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Articles on Gastrointestinal Cancer

A selection of peer-reviewed articles on Gastrointestinal Cancer. All content available on the Advances in Gastrointestinal Cancer Resource Center, including original and review articles, interviews, guidelines and congress highlights, is independently selected by the members of the Editorial Board.


  • Circulating tumor DNA (ctDNA) utilizing a high-sensitivity panel to detect minimal residual disease post liver hepatectomy and predict disease recurrence

    Michael J. Overman, Jean-Nicolas Vauthey, Thomas A. Aloia, Claudius Conrad, Yun Shin Chun, Allan Andresson Lima Pereira, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3522)

    Editorial comment from Dr Cremolini
    The potential interest of the quantitative and qualitative evaluation of cfDNA in liquid biopsy is a field of interest in many solid malignancies. With regard to colorectal cancer, the potential application of liquid biopsy has been mainly focused on the early identification of mechanisms of acquired resistance to anti-EGFRs, but in spite of interesting and promising proof-of-concept findings, their way toward clinical practice has been halted by the lack of high levels of evidence. These works, commented in the poster discussion session, highlight another potential application of cfDNA in colorectal cancer, focusing on its prognostic impact in locally advanced rectal cancer and in patients undergoing radical resection of their liver metastases. The detection of cfDNA after neoadjuvant chemoradiotherapy or after rectal surgery predicts relapse with high specificity, independently of the exposure to adjuvant chemotherapy and the histopathological complete response. Similarly, the detection of cfDNA after liver metastases’ surgical resection predicts both relapse free and overall survival. These findings continue and corroborate previous results achieved by Tie et al. (Sci Transl Med 2016), evidencing the ability of cfDNA in unveiling the minimal residual disease following resection of stage II colorectal cancer. A currently ongoing clinical trial in stage II resected patients (where tools able to estimate the risk of relapse are extremely needed) incorporates results of cfDNA as decision drivers to administer or not adjuvant chemotherapy.

  • The potential of circulating tumor DNA (ctDNA) to guide adjuvant chemotherapy decision making in locally advanced rectal cancer (LARC)

    Jeanne Tie, Joshua Cohen, Yuxuan Wang, Lu Li, Isaac Kinde, Hany Elsaleh, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3521)

    Editorial comment from Dr Cremolini
    The potential interest of the quantitative and qualitative evaluation of cfDNA in liquid biopsy is a field of interest in many solid malignancies. With regard to colorectal cancer, the potential application of liquid biopsy has been mainly focused on the early identification of mechanisms of acquired resistance to anti-EGFRs, but in spite of interesting and promising proof-of-concept findings, their way toward clinical practice has been halted by the lack of high levels of evidence. These works, commented in the poster discussion session, highlight another potential application of cfDNA in colorectal cancer, focusing on its prognostic impact in locally advanced rectal cancer and in patients undergoing radical resection of their liver metastases. The detection of cfDNA after neoadjuvant chemoradiotherapy or after rectal surgery predicts relapse with high specificity, independently of the exposure to adjuvant chemotherapy and the histopathological complete response. Similarly, the detection of cfDNA after liver metastases’ surgical resection predicts both relapse free and overall survival. These findings continue and corroborate previous results achieved by Tie et al. (Sci Transl Med 2016), evidencing the ability of cfDNA in unveiling the minimal residual disease following resection of stage II colorectal cancer. A currently ongoing clinical trial in stage II resected patients (where tools able to estimate the risk of relapse are extremely needed) incorporates results of cfDNA as decision drivers to administer or not adjuvant chemotherapy.

  • Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance)

    Heinz-Josef Lenz, Fang-Shu Ou, Alan P. Venook, Howard S. Hochster, Donna Niedzwiecki, Richard M. Goldberg, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3511)

    Editorial comment from Dr Cremolini
    The Consensus Molecular Subgroups (CMS) classification of colorectal cancer is based on the identification of different gene signatures characterizing different tumours. Authors of two recent and extremely relevant trials (FIRE-3 and CALGB80405) in the landscape of metastatic colorectal cancer investigated the prognostic and predictive impact of this classification in stage IV patients treated with a chemotherapy doublet plus bevacizumab or cetuximab. CMS1 subtype (immune, enriched in MSI-high and BRAF V600E mutants) is associated with the worse prognosis in both trials, thus confirming results in terms of survival after relapse already reported by Guinney et al. in the original series of mainly stage II and III patients. Less clear and consistent data emerge in terms of predictivity: while in FIRE-3 no differential effect of bevacizumab versus anti-EGFR is evident among CMS subtypes, in CALGB80405 CMS1 tumours seems to derive more benefit from bevacizumab than cetuximab, and CMS2 and 4 cancers seem more sensitive to EGFR than angiogenesis inhibition.

    As a major limitation, these analyses are conducted in the RAS (FIRE-3) or KRAS (CALGB80405) wild-type populations, thus not considering the potential impact of other biomarkers routinely used in the daily practice, such as BRAF V600E mutation or microsatellite instability. In spite of the obvious biologic and scientific interest of these findings, they will become relevant for clinical practice only when their added value (as compared with information provided by other easy-to-obtain markers) will be demonstrated.

  • Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial

    Sebastian Stintzing, Pratyaksha Wirapati, Heinz-Josef Lenz, Daniel Neureiter, Ludwig Fischer von Weikersthal, Thomas Decker, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 3510)

    Editorial comment from Dr Cremolini
    The Consensus Molecular Subgroups (CMS) classification of colorectal cancer is based on the identification of different gene signatures characterizing different tumours. Authors of two recent and extremely relevant trials (FIRE-3 and CALGB80405) in the landscape of metastatic colorectal cancer investigated the prognostic and predictive impact of this classification in stage IV patients treated with a chemotherapy doublet plus bevacizumab or cetuximab. CMS1 subtype (immune, enriched in MSI-high and BRAF V600E mutants) is associated with the worse prognosis in both trials, thus confirming results in terms of survival after relapse already reported by Guinney et al. in the original series of mainly stage II and III patients. Less clear and consistent data emerge in terms of predictivity: while in FIRE-3 no differential effect of bevacizumab versus anti-EGFR is evident among CMS subtypes, in CALGB80405 CMS1 tumours seems to derive more benefit from bevacizumab than cetuximab, and CMS2 and 4 cancers seem more sensitive to EGFR than angiogenesis inhibition.

    As a major limitation, these analyses are conducted in the RAS (FIRE-3) or KRAS (CALGB80405) wild-type populations, thus not considering the potential impact of other biomarkers routinely used in the daily practice, such as BRAF V600E mutation or microsatellite instability. In spite of the obvious biologic and scientific interest of these findings, they will become relevant for clinical practice only when their added value (as compared with information provided by other easy-to-obtain markers) will be demonstrated.

  • KEYNOTE-059 cohort 2: Safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer

    Yung-Jue Bang, Kei Muro, Charles S. Fuchs, Talia Golan, Ravit Geva, Hiroki Hara, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 4012)

    Editorial comment from Prof Lordick & Dr Smyth:
    The results from Keynote 059 cohort 2 show that the anti PD-1 antibody pembrolizumab can be safely combined with standard cisplatin and fluoropyrimidine chemotherapy for treating patients with gastric cancer.    In this relatively small study, radiological response rates were encouraging (ORR 60%) as was overall survival (13.8 months).  Depending on the results of ongoing trials chemotherapy plus checkpoint inhibitors may also be an option for patients with advanced gastroesophageal cancer.

  • Nivolumab 6 ipilimumab in pts with advanced (adv)/metastatic chemotherapyrefractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study

    Yelena Yuriy Janjigian, Patrick Alexander Ott, Emiliano Calvo, Joseph W. Kim, Paolo Antonio Ascierto, Padmanee Sharma, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 4014)

    Editorial comment from Prof Lordick & Dr Smyth:
    Checkmate 032 shows that the combination of two checkpoint inhibitors with different mechanisms of action (anti-PD1 plus anti-CTLA4: Nivolumab 1mg/kg and Ipilimumab 3mg/kg every three weeks) shows promise for the treatment of advanced and pretreated gastric cancers. Response rates for PD-L1 positive gastric cancers were reported to be as high as 40% for combination therapy in PD-L1 positive patients and survival rates after 18 months of treatment in patients with PD-L1 positive tumors were as high as 50%.    Whether or not this combination will be established as a chemotherapy free option in the treatment algorithm of gastric cancer depends on the results of ongoing randomized controlled trials.

  • KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer

    Charles S. Fuchs, Toshihiko Doi, Raymond Woo-Jun Jang, Kei Muro, Taroh Satoh, Manuela Machado, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 4003)

    Editorial comment from Prof Lordick & Dr Smyth:
    Keynote-059 confirms in a relatively big patient cohort, predominantly recruited in non-Asian populations, the efficacy of an anti-PD1-directed immune checkpoint therapy in advanced and pre-treated gastric cancer. Approximately every tenth patient responds to treatment. In case of a positive PD-L1-status (defined as ≥1% of cancer cells or tumor stroma cells stain positive for PD-L1) every fifth patient responds to Pembrolizumab. However, also PD-L1 negative cancers can respond. A very interesting response rate of 60% was seen in the relatively rare (4%) subgroup of patients with high microsatellite instability (MSI-H) gastric cancers.   The results of other ongoing clinical trials and decisions from regulatory authorities will determine in which lines of treatment and in which combination, if any pembrolizumab will be established in routinetreatment algorithms for gastric cancer. We hope that the authorities outside US will soon follow the good example of the FDA to register pembrolizumab for MSI-H irresectable and metastatic gastric cancer and other solid tumors.

  • Perioperative chemotherapy with docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) for resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma (FLOT4-AIO): ...

    Salah-Eddin Al-Batran, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Kim Barbara Luley, et al.

    J Clin Oncol 35, 2017 (suppl; abstr 4004)

    Editorial comment from Prof Lordick & Dr Smyth:
    The perioperative combination chemotherapy FLOT (5-FU, Leucovorin, Oxaliplatin und Docetaxel) achieved a better progression-free and overall survival compared with ECF/ECX (Epirubicin, Cisplatin, 5-FU/Capecitabine) in patients with locally advanced operable gastric cancer or adenocarcinoma of the oesophago-gastric junction. The safety of both regimens was comparable. Perioperative complications and mortality were not increased with FLOT. In conclusion, ECF/ECX should not be used anymore. Whether patients with concomittant diseases or old patients should be treated with less intensive chemotherapy, e.g. with FLO, remains an individual decision at the current timepoint. FLOT can now be regarded as a new standard regimen in patients with locally advanced gastric cancer and adenocarcinoma of the oesophago-gastric junction.

  • Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer

    Petty RD, Dahle-Smith A, Stevenson DAJ, Osborne A, Massie D, Clark C, et al.

    J Clin Oncol. 2017 May 24:JCO2016703934. [Epub ahead of print]

    Commentary by Prof Lordick and Dr Elizabeth Smyth:
    Several randomized controlled trials investigating EGFR-directed drugs - monoclonal antibodies and TKI’s - in upper gastrointestinal cancers, including EXPAND, REAL-3 and COG, were published over the last years.    All of these were negative for efficacy endpoints and there was only little hope that subgroups of tumours maybe identified which can be treated with EGFR-inhibitors.  The preplanned analysis of EGFR-FISH from the COG (Cancer Esophagus Gefitinib) Study indicates such a subgroup of patients who may derive benefit from Gefitinib after failure of previous chemotherapy. Patients with cancers that display EGFR high polysomy or amplification, which is the case in approximately every 5th patient, have a longer overall survival with Gefitinib compared to placebo.

    The working group should be congratulated on this important analysis which was based on sound methodological work-up as published previously by the same working group (Dahle-Smith et al. 2015).

    We believe that these results should re-stimulate the way how to investigate new treatments for upper GI cancers. Proper definition of molecular pathways and assessment of targeted drugs in promising subgroups is the way to move this difficult field forward. We hope that confirmation of the results from the COG trial will become available from independent studies in order to translate this promising finding into clinical practice. 

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