Less radiation, same bang, fewer bucks?

The optimal treatment strategy for esophageal squamous cell carcinoma (eSCC) remains unknown. Neoadjuvant therapy—a combination of chemotherapy and radiation therapy and plus surgery has become a standard recommendation for the treatment of locally advanced eSCC in surgically fit patients.

With its publication in 2012, the CROSS trial established neoadjuvant chemoradiation (nCRT) the standard of care for locally advanced esophageal carcinoma (1). In this study, median survival for squamous cell carcinoma (SCC) patients treated with nCRT was not reached within the initial study period. Long-term follow-up demonstrated median overall survival of 81.6 months for patients with eSCC who received nCRT (compared to 21.1 months in the surgery alone group) (2). Subsequently, NEOCRTEC 5010 randomized 451 patients with resectable eSCC to nCRT with vinorelbine and cisplatin and 40.0 Gy of radiation versus surgery alone. Median survival in the chemoradiation arm was 100.1 vs. 66.5 months in the surgery alone group. The pathologic complete response (pCR) rate was 43.2% (3). nCRT was associated with a durable long-term overall survival benefit (4). A subsequent meta-analysis concluded that nCRT (plus subsequent surgery) was the best available multi-modal approach for eSCC provided that perioperative mortality was low (5).

Although eSCC typically responds well to induction chemoradiation, there is a trend toward providing neoadjuvant systemic therapy without radiation (6-9). Strategies for neoadjuvant treatment regimens are evolving. A recent study of esophageal adenocarcinoma comparing FLOT (induction chemotherapy) to CROSS found FLOT to be associated with better outcomes (10).

Immune checkpoint inhibitors—effective against eSCC—are now used in induction treatment protocols with and without radiation have shown improved overall survival in eSCC (11).

Several studies have evaluated induction chemotherapy with immunotherapy (12-18). Yan et al. reported a major pathologic response (MPR) in 72% and 50% pCR in 45 patients with SCC treated with 3 cycles of tislelizumab, carboplatin and nab-paclitaxel (17). Li et al. reported a significant difference in T downstaging in patients receiving chemotherapy and immunotherapy compared to chemotherapy alone (37.9% vs. 3.5%) with a pCR of 41.4% vs. 27.6% (18).

This experience raises an important question: how can the benefits of systemic therapy, radiation, and surgery be combined to maximize efficacy while minimizing patient risk? Previous attempts to combine immunotherapy with conventional induction strategies have been plagued by excessive treatment-related morbidity and mortality.

In this context, Jiang et al. present SCALE-1, a phase Ib trial of safety and efficacy of induction chemotherapy, immunotherapy with short course radiotherapy (6). The SCALE-1 trial enrolled patients with T1-4aN+M0 or T4aN0M0 SCC. SCALE-1 uses a provocative strategy of a short course of chemotherapy and radiation therapy combined with immunotherapy in patients with locally advanced disease. This trial employed only two cycles of chemotherapy, two cycles of immunotherapy and a shorter course of radiation compared to more conventional nCRT protocols. The treatment protocol included two doses of intravenous toripalimab (240 mg) in combination with paclitaxel (135 mg/m²) and carboplatin (area under the curve =5) on day 1 and day 22. Concurrent radiotherapy (30 Gy in 12 fractions, 5 days per week) was administered as “sandwich therapy” from day 3 to day 18.

The salient findings of the SCALE-1 trail include:

• 21/23 patients completed induction therapy.
• 20 of 21 patients underwent surgery.
• There was marked reduction in perioperative complications after extending the time interval to surgery R0 resection rate was 95%.
• All patients experienced pathologic down staging with 80% of patients exhibiting MPR.
• pCR was 50% (11/22 patients).
• There was no difference in pCR rate between those who had a combined positive score (CPS) greater than 5% and less than 5%.

The most comparable studies to SCALE-1 are the NEOCRTEC1901 trial (19) and a small phase Ib study by Xu et al. (20). NEOCRETEC1901 was phase II open label trial that used a conventional chemoradiation protocol with immunotherapy and enrolled a similar patient population of locally advanced (T1-4N1-3N0 or T3-4N0M0) SCC. NEOCRTEC1901 specifically used four cycles of weekly pacilitaxel (50 mg/m²), cisplatin (25 mg/m²⁾ and two cycles of toripalimab (240 mg) combined with 44 Gy of concurrent radiation (19). There was a 50% pCR compared to historical controls of patients receiving nCRT alone (36%) which was not considered statistically significant (P=0.19). Xu et al. reported a trial of induction chemoradiation followed by immunotherapy in 21 patients, of whom 20 went on to undergo surgery. This protocol included 5 cycles of paclitaxel (45 mg/m²), cisplatin (25 mg/m²) with 41.4 Gy of radiation followed by two cycles of toripalimab (240 mg) on days 3 and 25 after the completion of radiation. The pCR was 47.4% and the MPR was 78.9% (20). The median survival and disease-free survival (DFS) was not reached at 24 months. Table 1 summarizes the results of SCALE-1 (6), NEOCRTEC1901 (19) and Xu et al. (20). Leukopenia and neutropenia (39% and 57% respectively) were the most frequent grade 3–4 treatment associated adverse events (TRAE) in all three studies. The safety profile of this regimen was also important. There were relatively few episodes of pneumonitis, and postoperative pulmonary complications. In SCALE-1, the perioperative outcomes improved after extending the interval between induction therapy and surgery to ≥8 weeks.

pCR rates were comparable to the SCC subgroup of the CROSS trial, Xu et al. and NEOCRTEC1901 with comparable TRAE, perioperative outcomes and 2-year oncologic outcomes. In a trial of adjuvant nivolumab after nCRT, Checkmate 577 reported 2-year DFS in eSCC of approximately 62% with median DFS of 29.7 months (11). This is similar to the SCALE-1 results. Both SCALE-1 and NEOCRTEC1901 achieved similar results with two cycles of induction torpalimab prior to surgery compared with adjuvant nivolumab given for up to one year after nCRT and surgery in Checkmate 577. The increased efficacy of the immune response to neoadjuvant immunotherapy may account for a near equivalent effect to post-operative immunotherapy with fewer cycles. Additionally, carboplatin may be better tolerated than cisplatin.

Two cycles of chemotherapy and fewer radiation therapy fractions may also have secondary benefits of decreased cost and extending the time interval to surgery would expedite completion of therapy secondary to a shorter period of induction therapy. Two cycles of the neoadjuvant immune checkpoint inhibitors would also be associated with significant cost savings compared with as many as potential for 17 cycles (1 year) of adjuvant immunotherapy reported in Checkmate 577.

Conclusions

SCALE-1 meets its primary objectives, the regimen appears to be safe with acceptable treatment associated events and perioperative outcomes. This study and its most comparable competitors (NEOCRTEC 1901 and Xu et al.) were early-stage trials designed to test safety and feasibility. SCALE-1 and Xu et al. provide some intermediate-term outcome data, which are promising. However, final judgement should be withheld until the data matures and long-term outcomes are available. The strategy of combining nCRT with immune checkpoint inhibitors for squamous carcinoma is attractive. SCC tends to respond better to both radiation and immunotherapy compared to adenocarcinoma. The advantages of this treatment strategy include comparable oncologic efficacy with acceptable treatment and surgical related morbidity. Induction therapy with immune checkpoint inhibitors appears to be more efficient than post-operative immunotherapy because of better immune response when the tumor is in situ. The cost savings when scaled to large patient populations are potentially enormous. This short course strategy deserves to be evaluated in a larger study comparing it to more conventional induction regimens.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-99/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-99/coif). S.I.R. is an investor in OncoNano. J.K.W. reports consulting fees from Astra Zeneca. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84. [Crossref] [PubMed]
2. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 2015;16:1090-8. [Crossref] [PubMed]
3. Yang H, Liu H, Chen Y, et al. Neoadjuvant Chemoradiotherapy Followed by Surgery Versus Surgery Alone for Locally Advanced Squamous Cell Carcinoma of the Esophagus (NEOCRTEC5010): A Phase III Multicenter, Randomized, Open-Label Clinical Trial. J Clin Oncol 2018;36:2796-803. [Crossref] [PubMed]
4. Yang H, Liu H, Chen Y, et al. Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial. JAMA Surg 2021;156:721-9. [Crossref] [PubMed]
5. Montagnani F, Fornaro L, Frumento P, et al. Multimodality treatment of locally advanced squamous cell carcinoma of the oesophagus: A comprehensive review and network meta-analysis. Crit Rev Oncol Hematol 2017;114:24-32. [Crossref] [PubMed]
6. Jiang N, Zhang J, Guo Z, et al. Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial. J Immunother Cancer 2024;12:e008229. [Crossref] [PubMed]
7. Kitagawa Y, Ishihara R, Ishikawa H, et al. Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 1. Esophagus 2023;20:343-72.
8. Wang H, Tang H, Fang Y, et al. Morbidity and Mortality of Patients Who Underwent Minimally Invasive Esophagectomy After Neoadjuvant Chemoradiotherapy vs Neoadjuvant Chemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Surg 2021;156:444-51. [Crossref] [PubMed]
9. Tang H, Wang H, Fang Y, et al. Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy for locally advanced esophageal squamous cell carcinoma: a prospective multicenter randomized clinical trial. Ann Oncol 2023;34:163-72. [Crossref] [PubMed]
10. Hoeppner J, Brunner T, Lordick F, et al. Prospective randomized multicenter phase III trial comparing perioperative che- motherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial). J Clin Oncol 2024;42:LBA1. [Crossref]
11. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med 2021;384:1191-203. [Crossref] [PubMed]
12. Fick CN, Dunne EG, Sihag S, et al. Immunotherapy for Resectable Locally Advanced Esophageal Carcinoma. Ann Thorac Surg 2024;118:130-40. [Crossref] [PubMed]
13. Liu Y. Perioperative immunotherapy for esophageal squamous cell carcinoma: Now and future. World J Gastroenterol 2023;29:5020-37. [Crossref] [PubMed]
14. Shang X, Zhao G, Liang F, et al. Safety and effectiveness of pembrolizumab combined with paclitaxel and cisplatin as neoadjuvant therapy followed by surgery for locally advanced resectable (stage III) esophageal squamous cell carcinoma: a study protocol for a prospective, single-arm, single-center, open-label, phase-II trial (Keystone-001). Ann Transl Med 2022;10:229. [Crossref] [PubMed]
15. Liu Y, Bao Y, Yang X, et al. Efficacy and safety of neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy in esophageal cancer: A systematic review and meta-analysis. Front Immunol 2023;14:1117448. [Crossref] [PubMed]
16. Qiao Y, Zhao C, Li X, et al. Efficacy and safety of camrelizumab in combination with neoadjuvant chemotherapy for ESCC and its impact on esophagectomy. Front Immunol 2022;13:953229. [Crossref] [PubMed]
17. Yan X, Duan H, Ni Y, et al. Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE). Int J Surg 2022;103:106680. [Crossref] [PubMed]
18. Li Y, Zhou A, Liu S, et al. Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial: A randomized clinical trial of neoadjuvant therapy for ESCC. BMC Med 2023;21:86. [Crossref] [PubMed]
19. Chen R, Liu Q, Li Q, et al. A phase II clinical trial of toripalimab combined with neoadjuvant chemoradiotherapy in locally advanced esophageal squamous cell carcinoma (NEOCRTEC1901). EClinicalMedicine 2023;62:102118. [Crossref] [PubMed]
20. Xu X, Sun Z, Liu Q, et al. Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer. J Immunother Cancer 2024;12:e008631. [Crossref] [PubMed]