Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka Neoadiuvant and adiuvant therapy for advanced gastric cancer Franco Roviello, IT
Neoadjuvant and adjuvant therapy for advanced gastric cancer Prof. Franco Roviello Unit of Surgical Oncology ADVANCED GASTRIC CANCER Local spread T1 T2 T2 T3 T4 mucosa mm submucosa pm subserosa serosa Franco Roviello, IT 41
Macroscopic Classification -Advanced Gastric Cancer- Type 1 Type 2 Type 3 Type 4 Type 5 Polypoid tumors, sharply demarcated from the surrounding mucosa, usually attached on a wide base Ulcerated carcinomas with sharply demarcated and raised margins Ulcerated carcinomas without definite limits, infiltrating into the surrounding wall Diffusely infiltrating carcinomas in which ulceration is usually not marked feature Non-classifiable carcinomas that cannot be classified into any of the above types PRINCIPLES OF TREATMENT 42 Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka
MULTIDISCIPLINARY APPROACH Neoadjuvant Chemotherapy Surgery Adjuvant Chemotherapy Clinical work-up MAIN FACTORS AFFECTING THE PROGNOSIS OF GASTRIC CANCER PATIENTS 1. Number of positive lymph nodes 2. Positive peritoneal cytology 3. Depth of invasion 4. Lauren histologic type 5. Sex, age, extent of lymphadenectomy, preoperative positivity for serum tumor markers Franco Roviello, IT 43
Advances in the drug therapy of gastric cancer have been much slower than desired Possible reasons: a relatively low incidence of gastric cancer in countries most able to advance clinical chemotherapeutic research the frequent presence of advanced disease at clinical presentation the importance of coordinated multidisciplinary participation (often lacking) in the optimum management of gastric cancer tumour traditionally identified for its negligible sensitivity to chemotherapy and radiotherapy A variety of chemotherapeutic agents have been found to display at least a 10% objective response rate in advanced gastric cancer Single-agent response rates in advanced gastric are typically between 15% and 25% Combinations of chemotherapeutic improve patient response rates and overall survival Major chemotherapeutic regimens in gastric cancer 44 Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka
Even after potentially curative surgery (R0), recurrence of gastric cancer frequently occurs (60%) and patients who are affected will die due to their disease The high risk of relapse after surgery has led to search strategies to prevent relapse and to improve survival for gastric cancer patients Neoadjuvant treatment NEO-ADJUVANT CHEMOTHERAPY POTENTIAL UTILITY downstaging the tumors, improving the curative resection rate theoretical benefit on elimination of micrometastases that are undetectable at the start of treatment. improved tolerance since chemotherapy carried out immediately after gastric surgery is often marred by surgery-related gastrointestinal symptoms reduction in drug resistance by early exposure to treatment damaged vascularisation of the tumour bed patients survival benefit? NEO-ADJUVANT CHEMOTHERAPY DISADVANTAGE potential risks of delaying surgery in favour of preoperative treatment in cases of resectable locally advanced gastric cancer (tumor progression) side-effects of preoperative treatment on patients general statuses (ex. nutritional status) an increase risk of peri-operative complications Franco Roviello, IT 45
NEO-ADJUVANT CHEMOTHERAPY Encouraging results on the efficacy of chemotherapy in patients with advanced gastric cancer were reported beginning since the early 1990s. Two independent studies in patients with non-resectable disease found that chemotherapy led to subsequent resection in 40 50% of patients, with an increase in total median survival of 18 months compared with unresected patients. Wilke H, J Clin Oncol 1989 Plukker JT, Br J Surg 1991 These preliminary observations encouraged the introduction of preoperative chemotherapy protocols for potentially resectable, locally advanced gastric cancer. 11 Ajani JA, Cancer 1991 12 Leichman L, J Clin Oncol 1992 14 Kang YK, Proc ASCO 1992 15 Ajani JA, J Natl Cancer Inst 1993 16 Rougier P, Ann Oncol 1994 18 Kelsen D, J Clin Oncol 1996 19 Crookes P, Cancer 1997 20 Songun I, Eur J Cancer 1999 21 Schuhmacher CP, Cancer 2001 22 Persiani R, J Surg Oncol 2005 4 Cunningham D, N Engl J Med 2006 5 Boige V, J Clin Oncol 2007 The first phase III trial results were not encouraging 46 Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka
In the small Dutch randomized trial, 59 pts randomly assigned to receive the FAMTX regimen before surgery or to surgery alone. Complete or partial response was registered in 32% of the FAMTX group and there was no difference in terms of resectability. With a median follow-up of 83 months, the overall survival (OS) since randomization was 18 months in the FAMTX-treated patients versus 30 months in the surgery-alone group (P = 0.17). The trial was closed prematurely due to low accrual of patients and it did not show a beneficial effect of preoperative FAMTX The UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial is the most important large phase III study that was also the first well-powered phase III neo-adjuvant chemotherapy study to assess the efficacy of perioperative chemotherapy MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial Between 1994 and 2002, 503 pts (74% gastric cancer, the remainder esophageal cancer) Randomized to 6 cycles of ECF (3 preoperatively + 3 postoperatively) vs surgery only Preoperative chemotherapy improved curative resection rates The resected tumors were significantly smaller and less advanced in the perioperative chemotherapy group More than 3 years of follow-up, 5-year survival rates 36% (ECF) vs 23% (surgery only) 25% reduction in hazard for recurrence (P 0.009) Franco Roviello, IT 47
MAGIC TRIAL OVERALL SURVIVAL MAGIC TRIAL PROGRESSION FREE SURVIVAL This large-scale trial further establishes the importance of systemic therapy in addition to surgery for the curative treatment of gastric cancer, and emphasizes the potential for neoadjuvant approaches in this setting MAGIC TRIAL However many authors have criticised the MAGIC trial for the persistence of methodological biases: poor staging accuracy selection of patients (about 1/4 had oesophageal or junctional tumours) poor quality of surgery (more than 15% had D1-gastrectomy) lack of precise criteria for response assessment 48 Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka
A number of clinical trials have shown that preoperative chemotherapy is feasible and able to increase the rate of R0 resection. In particular, several small phase II trials with different cisplatin-based neo-adjuvant chemotherapy regimens have reported response rate between 40% and 60% and R0 resection rates up to 80%. However, the results of these first trials are questionable mainly because of some problems with their methods: inaccurate preoperative staging process several authors based recruitment of patients on nonhomogeneous criteria commonly recruiting patients with locally advanced gastric cancer and others with disease of unclear stages no fixed distinction between resectable and non-resectable tumours use of different chemotherapeutic regimens missing or poorly detailed response criteria The French FFCD (Federation Francaise de Cancerologie Digestive) Group trial confirmed these important data with their phase III study Boige V, FNLCC ACCORD07-FFCD 9703 trial. ASCO Meeting Abstracts 2007 224 patients randomised to perioperative FUP (5-FU/cisplatin; surgery; 5-FU/cisplatin) or surgeryalone. The perioperative group presented significantly higher R0 resection rates, with the same mortality rates Progression-free survival improved by 15%, and 5-year survival doubled (40% vs 25% and 17% vs 34%, respectively) Franco Roviello, IT 49
Last evidence 2013 50 Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka
Last evidence Effects of NAC on overall survival Effects of NAC on R0 resection rate Last evidence Effects of NAC on postoperative complications Effects of NAC on perioperative mortality Last evidence 2013 Franco Roviello, IT 51
Last evidence Last evidence: ongoing trials Last evidence: ongoing trials 52 Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka
ADJUVANT THERAPY The South West Oncology Group - Intergroup (INT) 0116 trial randomised 556 patients prospectively between surgery alone and surgery plus postoperative chemoradiotherapy. The combined treatment resulted in both improved local control and overall survival and demonstrated the beneficial effects of chemoradiotherapy after curative gastrectomy for gastric cancer. This regime has consequently become standard treatment in the United States for patients with locallyadvanced gastric or gastroesophageal cancer. Franco Roviello, IT 53
However, several criticism may be pointed out: 3-year recurrence rates similar to the recurrence rate after a limited lymph node dissection in the Dutch D1 D2 trial after 5 years These results could be caused by poor surgical quality of the resections in the INT 0116 trial. Only 10% of patients had a D2 dissection, while 36% had a D1 dissection and 54% had a D0 dissection Considering both the MAGIC trial and the INT 0116 trial, the successive question is: Postoperative chemoradiotherapy improves survival and/or locoregional control in patients who receive neoadjuvant chemotherapy followed by a D1+ gastric resection? Ongoing trials comparing preoperative and postoperative therapy are expected in the near future 54 Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka
p<0.01 p=0.0493 Findings from the CLASSIC trial support the use of adjuvant capecitabine and oxaliplatin as a new treatment option for patients with resectable disease. The Dutch Gastric Cancer Group, 788 patients with resectable gastric cancer, perioperative ECX vs preoperative ECC followed by surgery and postoperative concurrent chemoradiation with cisplatin and capecitabine. Randomisation scheme of the CRITICS trial. R = randomisation; ECC = epirubicin, cisplatin and capecitabine. ITACA-S study group This randomised study failed to show any statistically significant benefit in terms of both DFS and OS in patients with radically resected GC receiving an adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus a 5-FU/LV regimen. A large proportion of patients (75%) underwent at least a D2 lymphadenectomy and the study confirmed the high survival rates observed in previous studies in adjuvant setting Different is the role of polychemotherapy in preoperative phase and ongoing studies such as CRITICS should give a response. Although chemoradiotherapy in the adjuvant setting improves survival based on the results of the INT-0116, the role of this approach after a D2 dissection need to be further investigated Therefore FU/LV can be considered the standard treatment in patients radically operated with D2 dissection. Franco Roviello, IT 55
2013 Conclusions The results of preoperative chemotherapy in the multimodal treatment of gastric adenocarcinoma are encouraging, especially in relation to the safety of delayed surgery Delayed resection does not exclude patients from the benefits of a potentially curative surgery and seems to not worsen surgical outcomes. Even the efficacy of post-operative chemotherapy needs to be further investigated by more extended randomized trials All these type of treatments cannot exclude the crucial role of a potentially curative surgical treatment 56 Adiuwantowe i neoadiuwantowe leczenie chorych na zaawansowanego raka żołądka