|Julia Draznin Maltzman, MD|
|Abramson Cancer Center of the University of Pennsylvania|
At the turn of the year, it is appropriate to stop and reflect about the progress that has been made in the fight against cancer in the preceding twelve months. Our relentless plight to improve available preventive tactics, diagnostic strategies, and cancer therapies is driven by our goal to save the lives and improve the well being of our patients and their families. We base many of our medical decisions on clinical trials that were designed by physicians, nurses, and statisticians to help us in this charge. Some clinical trials result in a change of the standard of care and others provide insight into a better course of action. This week's news flash will review the top ten pivotal trials that have already resulted in or will likely change the standard of care. These trials were either published in medical journals or presented in oncology conferences during the calendar year 2003. These ten trials were chosen because each had an effect on the way we practice oncology and may result in an improved survival and quality of life for our patients in the years ahead.
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 the Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741
Node positive breast cancer patients were randomized to receive doxorubicin, paclitaxel, and cyclophosphamide in one of four treatment arms. Two groups received the chemotherapeutics concurrently and the other two received them sequentially. One group in each of the above arms received the chemotherapy in a dose-dense fashion – therapy every two weeks with growth factor support, while the other two arms received therapy according to the accepted every three week schedule without growth factor support. The data showed that disease free survival was significantly improved in the dose-dense regiments compared to the traditional schedule. After a three-year follow up, 26% decrease in disease recurrence and a 31% decrease in mortality were noted. Overall survival was also improved in the dose-dense arms, 92% versus 90%. All these data were statistically significant. No difference was noted in any of these parameters when benefits of sequential versus concurrent therapy were analyzed.
This is an important study as it showed a significant improvement in outcome. Oncologists eagerly await a longer follow up period for a conclusive change in the standard of practice, although some practitioners are so convinced, they have already changed their practice.
Two trials showing the benefits of a new anti-angiogenesis drug called bevacizumab.
A Randomized Trial of Bevacizumab, an Anti–Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer
The first study compared bevacizumab (Avastin) to placebo in patients with advanced kidney cancer. Response rate and overall survival were the primary and secondary end points, respectively. This trial showed such a significant prolongation of time to disease progression in the bevacizumab arm, that it was stopped early upon an interim analysis. Unfortunately, there was no significant survival difference between the groups. The significance of this trial is that patients with advanced renal cell cancer can significantly prolong the time to disease progression with this new drug.
Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in fist-line colorectal cancer (CRC): Results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC.
This anti-angiogenesis, vascular growth factor receptor inhibitor, along with conventional chemotherapy did show an improvement in overall survival in previously untreated patients with metastatic colon cancer. The trial randomized patients to receive either bevacizumab plus standard chemotherapy of 5FU/Leucovorin and CPT-11 or chemotherapy alone. Median survival for the chemotherapy alone arm was 15.6 months as opposed to the 20.3 months of chemo plus bevacizumab. Overall response rate and progression free survival were also better for the bevacizumab group – 45% versus 35% and 10.6 months versus 6.24 months respectively. This significant trial has put this drug on the fast track process for consideration of approval by the FDA for the treatment of metastatic colorectal patients.
Results of the Randomized International Adjuvant Lung Cancer Trial (IALT): cisplatin-based chemotherapy (CT) versus no CT in 1867 patients (pts) with resected non-small cell lung cancer (NSCLC)
The rationale for this study was to confirm or deny a benefit of adjuvant chemotherapy in NSCLC. The IALT compared cisplatin-based chemotherapy to no further treatment (radiation was permitted but had to be decided on before randomization). Drugs used with cisplatin included etoposide, vinorelbine, and vinblastine. By the end of a five-year follow up, all end points favored the chemotherapy arm. Disease free survival was 39.4% compared to 34.3%in the control arm. Overall-survival was 44.5% in the chemotherapy arm compared with 40.4%. Median survival after chemotherapy was 50.8 months versus 44.4 months. Median disease-free survival after chemotherapy was 40.2 months versus 30.5 months in the control group. All of theses results were deemed statistically significant.
This significant finding indicates that adjuvant chemotherapy for NSCLC may be more beneficial than previously thought in patients with good performance status.
Whole abdominal radiotherapy versus combination doxorubicin-cisplatin chemotherapy in advanced endometrial carcinoma: A randomized phase III trial of the Gynecologic Oncology Group
This study underscored the important role for chemotherapy in the management of advanced endometrial cancer. The Gynecologic Oncology Group (GOG) randomized women with stage III and IV endometrial cancer to whole abdominal radiation and platinum based chemotherapy. Primary endpoint was progression-free survival with toxicity and quality of life outcomes being secondary. Results showed that combination chemotherapy reduced the risk of progression by 30% and death by 34%. Improved progression free and overall survival came at the price of increased toxicity, which was significantly greater in the chemotherapy arm. Many practitioners will be cautious in using this regiment for women with this diagnosis. However, it can certainly be applied to the high-risk, younger, patients.
Despite the lack of an overtly positivity, and the need for further studies, this trial represents a significant step forward in the attempt to investigate the options available for women with advanced endometrial carcinoma, whose treatment choices may be limited.
A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer
This double blind, placebo controlled trial, which looked at disease free survival as its primary end point, gave an aromatase inhibitor, letrozole, to postmenopausal women with early stage breast cancer who completed five years of tamoxifen therapy. A 43% reduction in risk of recurrence was reported. There was also a 46% reduction in the frequency of new primary cancers in the contralateral breast, a secondary end point. An estimated absolute improvement in a 4-year disease free survival was 6% – 93% for the letrozole arm and 87% for the placebo group. These data were so convincing that investigators stopped the trial early based on an interim analysis to allow women getting placebo to begin the study hormone.
This is the first study to look at patients who have already completed five years of adjuvant therapy. A Canadian led effort, recruited more than 5,000 women into this trial. The caveat being, that, the women enrolled in this study had to have discontinued tamoxifen less than three months before enrollment. It is unclear what role, if any, letrozole has in women who had been off tamoxifen for a longer time.
Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia
Although presented at the plenary session at ASCO 2002, the final data and analysis were published in the year 2003. Imatinib, a selective inhibitor of the tyrosine kinase BCR-ABL has revolutionized the treatment of chronic myeloid leukemia (CML). This trial compared the efficacy of imatinib with that of the standard therapy for CML – interferon alfa with low dose cytarabine. After a short nineteen-month follow up, the rate of complete cytogenetic (chromosomal) remission in the imatinib group was 76.2% compared to 14.5% in the control arm. Freedom from progression to an accelerated phase or blast crisis of this disease was 96.7% in the Imatinib arm and 91.5% in the combination therapy group. These data are statistically significant.
This trial is an enormous contribution to the oncology world as it changed the standard of care of first line therapy in newly diagnosed chronic-phase CML.
A Randomized Comparison of Sentinel-Node Biopsy with Routine Axillary Dissection in Breast Cancer
Prior to the publication of this trial, the sentinel-lymph node (SLN) biopsy for breast cancer was a contested procedure. Many trials proved its accuracy but the efficacy and safety of SLN procedure have not been validated. Women with breast cancer tumors less than 2 cm in diameter were randomized to either a SLN biopsy and a total axillary dissection or to SLN biopsy followed by an axillary dissection only if the sentinel node contained cancer. In the axillary dissection group the accuracy of the SLN was 96.9% and the sensitivity 91.2% with a specificity of 100%. The study found that there was less pain and better arm mobility in the patients who underwent a SLN procedure, than in those who had a total axillary dissection.
This trial proved that SLN biopsies are a safe and accurate method of screening the axillary nodes in small primary breast tumors.
A Phase II Study of Bortezomib in Relapsed, Refractory Myeloma
Bortezomib is a novel proteasome inhibitor that has been shown to have anti-multiple meyloma activity. This trial was a non-randomized phase II trial of patients with relapsed or refractory multiple meyloma (MM). The response rate was noted to be at a striking 35%. The median overall survival was 16 months with a median duration of response of 12 months.
This trial is significant as it offers an excellent and viable option for a disease, that, when relapsed, has few other alternatives. Bortezomib gained FDA approval for MM in the year 2003.
Value of Autologous Stem Cell Transplantation in First Line Therapy of Follicular Lymphoma with High Tumor Burden: Final Results of the Randomized GOELAMS 064 Trial
A multi-center study in France suggests that some patients with follicular lymphomas may benefit from high dose chemotherapy with autologous stem cell transplantation over conventional treatment with CHOP chemotherapy. Patients less than 60 years of age with newly diagnosed Non Hodgkin's Lymphoma were randomized into high dose chemotherapy with growth factor and autologous stem cell support versus conventional CHOP therapy. Although the response rates were similar (88% versus 84%), the five-year event free survival for patients undergoing transplant was 59% as opposed to 37% for those receiving CHOP. The number of therapy related deaths were the same in both groups.
These data call in question the standard of care therapy for this disease.
Superiority of Oxaliplatin and Fluorouracil-Leucovorin Compared with Either Therapy Alone in Patients with Progressive Colorectal Cancer after Irinotecan and Fluorouracil-Leucovorin: Interim Results of a Phase III Trial
After failing front line chemotherapy with irinotecan and 5-fluorouracil (5-FU) for metastatic colorectal cancer, patients had few other alternatives. This trial randomized patients to one of three arms: infusional 5FU and leucovorin (LV5FU2), single agent oxaliplatin, or the combination (FOLFOX4) and evaluated objective response rate (RR), time to tumor progression (TTP) in these patients. The clear winner in all parameters studied was FOLFOX4. The objective RR, as determined by in independent panel, was 9.9% for FOLFOX4 as opposed to 0% for LV5FU2. The median TTP for FOLFOX4 was 4.6 months versus 2.7 months for LV5FU2. Single agent Oxaliplatin was not superior to LV5FU2 in any way.
The significance of this trial is that it offered a viable option for patients who failed first line therapy for colorectal cancer. As these results were so impressive, trials are on the way comparing FOLFOX4 with the currently approved first line therapy.