neoadjuvant treatment for esophageal and gastric cancer
TRANSCRIPT
Neoadjuvant Treatment for Esophageal and Gastric Cancer
Karen Chee, MD October 24, 2015
Is this glass…
Half full? Half empty?
What is neoadjuvant therapy?
Administration of therapeutic agents before a “main” local treatment. For solid tumors, the “main” therapy can be one of several modalities. For esophageal and gastric cancer, the “main” local therapy is surgery.
What is the goal of neoadjuvant therapy?
Reduction of the size or extent of the cancer before using the local intervention
Makes the local procedure easier. Increasing the likelihood of success Reducing the consequences of a more extensive treatment technique that would normally be required if the tumor wasn’t reduced.
Acts on micrometastatic disease Increase chances on overall survival Convert untreatable disease to treatable disease by shrinking the volume.
Esophageal/Esophagogastric cancer
Background Aggressive disease. Majority of disease is diagnosed at a more advanced disease status. Incidence of adenocarcinoma on the rise world wide with squamous cell carcinoma decreasing.
Multimodality therapy is felt to be the best approach to locally advanced disease
Esophagectomy is the cornerstone of treatment for localized disease (T1a after EMR failure to T1b disease) Systemic nature of the disease attributes to the failure of surgery alone
Esophageal/esophagogastric cancers – Treatment options
Surgery Alone Median survival of surgery pts in 1 study vs. XRT was 1.3 years. In surgery-only studies, 5 yr OS rates were less than 50% for pt with stage II or higher disease
Radiotherapy Alone In pre-op setting, no OS benefit compared with surgery alone In meta-analysis of 5 trials, no benefit in post-op setting with some improvement in local tumor recurrence but at the expense of toxicity (better than pre-op setting)
Esophageal/esophagogastric cancer – Treatment options
Chemotherapy Preoperative: 4 randomized trials so no survival benefit with three showing benefit. (done between 1998-2006).
MRC study showed benefit using cisplatin/5FU (5yr OS 23% vs. 17%) MAGIC study showed benefit with periop chemotherapy using epirubicin/cisplatin/5FU
Postoperative: No good study in large numbers done. Mixed results with some showing no benefit and some results in question given statistics, pts able to complete study, and pt characteristics
Esophageal/esophagogastric cancer – Treatment options
Chemoradiation therapy At least 10 randomized trials compared neoadjuvant chemoradiotherapy followed by surgery to other treatments but majority of the trials are for SqCC pts and appropriate staging is an issue. 4 meta-analysis though have suggested benefit for tri-modality therapy with ¾ reporting a mortality benefit. CROSS (phase III study): Most recently done and randomized pt with chemoradiation with carboplatin/taxol followed by surgery vs. surgery alone with 75% having adenocarcinoma.
Median survival was 49.4 months vs. 24 months
Esophageal/esophagogastric cancer – Treatment options
Neoadjuvant chemotherapy vs. neoadjuvant chemoradiation therapy
2 trials have tried to directly compare these two modalities of therapy. Both did include pts with adenocarcinoma but were closed early and were underpowered to show a survival advantage. The metaanalysis of the 2 trials favored chemoradiation but was not statistically significant.
So…what is the conclusion
Neoadjuvant therapy prior to surgery should be considered for all pts with greater than T1 or node-positive disease who are surgical candidates. Majority of pts with LAEC especially those with SqCC cancer should receive chemoradiation like the CROSS trial. Neoadjuvant chemotherapy alone can be an option based on the MAGIC and MRC trial especially with esophagogastric cancer.
Gastric cancer
Background Majority of pts present with advance disease at presentation Incidence is declining since the 1930s.
Multimodality therapy is the best treatment option
5 yr OS for stage I disease that is resected is 70-75% but then drops to 35% and less for stage II disease and higher.
Gastric Cancer – Treatment Options
Chemoradiotherapy Adjuvant
Intergroup 0116: Most commonly cited in US where pts after surgery where given a chemotherapy/chemoradiotherapy/chemtx cocktail. Saw increase OS with median OS at 36 vs. 27 months. Major criticism was the limit of surgery in study which may have contributed to the high relapse rate in the surgery alone arm. Other trials like the CALGB 80101 and ARTIST trial also favor chemoradiation therapy with the later comparing it to chemotherapy in the adjuvant setting. Chemotherapy most often used is a 5FU based regimen.
Chemoradiation therapy Neoadjuvant therapy: More commonly used for esophagus, GEJ, and gastric cardia Neoadjuvant chemoradiation vs. neoadjuvant chemotherapy was compared in GEJ pts which favored the combined therapy. Unknown in other gastric cancer pts or in initially locally unresectable nonmetastatic disease.
Gastric Cancer – Treatment options
Chemotherapy Alone For many parts of Europe, standard of care is neoadjuvant or perioperative chemotherapy. In Japan and Southern Europe, they tend to get post-operative chemotherapy alone (is changing). 3 adequately powered trials directly compared surgery with our without IV chemotherapy with 2 showing survival benefit.
Chemotherapy MAGIC trial: 74% gastric, 11% distal esophageal/GEJ adenocarcinomas. Pts got perioperative therapy although only 42% where able to complete the treatment protocol. There was a 24% reduction in risk of death favoring chemotherapy. French FNLCC/FFCD trial: Perioperative therapy with cisplatin/5FU showed increase R0 resection, decreased risk of disease recurrence (34 vs. 19%) and lower risk of death (38 vs. 24%)
Chemotherapy EORTC 40954 trial: Closed early due to poor accrual. Showed higher R0 resections but no significant survival advantage (?underpowered) Meta-analysis: Included these 3 trials and 2 other trials which showed higher OS and R0 resection rates with neoadjuvant chemotherapy
Chemotherapy In the adjuvant setting, >30 randomized trials show mostly negative results when OS is the endpoint In a meta-analyses, all support a significant benefit for perioperative or adjuvant chemotherapy (with several studies indicating a somewhat better prognosis in Asian vs. Western populations)
Chemotherapy vs. chemoradiation Has been directly compared in the adjuvant setting in at least 6 trials and only one shows a significant OS benefit in adding radiation (N=68) ARTIST trial suggested a possible benefit in disease free survival adding XRT in pts with node-positive disease so this is being studied in future trial (ARTIST II) Meta-analysis of all trials show higher 5 yr disease-free survival and lower locoregional recurrence but only a trend to OS
So….What is the conclusion
There is strong support for adjuvant chemotherapy following complete resection of gastric cancer. Postoperative RT is still advised following surgery for locally advanced gastric cancer. What are options for chemotherapy regimen? XELOX, XP, EOF are all options
Where do we go next?
More chemotherapy? Targeted therapy?
Type of treatment that targets a cancer’s specific genes, proteins or tissue environment that contributes to cancer growth and survival Examples: EGFR in Lung cancer, KRAS in colon cancer, ER/PR/Her2 in breast cancer, VEGF in lung, colon, gynecologic malignancies
Where do we go next?
Immunotherapy? Use certain parts of a person’s immune system to fight disease by either stimulating your own immune system to work harder to attack cancer cells or give your immune system components to fight the cancer cells. Types: Monoclonal Antibodies, immune checkpoint inhibitors, vaccines
Where do we go next?
What is new in the neoadjuvant horizon?
For gastric cancer… More chemo?
In Europe, preop 5FU/cisplatin and docetaxel/cisplatin/5FU. DCX appears a good alternative to ECF. In Japan, preop S1 is being added to prior surgery/S1 standard. In US, response based therapy based on FOLFOX neoadjuvantly determines what they gets post-op
What about targeted therapy? In the UK, ECF +/- Bev was being studied in perioperative setting but one study with cisplatin/5FU +/- Bev was negative. In the US, role of additional herceptin is being evaluated.
For esophageal/esophagogastric cancer… What about chemo?
Navelbine/cisplatin/XRT being looked at… Other combos…cisplatin/taxol, 5FU/oxaliplatin/docetaxel (FLOT)
What about targeted therapy? Ongoing trial in US for XRT/carboplatin/taxol +/- herceptin Ongoing trial for XELOX + XRT/carboplatin/everolimus Other new targets: Smoothened Receptor Antagonist (LY29408), ganetespib (multi-enzyme blocker) More is not always better…(bev/erlotinib to standard chemotherapy was not better.
And for Immunotherapy…
Immune checkpoint inhibitors Immune system has checkpoint proteins like PD-1 and CTLA4 that help keep it from attacking other normal cells in the body. Cancer cells can use this system to avoid being attacked by the immune system. Example: nivolumab (PD-1), ipilimumab (CTLA4), pembrolizumab (PD-1)
Cancer vaccines Not as advanced. Sipuleucel-T for prostate cancer has been approved.
Future Directions
Immunotherapy: Ongoing primarily with gastric cancer
Vaccine therapy Immune checkpoint therapy: CTLA4 and PD1/PDL1 therapy
Nivolumab +/- iplitumumab Pembrolizumab: a Phase Ib trial of 165 pts with advanced gastric/GEJ disease showed 40% PDL1+ with 41% of those pts showing a response
Here’s the question….again…
Is the glass…
Half Full? Half empty?
If you answered half full both times… You are a budding oncologist and do not know it yet.
If you answered half full both times… You are a budding oncologist and do not know it yet.
If you answered half empty the first time and then half full the second time…
You have the potential to be an oncologist. Come back again next year.
If you answered half full the first time and then half empty the second time…
I clearly need to redo this talk again. Come back again next year.
If you answered half empty both times…
Keep in mind the glass is refillable. Please come back again next year!
Thank you. Question?