Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort.

BACKGROUND: Seminoma stage I is the most frequent testis cancer and single-dose carboplatin (AUC7) is an effective and widely used adjuvant treatment. Underdosing of carboplatin by 10% has been shown to almost double the rate of relapse and hence correct dosing based on accurate GFR measurement is crucial. The gold standard of GFR measurement with a radiolabelled isotope is expensive and not readily available. In many institutions, it is replaced by GFR estimation with the Cockcroft-Gault formula, which might lead to significant carboplatin underdosing and potentially inferior clinical outcome. METHODS: Retrospective analysis of all patients with stage I seminoma treated with adjuvant carboplatin between 1999 and 2012. All patients had serum creatinine measured and underwent GFR measurement with a radioisotope ((51)Cr EDTA or (99m)Tc DTPA), which was compared with seven standard GFR estimation formulae (Cockcroft-Gault, CKD-EPI, Jelliffe, Martin, Mayo, MDRD, Wright) and a flat dosing strategy. Bias, precision, rates of under- and overdosing of GFR estimates were compared with measured GFR. Bland-Altman plots were done. RESULTS: A total of 426 consecutive Caucasian male patients were included: median age 39 years (range 19-60 years), median measured GFR 118 ml/min (51-209), median administered carboplatin dose 1000 mg (532-1638). In comparison to isotopic GFR measurement, a relevant proportion of patients would have received ≤ 90% of carboplatin dose through the use of GFR estimation formulae: 4% using Mayo, 9% Martin, 18% Cockcroft-Gault, 24% Wright, 63% Jelliffe, 49% MDRD and 41% using CKD-EPI. The flat dosing strategy, Wright and Cockcroft-Gault formulae, showed the smallest bias with mean percentage error of +1.9, +0.4 and +2.1, respectively. CONCLUSIONS: Using Cockcroft-Gault or any other formula for GFR estimation leads to underdosing of adjuvant carboplatin in a relevant number of patients with Seminoma stage I and should not be regarded as standard of care.

Sex cord stromal testicular tumors: a clinical series--uniformly stage I disease.

PURPOSE: Sex cord stromal testicular tumors are rare. Historically 10% of lesions are said to be malignant but to our knowledge there are no clinical or histological features that can accurately predict potential malignant behavior. Because of this, groups at some centers have advocated prophylactic retroperitoneal lymph node dissection in patients with clinical stage I disease. We reviewed our experience with these tumors to determine whether this policy is justified. MATERIALS AND METHODS: We retrospectively reviewed the records of all 38 men older than 18 years with sex cord stromal testicular tumors who were referred to the Wessex regional cancer center for treatment or pathological review during the 25-year period of 1982 to 2006. We then compared our series with a malignant sex cord stromal testicular tumor database generated from the world literature. RESULTS: All Wessex patients were treated with excision of the primary tumor alone and metastatic disease developed in none. All remained disease-free with an overall median survival of 6.8 years (range 1.4 to 25). Features in the literature favoring malignant behavior, ie metastatic disease, included larger tumors (mean 6.43 vs 1.71 cm), a high mitotic rate, tumor necrosis, angiolymphatic invasion, infiltrative margins and extratesticular extension (each p <0.0001). The malignant group had an overall median survival of 2.3 years (range 0.02 to 17.3). CONCLUSIONS: No patient had disease progression in our study, which is to our knowledge the largest reported United Kingdom series of sex cord stromal testicular tumors. Our data suggest that malignancy is uncommon and prophylactic retroperitoneal lymph node dissection is unjustified for clinical stage I disease.

ABVD for Hodgkin's lymphoma: full-dose chemotherapy without dose reductions or growth factors.

BACKGROUND: We investigated whether administration of full-dose ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy without growth factors, and irrespective of the granulocyte count, caused treatment delays or increased the number of infective episodes, in patients with Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Thirty-eight patients with confirmed predominantly early-stage HL were treated with ABVD outside clinical trial protocols over a 5-year period on an outpatient basis. RESULTS: Ninety-five per cent of patients completed their scheduled ABVD regimen without adverse effects despite the development of neutropenia. Anaemia and thrombocytopenia did not present problems. Febrile neutropenia complicated 0.57% of combination chemotherapy injections. No growth factors were used and no dose modifications were carried out apart from the omission of bleomycin in one patient for the last two cycles of treatment due to the development of lung toxicity. All patients are currently disease-free, although three (7.8%) required salvage high-dose therapy (one relapsed and two with refractory disease). CONCLUSIONS: ABVD administration irrespective of granulocyte counts allowed the treatment to be given at full dose without delays or significant number of infective episodes. There was no need for growth factor support, minimising treatment costs. The use of full-dose ABVD irrespective of granulocyte count should be evaluated in future protocols for HL.

Case series: adult testicular dermoid tumours--mature teratoma or pre-pubertal teratoma?

Adult testicular dermoid tumours are rare tumours with no reported potential for recurrent or metastatic spread. Despite this they are currently classified as mature teratoma and managed as if they have equivalent malignant potential. This report describes two cases of adult mature teratoma of dermoid type and questions the classification and pathogenesis of this disease. In one of the cases there was a clear history of a testicular lump arising pre-pubertally, raising the possibility that some adult dermoid tumours may in fact be pre-pubertal teratomas that have persisted into adulthood. Classification as a mature teratoma carries with it a follow-up regimen that includes numerous radiological investigations with their attendant radiation exposure. A positive histological diagnosis and separate classification of adult dermoid tumours would allay clinical fears of recurrence and metastasis and negate the need for repeated radiological investigations.

Late relapse of metastatic non-seminomatous testicular germ cell tumours.

Although the majority of men presenting with non-seminomatous germ cell tumours (NSGCT) are cured, late relapse (occurring more than 2 years after obtaining a complete response to treatment) is increasingly recognized. The typical patterns of disease spread have been well-documented, but the findings at late relapse are more variable and less well-described. We discuss the phenomenon of late relapse, the characteristics of teratoma differentiated (TD), and the issue of long-term imaging surveillance of patients with NSGCT. The potential sites of late relapse of NSGCT and the associated spectrum of imaging appearances are illustrated.

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial.

BACKGROUND: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a risk of late non-germ-cell cancer and cardiovascular events. After good results in initial studies with one injection of carboplatin, we undertook a large randomised trial to compare the approaches of radiotherapy with chemotherapy in seminoma treatment. METHODS: Between 1996 and 2001, 1477 patients from 70 hospitals in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; n=904) or one injection of carboplatin (n=573; dose based on the formula 7x[glomerular filtration rate+25] mg), at two trial centres in the UK and Belgium. The primary outcome measure was the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN27163214. FINDINGS: 885 and 560 patients received radiotherapy and carboplatin, respectively. With a median follow-up of 4 years (IQR 3.0-4.9), relapse-free survival rates for radiotherapy and carboplatin were similar (96.7% [95% CI 95.3-97.7] vs 97.7% [96.0-98.6] at 2 years; 95.9% [94.4-97.1] vs 94.8% [92.5-96.4] at 3 years, respectively; hazard ratio 1.28 [90% CI 0.85-1.93], p=0.32). At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy-chemotherapy) were -1.0% (90% CI -2.5 to 0.5) by direct comparison of proportions, and 0.9% (-0.5 to 3.0) by a hazard-ratio-based approach. Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. New, second primary testicular germ-cell tumours were reported in ten patients allocated irradiation (all after para-aortic strip field) and two allocated carboplatin (5-year event rate 1.96% [95% CI 1.0-3.8] vs 0.54% [0.1-2.1], p=0.04). One seminoma-related death occurred after radiotherapy and none after carboplatin. INTERPRETATION: This trial has shown the non-inferiority of carboplatin to radiotherapy in the treatment of stage I seminoma. Although the absence of disease-related deaths and preliminary data indicating fewer second primary testicular germ-cell tumours favour carboplatin use, these findings need to be confirmed beyond 4 years' follow-up.

The continued value of central histopathological review of testicular tumours.

AIMS: Central histopathological review of testicular tumours prior to definitive treatment can have an important impact on patient management. This study was designed to assess the continued value of central review in the light of increasing subspecialization and increased numbers of consultant histopathologists. MATERIALS AND RESULTS: The original and review reports of 291 testicular cancer specimens from 1998 to 2002 were analysed, looking particularly at major diagnosis, vascular invasion and the tumour elements within non-seminomatous germ cell tumours (NSGCT). When a diagnosis was altered any effect on subsequent patient management was assessed. There was a discrepancy in tumour type in 11 cases (4%) compared with 6% in 1992-1997. The commonest change was from seminoma to NSGCT or combined germ cell tumour (5/11). There was also diagnostic difficulty with spermatocytic seminoma (3/11). The clinical management of all 11 cases was influenced as a result of the review diagnosis. Discrepancies in vascular invasion were noted in 13 of the 126 NSGCTs (10%) compared with 20% in 1992-1997. Differences in NSGCT tumour elements, though clinically less important, were frequent in both groups. CONCLUSIONS: There continues to be a small number of significant and clinically important errors identified following central histopathological review of testicular tumours. This study highlights the value of central review and supports its continued practice in the management of testicular tumours.

A phase II trial of TIP (paclitaxel, ifosfamide and cisplatin) given as second-line (post-BEP) salvage chemotherapy for patients with metastatic germ cell cancer: a medical research council trial.

This phase II trial describes the use of TIP chemotherapy (paclitaxel, ifosfamide and cisplatin) as salvage for patients with metastatic germ cell cancer (GCC) who have failed initial BEP (bleomycin, etoposide and cisplatin) chemotherapy. Patients with first relapse following BEP for metastatic GCC, confirmed by biopsy or sequentially rising markers, received four courses of TIP (paclitaxel 175 mg m(-2) day 1, followed on days 1-5 by ifosfamide 1 g m(-2) intravenously (i.v.) and cisplatin 20 mg2 i.v.) at 3-weekly intervals. The primary outcome measure was response to TIP. In all, 51 patients were registered, of whom 43 were eligible for response assessment. Eight achieved complete remission (CR) and 18 a partial remission with negative markers (PR(-ve)); favourable response rate (FRR = CR + PR(-ve)) 60%, 95% CI (44-75%); survival at 1 year was 70% (56-84%) and failure-free survival 36% (22-50%). In the group of 26 patients meeting the 'good-risk' criteria described by the Memorial Hospital, the FRR was 73% (52-88%) compared with 41% (18-67%) for the 17 'poor-risk' patients. These results are inferior to those previously reported for TIP in a single-centre study when it was given more intensively, at higher dose and with growth factor support. Nonetheless, TIP as described here can cure a substantial proportion of patients.

Adjuvant bleomycin, vincristine and cisplatin (BOP) for high-risk stage I non-seminomatous germ cell tumours: a prospective trial (MRC TE17).

Adjuvant BEP (bleomycin, etoposide, cisplatin) is effective treatment for high-risk clinical stage I (HRCS1) non-seminomatous germ cell tumours (NSGCT), but the known toxicities of etoposide, and the expansion of the HR group to any patient with vascular invasion (50% of patients), led the Medical Research Council to pilot the BOP regimen. Patients received two courses of BOP 14 days apart: cisplatin 50 mg m(-2) days 1 and 2, vincristine 1.4 mg m(-2) (max. 2 mg) days 2 and 8, bleomycin 30,000 IU days 2 and 8. Primary outcome was relapse rate; quality of life, fertility, hearing and lung function were assessed pre- and post-treatment. In all, 100 patients were required. A total of 115 eligible patients were registered, all received two courses of chemotherapy. Median follow-up is 70 months; two relapses have occurred and the 5-year relapse-free rate is 98.3% (95% confidence interval (CI) 95.5%, 99.9%). As assessed by clinicians during treatment, complete (reversible) alopecia was present in 20% of patients; World Health Organization (WHO) grade 1/2 neurotoxicity was present in 41%/5% of patients during treatment and 22%/1% at 6 months. However, 12% of patients reported 'quite a bit' or 'very much' pain/numbness/tingling in hands/feet 2 years after chemotherapy. Mature follow-up confirms high efficacy for two courses of cisplatin-based adjuvant chemotherapy in HRCS1 NSGCT. Substituting vincristine for etoposide decreases alopecia, but gives a low incidence of significant neuropathy. There are no clearcut advantages to 2 x BOP over 2 x BEP, except for patients who wish to maximise the chance of avoiding significant alopecia.

Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group.

PURPOSE: To determine clinical features and patterns of outcome of primary testicular diffuse large B-cell lymphomas (DLCL). PATIENTS AND METHODS: A retrospective international survey of 373 patients with primary testicular DLCL. RESULTS: Most patients presented with localized disease (stage I to II), and the median age at diagnosis was 66 years (range, 19 to 91 years). Anthracycline-based chemotherapy was administered to 255 patients (68%), and prophylactic intrathecal chemotherapy was given to 68 patients (18%); 133 patients (36%) received prophylactic scrotal radiotherapy. Median overall survival was 4.8 years, and median progression-free survival was 4 years. The survival curves showed no clear evidence of a substantial proportion of cured patients. A favorable international prognostic index score (IPI), no B-symptoms, the use of anthracyclines, and prophylactic scrotal radiotherapy were significantly associated with longer survival at multivariate analysis. However, even for patients with stage I disease and good-risk IPI, the outcome seems worse than what was reported for DLCL at other sites. At a median follow-up of 7.6 years, 195 patients (52%) had relapsed. Extranodal recurrence was reported in 140 cases. Relapses in CNS were detected in 56 patients (15%) up to 10 years after presentation. A continuous risk of recurrence in the contralateral testis was seen in patients not receiving scrotal radiotherapy. CONCLUSION: Testicular DLCL is characterized by a particularly high risk of extranodal relapse even in cases with localized disease at diagnosis. Anthracycline-based chemotherapy, CNS prophylaxis, and contralateral testicular irradiation seem to improve the outcome. Their efficacy is under evaluation in a prospective clinical trial.

Brain as sanctuary site of relapse in germ cell cancer patients previously treated with chemotherapy.

BACKGROUND: Post chemotherapy isolated relapse to the brain of germ cell cancer is potentially curable. PATIENTS AND METHODS: We reviewed the experience of germ cell cancer with cerebral metastases at the CRC Wessex Medical Oncology Unit in Southampton. Patients were classified according to their presentation (initial diagnosis, solitary relapse or widespread). Treatment and outcome of these patients is presented and compared with previous series. RESULTS: Of 1049 patients treated for metastatic germ cell cancer, 15 were diagnosed with cerebral metastases. Six patients had cerebral sanctuary site relapse, and underwent resection and cranial irradiation. Four of these are continuously disease free after treatment at 2, 67, 96, and 145 months from therapy, another is receiving chemotherapy for limited systemic relapse and the sixth has relapsed and died. Three further patients relapsed with cerebral disease in the presence of active disease elsewhere and each progressed and died. The final six patients had cerebral disease at presentation of whom five have progressed and died. CONCLUSIONS: Isolated cerebral metastases occurring after successful systemic chemotherapy for germ cell cancer are curable. An aggressive salvage approach with surgery followed by radiotherapy is indicated.

An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study.

BACKGROUND: Burkitt's lymphoma (BL) is a rare and rapidly progressive form of B-cell non-Hodgkin's lymphoma. Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC) is a highly effective alternating non-cross-resistant regimen developed by Magrath et al. (Magrath I., Adde M., Shad A. et al. J Clin Oncol 1996; 14: 925-934) at the US National Cancer Institute. The aim was to confirm these results in a larger, international, multi-centre study using International Prognostic Index-based criteria to assign prognostic groups, whilst slightly simplifying the protocol. PATIENTS AND METHODS: A phase II study where: (i) low risk (LR) patients were treated with three cycles of modified CODOX-M; and (ii) high risk (HR) patients received treatment with four cycles of alternating modified CODOX-M and IVAC chemotherapy. Target of 60 patients, fit for protocol treatment, from 16 to 60 years of age with locally diagnosed, non-HIV-related, non-organ-transplant-related BL. RESULTS: Results are given for 52 of 72 registered patients whose pathological eligibility was confirmed by central pathology review: 12 LR plus 40 HR. The majority of patients (n = 41) completed protocol treatment, but toxicity was severe, especially myelosuppression and mucositis. Overall, 2-year event-free survival (EFS) was 64.6% (95% CI 50.4% to 78.9%) and 2-year overall survival (OS) was 72.8% (95% CI 59.4% to 86.3%). For LR, 2-year EFS was 83.3% and OS was 81.5%. For HR, 2-year EFS was 59.5% and OS was 69.9%. CONCLUSIONS: This study confirms high cure rates with this CODOX-M/IVAC approach.

Orchidectomy after chemotherapy for patients with metastatic testicular germ cell cancer.

OBJECTIVE: To evaluate the contribution of routine orchidectomy in the management of patients who present with advanced, metastatic, testicular germ cell cancer and who are treated with initial chemotherapy. PATIENTS AND METHODS: Sixty consecutive patients presenting with metastatic testicular germ cell cancer and treated with initial chemotherapy followed by orchidectomy were identified. The results from a clinical and pathological review of these patients are presented. The pathological findings at orchidectomy were compared with the pathological findings from metastatic masses resected after chemotherapy, and are reviewed with the clinical outcome. RESULTS: Of the 60 orchidectomy specimens after chemotherapy, 24 (40%) contained significant histological abnormalities comprising residual invasive germ cell cancer, intratubular germ cell neoplasia and/or mature teratoma. The remaining 36 (60%) orchidectomy specimens contained fibrous scarring with or with no necrosis. Six (10%) orchidectomy specimens contained residual invasive germ cell cancer, three nonseminomatous germ cell cancer (NSGCT) and three seminoma. The patients with residual invasive NSGCT present within the testis had evidence of residual invasive NSGCT within extragonadal masses resected after chemotherapy; all three have relapsed and died from chemorefractory progressive disease. CONCLUSION: Orchidectomy after chemotherapy is recommended in all patients undergoing primary chemotherapy, as a significant proportion (40%) are left with histological abnormalities that predispose to subsequent relapse. Persistence of invasive NSGCT at the site of the primary tumour after chemotherapy is associated with persistence of invasive disease at other metastatic sites and is a poor prognostic finding.

Routine computerised tomographic scans of the thorax in surveillance of stage I testicular non-seminomatous germ-cell cancer--a necessary risk?

BACKGROUND: The standard management approach to stage I testicular non-seminomatous germ-cell tumours (NSGCT) in the UK is a surveillance programme with adjuvant bleomycin, etoposide, cisplatin (BEP) chemotherapy being offered to individuals with high risk disease. Conventionally, computed tomography (CT) scanning of the thorax has formed part of the surveillance programme. This paper evaluates the contribution of routine thoracic CT imaging in the management of this disease. PATIENTS AND METHODS: We retrospectively reviewed the case notes of 168 patients with stage I NSGCT referred to the Wessex Medical Oncology Unit over a period of 13 years (1986-1998). These patients entered onto a surveillance programme that included serial chest X-ray follow up rather than thoracic CT. RESULTS: Forty-two out of 168 patients (25%) evaluated suffered relapse during the follow up period. Eight of 42 patients (19%) relapsed with intrathoracic disease. Seven out of eight of these patients (87.5%) had at least one other indicator of disease recurrence (elevated serum marker, abnormal abdominal CT). One of 42 patients (2.4%) relapsed with isolated intrathoracic disease with no other indicator of relapse. All patients with intrathoracic relapse had evidence of disease on chest X-ray. Of the 42 relapsing patients, 93% could be categorised as having good prognosis metastatic disease. Seven per cent relapsed with intermediate or poor prognostic disease; relapse in these patients would not have been detected earlier with the inclusion of routine thoracic CT. Only one patient has died giving a cure rate of 98% for relapsing patients. CONCLUSIONS: The elimination of chest CT did not compromise outcome but significantly reduced radiation exposure thereby minimising the risk of radiation-induced secondary malignancy. Continued review of surveillance programmes is essential if we are to optimise management of this disease.

Management of spinal cord and cauda equina compression secondary to epidural metastatic disease in adults with malignant germ cell tumours.

AIM: To review the management and clinical outcome of 10 patients, presenting to a single centre with symptoms and signs of spinal cord or cauda equina compression secondary to epidural metastatic disease from a testicular germ cell cancer. METHODS: Clinical data regarding presenting history, physical examination, staging investigations, treatment and clinical outcome were retrospectively obtained from patient records. RESULTS: Eight patients exhibited neurological deficits at the time of initial presentation of germ cell cancer or as a first manifestation of relapse following dog leg irradiation. Four of these cases were managed with chemotherapy alone, with excellent neurological recovery, whilst four underwent decompressive laminectomy--in three cases prior to referral and in one case after commencing chemotherapy. Five of the eight patients relapsed. Four required further chemotherapy (high dose in two cases). The remaining patient underwent thoracic surgery, with resection of teratoma differentiated. Six of the eight patients are currently alive and disease free. Two patients had chemorefractory disease and died, though one was treated in the pre-cisplatin era. Two patients presented with cord compression as a feature of disease relapse following chemotherapy, and were managed with radiotherapy alone in an attempt to achieve local disease control and limit neurological dysfunction. However, both subsequently died with progressive disease. CONCLUSION: Epidural spinal cord or cauda equina compression is a rare complication of metastatic germ cell cancer, which can be successfully managed in chemo-naive patients with good neurological outcome.