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Indian Journal of Cancer, Vol. 47, No. 2, April-June, 2010, pp. 93-94 Guest Editorial Relapsed testicular leukemia: Local insights in to a vanishing disease Arora B, Kurkure PA Pediatric Oncology Division, Tata Memorial Hospital, Mumbai, India Correspondence Address: Dr PA Kurkure, Pediatric Oncology Division, Tata Memorial Hospital, Mumbai, India purna.kurkure@gmail.com Code Number: cn10029 PMID: 20448368 DOI: 10.4103/0019-509X.62992 Childhood acute lymphoblastic leukemia (ALL) is the single most common childhood malignancy. It comprises almost one-fourth of cancers in children ages 0-15 years. At least 25-30% of patients have relapse with current therapies, making relapsed ALL the fourth most common malignancy in children after newly diagnosed ALL, astrocytoma and neuroblastoma. Indeed, relapsed ALL is the second most common leukemia in children and is more common than newly diagnosed non-Hodgkin′s lymphoma, Wilms′ tumor, Hodgkin′s disease and primitive neuroectodermal tumors. [1] Results of treatment with chemotherapy in children after an ALL relapse remain unsatisfactory worldwide, especially in early relapses and heavily pretreated patients. Based on the available robust prognostic factors, ALL relapses are classified as very early, early or late according to time from diagnosis to relapse (< 18; > 18 and < 30; > 30 months, respectively). It is evident from the literature that about two-thirds of children with late extramedullary relapse and about one-third of those with early extramedullary relapses or late non-T marrow relapses or early combined non-T relapses can be rescued by chemotherapy; conversely, bone marrow relapses occurring early or with T-immunophenotype can be rescued only by bone marrow transplantation (BMT). [2] Extramedullary relapses in ALL draw a lot of attention, because of good outcome with salvage therapies and fascinating biology. Extramedullary relapses used to constitute approximately 40% of all relapses of which 20-25% used to be in central nervous system (CNS) and 10-15% used to be in testis. However, with the improved frontline treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. Currently, the incidence of isolated CNS relapse is less than 5% and testicular relapse is less than one to two per cent. [3],[4],[5] Testis is considered a barometer of extramedullary involvement in ALL. In majority of the children with isolated testicular relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques. [6] Before 1960, relapsed testicular leukemia was rare because of early death due to marrow disease in children with ALL. With the significant improvement of survival in 1980s, an increase in the testicular recurrence rate occurred; the reported frequency of overt testicular recurrence in children with ALL ranged between 2-8.8%. Currently, with the modern era methotrexate-based chemotherapy regimens, testicular relapses have virtually been eliminated and range from 0-1%. [3],[4],[5] In this issue of Indian Journal of Cancer, Kulkarni et al. share the pattern and outcome of testicular relapses at their center in the last two decades. The incidence in their series is a whopping 9.5% (27% of all relapses in boys), which is much like the middle era of ALL therapy and is higher than most current series. [7],[8] This seems to be obviously because of usage of 3 drug induction and non-methotrexate-based consolidation in all newcomers irrespective of risk-group. Biologic differences from the West are unlikely since in a recent Indian series, the incidence of testicular relapse was 4.4%. [9] Due to the absence of temporal trends over two decades, it is difficult to assess the impact of improving diagnostics and treatment quality over time. Interestingly, 80% patients in this series relapsed very early/early (within six months of therapy completion). In the seminal COG series, only 10% of isolated testes relapses occurred in the initial 12 months after diagnosis, and 59% occurred late after 36 months. [3] This might again reflect the low early treatment intensity used in this study permitting early relapses. Several factors such as high white blood cell (WBC) count (>20,000 per cmm), T-cell disease, bulky lymphadenopathy, splenomegaly, significant thrombocytopenia (< 30,000/cmm), high-risk cytogenetics (Bcr-Abl and MLL rearrangement) and poor early response have been shown to be risk factors for testicular relapses. [1],[3],[8],[10] This study attempts to analyze the risk factors for testicular relapses but could only confirm high WBC as the risk-factor. It seems most likely due to small patient population and non-availability of data on cytogenetics, immunophenotype or early response. However, the impact of differences in the protocol or biology of disease cannot be ruled out. Relapsed testicular ALL is highly curable. The results of treatment of isolated testicular relapse depend on the timing of the relapse. The three-year event-free survival (EFS) of boys with early testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse. [1],[2],[3],[8],[10] In a recent Indian series, 67% patients were long-term survivors. [11] However, the outcome data in this series is disturbing. Of 30 relapsers, only seven (20%) are on treatment and less than 10% of all patients are expected to be survivors with the current non-methotrexate based salvage regimen used in this study. This, unfortunately, is largely due to treatment abandonment due to a slew of socioeconomic factors in resource-challenged environments and perceived dismal outcome of relapse after a long mentally, physically as well as economically crippling therapy. Authors plan to introduce intermediate or high - dose methotrexate in their current therapy to prevent testicular relapses. While it is an important component of current/relapse therapy, equally important is to dispense with testicular radiotherapy using aggressive therapy incorporating high-dose methotrexate which has been shown to be feasible and prevents long-term endocrine and gonadal complications. [12],[13] Where do we go from here? The dictum of ′the first chance is the best chance′ is most relevant in resource-constrained settings since it is probably the last and only chance to motivate and support the family to take and comply with treatment. While it is imperative to provide socioeconomic support by leveraging the wide range of sources in India, it is equally important to focus on providing optimally intensive risk-stratified frontline therapy of ALL rather than trying to salvage after relapse. It is hoped that use of conventional risk factors, cytogenetics, early response assessment and minimal residual disease based risk-stratification coupled with optimal upfront chemotherapy would bring the outcome of Indian patients on par with the west in the near future. References
Copyright 2010 - Indian Journal of Cancer |
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