (25%) and IV (50%).
The average/ median overall survival for stage 4 stomach cancer is not high but there had been incremental increases in average/ median overall survival throughout the years with chemotherapy and lately, with biologic therapy.
Chemotherapy (Single Agent) vs Best Supportive Care (No Chemotherapy)
In the late 1990s, when palliative chemotherapy (single agent 5-FU) were compared with just best supportive care (BSC)/ no chemotherapy
- Median/ average overall survival (OS) improved in the chemotherapy group (8 months vs 5 months)
- Patients quality of life (QOL) also improved in the chemotherapy arm.
After establishing the importance of chemotherapy in improving the average/ median overall survival, multiple combination chemotherapy were subsequently studied in the first-line setting.
Some combination chemotherapy were with 2 drugs and some with 3 drugs combination.
Improvements in average/ median overall survival in various studies were observed:
- 1999: Japanese phase II study, combination (doublet) chemotherapy (Irinotecan+Cisplatin) successfully increased median OS to 10.4 months.
- 2006: V325 Study Group (large phase III study): DCF vs CF regime – median OS 9.2 months vs 8.6 months (TTP 5.6 months vs 3.7 months).
- 2007: Korean phase II trial, combination of irinotecan + 5FU with irinotecan + cisplatin – median OS was 10.7 months vs 10.5 months (PFS 4.8 months vs 6.2 months).
- 2008: REAL-2 (large phase III study) comparing triplet chemotherapy (ECF, ECX, EOF, EOX) reported median OS ranging from 9.9m ECF regime to 11.2 months for EOX regime (PFS 6.2 months to 7.0 months).
- 2009: ML17032 trial with capecitabine/ cisplatin vs 5-FU/ cisplatin – median OS 10.5 months vs 9.3 months (PFS 5.6 months vs 5.0 months).
- 2015: Median overall survival was 18.8 months and 12.6 months with modified DCF (mDCF) and DCF, respectively (Shah MA, 2015). This is especially useful for patients without HER2 over expression.
Combining Chemotherapy with Biologic Therapy
Instead of combining with 3 types of chemotherapy, some synergistic effects could be seen from combining chemotherapy with biologic therapy.
Addition of biologic therapies, bevacizumab (Avastin) and trastuzumab (Herceptin) had been proven effective in a few clinical trials.
- 2011: AVAGAST trial comparing Avastin + Cisplatin (C) + Xeloda (X) with CX regime but median OS was 12.1 months and 10.1 months respectively but not statistically significant (PFS 6.7 months vs 5.3 months).
For trastuzumab treatment, HER2 over expression is needed (over expressed in 20% of patients) in patient with stage 4 stomach cancer.
- 2010: ToGA clinical trial with T-CF vs CF – median overall survival was 13.8 months vs 11.1 months (16 months vs 11.8 months in subset analysis with Her2 over expressed only)
- 2016 CGOG1001 (phase II, small sample size) trial with T-XO with median OS of 19.5 months
C: cisplatin, X: Xeloda, F: 5-FU, O: oxaliplatin, T: trastuzumab, I: irinotecan, D: docetaxel, PFS: progression free survival, TTP: time to progression, OS: overall survival.
This is by no means an exhaustive list of regimes but it gives an indication of the progressive improvement in median overall survival with newer combinations and newer agents.
It’s important to note that the overall survival for different chemotherapy differs only a little.
In order to achieve the best outcomes, I think it is important for patients
- to complete all planned chemotherapy cycles
- at maximal recommended dosages
- with least side effects
By using doublets instead of triplet chemotherapy regimes (less chemotherapy agents, less toxicities) or use modified triplets chemotherapy regimes with better safety profile and tolerability.
Using chemotherapy agents without cumulative toxicity such as irinotecan instead of oxaliplatin (cumulative sensory neurotoxicity seen in 10%–15% of patients after cumulative doses of 780–850 mg/m2).
Using newer chemotherapy agents which have lesser side effects compared to their older versions:
- Capecitabine instead of 5-FU
- Oxaliplatin instead of cisplatin/ carboplatin
- Nab-paclitaxel instead of paclitaxel