Tumor Platinum Concentrations and Pathological Responses Following Cisplatin-Containing Chemotherapy in Gastric Cancer Patients
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There is a wide range in tumor response following preoperative chemotherapy in locally advanced gastric or gastroesophageal junction cancers. We investigated the relationship between tumor platinum levels and pathological responses in these patients.
Tumor and adjacent normal tissues were retrieved. Pathological responses were assessed per standard criteria. Tissue platinum concentrations were determined with high-performance liquid chromatography mass spectrometry. Platinum distribution in tissue components was evaluated with imaging mass cytometry. Collagen content was evaluated using trichrome staining.
Surgical specimens from 10 patients were available. Surgery was performed at a median time of 49 days (range: 28–72) after the last cycle of chemotherapy. The mean platinum level in tumor tissue in patients with any response was significantly higher than in those with no response (893 ± 460 vs. 38.8 ± 8.8 pg, P = 0.007), so was the collagen content (37.4 ± 6.8 vs. 11.5 ± 8.6%, P < 0.05). Platinum preferentially bound to collagen.
Platinum was detectable in surgical specimens up to 72 days after preoperative chemotherapy. Higher tumor platinum concentration correlated with improved pathological response. Collagen binding potentially explained the high interpatient variability in tumor platinum concentrations.
KeywordsStomach neoplasms Neoadjuvant therapy Platinum Treatment outcome Image cytometry
Epirubicin, cisplatin and 5-fluorouracil
Epirubicin, cisplatin and capecitabine
Docetaxel, oxaliplatin and 5-fluorouracil
Tumor regression grade
Imaging mass cytometry
High-performance liquid chromatography mass spectrometry
Non-small cell lung cancer
We thank Jing Xu for valuable technical assistance.
EC and YC conceived and designed the study and analyzed the data. QC performed IMC analysis. MC analyzed the trichrome and Ki67 data. WZ performed tissue platinum analysis. All authors made substantial contributions towards drafting the manuscript, reviewed the final manuscript for intellectual content, and authorized the submission. All authors read and approved the final manuscript.
This study was funded by the Princess Margaret Cancer Foundation.
Compliance with Ethical Standards
This study was approved by the Research Ethics Board at the University Health Network, Toronto, Canada and conducted in compliance with relevant Ethics Standards.
Conflict of Interest
Qing Chang and Olga Ornatsky are employees of Fluidigm Canada Inc. Olga Ornatsky is one of the co-founders of DVS Sciences Inc. (now part of Fluidigm) that invented, developed and manufactures mass cytometry technologies, including the Helios CyTOF system, the Imaging Mass Cytometer and metal-conjugated reagents.
No other authors declared any potential conflicts of interest.
- 3.Al-Batran S-E, Homann N, Schmalenberg H, Kopp H-G, Haag GM, Luley KB, et al. 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): A multicenter, randomized phase 3 trial. J Clin Oncol. 2017;35:4004. https://doi.org/10.1200/JCO.2017.35.15_suppl.4004.CrossRefGoogle Scholar
- 4.Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, et al. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK medical research council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncol. 2017;18:357–70. https://doi.org/10.1016/S1470-2045(17)30043-8.CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Smyth EC, Fassan M, Cunningham D, Allum WH, Okines AF, Lampis A, et al. Effect of pathologic tumor response and nodal status on survival in the Medical Research Council adjuvant gastric Infusional chemotherapy trial. J Clin Oncol. 2016;34:2721–7. https://doi.org/10.1200/JCO.2015.65.7692.CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Sprauten M, Darrah TH, Peterson DR, Campbell ME, Hannigan RE, Cvancarova M, et al. Impact of long-term serum platinum concentrations on neuro- and ototoxicity in Cisplatin-treated survivors of testicular cancer. J Clin Oncol. 2012;30:300–7. https://doi.org/10.1200/JCO.2011.37.4025.CrossRefPubMedGoogle Scholar
- 8.(June 2014). College of American Pathologists Protocol for the Examination of Specimens From Patients With Carcinoma of the Stomach Version: Stomach 184.108.40.206.Google Scholar
- 12.Davies AR, Gossage JA, Zylstra J, Mattsson F, Lagergren J, Maisey N, et al. Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol. 2014;32:2983–90. https://doi.org/10.1200/JCO.2014.55.9070.CrossRefPubMedGoogle Scholar
- 13.Saunders JH, Bowman CR, Reece-Smith AM, Pang V, Dorrington MS, Mumtaz E, et al. The role of adjuvant platinum-based chemotherapy in esophagogastric cancer patients who received neoadjuvant chemotherapy prior to definitive surgery. J Surg Oncol. 2017;115:821–9. https://doi.org/10.1002/jso.24601.CrossRefPubMedGoogle Scholar
- 19.Park SR, Lee JS, Kim CG, Kim HK, Kook MC, Kim YW, et al. Endoscopic ultrasound and computed tomography in restaging and predicting prognosis after neoadjuvant chemotherapy in patients with locally advanced gastric cancer. Cancer. 2008;112:2368–76. https://doi.org/10.1002/cncr.23483.CrossRefPubMedGoogle Scholar