Pivotal Trials

Table of Contents
1 Breast Cancer
        1.1 Prevention Trials
        1.2 Surgical Trials
        1.3 Adjuvant Endocrine Therapy Trials in Early Breast Cancer
        1.4 Adjuvant Chemotherapy in Early Breast Cancer
        1.5 Decision Tool on Chemotherapy in node negative Breast Cancer
        1.6 Adjuvant Chemotherapy in Trastuzumab in HER2 positive Early               Stage Breast Cancer
2 Colorectal Cancer
3 Gastric Cancer
        3.1 HER-2 Positive
        3.2 Metastatic
        3.3 Targeted Therapy
        3.4 Pancreatic Cancer
        3.5 Colorectal Cancer
4 Lung Cancer
        4.1 Adjuvant Chemotherapy
        4.2 Metastatic Lung Cancer
5 Lymphoma and Multiple Myeloma
6 Melanoma
7 Ovarian Cancer
8 Prostate Cancer
9 Testicular Cancer

Breast Cancer Pivotal Trials

Prevention Trials

Fisher B. Highlights from recent National Surgical Adjuvant Breast and Bowel Project studies in the treatment and prevention of breast cancer. CA Cancer J Clin. 1999;49(3):159-177

Davies C, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet.2013; 381:805-816.

Vogel VG, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res. 2010;3(6):696-706

Surgical Trials

Fisher B et al. Eight-Year Results of a Randomized Clinical Trial Comparing Total Mastectomy and Lumpectomy with or without Irradiation in the Treatment of Breast Cancer. N Engl J Med. 1989;320:822-828

Adjuvant Endocrine Therapy Trials in Early Breast Cancer

Coombes C et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081-92.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet.2005; 365:1687-1717.

ATAC Trialists Group. ATAC Trial Update. The Lancet. 2005;365(9466):1225-1226

Rae JM, et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012; 104:452-460.

Regan MM, et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial. J Natl Cancer Inst. 2012; 104:441-451.

Thürlimann BJ, Keshaviah A, Mouridsen H, et al. BIG 1-98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. ASCO. 2005 (Abstract 511)

Goss PE, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003; 349(19):1793-802.

Adjuvant Chemotherapy in Early Breast Cancer

Jones S, et al. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009; 27(8): 1177-83.

Roché H, Fumoleau P, Spielmann M, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006; 24(36):5664-71.

Bonnadonna, G et al. Adjuvant CMF chemotherapy in operable breast cancer: Ten years later. World J Surgery. 1985; 9:707-713

Carpenter JT, Velez-Garcia E, Aron BS, et al. Five year results of a randomized comparison of cyclophosphamide, doxorubicin and fluorouracil versus cyclophosphamide, methotrexate and fluorouracil for node positive breast cancer. Proc Am Soc Clin Oncol. 1994;13:66. Abstract 68.

Trudeau M, et al. Selection of adjuvant chemotherapy for treatment of node-positive breast cancer. Lancet Oncol. 2005; 6(11):886-98.

Citron ML, Berry DA, Cirrincione C, et al: Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent Combination Chemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 974. J Clin Oncol. 2003;21:1431-1439, 2003

Fisher B et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990;8:1483-96.

French Adjuvant Study Group. Benefit of high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year followup results of French Adjuvant Study Group 05 Randomized Trial. J Clin Oncol. 2001;19:602-11.

Gianni L, Munzone E, Capri G, et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol. 1995;13:2688-99.

Hutchins L, Green S, Ravidin P et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of intergroup trial INT 0102. Proc Am Soc Clin Oncol. 1998;17:1a.

Jin H, et al. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J ClinOncol.2012; 30:718-721.

Jonat W, Gnant M, Boccardo F, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta-analysis. Lancet Oncol. 2006 Dec;7(12):991-6.

Levine et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology 16(8)1998:2651-2658

Mouridsen HT, Andersen J, Andersson M, et al: Adjuvant anthracycline in breast cancer: Improved outcome in premenopausal patients following substitution of methotrexate in the CMF combination with epirubicin. Proc Am Soc Clin Oncol Oncol. 18:68a, 1999 (abstr 254)

Decision Tool on Chemotherapy in node negative Breast Cancer

Soon Paik et al. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cance. N Engl J Med. 2004; 351:2817-2826

Adjuvant Chemotherapy in Trastuzumab in HER2 positive Early Stage Breast Cancer

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl J Med. 2005;353(16):1659-1672

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Colorectal Cancer Pivotal Trials

Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol. 1989;7:1447-1456.pmid:2778478

Moertel CG, Fleming TR, MacDonald JS, et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med. 1995;122:321-326

Haller PJ, Catalano JS, Macdonald RJ and Mayer. Eastern cooperative Oncology Group (ECOG); Southwest Oncology Group (SWOG); Cancer and Leukemia Group B (CALGB) Fluorouracil (FU) leucovorin (LV) and levamisole (LEV) adjuvant therapy for colon cancer: Five year final report of Int-0089 D.G. Proc Am Soc Clin Oncol. 1998;17:256

MOSAIC Trial. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-51.

X-ACT: Twelves, C. et al. Capecitabine as Adjuvant Treatment for Stage III Colon Cancer. N Eng J Med. 2005;352:2696-2704.

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Gastric Cancer

HER-2 Positive

Bang YJ, et al. ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–697.


Fuchs CS, et al. Ramucirumabmonotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet.2014; 383(9911):31-9.

Hecht JR, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial.J ClinOncol. 2013; (suppl): abstr LBA4001.

Lordick F, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.Lancet Oncol.2013; 14(6):490-9.

Targeted Therapy

Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012; 30(28):3499-506.

Pancreatic Cancer

Fukutomi A, et al. JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer . J ClinOncol. 2013;31(suppl):abstr 4008.

Von Hoff DD, et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine.N Engl J Med. 2013; 369:1691-1703.

Colorectal Cancer

Cunningham D, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial.Lancet Oncol.2013; 14(11): 1077-85.

Douillard JY, et al. Panitumumab–FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013; 369(11):1023-34.

Falcone A, et al. FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group.J ClinOncol. 2013; (suppl): abstr 3505.

Domingo E, et al. Evaluation of PIK3CA Mutation As a Predictor of Benefit From Nonsteroidal Anti-Inflammatory Drug Therapy in Colorectal Cancer. J ClinOncol. 2013; 31(34):4297-305.

James RD, et al. Mitomycin or cisplatinchemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial.Lancet Oncol. 2013; 14(6): 516-24.

Koopman M, et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG).J ClinOncol.2013; (suppl): abstr 3502.

Liao X, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival.N Engl J Med. 2012; 367(17):1596-606.

Nishihara R, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy.N Engl J Med. 2013; 369(12):1095-105.

Shaukat A, et al. Long-term mortality after screening for colorectal cancer.N Engl J Med. 2013; 369(12):1106-14.

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Lung Cancer Pivotal Trials

Adjuvant Chemotherapy

Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Eng J Med. 2000; 343(17):1217-22

Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst. 2003; 95(19):1453-61

Metastatic Lung Cancer

Shaw AT, et al. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer.N Engl J Med. 2013; 368:2385-2394.

Paz-Ares L, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial.Lancet Oncol. 2012; 13(3):247-55.

Zukin M, et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2.J ClinOncol. 2013;31(23):2849-53.

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Lymphoma and Multiple Myeloma Pivotal Trials

Fisher et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced Non-Hodgkin’s Lymphoma. N Engl J Med. 1993;328:1002

Coiffier B et al. ASCO 2003, Abstract #2395: GELA study comparing CHOP and R-CHOP in Elderly Patients with Diffuse Large B-Cell Lymphoma: 3 year median follow-up with an analysis according to co-morbidity factors.

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Melanoma Pivotal Trials

Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7-17

Kirkwood JM, Ibrahim J, Sondak V. et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of Intergroup Trial E1690/S9111/C9190. J. Clin Oncol. 2000; 18(12):2444-2458

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Ovarian Cancer Pivotal Trials

William P. et al. Cyclophosphamide and Cisplatin Compared with Paclitaxel and Cisplatin in Patients with Stage III and Stage IV Ovarian Cancer. N. Engl J Med., 1996

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Prostate Cancer Pivotal Trials

Southwest Oncology Group, Berry DL, Moinpour CM, et al. Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J. Clin Oncol. 2006;24(18):2828-2835

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Testicular Cancer Pivotal Trials

Einhorn LH, Forester RS. Bleomycin, etoposide, and cisplatin for three cycles compared with etoposide and cisplatin for four cycles in good-risk germ cell tumours: is there a preferred regime? J Clin Oncol. 2006;24(16):2597-2598; author-reply 2598-2599

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