Total neoadjuvant chemotherapy: a silver lining during the COVID pandemic for a patient with locally advanced diffuse distal gastric adenocarcinoma

Abstract

Perioperative oncological therapies resulting in pathological complete response (pCR) in diffuse-type distal gastric adenocarcinoma are extremely rare. We report a case of locally advanced (cT3 N2 M0) diffuse-type distal gastric adenocarcinoma treated with ‘total neoadjuvant’ FLOT (eight cycles), due to the COVID-19 pandemic, and laparoscopic radical subtotal gastrectomy with D2 lymphadenectomy. The patient demonstrated a progressive radiological response on positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-d-glucose integrated with computed tomography (¹⁸F-FDG PET-CT) and pCR in the resected specimen (ypT0 N0). As far as we are aware, this is the first case of pCR in locally advanced T3 N2 diffuse distal gastric cancer to be reported in the literature. It introduces a novel approach of total neoadjuvant chemotherapy with ¹⁸F-FDG PET-CT to assess response, combined with radical minimally invasive surgical management to provide optimal care for patients with gastric cancer.

Background

Perioperative FLOT chemotherapy is the current standard of care for resectable gastric adenocarcinoma in Europe. Patients with gastric cancer have a 5-year survival of 36% using the MAGIC regimen.¹ Estimated 5-year survival in patients with gastric and junctional adenocarcinoma in the FLOT trial is 45%.² A pathological complete response (pCR) is the absence of residual cancer cells in the primary tumour and the dissected regional lymph nodes; ypT0 N0 according to the 8th AJCC tumour, node, metastasis staging system.³

In those receiving neoadjuvant FLOT for gastric primary tumours, pCR incidence is reported as 15% overall.⁴ However, pCR in diffuse histological-type distal gastric cancer is extremely rare and has been reported previously only in T2 N0 M0 disease.⁵ We report a case of a patient with locally advanced (cT3 N2 M0) diffuse-type distal gastric adenocarcinoma who changed treatment because of the COVID-19 pandemic and achieved pCR (ypT0 N0) in the resected specimen. We discuss the benefits of a ‘total neoadjuvant’ approach combined with radical minimally invasive surgical management, yielding optimal oncological and surgical outcomes while minimising the combined physiological insult of both treatment modalities. We also highlight the usefulness of positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-d-glucose integrated with computed tomography (¹⁸F-FDG PET-CT, hereafter PET-CT) as a tool to assess treatment response in this setting.

Case history

A 73-year-old male presenting with epigastric pain and weight loss underwent oesophagogastroduodenoscopy, which showed a bulky circumferential distal gastric mass from the incisura to pylorus (Figure 1). Gastric biopsies revealed diffuse-type (Lauren classification) invasive gastric adenocarcinoma (Figure 2). Staging computed tomography (CT) scan of his chest and abdomen showed a suspicious thickening in the paracolic region of the ascending colon, in addition to the gastric tumour, and locally enlarged lymph nodes. The patient therefore underwent PET-CT (Figure 3) in addition to colonoscopy and staging laparoscopy. These investigations detected no abnormalities in the paracolic region. He was staged clinically as T3 N2 M0 and deemed suitable for radical multimodality treatment. He did not undergo molecular profiling because he was being managed with curative intent. The primary gastric tumour and associated lymph nodes were FDG-avid, therefore the multidisciplinary team decided to continue with PET-CT scanning to aid in assessing his response to preoperative therapy and direct management strategies during the height of the COVID pandemic.

Figure 1 .

Bulky circumferential distal gastric tumour

Figure 2 .

Biopsy: poorly differentiated adenocarcinoma

Figure 3 .

(a) Tumour and adjacent node. First scan tumour SUVmax was 19.4g/ml and adjacent hot node was 9.2g/ml; second scan tumour was 5.2g/ml and adjacent node was negative; third scan tumour was 2.6g/ml and node was negative. (b) Left gastric node. First scan, SUVmax 12.1g/ml; second and third scans, no uptake.

The patient received four cycles of FLOT (docetaxel 50mg/m² intravenous injection on day 1, oxaliplatin 85mg/m² intravenous injection on day 1, leucovorin 200mg/m² intravenous injection on day 1 and 5-fluorouracil 2,600mg/m² intravenous infusion over 24h on day 1, with a 14-day cycle length) combined with immune checkpoint inhibitor durvalumab (10mg/kg intravenous injection on FLOT cycle day 1) as part of the LUDWIG 20015-005 phase Ib/II clinical trial (EudraCT number: 2015-005298-19) with a plan for four cycles of adjuvant FLOT plus durvalumab. After the first FLOT cycle, he developed neutropenia and subsequently had a dose reduction to 80% dose FLOT. Prophylactic granulocyte colony-stimulating factor was added. Post-neoadjuvant PET-CT showed a partial response with the tumour maximum standardised uptake value (SUVmax) decreased by 73% and regional lymph nodes no longer ¹⁸F-FDG avid (Figure 3).

Surgical resection scheduled for March 2020, during the height of the COVID-19 pandemic, had to be postponed for several months. After careful planning and risk assessment, the scheduled four cycles of postoperative FLOT were advanced into the preoperative setting to maintain tumour control while awaiting surgery: a ‘total neoadjuvant’ approach. These four cycles of FLOT (without durvalumab) were well tolerated. The patient underwent a final PET-CT with serial scans showing significant and progressive reduction in the SUVmax values of the primary tumour in the second scan, reaching near-normal values in the third scan (Figure 3). After prehabilitation including targeted daily physical activity and incentive spirometer use, the patient underwent laparoscopic radical subtotal gastrectomy with D2 lymphadenectomy and Roux-en-Y reconstruction, using the medial part of his previous open appendicectomy scar for specimen extraction (Figure 4). He had an uneventful recovery and was discharged from hospital on the fifth postoperative day.

Figure 4 .

Patient’s abdomen less than 4 weeks after laparoscopic radical subtotal gastrectomy with D2 lymphadenectomy

Histopathological analysis demonstrated extensive fibrosis, scarring and scattered mucin lakes with associated patchy chronic inflammation within the submucosa and muscularis propria of the stomach and four associated lymph nodes, suggestive of prior extensive malignancy, but no evidence of residual malignancy. None of the 20 lymph nodes examined showed active cancer. There was pCR (ypT0 N0) (Figure 5). Within the trial protocol, the patient subsequently received six cycles of adjuvant durvalumab and no further FLOT. He remains disease-free 12 months after surgery.

Figure 5 .

Macroscopic and microscopic histopathological pictures of the specimen. (a) Focal scarring and distortion of gastric wall. No clear gross tumour seen. (b) Resection specimen: gastric wall with residual mucin and fibrosis only. (c) Lymph node: fibrotic scarring consistent with treatment effect.

Discussion

This is the first reported case of pCR in locally advanced T3 N2 diffuse distal gastric cancer. There is evidence that pCR reduces the risk of recurrence and increases survival. Systematic reviews have reported 5-year overall survival of up to 85% in patients who achieve pCR.⁶ Specifically, absence of nodal disease in the resected specimen (ypN0) has survival benefit with a median overall survival of 10.2 years in those achieving ypT0 N0 compared with 2.56 years in those with ypT0 N+ (p=0.019).⁷

A study describing the use of total neoadjuvant chemotherapy with FLOT for gastric and junctional cancers has been published recently with a pCR rate of 18.2% in those treated with total neoadjuvant FLOT.⁸ However, this study does not give details of the site of the cancers (distal, proximal gastric or junctional) or response by histological type. Although perioperative FLOT is the standard of care and this study uses FLOT alone, the addition of durvalumab in our patient’s case is important. Novel immunotherapies targeting specific biomarkers such as programmed cell death protein 1 (PD-1), human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) have shown promise, particularly in the palliative setting.⁹ The presence of these markers and targeted immunotherapy should be incorporated into future trials.

Use of the total neoadjuvant approach to bridge the COVID-19 peak has yielded a ‘miracle’ for one patient who tolerated all eight cycles of FLOT and proceeded to curative surgical resection. We ask whether this approach should be adopted for all patients who respond to and tolerate the initial four cycles of neoadjuvant FLOT. Treatment response could be assessed by ¹⁸F-FDG PET-CT or other biomarkers of response to decide if the regimen should be extended or stopped. The total neoadjuvant approach may also enable more patients to complete the entire regimen because at present perioperative chemotherapy completion is severely hampered by decreased uptake after surgery due to various psychological and physiological factors, with only 46% of patients completing all cycles.²

The excellent minimally invasive surgical outcome coupled with the pCR in this patient has enabled good quality of life in the short term while increasing the likelihood of long-term survival. The benefits of laparoscopic surgery with regards to postoperative pain, enhanced recovery and patient-related quality of life are well documented. Recent trials have shown that surgical oncological outcomes of the laparoscopic approach are comparable to open surgery, even for advanced gastric cancer.¹⁰ Surgical management with perioperative oncological therapies is the standard of care to achieve long-term survival. However, a study of 66 patients managed with definitive chemoradiotherapy demonstrated a benefit in median survival time in those who achieve clinical complete response (30.7 vs 10.6 months, p<0.001). Similarly, it may be possible to achieve long-term survival using our approach in patients who are unfit or unwilling to undergo surgery if they demonstrate complete clinical response.¹¹

Conclusion

Our case demonstrates that total neoadjuvant therapy can be safely completed without preventing progression to curative surgery. For this patient, pCR offers a realistic chance of long-term survival: a true ‘silver lining’ during the COVID-19 pandemic. It warrants further investigation in the form of randomised controlled trials comparing total neoadjuvant regimens with current standards of care. Investigation of the value of ¹⁸F-FDG PET-CT or other novel predictive biomarkers such as circulating tumour DNA, to assess response to initial chemotherapy and decide on further treatment algorithms could be incorporated into trial designs. The focus of future treatment algorithms should aim for achieving pathological complete response in both tumour (ypT0) and nodal disease (ypN0).