Two decades of FDG-PET/CT in seminoma: exploring its role in diagnosis, surveillance and follow-up.

BACKGROUND: Survivors of testicular cancer may experience long-term morbidity following treatment. There is an unmet need to investigate techniques that can differentiate individuals who need additional therapy from those who do not. 2-18fluoro-deoxy-D-glucose (FDG) positron emission tomography (PET) with computerised tomography (CT) may be helpful in select settings and may be used outside of current evidence-based recommendations in real-world practice. METHODS: A institutional FDG-PET/CT database of scans performed between 2000 and 2020 for adults with testicular seminoma was interrogated. Endpoints of interest included the positive (PPV) and negative (NPV) predictive value of FDG-PET/CT for identifying active seminoma (defined by progressive radiology, response to treatment or biopsy); or no active seminoma within 24-months for patients with stage 1 and advanced seminoma. An exploratory analysis examining predictive role of SUVmax was also performed. RESULTS: 249 patients met eligibility criteria for the analysis, including 184 patients with stage 1 and 77 patients with advanced testicular seminoma. Of 193 FDG-PET/CT performed in stage 1 seminoma with available follow-up data, 79 were performed during active surveillance. 18 (23%) of these were positive, all of which had confirmed recurrent seminoma (PPV 100%). Of 45 negative FDG-PET/CT during active surveillance, 4 recurrences developed corresponding to a NPV 91%. When clinical suspicion precipitated FDG-PET/CT (n = 36): PPV 100%, NPV 86%. Of 145 FDG-PET/CT in advanced seminoma with available follow-up data, 25 (17%) were performed at baseline (within 2 months of diagnosis), 70 (48%) post-treatment for evaluation of treatment response and 50 (34%) during follow-up following prior curative treatment. 10 (14%) post-treatment FDG-PET/CT were positive corresponding to a PPV 60%. Of 46 negative FDG-PET/CT, 5 recurrences occurred (NPV 89%). During follow-up after prior curative treatment, 24 (50%) FDG-PET/CT were positive corresponding to a PPV 83%; of 20 negative FDG-PET/CT, 1 recurrence occurred, NPV 95%. When clinical suspicion indicated FDG-PET/CT (n = 36): PPV 100%, NPV 94%. CONCLUSION: FDG-PET/CT offers high PPV for identifying seminoma and accurately predicts non-recurrence across a clinically relevant 24-months. Notably, FDG-PET/CT may prevent unnecessary treatment in 45% of patients undergoing investigation for clinical suspicion of recurrence during follow-up of advanced seminoma. The use of FDG-PET/CT in selected patients now, may help prevent unnecessary treatment of people with testicular seminoma.

The impact of chemotherapy on cognitive function: a multicentre prospective cohort study in testicular cancer.

PURPOSE: The causal link between chemotherapy and cognitive impairment is unclear. We studied testicular cancer patients' objective and subjective cognitive function longitudinally, comparing a surgery group with a surgery + chemotherapy group, addressing prior methodological issues using a computerized test to limit assessment issues, and controlling for confounding variables. METHODS: Prospectively, of 145 patients from 16 centres with sufficient data, n = 61 receiving surgery + chemotherapy (etoposide and cisplatin ± bleomycin, BEP/EP; or single agent carboplatin) were compared to n = 41 receiving surgery alone. CogHealth assessed six objective cognitive tasks. The Cognitive Failures Questionnaire assessed self-perceived cognitive dysfunction. The Functional Assessment of Chronic Illness Therapy-Fatigue and the Hospital Anxiety and Depression Scale assessed psychological influences. Linear mixed models compared changes from baseline (< 6 months post-surgery/pre-chemotherapy) to follow-up (12-18 months post-baseline), controlling covariates. RESULTS: There were no significant interaction effects for five objective cognitive function tasks suggesting that changes over time were not due to group membership. However, psychomotor function (controlling for age) and physical well-being were significantly worse for the chemotherapy versus the surgery group at baseline, with groups converging by follow-up. Groups showed no differences in subjective cognitive dysfunction. The chemotherapy group showed higher anxiety, poorer functional well-being and worse fatigue compared to the surgery-only group at baseline, but not by follow-up. For both groups, emotional well-being, functional well-being and anxiety significantly improved over time. CONCLUSION: No substantive differences in objective or subjective cognitive dysfunction in either group persisted 12-18 months post-baseline. Patients undergoing chemotherapy for testicular cancer differ from findings in breast cancer populations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ACTRN12609000545268.

The prevalence, severity, and correlates of psychological distress and impaired health-related quality of life following treatment for testicular cancer: a survivorship study.

PURPOSE: This study aimed to establish the prevalence, severity, and correlates of psychological distress and impaired generic health-related quality of life (HRQOL) in testicular cancer (TC) survivors. METHODS: Men who had completed active anti-cancer treatment for TC between 6 months and 5 years previously showing no evidence of recurrence were recruited from 14 Australian cancer centers from September 2009 to February 2011. Participants completed a self-report questionnaire measuring demographic, disease, and treatment information, psychological distress (i.e., depression, anxiety, and stress; DASS21), generic health-related quality of life (HRQOL; SF-36v2), TC-specific HRQOL (EORTC QLQ-TC26), coping (MAC), social support (DUFSS), and unmet needs (CaSUN). RESULTS: Of 486 eligible TC survivors, 244 (50.2%) completed the questionnaire. Compared with normative data, TC survivors reported: small but statistically significant increases in mean levels of anxiety and depression; a greater prevalence of moderate to extremely severe anxiety (19%) and depression (20%); and significant deficits to mostly mental aspects of generic HRQOL. The most problematic TC-specific HRQOL issues (e.g., fear of recurrence) were also more mental than physical. In multiple regression analyses, the strongest correlates of psychological distress and impaired generic HRQOL were psychosocial (e.g., helpless/hopeless coping and lower social support) rather than disease or treatment factors. CONCLUSIONS: Generally, TC survivors appear to experience mild psychological distress and HRQOL impairments, while a vulnerable subgroup experience more severe morbidity. IMPLICATIONS FOR CANCER SURVIVORS: There is a need to identify TC survivors at risk of poorer outcomes and for interventions to target the areas of greatest impairment (i.e., psychological distress and mental HRQOL).

The prevalence and correlates of supportive care needs in testicular cancer survivors: a cross-sectional study.

OBJECTIVE: This cross-sectional study aimed to identify the prevalence and correlates of supportive care needs in testicular cancer (TC) survivors. METHODS: Men who had completed active anti-cancer treatment for TC between 6 months and 5 years previously showing no evidence of recurrence were recruited from 14 Australian cancer centers (September 2009-February 2011). Participants completed a self-report questionnaire measuring sociodemographics, disease, and treatment information, supportive care needs (CaSUN), psychological distress (DASS21) and health-related quality of life (HRQoL; SF36v2). RESULTS: Of the 486 eligible TC survivors invited to participate, 244 completed the questionnaire. Sixty-six percent reported one or more unmet supportive care needs. The mean number of unmet needs was 4.73 (SD = 7.0, Range = 0-34). The most common unmet needs related primarily to existential survivorship issues (e.g., life stress) and relationships (e.g., sex life). Younger age and presence of chronic illness other than TC were significantly associated with higher number of unmet needs. The number of unmet needs was more highly correlated with psychological distress and HRQoL than unmet need strength. CONCLUSIONS: The majority of TC survivors reported one or more unmet needs. Unmet needs regarding existential survivorship issues were frequently reported by TC survivors despite their favorable prognosis. Relationships unmet needs were less prevalent but still more common than in breast and gynecological cancer survivors. These findings appear to be related to the young age of TC survivors. As a higher number of unmet needs is significantly associated with psychological morbidity and impaired HRQoL, interventions addressing this constellation of issues are needed.

Patterns of management and surveillance imaging amongst medical oncologists in Australia for stage I testicular cancer.

OBJECTIVE: To determine the patterns of management and surveillance imaging amongst medical oncologists in Australia for stage I testicular cancer during 2010. METHODS: We conducted a survey comprising 14 questions about the management strategy and surveillance imaging for all patients with stage I testicular cancer treated over the previous 12 months. RESULTS: A total of 52 medical oncologists documented the management for an estimated 470 patients. For seminoma, management was in the form of surveillance in 33%, radiotherapy in 5% and adjuvant carboplatin in 62% of patients. For non-seminoma, management was surveillance in 73%, adjuvant chemotherapy in 23% and retroperitoneal lymph node dissection in 4% of patients. The frequency of surveillance imaging was highly variable, and ≥10 computed tomography (CT) scans were used by 38% of clinicians for seminoma and 46% of clinicians for non-seminoma. CONCLUSION: We found considerable variation in management patterns. The infrequent use of surveillance and frequent use of carboplatin for seminoma differs from international guidelines. Radiation exposure from CT imaging should be reduced through standardized follow-up protocols, and possibly by alternate imaging methods if validated in appropriate studies.

Pharmacodynamic analysis of tumour perfusion assessed by 15O-water-PET imaging during treatment with sunitinib malate in patients with advanced malignancies.

BACKGROUND: We evaluated pharmacodynamic changes in tumour perfusion using positron emission tomography (PET) imaging with 15O-water to assess biological response to sunitinib, a multitargeted tyrosine kinase inhibitor. METHODS: Patients with advanced malignancies received sunitinib 50 mg/day orally, once daily for 4 weeks on treatment, followed by 2 weeks off treatment, in repeated 6-week cycles. Quantitative measurement of tumour perfusion was assessed using 15O-water-PET at baseline and after 2 weeks of treatment. At least one reference tumour lesion was included in the fields of view and assessed at both time points. Patients also underwent 18 F-fluorodeoxyglucose (FDG)-PET imaging at baseline and after 2 and 4 weeks of treatment. Radiological response of the reference tumour lesion and overall radiological response were assessed at week 12. Serum pharmacokinetic and biomarker analyses were also performed. RESULTS: Data were available for seven patients. Compared with baseline, all patients experienced a decrease in reference tumour blood flow ranging from 20 % to 85 % and also a reduction in the FDG standard uptake value ranging from 29 % to 67 %. Six patients experienced a partial metabolic response based on FDG-PET criteria. Four patients had stable disease defined by radiological response (Response Evaluation Criteria in Solid Tumors) lasting between 4 and 12 cycles. An association between perfusion change and clinical benefit, and biomarker levels including vascular endothelial growth factor was observed. CONCLUSION: Administering sunitinib to patients with advanced malignancies is associated with early biological responses, including decreased blood flow in secondary tumour deposits.

R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study.

PURPOSE: The type 1 insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the pathogenesis of the Ewing sarcoma family of tumors (ESFT). We conducted a multicenter phase II study of the fully human IGF-1R monoclonal antibody R1507 in patients with recurrent or refractory ESFT. PATIENTS AND METHODS: Patients ≥ 2 years of age with refractory or recurrent ESFT received R1507 at doses of 9 mg/kg intravenously one a week or 27 mg/kg intravenously every three weeks. Response was measured by using WHO criteria. Tumor imaging was performed every 6 weeks for 24 weeks and then every 12 weeks. RESULTS: From December 2007 through April 2010, 115 eligible patients from 31 different institutions were enrolled. The median age was 25 years (range, 8 to 78 years). The location of the primary tumor was bone in 57% of patients and extraskeletal in 43% of patients. A total of 109 patients were treated with R1507 9 mg/kg/wk, and six patients were treated with 27 mg/kg/3 wk. The overall complete response/partial response rate was 10% (95% CI, 4.9% to 16.5%). The median duration of response was 29 weeks (range, 12 to 94 weeks), and the median overall survival was 7.6 months (95% CI, 6 to 9.7 months). Ten of 11 responses were observed in patients who presented with primary bone tumors (P = .016). The most common adverse events of grades 3 to 4 were pain (15%), anemia (8%), thrombocytopenia (7%), and asthenia (5%). CONCLUSION: R1507 was a well-tolerated agent that had meaningful and durable benefit in a subgroup of patients with ESFT. The identification of markers that are predictive of a benefit is necessary to fully capitalize on this approach.

Management of low-stage nonseminomatous germ cell tumors of testis: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009.

OBJECTIVE: To advise urologists and other clinicians on the appropriate management of low-stage (clinical Stage [CS] I, IS, IIA, and IIB) nonseminomatous germ cell tumors of the testis. METHODS: A panel was convened of experts from 5 countries. A literature search in MEDLINE was used to identify evidence from relevant studies on the outcome and toxicity of observational, surgical, and chemotherapeutic approaches for low-stage nonseminomatous germ cell tumors to form the basis of the panel's recommendations. RESULTS: The panel has recommended the treatment of nonseminomatous germ cell tumors in centers with medical, surgical, and diagnostic expertise in testicular cancer. The cancer-specific survival rate for CS I and CS IIA-IIB should approach 100% and 95%-100%, respectively. Patients with CS I should be made aware of all treatments (ie, surveillance, primary chemotherapy, and retroperitoneal lymph node dissection) and the potential side effects. For patients with CS I at low risk of occult metastasis, surveillance is preferred. For patients at high risk of occult metastasis, all 3 options can be considered. For immediate treatment, the choice between primary chemotherapy and retroperitoneal lymph node dissection should be determined by patient preference and the specific expertise of the treating institution. Patients with increasing postorchiectomy serum α-fetoprotein or human choriogonadotropin levels (CS IS and CS IIA-IIB) should receive induction chemotherapy. Induction chemotherapy or retroperitoneal lymph node dissection can be considered for patients with CS IIA-IIB with normal postorchiectomy α-fetoprotein and human choriogonadotropin levels. Surveillance can be considered for patients with equivocal computed tomography retroperitoneal findings who are otherwise at low risk of metastatic disease. CONCLUSION: These clinical practice guidelines are designed to improve clinical practice from the available evidence and the expert opinion of the panel. As such, deviation from these recommendations should be based on sound clinical judgment, considering the unique situation of the patient and the expertise of the treating physician and institution.

Comparison of two standard chemotherapy regimens for good-prognosis germ cell tumors: updated analysis of a randomized trial.

BACKGROUND: The Australian and New Zealand Germ Cell Trials Group conducted a multicenter randomized phase III trial in men with good-prognosis germ cell tumors of two standard chemotherapy regimens that contained bleomycin, etoposide, and cisplatin but differed in the scheduling and total dose of cisplatin, the total dose of bleomycin, and the scheduling and dose intensity of etoposide. The trial was stopped early at a median follow-up of 33 months after a planned interim analysis found a survival benefit for the more dose-intense regimen. The aim of this analysis was to determine if this survival benefit was maintained with long-term follow-up. METHODS: Between February 1994 and April 2000, 166 men with good-prognosis metastatic germ cell tumors defined by modified Memorial Sloan-Kettering criteria were randomly assigned to receive 3B(90)E(500)P (three cycles, repeated every 21 days, of 30 kU bleomycin on days 1, 8, and 15; 100 mg/m(2) etoposide on days 1-5; and 20 mg/m(2) cisplatin on days 1-5; n = 83) or 4B(30)E(360)P (four cycles, repeated every 21 days, of 30 kU bleomycin on day 1, 120 mg/m(2) etoposide on days 1-3, and 100 mg/m(2) cisplatin on day 1; n = 83). Endpoints included overall survival, progression-free survival, and quality of life and side effects, which were assessed using the Spitzer Quality of Life Index and the GLQ-8, respectively, before random assignment and during and after treatment. All analyses were by intention to treat. All P values are two-sided. RESULTS: The median follow-up was 8.5 years. All but five survivors (3%) were followed up for at least 5 years. Overall survival remained better in those assigned to 3B(90)E(500)P than in those assigned to 4B(30)E(360)P (8-year survival: 92% vs 83%; hazard ratio of death = 0.38, 95% confidence interval = 0.15 to 0.97, P = .037). Progression-free survival favored 3B(90)E(500)P but was not statistically significantly different between the treatment groups (8-year progression-free survival, 3B(90)E(500)P vs 4B(30)E(360)P: 86% vs 79%; hazard ratio of progression = 0.6, 95% confidence interval = 0.3 to 1.1, P = .15). At the end of treatment, average scores for most side effect scales favored 3B(90)E(500)P. After the completion of treatment, average GLQ-8 scores for numbness (P = .003) and hair loss (P = .04) and the Spitzer Quality of Life Index (P = .05) favored 3B(90)E(500)P. CONCLUSION: The survival benefit of 3B(90)E(500)P over 4B(30)E(360)P was maintained with long-term follow-up.

An open-label, single-arm phase two trial of gefitinib in patients with advanced or metastatic castration-resistant prostate cancer.

OBJECTIVE: To determine whether the oral epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839, Iressa has clinical efficacy in patients with castration-resistant prostate cancer (CRPC). METHODS: Multicenter open-label phase 2 study. Fifty-one male patients with CRPC and rising PSA levels were enrolled to obtain the target enrollment of 38 patients who completed at least 3 months of treatment with continuous gefitinib 500 mg/d. The primary end point was the prostate-specific antigen (PSA) response rate, as defined by a confirmed 50% decline in serum PSA. RESULTS: One patient had a confirmed PSA response, giving a response rate of 2.0% (95% CI 0.1-10.4%). The median time to progression was 28 days and the median time on study was 85 days. The majority of patients had a stable performance status while on study. Of the 51 patients who received at least 1 dose of gefitinib, 13 patients had a dose reduction and 9 patients withdrew because of an adverse event. CONCLUSIONS: There was minimal evidence of single-agent gefitinib activity in CRPC. The treatment was associated with clinically relevant toxicities, which responded to dose interruption or reduction.

Gender-specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood.

Good evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender-related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms.

Apical ballooning syndrome during treatment with a vascular endothelial growth factor receptor antagonist.

Apical ballooning syndrome (ABS) describes acute regional myocardial dysfunction and has a strong association with emotional stress and female sex. Whilst catecholamine excess has been described in this condition, the precise etiology remains elusive. We report the atypical case of a 61 year old male who developed ABS in the absence of a clear precipitant. His concurrent treatment with a vascular endothelial growth factor (VEGF) receptor antagonist may provide an insight into the pathogenesis of this enigmatic condition. We present a biologically plausible explanation as to why VEGF antagonism may have an important role through its modulation of nitric oxide and catecholamine effects. This hypothesis may also provide an important insight into the cardiovascular toxicities associated with this class of drug. In addition, we report the success of treatment with a beta blocker in ABS complicated by a severe left ventricular outflow tract obstruction.

PET for sarcomas other than gastrointestinal stromal tumors.

Positron emission tomography (PET) is increasingly used to diagnose, grade, and stage different types of tumors and to assess tumor response to therapy. Metabolic data acquired by fluorine-18-fluorodeoxyglucose (18FDG)-PET may facilitate accurate grading of sarcomas and have prognostic value when combined with other grading methods and various clinical/radiological features. In addition, 18FDG-PET is currently being evaluated in several cancer types for its utility in biopsy guidance. Whole-body 18FDG-PET also appears to be superior to other imaging modalities in detecting bone metastases in certain sarcoma patients. New PET tracers currently being investigated include 18F-fluorothymidine (18F-FLT) and 18F-misonidazole. 18F-FLT can help to determine tumor growth, rather than tumor shrinkage, which could be used to evaluate treatment response in sarcomas. PET imaging offers invaluable information to help maximize the clinical benefit of patients with sarcoma. This article reviews the use of PET in sarcoma management and its potential applications in the near future.

Sustained clinical responses to tyrosine kinase inhibitor sunitinib in thyroid carcinoma.

The limited therapeutic options available for patients with metastatic papillary thyroid carcinomas (PTC) and follicular thyroid carcinomas (FTC) necessitates the development of novel therapies. Identification of somatic rearrangements of the tyrosine kinase domain of the RET gene in PTC have improved our understanding of thyroid tumorigenesis. Sunitinib is active against the RET kinase and has both antineoplastic and antiangiogenic properties. Its role in the treatment of patients with thyroid carcinoma has yet to be evaluated in clinical trials. Two patients with progressive metastatic thyroid carcinoma (case 1: PTC, and case 2: FTC) were enroled in a phase I clinical trial to evaluate positron emission tomography (PET) in the monitoring of response to sunitinib. Tumour biopsies and PET were performed at baseline and 4 weeks after the commencement of sunitinib. Activation of the RET kinase pathway was evaluated using immunohistochemistry (IHC) and western blot analysis of total phosphorylated tyrosine and downstream signalling targets of the RET pathway. Both patients demonstrated sustained clinical responses to sunitinib over a duration of 4 years. In case 1, (PTC) PET confirmed evidence of a partial metabolic response, and IHC and western blot analysis demonstrated inhibition of the RET kinase pathway posttreatment. In case 2, (FTC) PET confirmed stable disease after sunitinib. IHC staining of the tumour showed low total phosphorylated tyrosine staining at baseline which did not change after treatment. These case studies highlight potential activity of sunitinib in patients with metastatic thyroid carcinoma. Sunitinib seems to be a promising agent in the treatment of thyroid cancers and this requires validation in future clinical trials.

The challenge of poor-prognosis germ cell tumors.

Patients who have a poor prognosis can be identified at presentation by well-defined prognostic factors. Prognostic groups as defined by the International Germ Cell Consensus Classification should be used in the clinic, in clinical trials, and when reporting results. No systemic treatment has been shown to improve outcome compared with four cycles of chemotherapy composed of bleomycin, etoposide, and cisplatin, which remains the standard of care. Surgery to resect residual masses after chemotherapy and in the salvage setting is a vital component of optimal care. The best outcomes occur with treatment at a center with experience and expertise in their management. Further major improvements are likely to require novel systemic therapies rather than modifications of existing approaches.

Clinical applications of molecular imaging in sarcoma evaluation.

A wide range of molecular imaging techniques are available that can provide complementary information to conventional, anatomical imaging for the evaluation of known or suspected bone and soft tissue sarcomas. In particular, positron emission tomography (PET), particularly in the form of hybrid PET/CT technology, offers many potential advantages over current imaging approaches by delineating not only the extent of disease but also the biological heterogeneity that can exist both between and within sarcomas. This review discusses the clinical situations where nuclear medicine techniques can aid in the management of patients with sarcoma. These include biopsy guidance, whole body staging, therapeutic response assessment and evaluation of residual mass lesions after treatment.