Increased adverse events associated with chemotherapy and radiotherapy in patients with second primary esophageal cancer after hematologic malignancy

Introduction

In recent decades, the number of cancer survivors has shown a steady annual increase of 2% as a result of earlier diagnoses and advances in treatment and supportive cares (1). However, these survivors face numerous challenges stemming from the lingering effects of treatment (2). In particular, the emergence of subsequent malignant neoplasm (SMN) poses a significant threat to the well-being of these patients. Previous studies have found that 2–18% of cancer survivors develop an SMN at some point in their lives (3-7).

SMN is a particularly serious concern among cancer survivors with a history of hematopoietic stem cell transplantation (HSCT) for hematologic malignancy (8-12). Several studies have highlighted this issue, with one from Japan finding that the risk of developing invasive solid cancer was 1.8-fold higher in patients who had undergone HSCT than in the general population (9). In this patient population, the standard incidence ratio (SIR) for SMN is elevated at specific anatomic sites, including the oral cavity/pharynx (SIR: 15.7), esophagus (SIR: 8.5), skin (SIR: 7.2), and brain (SIR: 4.1) (9). The incidence rate of SMN per 100,000 person-years according to time since transplantation has been reported to be 32–92 for the oral cavity/pharynx and 4–59 for the esophagus (12).

Patients with a history of hematologic malignancy especially those treated with HSCT, are considered to have impaired bone marrow function and vulnerable mucosa due to graft-versus-host disease (GVHD). Consequently, there are concerns regarding the risks of treatment-related adverse events (TRAEs) when these patients receive chemotherapy or radiotherapy. However, despite their significance, there is a scarcity of reports on the risks of TRAEs in these patients. Therefore, in this study, we assessed the incidence of adverse events related to non-surgical treatment of SMN with esophageal cancer (SMN-EC) in patients with a history of treatment for hematologic malignancy. We present this article in accordance with the STROBE reporting checklist (available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-17/rc).

Methods

Patients

We retrospectively extracted data from our database on all patients diagnosed with SMN-EC at the National Cancer Center Hospital between 1995 and 2014. The selection criteria were a history of hematologic malignancy before diagnosis of SMN-EC and initial treatment with chemotherapy, radiotherapy, or chemoradiotherapy for SMN-EC.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of the National Cancer Center (2017-229). The requirement for written informed consent was waived due to the retrospective nature of the study.

Treatment

The chemotherapy regimens consist of DCF (docetaxel 70 mg/m² and cisplatin 70 mg/m² on day 1 plus fluorouracil 750 mg/m² on days 1–5, every 3 weeks for 3 cycles as neoadjuvant chemotherapy) and CF (cisplatin 80 mg/m² on day 1 plus fluorouracil 800 mg/m² on days 1–5, every 3 weeks for 2 cycles in a neoadjuvant therapy or every 4 weeks in palliative chemotherapy). The chemoradiotherapy regimens consist of CF-RT (cisplatin 70 mg/m² on day 1 plus fluorouracil 700 mg/m² on days 1–4 every 4 weeks for 2 cycles) and NF-RT (nedaplatin 90 mg/m² on day 1 plus fluorouracil 800 mg/m² on days 1–5, every 4 weeks for 2 cycles). For the DCF regimen, prophylactic use of ciprofloxacin was mandatory from days 5–15. In the CF regimen, primary granulocyte colony-stimulating factor (G-CSF) was not performed. In the DCF regimen, primary G-CSF prophylaxis was considered if the patient was over 65 years old. In both CF and DCF regimens, secondary G-CSF prophylaxis was administered if patients developed febrile neutropenia (FN) or grade 4 neutropenia.

Radiation was delivered as megavoltage X-rays (≥6 MV) using two-dimensional or three-dimensional conformal radiotherapy. When radiation was delivered as part of chemoradiotherapy, primary tumors in patients with stage I disease were treated with 60 Gy/30 Fr, and primary tumors and metastatic lymph nodes (LN) in those with stage II/III/IV disease were treated with 60 Gy/30 Fr as reported previously (13-15).

Evaluations

Performance status (PS) was assessed according to the Eastern Cooperative Oncology Group (ECOG) criteria, and the eighth edition of the Union for International Cancer Control TNM classification was used for cancer staging. Adverse events were evaluated weekly using Common Terminology Criteria for Adverse Events version 5.0. The efficacy of the treatment was evaluated with computed tomography (CT) scan every 2–3 months for metastatic cases, with endoscopy for local cases.

Statistical analysis

The Fisher’s exact test was used to compare categorical data. Statistical significance was set at P<0.05.

Results

Patients’ characteristic

Thirty-nine patients with a history of hematologic malignancy who were diagnosed with SMN-EC were selected for this analysis. Among these, 23 patients who had initially undergone endoscopic or surgical resection were excluded from our analysis. Subjects for this study comprised 16 patients who had received treatment via chemotherapy (n=5), chemoradiotherapy (n=6), or radiotherapy (n=5) (Figure 1). The median age at diagnosis of SMN-EC was 65.5 years (range, 46–86 years). ECOG PS was categorized as 0 for 7 patients and 1 for 9 patients. Among these, 3 patients had clinical stage I disease, 11 had stage II or III, and 2 had stage IVB. The median duration between completion of treatment for hematologic malignancy and diagnosis of SMN-EC was 7.6 years (range, 0–24.3 years) (Table 1).

Figure 1 CONSORT diagram. CTx, chemotherapy; CRT, chemoradiotherapy; RT, radiotherapy; CF, cisplatin + fluorouracil; DCF, docetaxel + cisplatin + fluorouracil; Neo, neoadjuvant.

Prior hematologic malignancy was treated by HSCT in 6 patients, chemotherapy in 6, chemoradiotherapy in 2, and no treatment in 2. As shown in Table 2, patients with a history of HSCT tended to be younger than those who did not (HSCT vs. no HSCT: 57.3 vs. 72.4 years; P=0.001). All 6 patients who received HSCT had a history of GVHD, and 1 was still receiving immunosuppressive therapy at diagnosis of SMN-EC.

Chemoradiotherapy

Six patients were treated with chemoradiotherapy, 1 for the palliative setting and 5 for the definitive setting. The reasons why 5 patients were treated with definitive chemoradiotherapy instead of surgery were that 2 were unresectable, 2 wished organ preservation, and 1 received hematologist advice to avoid surgery due to the risk of perioperative complications due to the hematological malignancy.

Patients No. 1, No. 2, and No. 3 were started on a reduced dose from the initial treatment concerning severe toxicity. Patient No. 2 was treated with nedaplatin + 5-FU instead of cisplatin + 5-FU because of renal dysfunction. Concerning a potential for severe toxicity due to a history of HSCT, radiation therapy (RT) was delivered sequentially after the completion of nedaplatin + 5-FU.

One treatment-related death occurred in patient No. 1 who was treated with CF-RT for stage I disease due to interstitial pneumonia. The patient had a history of HSCT and was receiving immunosuppressive therapy for chronic GVHD. Mild bilateral lung fibrosis had been detected by CT before treatment for SMN-EC. Chemotherapy was started with a reduced dosage because the patient seemed to have a higher risk of infection due to immunosuppressive therapy. However, the patient developed grade 3 neutropenia during the first cycle. Despite further reduction of the cisplatin dosage in the second cycle, the patient developed grade 4 neutropenia and grade 3 esophagitis, FN, and lung infection. Therefore, chemoradiotherapy was terminated at the point of receiving 44 Gy of radiation, and an antibiotic and G-CSF was started. Although the neutropenia recovered within a week, the patient’s general condition deteriorated because of lung infection, and a prolonged period of hospitalization was needed. Sixty-five days after the termination of chemoradiotherapy, the patient developed pneumonitis and was started on intravenous high-dose (1 g for 3 days) methylprednisolone therapy. However, the pneumonitis did not improve, ultimately leading to the patient’s death 2 weeks later.

Chemotherapy

Five patients were treated with chemotherapy. Three patients received the DCF regimen, 1 received the CF regimen for the neoadjuvant setting, and 1 received CF for the palliative setting. Patient No. 10 received the CF regimen because he was not expected to tolerate the DCF regimen due to his older age. Patients No. 7, No. 9, and No. 10 started on a reduced dose from the initial treatment concerning severe hematologic toxicity.

Radiotherapy

Five patients were treated with radiotherapy alone for the following reasons: 3 patients were elderly (aged 77, 78, and 86 years), 1 patient had hepatic impairment with indocyanine green retention rate at 15 minutes of 40%, and 1 patient had inactive chronic lymphoid leukemia (CLL), which did not require treatment.

TRAEs in the overall population

The TRAEs and treatment outcomes for all 16 patients are shown in Table 3. Grade ≥3 hematologic toxicities were neutropenia in 10 patients (62.5%), anemia in 7 (43.8%), and thrombocytopenia in 5 (31.3%). Grade ≥3 non-hematologic toxicities were esophagitis in 8 patients (50%), oral mucositis in 4 (25%), sepsis (unrelated to FN) in 1 (6.3%), and FN in 3 (18.8%). As shown in Table 4, it was observed that grade ≥3 hematological TRAEs tended to be common among patients with a prior history of HSCT, although the difference was not statistically significant; neutropenia (HSCT vs. no HSCT: 83.3% vs. 50%; P=0.31), anemia (66.7% vs. 30%; P=0.30), FN (33.3% vs. 10%; P=0.52).

Discussion

Due to the number of patients and their different backgrounds, comparisons with previous reports should be made with caution. However, the results of this study suggest that the incidence of TRAEs in patients with SMN-EC after hematologic malignancy might be higher when treated by chemotherapy or radiotherapy than indicated by data from the pivotal studies of the standard treatment for each stage of EC (Table 5).

First, in the pivotal studies for chemotherapy, the frequency of grade ≥3 FN associated with the CF regimen was reported to be 0–1% (17,18), and with the DCF regimen was 16.3–22.9% (16,18). However, in our study, the incidence of FN was 40% (2 out of 5) for the chemotherapy group. Moreover, there were no reports of sepsis with the CF nor DCF regimens in the pivotal studies. In this study, it was 20% for the chemotherapy group.

Second, the frequency of grade ≥3 TRAEs of chemoradiotherapy in the pivotal studies was reported to be neutropenia in 11.4–55.3%, FN in 0–7.4%, and esophagitis in 0–22.4%, with a treatment-related death rate of 0–7.1% in the previous reports (13-15). In our study, neutropenia occurred in 66.7% of patients, FN in 16.7%, and esophagitis in 66.7%, with treatment-related death in 16.7%.

Third, in our study, all 5 patients who received radiotherapy alone had stage I–III diseases and were expected to be intolerant of chemotherapy because of their advanced age, hepatic impairment, or myelosuppression due to CLL. The grade ≥3 TRAEs of radiotherapy for older patients in the previous studies were reported to be neutropenia in 1.3–3.5%, thrombocytopenia in 0–0.7%, anemia in 0–2.0%, and esophagitis in 5.6–6.0% (19,20). In our study, neutropenia occurred in 40% of patients, thrombocytopenia in 20%, anemia in 40%, and esophagitis in 80%.

The increased frequency of toxicities observed in our study may be attributed to cumulative damage to multiple organ systems resulting from previous treatments for hematologic malignancy. While many patients with acute myelosuppression recover rapidly, some may develop residual bone marrow injury (RBMI) (21), which is believed to occur because of depletion of hematopoietic stem cell reserves and stromal cells in bone marrow, which play a supportive role in hematopoiesis (22). Furthermore, chemotherapy and radiotherapy can impair the self-renewal ability of hematopoietic stem cells, contributing to the development of RBMI (23-25). RBMI is often masked by apparent recovery of peripheral blood cell counts but is a long-lasting condition with limited potential for recovery (21,25,26). Underlying RBMI can lead to the development of hypoplastic bone marrow when additional hematopoietic stress is induced by subsequent chemotherapy and radiotherapy (21,25-27). The treatment-related death that occurred in our study was in a patient with a history of HSCT. This patient may have had RBMI that led to grade 4 neutropenia and increased susceptibility to infection, rendering him more vulnerable to lung infection.

In addition to RBMI, the frequency of esophagitis was higher in our patients who had undergone HSCT than in previous reports (13-15). In our study, all 6 patients with a history of HSCT also had a history of GVHD. Notably, only 1 patient had GVHD at diagnosis of EC and was receiving immunosuppressant therapy. The injury to epithelial cells caused by GVHD can result in an altered tissue microenvironment and disruption of tissue homeostasis (28). These changes can contribute to an increased risk of complications, such as esophagitis, in patients with a history of HSCT and GVHD. In addition to the effect of GVHD, RBMI may contribute to the fragility of mucosal tissue in the esophagus, potentially leading to increased frequency and severity of esophagitis.

For patients after hematologic malignancy, early detection and treatment of SMN is essential. Although the lack of data on the safety of endoscopic treatment after HSCT makes it speculative, it would be significant to perform surgical treatment such as endoscopic mucosal resection/endoscopic submucosal dissection for SMN-EC and transoral videolaryngoscopic surgery for SMN in head and neck area to avoid the risk of chemotherapy and radiotherapy.

This study has several limitations. First, it had a retrospective design, which means that there was a risk of bias, and our ability to control for confounding variables was limited. Second, due to the small number of patients in this study and the different patient backgrounds, it is not possible to conclude that TRAEs are more common compared with previous reports. However, reviewing the patient backgrounds of this study and the previous reports, the median age is almost the same, there is no substantial difference in PS at 0 or 1, there is no difference in treatment regimens, and supportive care was well provided by following the protocols of the previous clinical trial. Considering the above, TRAEs might be more common. Therefore, we believe that large prospective multicenter studies should be conducted in the future to investigate whether TRAEs is truly common and select what populations should truly receive real attention for chemotherapy and radiotherapy. Third, there is no data on the rate of patients with a history of hematologic malignancy who developed SMN-EC during this observation period. It has been reported that SMN-EC develops in approximately 1% of patients who have undergone HSCT (29), and during the 20-year observation period in this study, there were 36 cases of SMN-EC, which we assume is not substantially different from this reported rate.

Conclusions

The findings of this study suggest that TRAEs might be more common when patients with a history of hematologic malignancy who develop SMN-EC are treated non-surgically. Non-surgical treatment of SMN-EC patients with a history of hematologic malignancy should be carefully monitored for potential severe toxicity.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-17/rc

Data Sharing Statement: Available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-17/dss

Peer Review File: Available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-17/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.org/article/view/10.21037/aoe-24-17/coif). K.K. serves as an unpaid editorial board member of Annals of Esophagus from December 2023 to November 2025. S.Y. reports honoraria from Ono Pharmaceuticals and Bristol Myers Squibb, Merck Sharp & Dohme, and Taiho Pharmaceutical. K.K reports consulting fees from Bristol Myers Squibb and Merck Sharp & Dohme, BeiGene, Roche, AstraZeneca, and Bayer; honoraria from Ono Pharmaceutical, Bristol Myers Squibb, and Taiho; research funding from Ono Pharmaceutical, Bristol Myers Squibb, Merck Sharp & Dohme, BeiGene, Chugai Pharmaceutical, Shionogi Pharma, AstraZeneca, and Bayer. Y.H. reports honoraria from Novartis, Chugai Pharmaceutical, MSD, Ono pharmaceuticals, Bristol Myers Squibb, Merck Biopharma, Eisai, Eli Lilly, Nutri, Teijin pharma. Y.O. reports honoraria from AstraZeneca, Chugai, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Nippon Kayaku, Kyowa Hakko Kirin, Eisai, and Daiichi-Sankyo, research funding from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, BMS, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics Inc. and PharmaMar. The other authors have no 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of the National Cancer Center (2017-229). The requirement for written informed consent was waived due to the retrospective nature of the study.

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. Howlader N, Noone AM, Krapcho M, et al., editors. SEER Cancer Statistics Review, 1975-2018. Bethesda, MD: National Cancer Institute; 2021.
2. Tabuchi T, Ito Y, Ioka A, et al. Incidence of metachronous second primary cancers in Osaka, Japan: update of analyses using population-based cancer registry data. Cancer Sci 2012;103:1111-20. [Crossref] [PubMed]
3. Odani S, Tabuchi T, Nakata K, et al. Incidence and relative risk of metachronous second primary cancers for 16 cancer sites, Osaka, Japan, 2000-2015: Population-based analysis. Cancer Med 2022;11:507-19. [Crossref] [PubMed]
4. Pacheco-Figueiredo L, Antunes L, Bento MJ, et al. Incidence of second primary cancers in North Portugal-a population-based study. J Cancer Surviv 2016;10:142-52. [Crossref] [PubMed]
5. Sung H, Hyun N, Leach CR, et al. Association of First Primary Cancer With Risk of Subsequent Primary Cancer Among Survivors of Adult-Onset Cancers in the United States. JAMA 2020;324:2521-35. [Crossref] [PubMed]
6. Travis LB, Demark Wahnefried W, Allan JM, et al. Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nat Rev Clin Oncol 2013;10:289-301. [Crossref] [PubMed]
7. Vogt A, Schmid S, Heinimann K, et al. Multiple primary tumours: challenges and approaches, a review. ESMO Open 2017;2:e000172. [Crossref] [PubMed]
8. Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med 1997;336:897-904. [Crossref] [PubMed]
9. Atsuta Y, Suzuki R, Yamashita T, et al. Continuing increased risk of oral/esophageal cancer after allogeneic hematopoietic stem cell transplantation in adults in association with chronic graft-versus-host disease. Ann Oncol 2014;25:435-41. [Crossref] [PubMed]
10. Martin PJ, Counts GW Jr, Appelbaum FR, et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol 2010;28:1011-6. [Crossref] [PubMed]
11. Rizzo JD, Curtis RE, Socié G, et al. Solid cancers after allogeneic hematopoietic cell transplantation. Blood 2009;113:1175-83. [Crossref] [PubMed]
12. Inamoto Y, Shah NN, Savani BN, et al. Secondary solid cancer screening following hematopoietic cell transplantation. Bone Marrow Transplant 2015;50:1013-23. [Crossref] [PubMed]
13. Kato K, Ito Y, Nozaki I, et al. Parallel-Group Controlled Trial of Surgery Versus Chemoradiotherapy in Patients With Stage I Esophageal Squamous Cell Carcinoma. Gastroenterology 2021;161:1878-1886.e2. [Crossref] [PubMed]
14. Takeuchi H, Ito Y, Machida R, et al. A Single-Arm Confirmatory Study of Definitive Chemoradiation Therapy Including Salvage Treatment for Clinical Stage II/III Esophageal Squamous Cell Carcinoma (JCOG0909 Study). Int J Radiat Oncol Biol Phys 2022;114:454-62. [Crossref] [PubMed]
15. Shinoda M, Ando N, Kato K, et al. Randomized study of low-dose versus standard-dose chemoradiotherapy for unresectable esophageal squamous cell carcinoma (JCOG0303). Cancer Sci 2015;106:407-12. [Crossref] [PubMed]
16. Yokota T, Kato K, Hamamoto Y, et al. Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer. Br J Cancer 2016;115:1328-34. [Crossref] [PubMed]
17. Doki Y, Ajani JA, Kato K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med 2022;386:449-62. [Crossref] [PubMed]
18. Kato K, Machida R, Ito Y, et al. Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial. Lancet 2024;404:55-66. [Crossref] [PubMed]
19. Wang X, Han W, Zhang W, et al. Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial. JAMA Netw Open 2023;6:e2312625. [Crossref] [PubMed]
20. Ji Y, Du X, Zhu W, et al. Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients With Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial. JAMA Oncol 2021;7:1459-66. [Crossref] [PubMed]
21. Wang Y, Probin V, Zhou D. Cancer therapy-induced residual bone marrow injury-Mechanisms of induction and implication for therapy. Curr Cancer Ther Rev 2006;2:271-9. [Crossref] [PubMed]
22. Zweegman S, Kessler FL, Kerkhoven RM, et al. Reduced supportive capacity of bone marrow stroma upon chemotherapy is mediated via changes in glycosaminoglycan profile. Matrix Biol 2007;26:561-71. [Crossref] [PubMed]
23. Testa NG, Hendry JH, Molineux G. Long-term bone marrow damage in experimental systems and in patients after radiation or chemotherapy. Anticancer Res 1985;5:101-10. [PubMed]
24. Mauch P, Constine L, Greenberger J, et al. Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys 1995;31:1319-39. [Crossref] [PubMed]
25. Shao L, Wang Y, Chang J, et al. Hematopoietic stem cell senescence and cancer therapy-induced long-term bone marrow injury. Transl Cancer Res 2013;2:397-411. [PubMed]
26. Wang Y, Liu L, Pazhanisamy SK, et al. Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells. Free Radic Biol Med 2010;48:348-56. [Crossref] [PubMed]
27. Shao L, Luo Y, Zhou D. Hematopoietic stem cell injury induced by ionizing radiation. Antioxid Redox Signal 2014;20:1447-62. [Crossref] [PubMed]
28. Ara T, Hashimoto D. Novel Insights Into the Mechanism of GVHD-Induced Tissue Damage. Front Immunol 2021;12:713631. [Crossref] [PubMed]
29. Nomura K, Iizuka T, Kaji D, et al. Secondary esophageal squamous cell carcinoma after hematopoietic stem cell transplantation. J Cancer Res Clin Oncol 2021;147:2137-44. [Crossref] [PubMed]