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Keywords:

  • chemoradiation therapy;
  • esophageal cancer;
  • myelodysplastic syndrome;
  • small cell lung cancer

Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. CONCLUSION
  6. REFERENCES

Abstract  A 50-year-old man was referred to our department with esophageal cancer. He had past history of small cell lung cancer treated with chemoradiation therapy 10 years prior. The disease was evaluated as complete remission after chemoradiation therapy and no recurrence had been observed. Esophagectomy accompanying postoperative chemotherapy was applied, but he died of secondary myelodysplastic syndrome with its acute myeloblastic transformation. Risk evaluation revealed a high incidence of esophageal cancer after radiation therapy and hematological malignancies after chemoradiation therapy in usual regimen with topoisomerase inhibitor or alkylating agents. Chemoradiation therapy is thought to be one of a few highly effective therapeutic alternatives and many complete remission cases have been reported in small cell lung cancer or esophageal cancer. In post-therapeutic follow up of patients with such past therapeutic histories, we should be cautious about secondary malignancies even if primary malignant disease was evaluated as complete remission in long past history.


CASE REPORT

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. CONCLUSION
  6. REFERENCES

A 50-year-old man was referred to our department with thoracic esophageal cancer, with a chief complaint of dysphagea. He had a past history of small cell lung cancer (SCLC) treated with chemoradiation therapy (CRT) approximately 10 years ago. He received 60 Gy of irradiation to the mediastinum and lung field accompanied by chemotherapy consistent with etoposide, nimustine and cisplatin. The dose of chemotherapeutic agents was not known due to the lack of past medical records. The disease was evaluated as complete remission (CR) after initial CRT and no recurrent evidence had been observed since then. When the patient came to us he had not had any follow up concerning the SCLC for 2 years. Esophageal cancer was located in the upper to middle thoracic esophagus (Fig. 1a), endoscopical examination revealed type 2, 50 mm in diameter (Fig. 1b) and no lymph node swelling was observed by computed tomography in the mediastinum (Fig. 1c). The location of the tumor was within the area of former radiation therapy. Transthoracic esophagectomy, laparotomic gastric tube formation and cervical esophago-gastric anastomosis through the post-sternal route accompanied by super-drainage microvascular anastomosis from the left gastric vein to the left external jugular vein were performed. He was discharged on postoperative day 14 without any complications. Pathological findings revealed advanced carcinoma of the esophagus, consisted with moderately differentiated squamous cell carcinoma; macroscopically the tumor was type 2 and measured 57 mm in diameter. The tumor was invaded to the depth of adventitial layer. No intramural metastasis, no lymphatic vessels invasion and no lymph node metastasis were observed. Surgical margin was diagnosed as very slightly positive microscopically at the adjacent point to the left bronchus.

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Figure 1. (a) Upper gastrointestinal series. Well defined protruding 5 cm in length lesion was located in the middle to upper thoracic esophagus. (b) Gastrointestinal fiberscope. Well marginated centrally ulcerated lesion 50% circulated 5 cm in diameter lesion was located in the thoracic esophagus. (c) Computed tomography of the chest. Thickness of the esophageal wall and adjacent to the left bronchus was observed. No mediastinal lymph nodes were swollen.

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The patient received adjuvant chemotherapy consisting of 160 mg of nedaplatin (day 1) and 6000 mg in total (1200 mg/day, days 1–5) of 5-FU continuous administration 3 months after surgery. After this chemotherapy he experienced neutrocytopenia down to 510 counts/mL in nadir. Granulocyte colony stimulating factor (G-CSF) was given. Transiently, administration of G-CSF was effective in increasing neutrocytes but refractory and persistent neutrocytopenia and additional hematological changes including anemia and thrombocytopenia were observed. Because of the appearance of the blast in the peripheral blood, he was referred to the department of hematology concerning pancytopenia (Fig. 2). Bone marrow biopsy revealed a few fragments of hypercelluar marrow with hemopoietic dysplasia suggesting myelodysplastic syndrome (MDS) and multiple chromosomal abnormalities, especially in chromosome numbers 5 and 7, indicated secondary MDS (Fig. 3) caused by former CRT and chemotherapy. Bone marrow transplantation was considered but not indicated by the unmatched HLA. Best supportive care was performed in the outpatient clinic. Eight months after the esophagectomy, acute myeloblastic transformation occurred and the patient died of acute leukemia followed by secondary myelodysplastic syndrome and acute myeloblastic transformation.

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Figure 2. Hematological changes in clinical course. Persistent pancytopenia and blast cells were found after adjuvant chemotherapy. WBC, white blood cell count; Hb, hemoglobin; Plt, platelet cell count.

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Figure 3. Chromosomal analysis. One sample showed chromosomal abnormalities in chromosome number 5 and number 17.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. CONCLUSION
  6. REFERENCES

The recent progress of chemotherapy and CRT against SCLC and esophageal cancer is very remarkable. Many complete remission cases are reported in both malignancies and the efficacies are phenomenal. In contrast, metachronous multiple cancers secondary malignancies were observed in such long-term follow up cases after CRT or chemotherapy for the patient of SCLC. In our opinion there should be at least four associations with this kind of carcinogenesis, the relationships with: (i) SCLC and esophageal cancer; (ii) esophageal cancer after radiation therapy; (iii) leukemia after radiation therapy; and (iv) leukemia after chemotherapy. Miyake reported on metachronous multiple cancer associating with SCLC. By long-term follow up of 337 cases of this disease, 14 (4.2%) patients developed metachronous multiple cancer including one case of esophageal cancer and two cases of leukemia. The patients who had SCLC have an estimated greater relative risk of 4.4 times for esophageal cancer and 37.8 times for hematological malignancy than the age-matched normal population.1

Radiation-induced esophageal cancer is reviewed by several authors in detail. Ueda et al.2 reported 11 cases of esophageal cancer after radiation therapy (RT) for breast cancer. They concluded that radiation-induced esophageal cancer was observed 2–19 years after initial RT, relative risk was estimated 7.7 times and additional RT seemed to be effective. Goffmann et al.3 summarized 17 cases of esophageal cancer after RT and conventional risk factors for sporadic esophageal cancer such as smoke or alcohol consumption were not likely risk factors for radiation-induced esophageal cancer. Fekete et al.4 reported pathological aspects of esophageal cancer after RT. They reported cancer lesions had remarkable fibrosis around the lesion, the incidence of lymph node metastasis in the irradiated field was lower than that of the sporadic cases and prognosis was statistically the same as the sporadic cases.

In hematological aspects, leukemia after RT was also reviewed and Curtis et al.5 estimated the relative risk for leukemia after radiation therapy is 2.5 times and the risk is increased up to 17.4 times if accompanied by alkylating agents.

Other aspects of carcinogenesis such as the association of chemotherapy and secondary hematologic malignancies need to be studied. There are thought to be two types of hematological carcinogenesis after chemotherapy.6 One is associated with topoisomerase inhibitors such as etoposide. This type of hematologic malignancy occurs within 6 months after chemotherapy in shortest cases and the average time to occur is thought to be 2–3 years. This is not followed by myelodysplastic syndrome and would transform to acute myelomonocystic leukemia in major cases. In this type, chromosomal abnormality in chromosome number 11 is frequently observed and in many cases treatments are effective. The other type is associated with alkylating agents such as nimusutin. Cisplatin and nedaplatin are thought to partially act as alkyrating agents and these are also categorized as arklyrating agents. This type of hematologic malignancy occurs 4–5 years after chemotherapy on average. In 60% cases, myelodysplastic syndrome or thrombocytopenia are predisposed. In more than 90% cases chromosomal abnormality is observed and number 5 or number 7 chromosomes are likely to be susceptible in this situation. In 90% cases, transformation to acute non-lymphatic leukemia was observed. In most cases, anticancerous therapy is not effective and complete remission is expected only in 25% cases and median survival is reported as only 3–6 months. Relative risk for secondary hematologic malignancy is reported as 10.0 times with arkylating agent regimen.

In our case, the clinical course of acute transformation after MDS and chromosomal abnormalities in numbers 5, 7 and 19 indicated that most suspicious agents for hematological malignancy to our patients were Nimustin or Cisplatin.

A recent study indicated a high incidence of point mutation of p53 suppressor oncogene in patients with myelodysplastic syndrome after irradiation.7 In our opinion, genomical examination will be expected to make risk evaluation after RT in considering the induction of RT.

CONCLUSION

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. CONCLUSION
  6. REFERENCES

We experienced a case of secondary MDS followed by CR of SCLC with CRT and thoracic esophageal cancer treated with esophagectomy accompanied by chemotherapy. Potential carcinogenetic risks of esophageal cancer and myelodysplastic syndrome by chemotherapy and CRT for SCLC and esophageal cancer were reviewed. It revealed a high incidence in our patient's situation. Chemotherapy and CRT are thought to be high potential therapeutic alternatives to SCLC and esophageal cancer but long-term follow up is mandatory especially for understanding hematological changes.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. CONCLUSION
  6. REFERENCES
  • 1
    Miyake K. Development of double cancer un small cell lung cancer patients treated with intensive chemotherapy. Okayama Igakkai Zasshi 1992; 104: 91522 (in Japanese with English abstract).
  • 2
    Ueda M, Matsubara T, Kasumi F, Nishi M, Kajitani T. Possible radiation induced cancer of the thoracic esophagus after postoperative irradiation for the breast cancer. Nihon Kyoubu Gekagakkai Zasshi 1991; 39: 18527 (in Japanese with English abstract).
  • 3
    Goffman TE, McKeen EA, Curtis RE, Schein PS. Esophageal carcinoma following irradiation for breast cancer. Cancer 1983; 52: 18089.
  • 4
    Fekete F, Monsnier H, Belghiti J, Uribe M, Sauvanet A. Esophageal cancer after mediastinal irradiation. Dysphagea 1993; 8: 28991.
  • 5
    Curtis RE, Boice JD, Stavall M et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N. Engl. J. Med. 1992; 326: 174551.
  • 6
    Yokouchi J, Yamagishi T, Kanesaka N, Abe K, Seki M, Hirabayasho S. A case of radiation-induced esophageal cancer. A radiotherapy case report. Jpn J. Cancer Clin. 1999; 45: 13414. (in Japanese with English abstract).
  • 7
    Inamura N, Abe K, Oguma N. High incidence of point mutation of p53 suppressor oncogene in patients with myelodysplastic syndrome among atomic-bomb survivors: a 10-year follow-up. Leukemia 2002; 16: 1546.