LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951)☆
Introduction
An enhanced understanding of key prognostic variables in melanoma has emerged in the last 10 years, primarily due to new biologic techniques and large-scale, population-based analyses.1 As a result, clinical trials now often include risk factors for stratification and identification of patient subpopulations that may achieve maximum therapeutic benefit.2, 3, 4
Serum lactate dehydrogenase (LDH) level is one of the most useful independent prognostic factors in metastatic melanoma.1 Numerous studies investigating various prognostic factors confirm the correlation between increased LDH and decreased survival among patients with advanced melanoma.5, 6, 7, 8, 9, 10, 11, 12, 13 This association is evident even after accounting for the number of metastases and location of distant metastatic involvement.14, 15
Solid tumours require a blood supply to grow and metastasise and are highly adaptable in meeting this need, as well as thriving in a hypoxic state. Increased serum LDH is believed to be related to the hypoxic environment of tumour cells. Unlike normal cells that produce the majority of ATP from glucose through oxidative phosphorylation, many cancer cells produce ATP by converting glucose to lactate,16 a process essential to the hypoxic environment in which many cancer cells exist. LDH is composed of 2 peptides – LDH-A and LDH-B. It is LDH-A (also known as LDH-5 in its tetrametric form) that is upregulated in the hypoxic environment. This enzyme catalyses the conversion of pyruvate to lactate, probably via the activity of the HIF1α transcription factor.17, 18 As LDH is not a secreted enzyme, the finding of elevated LDH in the serum of patients with advanced melanoma is probably due, at least in part, to melanoma-cell necrosis or apo-necrosis and the spillage of LDH, which likely occurs when part of a tumour outgrows its blood supply. The remaining poorly perfused, hypoxic tumour cells may be highly refractory to cytotoxic chemotherapy in light of abnormalities in their vasculature and microenvironment,19 and they may eventually recover and proliferate.
Little progress in the treatment of advanced melanoma has been made over the last several decades. The standard therapy remains dacarbazine. Various agents, including cytotoxic drugs, interferon-α and IL-2 and tamoxifen, have been used in combination with dacarbazine in clinical studies.20 Nevertheless, randomised trials of single-agent dacarbazine versus dacarbazine-containing combination regimens have failed to show a survival benefit with the multiple-drug regimens.20
The largest randomised study in advanced melanoma conducted to date is a multinational, Phase 3 trial (Study GM301) in 771 patients, including 760 for whom baseline serum LDH was recorded. This study was performed to evaluate the potential of the antisense oligonucleotide oblimersen to enhance the efficacy of dacarbazine in a chemotherapy-naïve population.21 Prior to randomisation, patients were stratified according to 3 prognostic factors: Eastern Cooperative Oncology Group performance status (0 versus 1 or 2), liver metastases (present versus absent) and disease site in combination with baseline LDH (non-visceral disease and normal LDH, defined as a baseline serum LDH level ⩽ 1.1 times the upper limit of normal [×ULN], versus visceral disease [excluding liver metastases] or elevated LDH, defined as a baseline serum LDH level >1.1 × ULN). Every 3 weeks patients received either dacarbazine 1000 mg/m2 intravenously (i.v.) or the same dacarbazine dose preceded by a 5-d continuous intravenous infusion of oblimersen 7 mg/kg/d. Patients were assessed by RECIST22 at the end of every two cycles.
Overall survival (the primary end-point) showed an improvement in the oblimersen–dacarbazine group at 24-month minimum follow-up that approached statistical significance (median 9.0 months versus 7.8 months in the dacarbazine group; P = 0.077). Other efficacy end-points consistently demonstrated a highly significant between-treatment difference favouring the oblimersen–dacarbazine regimen, including progression-free survival (median 2.6 months versus 1.6 months; P < 0.001), overall response rate (13.5% versus 7.5%; P = 0.007) and durable response rate (7.3% versus 3.6%; P = 0.03).21 Particularly noteworthy was a separation of the survival curves beginning at about 6 months, which suggested the existence of a heterogeneous population. Thus, we assessed whether there was a subset of patients who derived increased benefit from the addition of oblimersen to dacarbazine.
Each of the three stratification factors in this study (performance status, metastatic site and LDH) was assessed for an interaction with treatment on survival. An interaction was detected only between LDH and treatment.21 Given the heterogeneity of the population, treatment effect was then analysed in both the normal and elevated LDH subpopulations. The normal LDH population included 508 of the 760 patients, representing a sample size greater than that used in any previous randomised study in advanced melanoma.21 Statistically significantly superior results were observed for multiple efficacy end-points in patients with normal LDH who were treated with the oblimersen–dacarbazine regimen, including overall survival (median 11.4 months versus 9.7 months; P = 0.02), progression-free survival (median 3.1 months versus 1.6 months; P < 0.001), overall response rate (17.2% versus 9.3%; P = 0.009) and durable response rate (9.6% versus 4.0%; P = 0.01). In contrast, the elevated LDH population (N = 252) was neutral with respect to treatment effect; no significant between-treatment differences in efficacy parameters were apparent.21
Per protocol, the cutoff for defining normal LDH and elevated LDH had been established as 1.1 × ULN. Given the interaction between baseline LDH and treatment, two important questions arose: (1) Would a different cutoff to define ‘normal LDH’ have led to different conclusions? and (2) What is the medical relevance of this observation? This article attempts to provide answers to these two questions, as well as the medical basis for our findings.
Section snippets
Patients and methods
LDH values from both treatment groups in Study GM301 were combined, and the distribution of these values was compared to the distribution in the general population (i.e. expected Gaussian distribution) from whom the normal reference range is established.
LDH cutoffs above and below 1 × ULN were used to assess the robustness of the definition of normal LDH.23 Five LDH categories were considered: ⩽0.8 × ULN, >0.8 to ⩽ 1.1 × ULN (cutoff point used for stratification in Study GM301), >1.1 to ⩽2 × ULN (cutoff
Results
With a Gaussian distribution, one would expect 50% of LDH values to fall below the median. For the 760 patients in Study GM301, the median midpoint value between the upper and lower limits of the normal range was 0.75, but the median ratio of baseline LDH to the upper limit of normal range was 0.9, demonstrating a shift to the right in the median by approximately 20%. In fact, in Study GM301, one-third of the values fell between 0.8 and 1.1 × ULN, one-third fell below 0.8 × ULN and one-third fell
Discussion
Elevated serum baseline LDH is widely recognised as an important prognostic factor in melanoma. As with all laboratory values, the normal limits for LDH are derived from the general healthy population. Based on our findings, the applicability of the upper limit of the normal range is questionable in the setting of advanced melanoma. The overrepresentation of values close to but not exceeding the upper limit of normal implies that these values may actually be elevated rather than normal in a
Conclusions
The consistency in efficacy demonstrated in Study GM301 has not previously been observed in any other completed, randomised study in advanced melanoma. In this study, low baseline LDH (⩽0.8 × ULN) was found to be predictive of the treatment effect of oblimersen in combination with dacarbazine. A confirmatory study is ongoing. Whether the low LDH cutoff point of 0.8 × ULN is disease- or drug-specific warrants exploration.
In the setting of advanced melanoma, baseline serum LDH is not a simple marker
Trial registration numbers
Study GM301 – NCT00016263; EORTC Study 18951 – NCT00002669
Conflict of interest statement
Sanjiv S. Agarwala – none declared.
Ulrich Keilholz – none declared.
Erard Gilles – employment (Genta; compensated).
Agop Y. Bedikian – none declared.
Jane Wu – employment (Genta; compensated).
Richard Kay – consultant (Genta Incorporated; compensated).
Cy A. Stein – consultant (Genta; uncompensated); honoraria (Genta); expert testimony (Genta, compensated).
Loretta M. Itri – employment (Genta; compensated); stock ownership (Genta).
Stefan Suciu – none declared.
Alexander M.M. Eggermont – consultant
Acknowledgements
Study GM301 was sponsored by Genta Incorporated. EORTC Study 18951 was supported by Chiron BV, Schering Plough and the National Cancer Institute. We thank Janet Ehlert and Steven Novick (both of Genta Incorporated) for writing assistance.
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Presented in part at the 2007 annual meeting of the American Society of Clinical Oncology and at the 3rd annual International Melanoma Research Congress in 2006.