Comparing two chemo regimen and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced oesophageal cancer

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Published: 25 Jan 2022
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Dr Ken Kato - National Cancer Center Hospital, Tokyo, Japan

Dr Ken Kato speaks to ecancer about the JCOG1109 NExT study which is a randomised controlled phase III trial comparing two chemotherapy regimens and chemoradiotherapy regimens as neoadjuvant treatment for locally advanced oesophageal cancer.

He initially, talks about the background and methodology of the study.

He says that for this trial, researchers compared neoadjuvant DCF, cisplatin plus fluorouracil (CF), and CF plus radiotherapy (RT). The trial included 601 patients with stage IB-III ESCC.

Their median age was 65 (range, 30-75) years, 63% had stage III (non-T4) disease, and 88% were men.

Dr Kato explains that adding docetaxel to neoadjuvant cisplatin and fluorouracil prolonged overall survival for patients with locally advanced oesophagal squamous cell carcinoma (ESCC). These results suggest that neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) “represents a new standard treatment for locally advanced ESCC”.

He concludes by discussing the impact of these results on the future treatment of oesophageal cancer.

 

Oesophageal cancer, especially squamous cell carcinoma, mainly arises from the East Asian
countries. Many oesophageal squamous cell carcinoma patients are in Japan and, indeed, the
prognosis of oesophageal cancer is poor. So even for the locally advanced cases the really common
use is of a neoadjuvant therapy for such kinds of patient. In Western countries neoadjuvant
chemoradiotherapy is the standard of care for such kinds of patients but in Japan the JCOG9907 trial
showed a positive effect of neoadjuvant chemotherapy over adjuvant chemotherapy.
So our standard of care was neoadjuvant, two courses of 5FU cisplatin followed by surgery. We
conducted our study, JCOG1109, to enhance and prolong the prognosis for oesophageal squamous
cell carcinoma patients.

To enhance the neoadjuvant trial and improve the outcome we hypothesised two hypotheses for the
more intensive neoadjuvant treatment. One is that stronger local control by radiation therapy, like
cross trials used in Western countries, so one experimental arm was the chemo plus radiation arm as
a neoadjuvant therapy and one more experimental arm with a more intensive systemic therapy using
triplet chemotherapy – 5FU cisplatin plus docetaxel. This combination triplet therapy is already used
for the induction chemotherapy for head and neck carcinoma. This showed a positive result as
induction therapy over 5FU and cisplatin. So we set the standard of care as 5FU and cisplatin and
DCF and CF RT were the two experimental arms.

So our trial has three arms – one standard of care and two experimental arms. We assumed a 10%
increase at three year survival from 62% to 72% for the experimental arms. So we calculated some
precise as 200 patients for each arm. So we started and collected various ESCC patients from 2012.
Enrolment was terminated in 2018 and after a three-year follow-up the overall survival comparison
was done. For the control arm, the 5FU cisplatin arm, the three-year overall survival rate is 62.6% and
in the DCF arm shows 72.1%. The hazard ratio was 0.68 and the p-value was less than 0.025 that
means a statistically significant survival benefit. On the other hand, the CF RT arm showed a 68.3%
three-year overall survival rate and in a comparison to the [?? 4:34] 5FU cisplatin shows a hazard
ratio of 0.84 that’s not statistically significant.

So, among the two experimental arms only the DCF regimen shows a survival benefit over 5FU
cisplatin. The CF plus radiation arm did not show a statistically significance over 5FU and cisplatin. So
that means the more intensive systemic therapy shows a more improved survival of the locally
advanced oesophageal squamous cell carcinoma patients.

This means that radiation is a very strong treatment for oesophageal squamous cell carcinoma but
sometimes harmful for the patient after the surgery. So our findings show that the patients dying from
other cancers or unknown reason cancers is more common in the chemoradiation arm than the other
chemotherapy arm. So maybe 10-20% of the patients died with late toxicity of the radiation therapy.
So more systemic control could be effective for the long-term survival of the ESCC patients. More, the
CheckMate 577 trial shows a positive effect for oesophageal carcinoma as an adjuvant treatment. So
we expect an additional factor for the immune checkpoint inhibitor as a neoadjuvant chemotherapy.
A recent phase II trial shows that additional frequency of the immune checkpoint inhibitor to the
neoadjuvant chemoradiotherapy of oesophageal cancer is not so high so it is better for the
combination of the immune checkpoint inhibitor as a neoadjuvant chemotherapy rather than
neoadjuvant chemoradiotherapy. So further investigation with immune checkpoint inhibitors to
neoadjuvant chemotherapy would be expected.

In this trial the surgical procedure is surgery defined from Western countries. As a discussant of the
ESMO GI symposium, it was pointed out that the highest number of lymphocytes is more in the
Japanese procedures than Western procedures because for decades the more intensive lymph node
dissection is standard procedure in Japan but in many Western countries not so much intensive
radical lymph node dissection was not performed. So that’s a difference from the results of Western
procedures. So local control of ESCC was already done by radical lymph node dissection so the
magnitude of radiation therapy was less than in Western countries.