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Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 3069-3075 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.4046 Phase III Randomized Controlled Trial Comparing the Survival of Patients With Unresectable Hepatocellular Carcinoma Treated With Nolatrexed or Doxorubicin
From the California Pacific Medical Center, San Francisco, CA; University of Miami, FL; Albert Einstein Medical Center, Philadelphia, PA; GPC Biotech Inc, Princeton, NJ; MGI Pharma, Bloomington, MN; IRCCS San Matteo University Hospital, Pavia, Italy; Oncology Institute Ion Chiricuta, Cluj-Napoca; Fundeni Clinical Institute, Bucharest, Romania; The University of Witwatersrand, Johannesburg, South Africa; Princess Margaret Hospital, Toronto, Canada; the Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland; and Eximias Pharmaceutical Corp, Berwyn, PA Address reprint requests to Robert G. Gish, MD, California Pacific Medical Center, 2340 Clay St 423, San Francisco, CA 94115; e-mail: gishr{at}sutterhealth.org
Purpose The study objective was to compare the overall survival (OS) of patients with unresectable or metastatic hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX).
Patients and Methods Patients from North America, Europe, and South Africa (N = 445) with HCC were randomly assigned to receive NOL or DOX. Eligible patients had Karnofsky performance status (KPS) Results At the time of the final analysis, 377 patients had died. Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068). The hazard ratio was 0.753 in favor of DOX. Objective response rate (complete response [CR] plus partial response [PR]) was 1.4% for NOL and 4.0% for DOX. Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091). Median time to treatment failure was 8.4 weeks for NOL and 9.1 weeks for DOX (P = .0969). Grade 3 and 4 stomatitis, vomiting, diarrhea, and thrombocytopenia were more common in the NOL arm. Alopecia was more common in the DOX arm. More patients were withdrawn from study for toxicity in the NOL arm than in the DOX arm. Conclusion NOL showed minimal activity in this phase III trial. Further exploration at this dose and schedule in HCC is not warranted.
Hepatocellular carcinoma (HCC) is one of the most common solid organ malignancies in the world, with a global incidence between 500,000 and 1 million. HCC is the world's fifth most common cancer overall in men, the eighth in women, and the third most frequent cause of cancer death.1,2 This high incidence is a result of the high prevalence of chronic liver damage caused by hepatitis B and C as well as other causes of cirrhosis.3 Already a malignancy of worldwide significance and an epidemiological concern in both developed and developing countries, HCC has also become increasingly important in the United States.4 This is likely because of complex factors including the evolution of hepatitis C to cirrhosis as well as an increase in prevalence of hepatitis B as a result of immigration patterns. A disease of multifactorial etiology, HCC confers many management challenges including variable tumor differentiation, late clinical presentation, concomitant advanced liver disease in many patients, and the lack of validated serologic markers, variable imaging techniques, and diagnostic criteria. There is clearly a need for coordinated multidisciplinary medical care and better and universally applied screening strategies.5 The 5-year survival of HCC is typically less than 5% without treatment.6-12 Early stage disease can be treated with percutaneous therapies and transcatheter treatments such as radiofrequency thermal ablation, percutaneous ethanol injection, and transcatheter arterial chemoembolization, resection, and liver transplantation. Resection and liver transplantation remain as the only two potentially curative modalities of therapy, although there have been case reports of cures with other treatments. Because HCC is a disease predominantly seen in developing countries, the majority of patients present with late stage disease that is not amenable to many of these options thus demonstrating the need for a better systemic treatment approach for most patients worldwide.
A number of different clinical and pathological staging systems have been used in this disease, but the correlation with overall survival (OS) is modest. The CLIP score (derived from the Cancer of the Liver Italian Program) incorporates anatomic, biochemical, and tumor characteristics.13 The CLIP scoring system is defined by the following variables: Child-Pugh stage: A = 0, B = 1, C = 2; tumor morphology: uninodular and extension Nolatrexed (NOL; THYMITAQ; Eximias Pharmaceutical Corp, Berwyn, PA) is a novel inhibitor of thymidylate synthase (TS) developed as a potential antitumor agent by virtue of the rate limiting role of TS in the biosynthesis of thymidine. NOL differs from other TS inhibitors such as pemetrexed, raltitrexed, CB3717, and fluorouracil in that it does not require active transport for uptake into cells. NOL also lacks a glutamate moiety and thus does not require polyglutamation for antitumor activity. More than 800 patients with various malignancies have been treated with NOL to date in various clinical trials. The three phase II trials utilizing NOL in HCC enrolled a total of 143 patients. In AG337-008, 41 patients were enrolled at a single center in the United States and received a 5-day continuous infusion at a dose of 795 mg/m2. The overall median survival was 10 months.14 In a second study conducted in North America, 48 patients with HCC were treated with a dose of 725 mg/m2 per day as a continuous infusion for 5 days. Median survival in this trial was approximately 24 weeks.15 Mok et al16 conducted a multicenter randomized phase II study of NOL or doxorubicin (DOX) in Chinese patients with advanced HCC. Fifty-four patients were randomly assigned in a 2:1 ratio to receive NOL or DOX. NOL was again given at a dose of 725 mg/m2 as a 5-day infusion and DOX was given at a dose of 60 mg/m2. Both cycles were 3 weeks in length. The median survival in the NOL patients was 19.6 weeks and 14.9 weeks in the DOX patients.16 The toxicity from NOL in these trials was deemed acceptable in this patient population. Due to these preliminary clinical trial results, a phase III clinical trial of NOL was initiated. Although there is no approved treatment for HCC in the United States, the European Union, or elsewhere in the world, DOX is commonly used as a first-line chemotherapy treatment for this disease. First approved by the US Food and Drug Administration in 1974 for breast cancer, DOX has been the subject of multiple clinical trials in HCC. The clinical trials that occurred from 1977 to 1990 performed in HCC with DOX as a single agent at doses ranging from 40 to 75 mg/m2 demonstrated a survival range from 3.0 to 4.1 months.17-24 As the modest survival data for NOL patients in the phase II experience described above for HCC appeared to be superior to the available historical survival data for the commonly used therapy, DOX, it was decided to test the compound against DOX in the phase III study.
Recruitment to this phase III trial began in October 2000 (Fig 1, Table 1). The 445 patients were enrolled over the next 55 months, ending in April 2005. Patients were entered onto the trial from 62 sites in North America, Europe, and South Africa. The distribution of sites and patients by country is as follows: United States (n = 204; 45.8%), Italy (n = 65; 14.6%); Romania (n = 44; 9.9%), South Africa (n = 41; 9.2%), Canada (n = 32; 7.2%), Germany (n = 31; 7.0%), Poland (n = 15; 3.4%), Czech Republic (n = 7; 1.6%), and United Kingdom (n = 6; 1.3%). The study was approved by the appropriate scientific, ethical, and regulatory authorities, conducted in compliance with good clinical practice, and all patients gave written informed consent.
Eligibility Criteria Patients were entered onto this open phase III trial if they had histological or cytologically confirmed unresectable or metastatic HCC. Patients with elevated and rising AFP levels over two assessments were also eligible for entry into the trial. At the time of primary screening, patients had to be at least 18 years old with a Karnofsky performance status of  60% and a CLIP score of  3. At baseline, patients had to have adequate renal function and hematological parameters function. Liver function criteria included total bilirubin 3.0 mg/dL and prothrombin time 1.5 times the upper limit of normal. The liver enzyme parameter of AST 5 times the upper limit of normal was also part of the inclusion criteria. Patients were also required to have adequate cardiac function as evidenced by a left ventricular ejection fraction (LVEF) 50%.
Patients were excluded in the initial phase of the study if they had surgically resectable lesions, including being candidates for liver transplantation or had received prior systemic DOX and/or liposomal DOX therapy. After the protocol was modified in 2002, there was the ability to enter patients onto the study if they were considered transplant candidates. Patients receiving any other investigational agent, those with CLIP scores of
Sample Size
Study Medication
Study Procedures Patients were randomly assigned on a 1:1 basis to receive either NOL or DOX. The randomization was stratified according to CLIP score (0 and 1 and v 2 and 3) and Karnofsky performance status (60% to 80% v 90% to 100%). The primary end point was OS and the secondary end points included progression-free survival (PFS), objective response, and confirmed response rates and safety. Confirmed responses were defined as per the Response Evaluation Criteria in Solid Tumors criteria. The primary analysis was based on the intent-to-treat (ITT) patient population.
Baseline demographic characteristics were well-balanced between the two treatment groups. The only potentially important difference was a slightly higher numerical prevalence of hepatitis B in the NOL arm and corresponding preponderance of hepatitis C in the DOX arm (Table 2).
Survival Analysis At the time of the primary ITT analysis for survival, 377 of 445 patients had died (84.7%), 191 in the NOL arm and 178 in the DOX arm. The median survival in the NOL arm was 22.3 weeks and in the DOX arm was 32.3 weeks. The hazard ratio was 0.753 and was statistically significant in favor of DOX (P = .0068). The Kaplan-Meier curve for OS is shown in Figure 3.
An analysis of PFS was also conducted for the ITT patient population. The median PFS for the NOL arm was 12 weeks and 10 weeks for the DOX arm (Fig 4). This difference was not statistically significant (P = .7091). An analysis of the objective response (complete response was defined as the disappearance of all demonstrable disease; partial response was defined as 50% decrease from baseline in the product of the largest perpendicular diameters of the most clearly measured mass [must be 1 cm] with no worsening of all other disease that was not measured or assessable disease; and stable disease is no significant change in disease [ 50% decrease or < 50% increase], no worsening in nonmeasurable or assessable disease and no new metastatic lesions; or conversion of inoperable to operable) was also carried out. There were only two confirmed responses in the NOL arm and six in the DOX arm.
Because the observed shortened time-to-death results for NOL compared with DOX were not expected, an extensive analysis of the patient subgroups was performed. Factors examined included age, sex, race/ethnic origin, geographic region (North America, Europe, South Africa), CLIP score, Karnofsky performance status, presence or absence of metastatic disease, etiology, histopathology, foci, presence or absence of portal vein thrombosis, number of treatment cycles received, total bilirubin on study entry, prior therapy for HCC, subsequent therapy, time from diagnosis to random assignment, model for end-stage liver disease, and development of neutropenia. In cases where the result of the subgroup analysis differed substantially from the main analysis, the case records were examined by the study physician at Eximias Pharmaceutical Corporation (G.T.K.) for a signal that suggested reasons for this result. No treatment group characteristics were found that would explain the survival outcome seen in this study.
Safety Table 3 shows the incidence of grade 3 and 4 adverse experiences. Stomatitis, diarrhea, and thrombocytopenia were more common in the NOL arm.
An analysis of reasons for withdrawal from the study was also carried out and is presented in Table 4. Withdrawals for adverse events, deaths, and patient refusal were more common in the NOL arm than in the DOX arm, suggesting that NOL, despite adverse event management, is more toxic than DOX.
To our knowledge, this is the largest randomized controlled trial utilizing DOX as a control arm performed to date for the treatment of unresectable HCC with chemotherapy. While the outcome of this study did not demonstrate improved survival for NOL compared with DOX, it is important to emphasize that the OS in the NOL arm of 20.7 weeks was very similar to the OS seen in the three phase II trials. The extended survival on the DOX arm was unexpected, based on the information available at the time of the origination of the phase III trial. The higher than expected survival in both treatment groups may relate to advances in the management of patients with HCC including better supportive therapies, such as growth factors and greater expertise in the treatment of patients with cirrhosis. Due to advances in the frequency and initiation of more standard screening for HCC and further advances in imaging technology, thus, it is likely that patients were diagnosed at earlier stages of their cancer and liver disease which would create a lead time bias. The survival rates demonstrated in the DOX-treated patients are of interest and could support further licensing trials that may lead to the approval by regulatory authorities as a primary treatment of HCC. Both medications also showed modest antitumor effects. Subsequent data on DOX, in both phase II and phase III trials, however, have consistently shown a greater median survival than the pre-1998 data available at the time of initiation. The largest of these trials, a phase III comparison of DOX versus T138067 published in abstract format, 25 yielded a median survival of 5.6 months or 24 weeks in the DOX arm. Another recent trial, albeit a smaller phase II trial, showed a median survival of 25 weeks in patients treated with the epidermal growth factor receptor inhibitor, erlotinib (OSI-774).26 Other recent studies with HCC patients receiving DOX or liposomal DOX include: DOX and PIAF (cisplatinum, interferon, adriamycin, fluorouracil) with a median survival of 7.1 versus 8.4 months27; DOX and cisplatin with a median survival of 7.3 months (assessable patients only)28; DOX, interferon, and tamoxifen with a median survival of 6.0 months (assessable patients only)29; DOX and gemcitabine with a median survival of 4.6 months30; liposomal DOX with a median survival of 6.5 months31; liposomal DOX with a median survival of 6.1 months32; liposomal DOX with a median survival of 3.0 months33; liposomal DOX with a median survival of 5.1 months (all patients)34; and liposomal DOX with a median survival of 5.3 months.35 The finding of similar PFS results in the face of a substantial survival difference is more difficult to explain. The determination of progression in HCC is often quite challenging, as measurements of changes on imaging studies of the liver against the background of advanced cirrhosis can be quite difficult. The variability in imaging techniques and intercenter interpretation variability may all have played a role. Obviously, the primary end point of survival is easy to document and in this trial with 83% of patients observed until the protocol event supports the reliability of this end point. NOL has a half-life of 11 hours and was thus given as a prolonged intravenous infusion. On the basis of the findings from the early phase I and II studies, an infusion period of 120 hours (5 days) was chosen. In retrospect, this may have been too long and may have contributed to the high incidence of serious toxicities seen with this regimen. In the future, physicians planning to use NOL should consider either a shorter duration of treatment, local tumor applications, or a slightly lower systemic dose—or a combination of two or more, to minimize the toxicities seen in this trial. In summary, both medications may have modest activity in HCC, with DOX showing greater activity and a more favorable safety profile. NOL should not be tested again in this disease at this dose and schedule. However, NOL does have high bioavailability, has the potential to be effective in other tumors, and may have potential in pancreatic or head and neck cancer based on phase II data.36-38 This study contributes further evidence of the minimal to moderate efficacy of DOX in HCC. A decision to use DOX as primary chemotherapy for the treatment of HCC must involve a discussion between a patient and their managing medical practitioners, as well as consideration of other drugs in late-stage clinical testing for this disease. After completion of a small phase II study, a large randomized placebo-control trial of the oral agent sorafenib completed recruitment in May 2006 and the results are awaited with interest to see if this agent alone, or in combination, may be a useful adjunct to our armamentarium. This study also demonstrated that large, international, randomized studies for the treatment of HCC can be completed, and the format of these trials continues to evolve as new data with new agents emerges from ongoing research.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Robert G. Gish, Eximias Pharmaceutical Corporation; Camillo Porta, Eximias Pharmaceutical Corporation; Ronald Feld, Eximias Pharmaceutical Corporation Stock: N/A Honoraria: Robert G. Gish, Eximias Pharmaceutical Corporation; Paul Ruff, Eximias Pharmaceutical Corporation Research Funds: Robert G. Gish, Eximias Pharmaceutical Corporation; Camillo Porta, Eximias Pharmaceutical Corporation; Lucian Lazar, Eximias Pharmaceutical Corporation; Paul Ruff, Eximias Pharmaceutical Corporation; Ronald Feld, Eximias Pharmaceutical Corporation; Adina Croitoru, Eximias Pharmaceutical Corporation; Lynn Feun, Eximias Pharmaceutical Corporation; Krzysztof Jeziorski, Eximias Pharmaceutical Corporation; John Leighton, Eximias Pharmaceutical Corporation Testimony: N/A Other: N/A
Conception and design: Robert G. Gish, Ronald Feld, Jennifer Knox, Gerard Kennealey Financial support: Gerard Kennealey Administrative support: Gerard Kennealey Provision of study materials or patients: Robert G. Gish, Camillo Porta, Lucian Lazar, Paul Ruff, Ronald Feld, Adina Croitoru, Lynn Feun, Krzysztof Jeziorski, John Leighton, Jennifer Knox, Gerard Kennealey Collection and assembly of data: Robert G. Gish, Camillo Porta, Adina Croitoru, Krzysztof Jeziorski Data analysis and interpretation: Robert G. Gish, Camillo Porta, Paul Ruff, Ronald Feld, Jose Gallo Manuscript writing: Robert G. Gish, Camillo Porta, Paul Ruff, John Leighton, Jennifer Knox, Gerard Kennealey Final approval of manuscript: Robert G. Gish, Camillo Porta, Lucian Lazar, Paul Ruff, Ronald Feld, Adina Croitoru, Lynn Feun, Krzysztof Jeziorski, John Leighton, Jennifer Knox, Jose Gallo, Gerard Kennealey
We thank the following physicians who enrolled patients into the Evaluation of THYMITAQ in Unresectable Hepatocellular Carcinoma (ETHECC) trial (alphabetical by country); Canada, Dr Ronald Feld, Dr Rakesh Goel, Dr Charles Olweny; Czech Republic, Prof Rostislav Vyzula; Germany, Prof D.K. Hossfeld, Dr Wolff Schmiegel; Italy, Prof Vincenzo Adamo, Prof Stefano Cascinu, Prof Giuseppe Colucci, Dr Sergio Frustaci, Dr Gian Piero Gasperini, Prof Sergio Palmeri, Dr Camillo Porta; Poland, Dr Krzysztof Jeziorski; Romania, Dr Adina Croitoru, Prof Lucian Lazar; South Africa, Dr Christina Geddes, Dr Bernardo Rapoport, Prof Paul Ruff, Dr Coenraad Slabber; United Kingdom, Dr Phillip Harrison; United States, Dr Lowell Anthony, Dr Al Benson, Dr Irving Berkowitz, Dr Eric Bonnem, Dr Lewis Campos, Dr Brian Carr, Dr Adrian Di Bisceglie, Dr Lynn Feun, Dr Jose Figueroa, Dr Christopher Garrett, Dr Jeffery Giguere, Dr Robert Gish, Dr Edward Greeno, Dr Solomon Hamburg, Dr Jimmy Hwang, Dr Brian Issel, Dr Padmini Iyer, Dr Antoine Jakiche, Dr Andrew Jennis, Dr Leonard Kalman, Dr Mark Karwal, Dr Andreas Kaubisch, Dr Ann Kessinger, Dr John Leighton, Dr Issam Makhoul, Dr Divyesh Mehta, Dr William Miller, Dr Barry Mirtsching, Dr Manuel Modiano, Dr Prakash Neupane, Dr Eileen Pacheco-Hernandez, Dr Warren Paroly, Dr Joel Picus, Dr Leland Powell, Dr Harry Raftopoulos, Dr David Rinaldi, Dr Timothy Spiro, Dr Max Sung, Dr Mark Taylor, Dr James Thomas, and Dr Scott Wadler. We also thank Peggy Senico, RN, BSN, OCN, and Karen Jones for their assistance in the creation and submission of this manuscript.
Presented in part in abstract format at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA, 2006; International Liver Congress, Shanghai, 2006; and at the 41st Annual Meeting of the European Association for the Study of the Liver, Vienna, Austria, 2006. Supported by the Eximias Pharmaceutical Corporation. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Bosch FX, Ribes J, Cleries R, et al: Epidemiology of hepatocellular carcinoma. Clin Liver Dis 9:191-211, 2005[CrossRef][Medline] 2. Parkin DM, Bray F, Ferlay J, et al: Global cancer statistics, 2002. CA Cancer J Clin 55:74-108, 2005 3. Michielsen PP, Francque SM, van Dongen JL: Viral hepatitis and hepatocellular carcinoma. World J Surg Oncol 3:27, 2005[CrossRef][Medline] 4. Russo MW, Wei JT, Thiny MT, et al: Digestive and liver diseases statistics, 2004. Gastroenterology 126:1448-1453, 2004[CrossRef][Medline] 5. Gish RG: Hepatocellular carcinoma: Overcoming challenges in disease management. Clin Gastroenterol Hepatol 4:252-261, 2006[CrossRef][Medline] 6. Pawarode A, Voravud N, Sriuranpong V, et al: Natural history of untreated primary hepatocellular carcinoma: A retrospective study of 157 patients. Am J Clin Oncol 21:386-391, 1998[CrossRef][Medline] 7. Pawarode A, Tangkijvanich P, Voravud N: Outcomes of primary hepatocellular carcinoma treatment: An 8-year experience with 368 patients in Thailand. J Gastroenterol Hepatol 15:860-864, 2000[CrossRef][Medline] 8. Bialecki ES, Di Bisceglie AM: Clinical presentation and natural course of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 17:485-489, 2005[CrossRef][Medline] 9. Barbara L, Benzi G, Gaiani S, et al: Natural history of small untreated hepatocellular carcinoma in cirrhosis: A multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 16:132-137, 1992[Medline] 10. Cottone M, Virdone R, Fusco G, et al: Asymptomatic hepatocellular carcinoma in Child's A cirrhosis: A comparison of natural history and surgical treatment. Gastroenterology 96:1566-1571, 1989[Medline] 11. Farinati F, Marino D, De Giorgio M, et al: A reappraisal of the Barcelona Clinic Liver Cancer model: Natural history of untreated ‘intermediate stage’ hepatocellular carcinoma. J Intern Med 256:529-530, 2004[CrossRef][Medline] 12. Kim UB, Doo CJ, Baek SH, et al: Natural history and prognostic factors of primary hepatocellular carcinoma: Study of 70 untreated patients. Korean J Intern Med 4:136-141, 1989[Medline] 13. Llovet JM, Bruix J: Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: A new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology 32:679-680, 2000[CrossRef][Medline] 14. Stuart K, Tessitore J, Rudy J, et al: A phase II trial of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma. Cancer 86:410-414, 1999[CrossRef][Medline] 15. Hamburg S, Miller W, García-Vargas J, et al: Survival benefit of nolatrexed in advanced hepatocellular carcinoma (aHCC). Proc Am Soc Clin Oncol 22:288, 2003 (abstr 1157) 16. Mok TSK, Leung TWT, Lee S-D, et al: A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 44:307-311, 1999[CrossRef][Medline] 17. Ihde DC, Kane RC, Cohen MH, et al: Adriamycin therapy in American patients with hepatocellular carcinoma. Cancer Treat Rep 61:1385-1387, 1977[Medline] 18. Johnson PJ, Williams R, Thomas H, et al: Induction of remission in hepatocellular carcinoma with doxorubicin. Lancet 1:1006-1009, 1978[Medline] 19. Falkson G, MacIntyre JM, Schutt AJ, et al: Neocarzinostatin versus m-AMSA or doxorubicin in hepatocellular carcinoma. J Clin Oncol 2:581-584, 1984[Abstract] 20. Falkson G, MacIntyre JM, Moertel CG, et al: Primary liver cancer: An Eastern Cooperative Oncology Group trial. Cancer 54:970-977, 1984[CrossRef][Medline] 21. Colombo M, Tommasini MA, Del Ninno E, et al: Hepatocellular carcinoma in Italy: Report of a clinical trial with intravenous doxorubicin. Liver 5:336-341, 1985[Medline] 22. Melia WM, Johnson PJ, Williams R: Controlled clinical trial of doxorubicin and tamoxifen versus doxorubicin alone in hepatocellular carcinoma. Cancer Treat Rep 71:1213-1216, 1987[Medline] 23. Lai CL, Wu PC, Chan GC, et al: Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma: A prospective randomized trial. Cancer 62:479-483, 1988[CrossRef][Medline] 24. Kalayci C, Johnson PJ, Raby N, et al: Intraarterial adriamycin and lipiodol for inoperable hepatocellular carcinoma: A comparison with intravenous adriamycin. J Hepatol 11:349-353, 1990[CrossRef][Medline] 25. Posey J, Johnson P, Mok T, et al: Results of a phase 2/3 open-label, randomized trial of T138067 versus doxorubicin (DOX) in chemotherapy-naïve, unresectable hepatocellular carcinoma (HCC). J Clin Oncol 23:16S, 2005 (abstr 4035) 26. Thomas MB, Dutta A, Brown T, et al: A phase II open-label study of OSI-774 (NSC 718781) in unresectable hepatocellular carcinoma. J Clin Oncol 23:16S, 2005 (abstr 4038) 27. Yeo W, Zee B, Leung WT, et al: A phase III study of doxorubicin (A) versus cisplatin (P)/ interferonA-2B (I)/ doxorubicin (A)/ fluorouracil (F) combination chemotherapy (PIAF) for inoperable hepatocellular carcinoma (HCC). J Clin Oncol 22: 2004 (abstr 4026) 28. Lee J, Park JO, Kim WS, et al: Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma. Cancer Chemother Pharmacol 54:385-390, 2004[CrossRef][Medline] 29. Lu YS, Hsu C, Li CC, et al: Phase II study of combination doxorubicin, interferon-alpha, and high-dose tamoxifen treatment for advanced hepatocellular carcinoma. Hepatogastroenterology 51:815-819, 2004[Medline] 30. Yang TS, Wang CH, Hsieh RK, et al: A 2-stage phase II study of gemcitabine and doxorubicin in patients with advanced hepatocellular carcinoma. Proc Am Soc Clin Oncol 19:168a, 2001 (abstr 670) 31. Cartei G, Zustovich F, Murrone A, et al: A phase I-II study of liposomal doxorubicin (LD) in the treatment of hepatocellular carcinoma (HCC) not suitable for loco-regional therapy. J Clin Oncol 23:364s, 2005 (abstr 4227) 32. Dangoor A, Ranson M, Lee SM, et al: Treatment of inoperable hepatocellular carcinoma (HCC) with pegylated liposomal doxorubicin: A phase II study. Proc Am Soc Clin Oncol 21:361, 2003 (abstr 1450) 33. Hong RL, Tseng YL: A phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 51:433-438, 2003[Medline] 34. Miller RL, Bowen KE, Chun HG: A phase II study of liposomal doxorubicin (LD, Doxil) in patients with advanced hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC). Proc Am Soc Clin Oncol 20:155b, 2002 (abstr 2324) 35. Ruff P, Moodley SD, Rapoport BL, et al: Long term follow-up of pegylated liposomal doxorubicin (CAELYX): A well tolerated and effective agent in advanced hepatocellular carcinoma (HCC). Proc Am Soc Clin Oncol 19:167a, 2001 (abstr 667) 36. Clendeninn NJ, Johnston A: Phase II trials of ThymitaqTM (AG337) in six solid tumor diseases. 9th NCI-EORTC, 1996 (abstr 296) 37. Pivot X, Wadler S, Kelly C, et al: Result of two randomized trials comparing nolatrexed (ThymitaqTM) versus methotrexate in patients with recurrent head and neck cancer. Ann Oncol 12:1595-1599, 2001 38. Hughes AN, Rafi I, Griffin MJ, et al: Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days. Clin Cancer Res 5:111-118, 1999 Submitted August 1, 2006; accepted April 18, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .05. This resulted in the need to observe 371 deaths. Given that the trial was expected to accrue 12 patients per month over at least a 37-month period with a minimum follow-up of 6 months, it was estimated that the trial would need 445 patients in order to observe the required 371 deaths. This sample of 445 patients also provided an 80% power to detect a 32.5% improvement in survival. In addition, the longer recruitment time (55 months) and the increased number of events (377) strengthened the statistical power of the trial. 
