A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606)

H Kunitoh, T Tamura, T Shibata, K Takeda, N Katakami, K Nakagawa, A Yokoyama, Y Nishiwaki, K Noda, K Watanabe, N Saijo, JCOG Lung Cancer Study Group, Yutaka Nishiwaki, Kaoru Kubota, Nagahiro Saijo, Tomohide Tamura, Noboru Yamamoto, Hideo Kunitoh, Kazumasa Noda, Fumihiro Oshita, Koshiro Watanabe, Hiroaki Okamoto, Akira Yokoyama, Yuko Tsukada, Kazuhiko Nakagawa, Isamu Okamoto, Koji Takeda, Haruko Daga, Nobuyuki Katakami, Hisashi Nishimura, H Kunitoh, T Tamura, T Shibata, K Takeda, N Katakami, K Nakagawa, A Yokoyama, Y Nishiwaki, K Noda, K Watanabe, N Saijo, JCOG Lung Cancer Study Group, Yutaka Nishiwaki, Kaoru Kubota, Nagahiro Saijo, Tomohide Tamura, Noboru Yamamoto, Hideo Kunitoh, Kazumasa Noda, Fumihiro Oshita, Koshiro Watanabe, Hiroaki Okamoto, Akira Yokoyama, Yuko Tsukada, Kazuhiko Nakagawa, Isamu Okamoto, Koji Takeda, Haruko Daga, Nobuyuki Katakami, Hisashi Nishimura

Abstract

Background: This study aimed to evaluate the safety and efficacy of dose-dense weekly chemotherapy, followed by resection and/or thoracic radiotherapy.

Methods: Patients with histologically documented thymoma with unresectable stage III disease received 9 weeks of chemotherapy: cisplatin 25 mg m(-2) on weeks 1-9; vincristine 1 mg m(-2) on weeks 1, 2, 4, 6 and 8; and doxorubicin 40 mg m(-2) and etoposide 80 mg m(-2) on days 1-3 of weeks 1, 3, 5, 7 and 9. Patients went on to surgery and post-operative radiotherapy of 48 Gy; those with unresectable disease received 60 Gy radiotherapy.

Results: total of 23 patients were entered. The main toxicities of the chemotherapy regimen were neutropenia and anaemia, and 57% of patients completed the planned 9 weeks of therapy. There were no toxic deaths. Of the 21 eligible patients, 13 (62%) achieved a partial response (95% confidence interval: 38-82%). Thirteen patients underwent a thoracotomy and nine (39%) underwent complete resection. Progression-free survival at 2 and 5 years was 80 and 43%, respectively. Overall survival at 5 and 8 years was 85 and 69%, respectively. Survival did not seem to be affected by resection.

Conclusion: In thymoma patients, weekly dose-dense chemotherapy has activity similar to that of conventional regimens. Although some patients could achieve complete resection, the role of surgery remains unclear.

Figures

Figure 1
Figure 1
Study schema of the Japan Clinical Oncology Group (JCOG) 9606 trial, with the number of patients who actually received each of the protocol therapies. Cx, chemotherapy; RT, radiotherapy.
Figure 2
Figure 2
Progression-free survival (PFS) and overall survival (OS) of the 21 eligible patients.
Figure 3
Figure 3
Progression-free survival of the 21 eligible patients, according to the surgery undergone. Resection was performed in 11 patients (complete resection in nine), and 10 patients did not undergo resection (including two with probe thoracotomy). There was no significant difference (log rank P=0.75).
Figure 4
Figure 4
Overall survival of the 21 eligible patients, according to the surgery undergone. Resection was performed in 11 patients (complete resection in nine), and 10 patients did not undergo resection (including two with probe thoracotomy). There was no significant difference (log rank P=0.59).

References

    1. Berruti A, Borasio P, Gerbino A, Gorzegno G, Moschini T, Tampellini M, Ardissone F, Brizzi MP, Dolcetti A, Dogliotti L (1999) Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience. Br J Cancer 81: 841–845
    1. Ciernik IF, Meier U, Lutolf UM (1994) Prognostic factors and outcome of incompletely resected invasive thymoma following radiation therapy. J Clin Oncol 12: 1484–1490
    1. Curran Jr WJ, Kornstein MJ, Brooks JJ, Turrisi III AT (1988) Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 6: 1722–1727
    1. Eng TY, Fuller CD, Jagirdar J, Bains Y, Thomas Jr CR (2004) Thymic carcinoma: state of the art review. Int J Radiat Oncol Biol Phys 59: 654–664
    1. Fukuoka M, Masuda N, Negoro S, Matsui K, Yana T, Kudoh S, Kusunoki Y, Takada M, Kawahara M, Ogawara M, Kodama N, Kubota K, Furuse K (1997) CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 75: 306–309
    1. Furuse K, Fukuoka M, Nishiwaki Y, Kurita Y, Watanabe K, Noda K, Ariyoshi Y, Tamura T, Saijo N (1998) Phase III study of intensive weekly chemotherapy with recombinant human granulocyte colony-stimulating factor versus standard chemotherapy in extensive-disease small-cell lung cancer. The Japan Clinical Oncology Group. J Clin Oncol 16: 2126–2132
    1. Giaccone G (2005) Treatment of malignant thymoma. Curr Opin Oncol 17: 140–146
    1. Giaccone G, Ardizzoni A, Kirkpatrick A, Clerico M, Sahmoud T, van Zandwijk N (1996) Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14: 814–820
    1. Girard N, Mornex F, Van Houtte P, Cordier JF, van Schil P (2009) Thymoma: a focus on current therapeutic management. J Thorac Oncol 4: 119–126
    1. Goldie JH, Coldman AJ (1983) Quantitative model for multiple levels of drug resistance in clinical tumors. Cancer Treat Rep 67: 923–931
    1. Kim ES, Putnam JB, Komaki R, Walsh GL, Ro JY, Shin HJ, Truong M, Moon H, Swisher SG, Fossella FV, Khuri FR, Hong WK, Shin DM (2004) Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer 44: 369–379
    1. Kunitoh H, Tamura T, Shibata T, Nakagawa K, Takeda K, Nishiwaki Y, Osaki Y, Noda K, Yokoyama A, Saijo N (2009) A phase-II trial of dose-dense chemotherapy in patients with disseminated thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9605). Br J Cancer 101: 1549–1554
    1. Levin L, Hryniuk WM (1987) Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 5: 756–767
    1. Liu HC, Chen YJ, Tzen CY, Huang CJ, Chang CC, Huang WC (2006) Debulking surgery for advanced thymoma. Eur J Surg Oncol 32: 1000–1005
    1. Loehrer Sr PJ, Chen M, Kim K, Aisner SC, Einhorn LH, Livingston R, Johnson D (1997) Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 15: 3093–3099
    1. Loehrer Sr PJ, Jiroutek M, Aisner S, Aisner J, Green M, Thomas Jr CR, Livingston R, Johnson DH (2001) Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 91: 2010–2015
    1. Loehrer Sr PJ, Kim K, Aisner SC, Livingston R, Einhorn LH, Johnson D, Blum R (1994) Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 12: 1164–1168
    1. Lucchi M, Melfi F, Dini P, Basolo F, Viti A, Givigliano F, Angeletti CA, Mussi A (2006) Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up. J Thorac Oncol 1: 308–313
    1. Mangi AA, Wain JC, Donahue DM, Grillo HC, Mathisen DJ, Wright CD (2005) Adjuvant radiation of stage III thymoma: is it necessary? Ann Thorac Surg 79: 1834–1839
    1. Masaoka A, Monden Y, Nakahara K, Tanioka T (1981) Follow-up study of thymomas with special reference to their clinical stages. Cancer 48: 2485–2492
    1. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47: 207–214
    1. Murray N (1987) The importance of dose and dose intensity in lung cancer chemotherapy. Semin Oncol 14: 20–28
    1. Murray N, Shah A, Osoba D, Page R, Karsai H, Grafton C, Goddard K, Fairey R, Voss N (1991) Intensive weekly chemotherapy for the treatment of extensive-stage small-cell lung cancer. J Clin Oncol 9: 1632–1638
    1. Ogawa K, Uno T, Toita T, Onishi H, Yoshida H, Kakinohana Y, Adachi G, Itami J, Ito H, Murayama S (2002) Postoperative radiotherapy for patients with completely resected thymoma: a multi-institutional, retrospective review of 103 patients. Cancer 94: 1405–1413
    1. Okumura M, Ohta M, Tateyama H, Nakagawa K, Matsumura A, Maeda H, Tada H, Eimoto T, Matsuda H, Masaoka A (2002) The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94: 624–632
    1. Regnard JF, Magdeleinat P, Dromer C, Dulmet E, de Montpreville V, Levi JF, Levasseur P (1996) Prognostic factors and long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 112: 376–384
    1. Strobel P, Bauer A, Puppe B, Kraushaar T, Krein A, Toyka K, Gold R, Semik M, Kiefer R, Nix W, Schalke B, Muller-Hermelink HK, Marx A (2004) Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol 22: 1501–1509
    1. Tobinai K, Kohno A, Shimada Y, Watanabe T, Tamura T, Takeyama K, Narabayashi M, Fukutomi T, Kondo H, Shimoyama M, Suemasu K (1993) Toxicity grading criteria of the Japan Clinical Oncology Group. The Clinical Trial Review Committee of the Japan Clinical Oncology Group. Jpn J Clin Oncol 23: 250–257
    1. Travis WB, Brambilla E, Muller-Hermelinck HK, Harris CC (2004) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press: Lyon
    1. Urgesi A, Monetti U, Rossi G, Ricardi U, Casadio C (1990) Role of radiation therapy in locally advanced thymoma. Radiother Oncol 19: 273–280
    1. Yokoi K, Matsuguma H, Nakahara R, Kondo T, Kamiyama Y, Mori K, Miyazawa N (2007) Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J Thorac Oncol 2: 73–78

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj