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1.  Improved Outcome of Central Nervous System Germ Cell Tumors: Implications for the Role of Risk-adapted Intensive Chemotherapy 
Journal of Korean Medical Science  2010;25(3):458-465.
To determine the impact of treatment protocols on the outcome of central nervous system germ cell tumors (CNS-GCTs), we reviewed the medical records of 53 patients who received front-line chemotherapy from September 1997 to September 2006. Pure germinoma, normal alpha-fetoprotein level and beta-human chorionic gonadotropin level <50 mIU/mL were regarded as low-risk features and the others as high-risk. Patients from different time periods were divided into 3 groups according to the chemotherapy protocols. Group 1 (n=19) received 4 cycles of chemotherapy comprising cisplatin, etoposide and bleomycin. Group 2 (n=16) and group 3 (n=18) received 4 cycles of chemotherapy with cisplatin, etoposide, cyclophosphamide and vincristine in the former and with carboplatin, etoposide, cyclophosphamide and bleomycin in the latter. In group 2 and group 3, high-risk patients received double doses of cisplatin, carboplatin and cyclophosphamide. Radiotherapy was given after chemotherapy according to the clinical requirements. The event-free survivals of groups 1, 2, and 3 were 67.0%, 93.8%, and 100%, respectively (group 1 vs. 2, P=0.06; group 2 vs. 3, P=0.29; group 1 vs. 3, P=0.02). Our data suggest that risk-adapted intensive chemotherapy may improve the outcome of patients with malignant CNS-GCTs.
doi:10.3346/jkms.2010.25.3.458
PMCID: PMC2826748  PMID: 20191048
Neoplasms, Germ Cell and Embryonal; Central Nervous System; Drug Therapy; Survival
2.  TI-CE High-Dose Chemotherapy for Patients With Previously Treated Germ Cell Tumors: Results and Prognostic Factor Analysis 
Journal of Clinical Oncology  2010;28(10):1706-1713.
Purpose
We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients.
Patients and Methods
Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide-cisplatin–based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed.
Results
Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin ≥ 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models.
Conclusion
TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome.
doi:10.1200/JCO.2009.25.1561
PMCID: PMC3651604  PMID: 20194867
3.  Optimal chemotherapy treatment for women with recurrent ovarian cancer 
Current Oncology  2007;14(5):195-208.
Question
What is the optimal chemotherapy treatment for women with recurrent ovarian cancer who have previously received platinum-based chemotherapy?
Perspectives
Currently, standard primary therapy for advanced disease involves a combination of maximal cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel or with carboplatin alone. Despite initial high response rates, a large proportion of patients relapse, resulting in a therapeutic challenge. Because these patients are not curable, the goal of therapy becomes improvement in both quality and length of life. The search has therefore been to find active agents for women with recurrent disease following platinum-based chemotherapy.
Outcomes
Outcomes of interest included any combination of tumour response rate, progression-free survival, overall survival, adverse events, and quality of life.
Methodology
The medline, embase, and Cochrane Library databases were systematically searched for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. The systematic review and recommendations were approved by the Report Approval Panel of the Program in Evidence-Based Care, and by the Gynecology Cancer Disease Site Group (dsg). The practice guideline was externally reviewed by a sample of practitioners from Ontario, Canada.
Results
Thirteen randomized trials compared various chemotherapy regimens for patients with recurrent ovarian cancer.
In five of the thirteen trials in which 100% of patients were considered sensitive to platinum-containing chemotherapy, further platinum-based combination chemotherapy significantly improved response rates (two trials), progression-free survival (four trials), and overall survival (three trials) when compared with single-agent chemotherapy involving carboplatin or paclitaxel. Only two of these randomized trials compared the same chemotherapy regimens: carboplatin alone versus the combination of carboplatin and paclitaxel. Both trials were consistent in reporting improved survival outcomes with the combination of carboplatin and paclitaxel. In one trial, the combination of carboplatin and gemcitabine resulted in significantly higher response rates and improved progression-free survival when compared with carboplatin alone. Median survival with carboplatin alone ranged from 17 months to 24 months in four trials.
In eight of the thirteen trials in which 35%–100% of patients had platinum-refractory or -resistant disease, one trial reported a statistically significant 2-month improvement in overall survival with liposomal doxorubicin as compared with topotecan (15 months vs. 13 months, p = 0.038; hazard ratio: 1.23; 95% confidence interval: 1.01 to 1.50). In that trial, because of the limited clinical benefit and the unusual finding that a survival difference emerged only after a year of treatment with no corresponding improvement in the rate of response or of progression-free survival, the authors concluded that further confirmation by results from randomized trials were needed to establish the superiority of one agent over another in their trial. In one trial, topotecan was superior to treosulphan in patient progression-free survival by a span of approximately 2 months (5.4 months vs. 3.0 months, p < 0.001).
Toxicity was reported in all of the randomized trials, and although data on adverse events varied by treatment regimen, the observed adverse events correlated with known toxicity profiles. As expected, combination chemotherapy was associated with higher rates of adverse events.
Practice Guideline
Target Population
This clinical recommendation applies to women with recurrent epithelial ovarian cancer who have previously received platinum-based chemotherapy. Of specific interest are women who have previously shown sensitivity to platinum therapy and those who previously were refractory or resistant to platinum-based chemotherapy. As a general categorization within what is actually a continuum, “platinum sensitivity” refers to disease recurrence 6 months or more after prior platinum-containing chemotherapy, and “platinum resistance” refers to a response to platinum-based chemotherapy followed by relapse less than 6 months after chemotherapy is stopped. “Platinum-refractory disease” refers to a lack of response or to progression while on platinum-based chemotherapy.
Recommendations
Although the body of evidence that informs the clinical recommendations is based on randomized trial data, those data are incomplete. Based on the available data and expert consensus opinion, the Gynecology Cancer dsg makes these recommendations:
Systemic therapy for recurrent ovarian cancer is not curative. It is therefore recognized that each patient must be individually assessed to determine optimal therapy in terms of recurrence, sensitivity to platinum, toxicity, ease of administration, and patient preference. All suitable patients should be offered the opportunity to participate in randomized trials, if available.
In the absence of contraindications, combination platinum-based chemotherapy should be considered for patients with prior sensitivity to platinum-containing chemotherapy. As compared with carboplatin alone, the combination of carboplatin and paclitaxel significantly improved both progression-free and overall survival.
If combination platinum-based chemotherapy is not indicated, then a single platinum agent should be considered. Carboplatin has demonstrated efficacy across trials and has a manageable toxicity profile.
If a single platinum agent is not being considered, then monotherapy with paclitaxel, topotecan, or pegylated liposomal doxorubicin are seen as reasonable treatment options.
Some patients may be repeatedly sensitive to treatment and may benefit from multiple lines of chemotherapy.
For patients with platinum-refractory or platinum-resistant disease, the goals of treatment should be to improve quality of life by extending the symptom-free interval, by reducing symptom intensity, and by increasing progression-free interval, and, if possible, to prolong life.
With non-platinum agents, monotherapy should be considered because no advantage appears to accrue to the use of non-platinum-containing combination chemotherapy in this group of patients. Single-agent paclitaxel, topotecan, or pegylated liposomal doxorubicin have demonstrated activity in this patient population and are reasonable treatment options.
No evidence either supports or refutes the use of more than one line of chemotherapy in patients with platinum-refractory or platinum-resistant recurrence. Many treatment options have shown modest response rates, but their benefits over best supportive care have not been studied in clinical trials.
PMCID: PMC2002482  PMID: 17938703
Chemotherapy; drug therapy; ovarian cancer; ovarian neoplasms; practice guideline; systematic review
4.  The risk of thrombo-embolic events is increased in patients with germ-cell tumours and can be predicted by serum lactate dehydrogenase and body surface area 
British Journal of Cancer  2005;93(8):909-914.
The aim of this study was to evaluate the risk of thrombo-embolic events (TEE) in patients with germ-cell tumours (GCT) who receive cisplatin-based chemotherapy, to compare this risk to that of a matched control group of non-GCT cancer patients, and to identify risk factors of TEE. The rate of TEE during the 6 months following the initiation of chemotherapy was assessed in 100 consecutive patients with GCT and in 100 controls with various neoplasms who were matched on sex and age, and who received first-line cisplatin-based chemotherapy during the same period of time at Institut Gustave Roussy, Villejuif, France. Data were subsequently tested on a validation group of 77 GCT patients treated in Lyon, France. A total of 19 patients (19%) (95% confidence interval (CI): 13–28) and six patients (6%) (95% CI: 3–13) had a TEE in the GCT group and the non-GCT control group, respectively (relative risk (RR): 3.4; P<0.01). Three patients from the GCT group died of pulmonary embolism. In multivariate analysis, two factors had independent predictive value for TEE: a high body surface area (>1.9 m2) (RR: 5 (1.8–13.9)) and an elevated serum lactate dehydrogenase (LDH) (RR: 6.4 (2.3–18.2)). Patients with no risk factor (n=26) and those with at least one risk factor (n=71) had a probability of having a TEE of 4% (95% CI: 1–19) and 26% (95% CI: 17–37), respectively. In the GCT validation set, 10 (13%) patients had a TEE; patients with no risk factor and those with at least one risk factor had a probability of having a TEE of 0 and 17% (95% CI: 10–29), respectively. Patients with GCT are at a higher risk for TEE than patients with non-GCT cancer while on cisplatin-based chemotherapy. This risk can be accurately predicted by serum LDH and body surface area. This predictive index may help to study prospectively the impact of thromboprophylaxis in GCT patients.
doi:10.1038/sj.bjc.6602791
PMCID: PMC2361657  PMID: 16205699
cancer of the testis; chemotherapy; cisplatin; germ-cell tumour; thrombosis
5.  Pediatric primary central nervous system germ cell tumors of different prognosis groups show characteristic miRNome traits and chromosome copy number variations 
BMC Genomics  2010;11:132.
Background
Intracranial pediatric germ cell tumors (GCTs) are rare and heterogeneous neoplasms and vary in histological differentiation, prognosis and clinical behavior. Germinoma and mature teratoma are GCTs that have a good prognosis, while other types of GCTs, termed nongerminomatous malignant germ cell tumors (NGMGCTs), are tumors with an intermediate or poor prognosis. The second group of tumors requires more extensive drug and irradiation treatment regimens. The mechanisms underlying the differences in incidence and prognosis of the various GCT subgroups are unclear.
Results
We identified a distinct mRNA profile correlating with GCT histological differentiation and prognosis, and also present in this study the first miRNA profile of pediatric primary intracranial GCTs. Most of the differentially expressed miRNAs were downregulated in germinomas, but miR-142-5p and miR-146a were upregulated. Genes responsible for self-renewal (such as POU5F1 (OCT4), NANOG and KLF4) and the immune response were abundant in germinomas, while genes associated with neuron differentiation, Wnt/β-catenin pathway, invasiveness and epithelial-mesenchymal transition (including SNAI2 (SLUG) and TWIST2) were abundant in NGMGCTs. Clear transcriptome segregation based on patient survival was observed, with malignant NGMGCTs being closest to embryonic stem cells. Chromosome copy number variations (CNVs) at cytobands 4q13.3-4q28.3 and 9p11.2-9q13 correlated with GCT malignancy and clinical risk. Six genes (BANK1, CXCL9, CXCL11, DDIT4L, ELOVL6 and HERC5) within 4q13.3-4q28.3 were more abundant in germinomas.
Conclusions
Our results integrate molecular profiles with clinical observations and provide insights into the underlying mechanisms causing GCT malignancy. The genes, pathways and microRNAs identified have the potential to be novel therapeutic targets.
doi:10.1186/1471-2164-11-132
PMCID: PMC2837036  PMID: 20178649
6.  Ovarian cancer (advanced) 
Clinical Evidence  2009;2009:0816.
Introduction
Ovarian cancer is the fourth most common cause of cancer deaths in the UK. The 5-year relative survival rate in the UK at diagnosis for women aged 15-39 years is nearly 70%. In comparison, it is only 12% for women diagnosed aged over 80 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgical treatments for ovarian cancer that is advanced at first presentation? What are the effects of platinum-based chemotherapy for ovarian cancer that is advanced at first presentation? What are the effects of taxane-based chemotherapy for ovarian cancer that is advanced at first presentation? What are the effects of intraperitoneal chemotherapy for ovarian cancer that is advanced at first presentation? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding taxanes to platinum-based chemotherapy, carboplatin plus a taxane, cisplatin plus a taxane, combination or single-agent platinum-based chemotherapy, docetaxel, intravenous and intraperitoneal chemotherapy, interval debulking, paclitaxel, primary surgery, and second-look surgery.
Key Points
Ovarian cancer is the fourth most common cause of cancer deaths in the UK. Incidence rises with age, and peaks in the seventh and eighth decades of life.Risk factors include family history of ovarian cancer, increasing age, and low parity. Risks are reduced by using the oral contraceptive pill for more than 5 years, tubal ligation, hysterectomy, breastfeeding, increased age at menarche, decreased age at menopause, and use of NSAIDs.In the UK, the 5-year relative survival rate at diagnosis for women aged 15-39 years is nearly 70%. In comparison, it is only 12% for women diagnosed over 80 years of age.
Standard treatment for advanced ovarian cancer is primary surgical debulking, followed by chemotherapy. We found no direct evidence on the effects of primary surgery versus no surgery, or primary surgery plus chemotherapy versus surgery or chemotherapy alone.Although we found no direct evidence, subgroup analysis comparing groups by the degree to which maximal surgical debulking was acheived or not, suggests that maximal surgical cytoreduction at primary surgery is strongly associated with improved survival in advanced ovarian cancer.Subsequent debulking and second-look surgery seem unlikely to improve survival, especially if initial surgery achieved optimal cytoreduction.
Platinum-based regimens are now standard first-line chemotherapy and have been shown to be beneficial in prolonging survival compared with non-platinum-based regimens. Platinum compounds seem to be the main beneficial agent, with little additional survival benefit from adding non-platinum (excluding taxanes) chemotherapeutic agents to platinum. Carboplatin is as effective as cisplatin in prolonging survival, but with less-severe adverse effects.
Taxanes may increase survival if added to platinum chemotherapy compared with platinum-based regimens alone, but studies have given conflicting results. One RCT suggests paclitaxel is as effective at prolonging survival as docetaxel when combined with a platinum drug.
Platinum-based chemotherapy can also be delivered directly into the intraperitoneal cavity, as well as by the intravenous route.
We found limited evidence that intraperitoneal platinum-based chemotherapy may increase survival compared with intravenous administration but at the cost of increased adverse effects, both those associated with the use of an intraperitoneal catheter and from increased doses of chemotherapy. Any benefit seen with intraperitoneal rather than intravenous administration may be due to different chemotherapy doses, rather than the route of administration.
Limited evidence suggests that consolidation treatment given intraperitoneally does not confer any survival benefit compared with no further treatment in women who have undergone primary surgery and chemotherapy and who have no disease at second-look laparotomy. However, consolidation treatment may be associated with increased adverse effects.
PMCID: PMC2907795  PMID: 19445772
7.  Recent Advances in Granulosa Cell Tumor Ovary: A Review 
Granulosa cell tumors constitute less than 5 % of all ovarian tumors. Unlike epithelial ovarian tumors, they occur in a younger age group, are usually detected in an early stage and often have features of hyperestrogenism. The presenting symptoms are usually nonspecific with abdominal pain or distension. They follow an indolent course and are characterized by a long natural history. Mutation of FOXL2 (402C->G) seen in 97 % of adult GCT may be pathognomonic for adult GCT. Only stage of the disease has been consistently shown in various studies to affect survival of patients with GCT. The initial management of patients, for whom fertility is not an issue, is total abdominal hysterectomy, bilateral salpingo-oophorectomy and removal of all gross disease. Nodal dissection is not a significant factor for survival and is not recommended in surgical staging of GCT. Fertility preserving surgery with unilateral salpingo-oophorectomy is feasible in young patients with stage Ia GCT. Patients with early stage disease (stage I and II) have a very good prognosis with 5 year DFS and OS of 89 % and 99 % respectively and these groups of patients usually don’t require any postoperative treatment. Patients with stage Ic disease associated with poor prognostic factors like large tumor size or high mitotic index and stage II, have a higher chance of relapse, and may benefit with postoperative treatment but role of chemotherapy is still debatable. In advanced stage disease (stage III and IV) the 5 year DFS and OS disease was 72 % and 80 % respectively hence the option of postoperative treatment with 6 cycles of BEP should be considered in this group. Recently paclitaxel is being investigated as an effective tool in GCT. The efficacy of radiation in GCT is not well defined but in optimally debulked cases postoperative radiation is a viable option. Due to high chance of recurrence even years after apparent clinical cure of the primary tumor, lifelong follow up with clinical examination and tumor markers like inhibin B is recommended. About 25 % GCT develop recurrence and the median time to recur is usually 4–5 years. Most recurrences are intraperitoneal and usually a complete debulking of the disease is feasible even in the recurrent setting. Postoperative chemotherapy (platinum based) is usually given after surgery more so in cases with widespread disease or after suboptimal cytoreduction. Recurrent chemoresistant, progressive non-responding GCT or patients with high surgical risk are ideal candidates for targeted therapy.
doi:10.1007/s13193-012-0201-z
PMCID: PMC3578540  PMID: 24426698
Granulosa cell tumor; Inhibin B
8.  Quality of life in advanced non-small cell lung cancer patients receiving palliative chemotherapy: A meta-analysis of randomized controlled trials 
For advanced non-small cell lung cancer (NSCLC) patients, the only treatment option is palliative therapy, with the aim of prolonging overall survival and improving disease-related symptoms and quality of life (QOL). However, to date, the effect of palliative care on QOL has not yet been thoroughly examined, and there has been no meta-analysis of previous studies reporting QOL outcomes following palliative care. We consider that it is important to evaluate not only survival and/or response rates, but also QOL in patients with advanced NSCLC receiving palliative chemotherapy. The aim of the present study was to obtain useful information for the selection of suitable chemotherapy regimens for advanced NSCLC patients, taking into consideration QOL, and to demonstrate the importance of QOL assessments during treatment. We performed a meta-analysis of QOL outcomes following treatments that compared carboplatin- to cisplatin-based chemotherapy. Trials were eligible for analysis if they had compared carboplatin- to cisplatin-based chemotherapy in advanced NSCLC patients who had not received prior chemotherapy, and if these studies reported QOL data. In the six trials eligible for analysis, 2,405 patients were randomized to receive cisplatin-based or carboplatin-based chemotherapy. The patients who received carboplatin-based chemotherapy had higher global QOL and less severe symptoms than those who received cisplatin-based chemotherapy. The survival rate, which was the primary outcome in clinical trials, and the response rate did not differ significantly between the two treatment groups. It is important to evaluate QOL in addition to the survival and response rates for advanced NSCLC, particularly when the treatment is palliative.
doi:10.3892/etm.2011.368
PMCID: PMC3438671  PMID: 22969858
palliative care; quality of life; meta-analysis; advanced non-small cell lung cancer; chemotherapy
9.  Auditory Late Effects of Childhood Cancer Therapy: a report from the Children’s Oncology Group 
Pediatrics  2010;125(4):e938-e950.
Children treated for childhood malignancies may be at risk for early or delayed onset hearing loss that can impact learning, communication, school performance, social interaction, and overall quality of life (QOL). Survivors at particular risk include those treated with platinum compounds (cis-and/or carboplatin) for neuroblastoma, hepatoblastoma, osteosarcoma, or germ cell tumors and/or those treated with radiation impacting the ear at doses greater than 30 Gray (Gy) for pediatric head and neck tumors. The aims of the Auditory/Hearing Late Effects Task Force of Children’s Oncology Group in this report were: 1) to review ototoxicity resulting from childhood cancer therapy including platinum compounds (cisplatin and carboplatin) and radiation; 2) to describe briefly cochlear pathophysiology and genetics of cisplatin-related hearing loss; 3) to explain the impact of hearing loss resulting from chemotherapy and radiation; and 4) to offer recommendations regarding evaluation and management of pediatric patients at risk for treatment-related hearing loss. A questionnaire is included as a tool to assist pediatricians in assessment.
doi:10.1542/peds.2009-1597
PMCID: PMC3106205  PMID: 20194279
Ototoxicity; Carboplatin; Cisplatin; Radiation; Hearing loss
10.  Predictors of viable germ cell tumor in postchemotherapeutic residual retroperitoneal masses 
Urology Annals  2014;6(1):27-30.
Objective:
The aim of this study was to identify predictors of viable germ cell tumor (GCT) in postchemotherapeutic residual retroperitoneal masses.
Materials and Methods:
The pertinent clinical and pathologic data of 16 male patients who underwent postchemotherapeutic retroperitoneal lymph node dissection (PC-RPLND) at King Faisal Specialist Hospital and Research Centre between 1994 and 2005 were reviewed retrospectively. It was found that all patients received cisplatin-based chemotherapy for advanced testicular GCT.
Results:
Out of the 16 male patients, 2 (13%), 8 (50%), and 6 (37%) had viable GCT, fibrosis, and teratoma, respectively. Ten (10) of the patients with prechemotherapeutic S1 tumor markers did not have viable GCT, and two of the six patients who had prechemotherapeutic S2 tumor markers have viable GCT. All tumor marker levels normalized after chemotherapy even in patients with viable GCT. Four patients had vascular invasion without viable GCT. Furthermore, four patients had more than 60% embryonal elements in the original pathology, but only 1 had viable GCT at PC-RPLND. Four of the five patients with immature teratoma had teratoma at PC-RPLND but no viable GCT; however, out of the four patients with mature teratoma, one had viable GCT and two had teratoma at PC-RPLND. Of the two patients with viable GCT, one had 100% embryonal cancer in the original pathology, prechemotherapeutic S2 tumor markers, history of orchiopexy, and no vascular invasion; the other patient had yolk sac tumor with 25% embryonal elements and 40% teratoma in the original pathology, and prechemotherapeutic S2 tumor markers.
Conclusion:
None of the clinical or pathological parameters showed a strong correlation with the presence of viable GCT in PC-RPLND. However, patients with ≥S2 may be at higher risk to have viable GCT. Further studies are needed to clarify this.
doi:10.4103/0974-7796.127017
PMCID: PMC3963339  PMID: 24669118
Chemotherapy; germ cell tumor; predictor; retroperitoneal lymph node dissection
11.  A Medical Research Council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma 
British Journal of Cancer  2000;83(12):1623-1629.
The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m2 to be corrected for glomerular filtration rate outside the range 81–120 ml min–1 and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60–82%) in patients allocated C and 81% (71–90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was – 6% to +19%. The hazard ratio of 0.64 (95% CI 0.32–1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75–92%) in those allocated C, and 89% (81–96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35–2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies. © 2000 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2000.1498
PMCID: PMC2363456  PMID: 11104556
seminoma; germ cell tumour; chemotherapy; cisplatin; carboplatin; randomized control trial
12.  Gonadal germ cell tumors in children and adolescents 
Pediatric germ cell tumors (GCT) are rare tumors: 80% are benign, 20% malignant (2-3% of all malignant pediatric tumors). The gonadal sites (ovary and testis) account for 40% of cases.
Ovarian GCTs:
Represent 30% of GCTs and 70% of neoplastic ovarian masses, being the most common ovarian neoplasms in children and teenagers. Benign and immature forms (teratomas) constitute about 80% of all ovarian GCTs, malignant forms represent 20% increasing during adolescence. The most common malignant entity in children is the yolk sac tumors (YST); dysgerminoma is frequent during adolescence and being bilateral in 10% of cases. Presentation is similar in malignant and benign lesions; abdominal pain (70-80%) and lower abdominal mass are common symptoms. Evaluation of alpha-fetoprotein (αFP) or beta subunit of human chorionic gonadotropin (βHCG) is essential to address the nature of the tumors: Their elevation means presence of malignancy. Surgery includes intraoperative staging procedures and requires ovariectomy or ovarosalpingectomy for malignant lesions, but may be conservative in selected benign tumors. Since malignant GCTs are very chemosensitive, primary chemotherapy is recommended in metastatic or locally advanced tumors.
Testicular GCT:
Represent 10% of pediatric GCT, and about 30% of malignant GCT with two age peaks: Children <3 years may experience mature teratoma and malignant GCTs, represented almost exclusively by YST, while adolescents may also show seminomas or other mixed tumors. The main clinical feature is a painless scrotal mass. Surgery represents the cornerstone of the management of testicular GCTs, with an inguinal approach and a primary high orchidectomy for malignant tumors, while a testis-sparing surgery can be considered for benign lesions. A retroperitoneal lymph node (LN) biopsy may be necessary to define the staging when the involvement of retroperitoneal LN is uncertain at imaging investigations.
Conclusion:
Patients with gonadal malignant GCTs fare better than those with extragonadal mediastinal germ cell tumors (MGCTs) and survival rate exceeds 90% in localized forms. Chemotherapy has significantly improved the outcome of malignant forms since the introduction of platinum based regimens. The surgical procedure has to be performed in agreement with the ongoing protocols.
doi:10.4103/0971-9261.141995
PMCID: PMC4204242  PMID: 25336799
Children; germ cell tumors; gonadal
13.  Efficacy of taxane and platinum-based chemotherapy guided by extreme drug resistance assay in patients with epithelial ovarian cancer 
Journal of Gynecologic Oncology  2009;20(2):96-100.
Objective
To evaluate the efficacy of taxane and platinum-based chemotherapy guided by extreme drug resistance assay (EDRA) in patients with epithelial ovarian cancer.
Methods
Thirty-nine patients were enrolled, who were diagnosed as epithelial ovarian cancer, tubal cancer or primary peritoneal carcinoma and received both debulking surgery and EDRA in Asan Medical Center between August 2004 and August 2006. Another thirty-nine patients were enrolled, who did not receive EDRA as control. Paclitaxel 175 mg/m2 and carboplatin AUC 5 were administered as primary combination chemotherapy to both EDRA group and the control group. In the EDRA group, paclitaxel was replaced by docetaxel 75 mg/m2 if a patient showed extreme drug resistance (EDR) to paclitaxel and not to docetaxel. Carboplatin was replaced by cisplatin 75 mg/m2 if a patient showed EDR to carboplatin and not to cisplatin. If only one drug showed low drug resistance (LDR), it was allowed to add another drug which showed LDR such as gemcitabine 1,000 mg/m2. CT scan was performed every three cycles and CA-125 was checked at each cycle.
Results
There was no significant difference in overall response rate between EDRA group and the control group (84.5% vs. 71.8%, p=0.107). However, 93.8% of patients in EDRA group did not show EDR to at least one drug and its response rate was significantly higher than that of the control group (93.3% vs. 71.8%, p=0.023).
Conclusion
we could choose a combination of taxane and platinum which did not show EDR and could obtain a good response in the patients with ovarian cancer.
doi:10.3802/jgo.2009.20.2.96
PMCID: PMC2705007  PMID: 19590720
Ovarian neoplasms; Antineoplastic combined chemotherapy protocol; Drug resistance; neoplasm; Biologic assay
14.  Comparative study analyzing survival and safety of bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed in chemotherapy-naïve patients with advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation 
OncoTargets and therapy  2013;6:803-809.
Purpose
The majority of Egyptian patients with lung cancer present at a late stage of the disease. Bevacizumab/carboplatin/paclitaxel, as well as cisplatin plus pemetrexed, are both standard regimens for advanced non-squamous bronchogenic cancer. This study compares both regimens, in terms of efficacy and toxicity profile, in Egyptian patients.
Patients and methods
This is a randomized Phase II study comparing toxicity profile and survival in 41 chemotherapy-naïve patients with stage IIIB or IV non-squamous NSCLC, with an ECOG performance status of 0 to 2. The epidermal growth factor receptor (EGFR) mutation detection was performed prior to treatment of all patients. Patients in the first group received: bevacizumab 7.5 mg/m2 on Day 1 and Day 15; carboplatin area under the curve-5 on Day 1; and paclitaxel 60 mg/m2 on Day 1, Day 8, and Day 15 every 4 weeks. In the second group, patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 every 3 weeks.
Results
The combination of bevacizumab/carboplatin/paclitaxel demonstrated higher Grade III–IV toxicity than cisplatin/pemetrexed regarding sensory/motor neuropathy (P = 0.06), DVT (P = 0.23), proteinuria (P = 0.23), and hypertension (P = 0.11), as well as Grade II alopecia (P = 0.001); however, no significant difference in toxicities between both arms was recorded regarding nausea and vomiting (P = 0.66), hematological toxicity, febrile neutropenia (P = 1) and fatigue (P = 0.66). Progression-free survival was similar for both treatment arms with a median of 6 months (P = 0.978). Overall median survival was comparable in both arms, 16.07 months versus 16.01 months (P = 0.89).
Conclusion
Bevacizumab/carboplatin/paclitaxel and cisplatin/pemetrexed provided meaningful and comparable efficacy in advanced non-squamous bronchogenic carcinoma not harboring EGFR mutation. No significant difference in toxicity was observed between both treatment arms, apart from bevacizumab/carboplatin/paclitaxel-related risks as DVT, hypertension, proteinuria, sensory/motor neuropathy, and alopecia.
doi:10.2147/OTT.S45906
PMCID: PMC3702548  PMID: 23836994
bevacizumab; non-small cell lung cancer; NSCLC; pemetrexed
15.  Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study 
The Lancet Oncology  2013;14(9):834-842.
Summary
Background
The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma.
Methods
SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1–A3: cisplatin 80 mg/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m2 per day in 24 h on days 1–3 and 22–24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m2 per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00077389.
Findings
We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91–100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour lesions was achieved in 46 patients (74%). At the end of therapy, 49 (79%, 95% CI 67–88) of 62 patients were in complete remission. With a median follow-up of 52 months, 3-year event-free survival was 76% (95% CI 65–87) and 3-year overall survival was 83% (73–93). 60 (97%) patients had grade 3–4 haematological toxicity (anaemia, neutropenia, or thrombocytopenia) and 44 (71%) had at least one episode of febrile neutropenia. Other main grade 3 or 4 toxicities were documented infections (17 patients, 27%), anorexia (22, 35%), and mucositis (seven, 11%). One child died of fungal infection in neutropenia. Moderate-to-severe ototoxicity was documented in 31 (50%) patients. 18 serious adverse events (including two deaths) reflecting the observed side-effects were reported in the trial (the most common was ototoxicity in five patients).
Interpretation
The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma.
Funding
Cancer Research UK and Cancer Research Switzerland/Oncosuisse.
doi:10.1016/S1470-2045(13)70272-9
PMCID: PMC3730732  PMID: 23831416
16.  Concurrent Docetaxel-Based Chemoradiotherapy in Squamous Cell Esophageal Cancer 
Background:
The incidence of esophageal cancer has risen worldwide in recent decades. In Romania, the incidence is 5.3/100,000 population in males and 0.7/100,000 in females, with mortality rates of 4.8/100,000 and 0.5/100,000 in males and females, respectively. Esophageal cancer is a treatable but rarely curable cancer, as many patients have advanced-stage disease at diagnosis. We evaluated a multimodality approach of preoperative radiochemotherapy for patients with squamous cell esophageal carcinoma in terms of safety, tumor response, and resectability rate.
Methods:
From January 2004 to May 2007, 87 patients were included in the study. Inclusion criteria were histologically confirmed squamous esophageal cancer not amenable to curative surgery, no distant metastases, ECOG performance status ≤ 2, and no previous anticancer therapy. The preoperative treatment schedule was conformal radiotherapy (40 Gy) with concomitant weekly docetaxel (25 mg/m2) and carboplatin (AUC=2). Patients were evaluated at baseline, after having received 40 Gy radiotherapy, and 3 months after treatment ended. Endoscopy, barium swallow X-ray, and CT scan of the chest and upper abdomen were used to evaluate patients. Patients whose tumors were resectable underwent surgery; those with unresectable tumors continued radiotherapy to a total dose of 60 Gy and received four cycles of docetaxel (75 mg/m2) and carboplatin (AUC=6) (q3wk regimen). The resected patients received adjuvant chemotherapy with four cycles of the same docetaxel/carboplatin q3wk regimen.
Results:
The median patient age was 53.6 years (range, 32–70 years); 78 of the patients were males and 9 were females. Median follow-up time was 35 months. Survival rate at 1 year was 57.5% and at 2 years, 44.8%. After patients had received 40 Gy radiotherapy, 39 were determined to have resectable disease and 30 underwent surgery (6 patients refused surgery and 3 had contraindications for surgery); 48 patients had tumor regression with clinical benefit but were not operable. No patient progressed. Six of the 30 patients undergoing surgery had complete remissions. The treatment schedule was well tolerated, with no treatment-related deaths or additional hospitalizations. All except 5 of the patients were able to receive the intended chemoradiotherapy regimen. These 5 patients stopped chemoradiotherapy because of hematologic toxicity; radiotherapy was continued (after an approximate 1-week delay) following hematologic recovery. The operated patients had no additional perioperative complications. Radiation therapy was delivered as intended with no toxicity-related interruptions, except in the 5 patients mentioned above. Chemotherapy was delayed in 15 additional cases due to grade 3–4 hematologic effects; a 25% dose reduction was necessary in 9 cases.
Conclusions:
Multimodality treatment of locally advanced esophageal cancer (concurrent radiochemotherapy ± surgery) can be considered superior to each method as single-agent therapy. Radiotherapy and chemotherapy may convert some tumors considered initially unresectable to resectable status. The weekly docetaxel/carboplatin regimen was well tolerated when administered concurrently with radiation therapy. This regimen resulted in a 44.8% resectability rate in patients considered initially unresectable, and 15.4% of patients undergoing surgery had complete remissions. Further investigation of this regimen is warranted.
PMCID: PMC3056309
17.  Phase II Study of Consolidation Chemotherapy after Adjuvant or Primary Concurrent Chemoradiation Using Paclitaxel and Carboplatin to Treat High-Risk Early-Stage or Locally Advanced Cervical Cancer 
Purpose
This study investigated the efficacy and toxicity associated with consolidation chemotherapy using paclitaxel and carboplatin after concurrent chemoradiation (CCR) in cervical cancer patients.
Materials and Methods
From a total of 37 patients, 19 with International Federation of Gynecology and Obstetrics (FIGO) stage IB1-IIA cervical cancer (group 1) underwent surgery followed by consolidation chemotherapy after CCR, and 18 with stage IIB-IVA disease (group 2) received consolidation chemotherapy after primary CCR. Three cycles of chemotherapy using paclitaxel (135 mg/m2) and carboplatin (AUC 5.0) were administered every 3 weeks for CCR therapy, and three cycles of consolidation chemotherapy using paclitaxel (175 mg/m2) and carboplatin (AUC 5.0) were used every 3 weeks after CCR.
Results
The complete and partial response rates were 77.8% and 22.2% in group 2. Moreover, the 3-year progression-free and overall survival rates were 62.7% and 90.9% in group 1, and 51.9% and 60% in group 2, respectively. The most common grade 3 or 4 hematologic toxicities observed were leukopenia (group 1, 10.5%; group 2, 13.0%) and neutropenia (group 1, 7.0%; group 2, 14.8%), and grade 3 or 4 diarrhea (group 1, 1.8%) and febrile illness (group 2, 1.9%) were the most frequently observed non-hematologic toxicities. When we compared these results with previous reports, consolidation chemotherapy after CCR using paclitaxel and carboplatin revealed a relatively lower complete response rate (77.8% vs. 87-100%, respectively) and shorter progression-free survival (51.9-62.7% vs. 81-86%, respectively) and overall survival (60-90.9% vs. 81-95%, respectively) in spite of similar toxicity findings.
Conclusion
Due to low efficacy results, consolidation chemotherapy using paclitaxel and carboplatin after CCR is not a feasible treatment regimen for high-risk early-stage or locally advanced cervical cancer.
doi:10.4143/crt.2012.44.2.97
PMCID: PMC3394869  PMID: 22802747
Consolidation chemotherapy; Chemoradiotherapy; Paclitaxel; Carboplatin; Uterine cervical neoplasms
18.  Elderly Subset Analysis of Randomized Phase III Study Comparing Pemetrexed Plus Carboplatin with Docetaxel Plus Carboplatin as First-Line Treatment for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer 
Drugs in R&d  2013;13:289-296.
Background
Many physicians consider platinum-doublet chemotherapy inappropriate for elderly patients, regardless of their medical fitness.
Objective
This was a retrospective subgroup analysis of data from a multicenter, randomized, phase III clinical trial evaluating pemetrexed + carboplatin versus docetaxel + carboplatin in elderly chemo-naive patients with advanced, nonsquamous non-small cell lung cancer (NSCLC).
Methods
Data from elderly patients (aged ≥65 years and ≥70 years) were evaluated using the same statistical methods as those used in patients aged <70 years and qualified intent-to-treat (Q-ITT) populations. The primary objective of the clinical trial was comparison of pemetrexed + carboplatin with docetaxel + carboplatin in terms of survival without grade 3 or 4 toxicity in chemo-naive NSCLC patients.
Results
The ≥65- and ≥70-year age groups had 68 and 37 patients, respectively. Among patients aged ≥65 years, the adjusted hazard ratio (HR) for survival without grade 3–4 toxicity (HR 0.40, 95 % confidence interval [CI] 0.23–0.70) favored pemetrexed + carboplatin; this was similar to the HRs in patients aged ≥70 years (HR 0.43, 95 % CI 0.20–0.92), patients aged <70 years (HR 0.44, 95 % CI 0.32–0.62), and the Q-ITT population (HR 0.45, 95 % CI 0.34–0.61). The median values for overall survival (OS) and progression-free survival (PFS) were similar across all age-group subsets and the Q-ITT population. The HRs for OS and PFS were similar for all age-group subsets, except for the ≥70-year age group, which favored pemetrexed + carboplatin to a greater extent. The toxicity profile was similar across age groups, with the exception of diarrhea, mucosal inflammation, and grade 3–4 neutropenia and leukopenia, which were slightly more common in elderly patients in both treatment arms. Between-arm differences in the toxicity profiles for the ≥65-, ≥70- and <70-year age subgroups were similar to those in the Q-ITT population. There were no on-study deaths or unexpected toxicities.
Conclusion
The benefits of pemetrexed + carboplatin were maintained, and toxicity was manageable in both elderly subgroups. The favorable risk–benefit profile of pemetrexed + carboplatin makes it an appropriate first-line treatment option for elderly patients with advanced nonsquamous NSCLC.
doi:10.1007/s40268-013-0032-6
PMCID: PMC3851706  PMID: 24277116
19.  Elderly Subset Analysis of Randomized Phase III Study Comparing Pemetrexed Plus Carboplatin with Docetaxel Plus Carboplatin as First-Line Treatment for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer 
Drugs in R&D  2013;13(4):289-296.
Background
Many physicians consider platinum-doublet chemotherapy inappropriate for elderly patients, regardless of their medical fitness.
Objective
This was a retrospective subgroup analysis of data from a multicenter, randomized, phase III clinical trial evaluating pemetrexed + carboplatin versus docetaxel + carboplatin in elderly chemo-naive patients with advanced, nonsquamous non-small cell lung cancer (NSCLC).
Methods
Data from elderly patients (aged ≥65 years and ≥70 years) were evaluated using the same statistical methods as those used in patients aged <70 years and qualified intent-to-treat (Q-ITT) populations. The primary objective of the clinical trial was comparison of pemetrexed + carboplatin with docetaxel + carboplatin in terms of survival without grade 3 or 4 toxicity in chemo-naive NSCLC patients.
Results
The ≥65- and ≥70-year age groups had 68 and 37 patients, respectively. Among patients aged ≥65 years, the adjusted hazard ratio (HR) for survival without grade 3–4 toxicity (HR 0.40, 95 % confidence interval [CI] 0.23–0.70) favored pemetrexed + carboplatin; this was similar to the HRs in patients aged ≥70 years (HR 0.43, 95 % CI 0.20–0.92), patients aged <70 years (HR 0.44, 95 % CI 0.32–0.62), and the Q-ITT population (HR 0.45, 95 % CI 0.34–0.61). The median values for overall survival (OS) and progression-free survival (PFS) were similar across all age-group subsets and the Q-ITT population. The HRs for OS and PFS were similar for all age-group subsets, except for the ≥70-year age group, which favored pemetrexed + carboplatin to a greater extent. The toxicity profile was similar across age groups, with the exception of diarrhea, mucosal inflammation, and grade 3–4 neutropenia and leukopenia, which were slightly more common in elderly patients in both treatment arms. Between-arm differences in the toxicity profiles for the ≥65-, ≥70- and <70-year age subgroups were similar to those in the Q-ITT population. There were no on-study deaths or unexpected toxicities.
Conclusion
The benefits of pemetrexed + carboplatin were maintained, and toxicity was manageable in both elderly subgroups. The favorable risk–benefit profile of pemetrexed + carboplatin makes it an appropriate first-line treatment option for elderly patients with advanced nonsquamous NSCLC.
doi:10.1007/s40268-013-0032-6
PMCID: PMC3851706  PMID: 24277116
20.  Adjuvant Therapy Choices in Patients With Resected Non-Small-Cell Lung Cancer: Correlation of Doctors' Treatment Plans and Relevant Phase III Trial Data 
Journal of Oncology Practice  2005;1(2):37-42.
Purpose
To evaluate case-based choices selected from among preselected options for adjuvant therapy management in patients with completely resected non-small-cell lung cancer (NSCLC).
Methods
In a series of meetings in which US oncologists participated in case-based discussions, market research data were acquired using audience response keypad technology. Participant's anonymous responses to specific case-based questions were recorded electronically and tabulated.
Results
Core behaviors among the majority of physician participants are driven by emerging level 1 evidence. However, a “more aggressive than literature-supported treatment posture” is frequently selected. For the scenario involving a patient with completely resected pT1N0 disease, approximately 60% recommended observation but one third of respondents indicated they would propose three to four cycles of platinum-based adjuvant chemotherapy. Twenty-three percent would recommend adjuvant radiation following adjuvant chemotherapy for a patient with completely resected pT2N1 (stage IIB) disease. In the stage IIB setting, when cisplatin or carboplatin chemotherapy choices were specified, carboplatin-based combinations were selected by 43.6% compared with 30% for cisplatin regimens. Eight respondents (3.5%) favored observation for the stage IIB setting. This is consistent with the preponderance of level 1 evidence for adjuvant management. Carboplatin combinations are also recommended despite the availability of only abstract data and a meeting report for a single phase III trial showing a survival benefit for carboplatin based management in stage IB disease. The use of radiation as an element in adjuvant therapy in the settings assessed in this research is not supported by prospective data.
Conclusions
Treatment plans that include adjuvant platinum-based chemotherapy have been widely adopted by US oncologists for a large fraction of patients with completely resected NSCLC. Recommendations for adjuvant chemotherapy for the patient described here with stage IA disease, or for adjuvant radiation alone or after adjuvant chemotherapy, for the stage IIB disease patient presented are overly aggressive, not evidence based, and carry potential harm. In settings in which level 1 evidence for a survival benefit from adjuvant chemotherapy does exist, some of the specific adjuvant chemotherapy regimens selected, while widely used in NSCLC patients with more advanced disease, have not yet been demonstrated to provide improved disease-free or overall survival as adjuvant treatment. Individualized adjuvant treatment recommendations not specifically grounded in level 1 evidence appear to be widely recommended by US medical oncologists for patients with completely resected NSCLC.
PMCID: PMC2793579  PMID: 20871677
21.  Multiple Roles of Cyclin-Dependent Kinase 4/6 Inhibitors in Cancer Therapy 
Background
Cyclin-dependent kinases (CDKs) regulate cell proliferation and coordinate the cell cycle checkpoint response to DNA damage. Although inhibitors with varying selectivity to specific CDK family members have been developed, selective CDK4/6 inhibitors have emerged as the most attractive antineoplastic agents because of the importance of CDK4/6 activity in regulating cell proliferation and the toxic effects associated with inhibition of other CDKs (eg, CDK1 and CDK2).
Methods
FVB/N wild-type mice (n = 13) were used to evaluate carboplatin-induced myelosuppression in bone marrow by complete blood cell counts after treatment with the CDK4/6 inhibitor PD0332991. Genetically engineered murine models of retinoblastoma (Rb)-competent (MMTV-c-neu) and Rb-incompetent (C3-TAg) breast cancer (n = 16 MMTV-c-neu mice in the carboplatin plus vehicle control group, n = 17 MMTV-c-neu mice in the carboplatin plus PD0332991 group, n = 17 C3-TAg mice in the carboplatin plus vehicle control group, and n = 14 C3-TAg mice in the carboplatin plus PD0332991 group) were used to investigate the antitumor activity of PD0332991 alone or in combination with chemotherapy. All statistical tests were two-sided.
Results
Coadministration of PD0332991 with carboplatin compared with carboplatin alone in FVB/N wild-type mice increased hematocrit (51.2% vs 33.5%, difference = 17.7%, 95% confidence interval [CI] = −26.7% to −8.6%, P < .001), platelet counts (1321 vs 758.5 thousand cells per μL, difference = 562.5 thousand cells per μL, 95% CI = −902.8 to −222.6, P = .002), myeloid cells (granulocytes and monocytes; 3.1 vs 1.6 thousand cells per μL, difference = 1.5 thousand cells per μL, 95% CI = −2.23 to −0.67, P < .001), and lymphocytes (7.9 vs 5.4 thousand cells per μL, difference = 2.5 thousand cells per μL, 95% CI = −4.75 to −0.18, P = .02). Daily administration of PD0332991 exhibited antitumor activity in MMTV-c-neu mice as a single agent. However, the combination of carboplatin plus PD0332991 decreased antitumor activity compared with carboplatin alone in Rb-competent mice (mean percent change in tumor volume at day 21 = −52.6% vs 3.7% for carboplatin and carboplatin plus PD0332991, respectively, difference = 56.3%, 95% CI = −109.0% to −3.6%, P = .04). In contrast, Rb-deficient tumors in C3-Tag mice were resistant to PD0332991, and coadministration of PD0332991 plus carboplatin had no effect on in vivo tumor growth (mean percent change in tumor volume at day 21 = 118.8% and 109.1% for carboplatin and carboplatin plus PD0332991, respectively, difference = 9.7%, 95% CI = −183.5% to 202.9%, P = .92). Finally, in tumor-bearing mice, coadministration of PD0332991 with carboplatin provided statistically significant protection of platelets (P = .04).
Conclusion
We believe that the present data support a possible role for CDK4/6 inhibitors in a majority of patients with advanced cancer: to either inhibit tumor growth in CDK4/6-dependent tumors or ameliorate the dose-limiting toxicities of chemotherapy in CDK4/6-indepdendent tumors. Our data also suggest CDK4/6 inhibitors should not be combined with DNA-damaging therapies, such as carboplatin, to treat tumors that require CDK4/6 activity for proliferation.
doi:10.1093/jnci/djs002
PMCID: PMC3309128  PMID: 22302033
22.  Epithelial ovarian cancer: A case report 
An 82-year-old female was diagnosed with ovarian cancer in May 2004. Following gynecological surgery, pathological evaluation showed stage IIIC epithelial ovarian cancer. From June 2004 to January 2005, the patient received six cycles of conventional treatment combined with intravenous paclitaxel (Taxol®) and cisplatin. The patient developed abdominal distension and experienced a gradual deterioration in health during 2007, with admission to The First Affiliated Hospital in May 2007. The patient presented with severe abdominal distension and breathing difficulty on May 15 and appeared to be in critical condition. Ultrasound examination revealed massive ascites and left-side pleural effusion. Thoracentesis and abdominocentesis were performed, and 300 mg carboplatin was administered intraperitoneally on May 19, followed by a second abdominocentesis on May 21. However, these treatments did not alleviate the symptoms, and 200 mg bevacizumab was administered by intravenous infusion on May 27. The condition of the patient gradually improved and 400 mg bevacizumab was administered by intravenous infusion every two weeks from June 9. From December, the dosage of bevacizumab was reduced to 200 mg every two weeks. In addition, 300 mg carboplatin was administered intraperitoneally on November 4 and intraperitoneal carboplatin chemotherapy was repeated thereafter. The patient exhibited disease-free survival until July 2009, at which time disease progression was observed and the cancer recurred in August 2009. The patient died of multiple organ failure in September 2009. Bevacizumab rapidly eliminated the patient’s massive ascites and pleural effusion, and achieved an effect that was not possible with other treatments. Therefore, bevacizumab is an effective therapy for late-stage relapse and refractory ovarian cancer.
doi:10.3892/etm.2014.1970
PMCID: PMC4186346  PMID: 25289055
recurrent epithelial ovarian cancer; bevacizumab; carboplatin; chemotherapy; massive pleural effusions
23.  Prospective evaluation of cisplatin- and carboplatin-mediated ototoxicity in paediatric and adult soft tissue and osteosarcoma patients 
Oncology Letters  2012;5(1):311-315.
Platinum-compound chemotherapy is known to have ototoxic side-effects. However, there is a paucity of literature examining hearing function prospectively and longitudinally in cohorts containing paediatric and adult patients treated within the same cisplatin- or carboplatin-containing treatment trial protocols. In Germany, Austria and Switzerland, late effects of treatment for osteosarcoma and soft tissue sarcoma have been prospectively and longitudinally registered by the Late Effects Surveillance System since 1998. The aim of this study was to analyse cisplatin- and carboplatin-induced ototoxity in a group of 129 osteosarcoma and soft tissue sarcoma patients treated within the COSS-96, CWS-96 and CWS-2002P treatment trials. The cohort consisted of 112 children and 17 adults. The median age at diagnosis was 13.56 (IQR, 10.26–16.27) years. Follow-up was 6.97 (IQR, 0.87–15.63) months. Hearing function was examined by audiometry before and after platinum treatment. A total of 108 patients were treated with cisplatin with a median cumulative dose of 360 mg/m2. Thirteen patients received carboplatin with a median cumulative dose of 1500 mg/m2 and 8 patients were treated with both platinum compounds (median cisplatin dose, 240 mg/m2; IQR, 240–360 mg/m2 and median carboplatin dose: 1200 mg/m2; IQR, 600–3000 mg/m2). Following cessation of therapy, 47.3% of the patients demonstrated a hearing impairment, namely 55 children (49.1%) and 6 adults (42.1%). Out of thirteen children treated with carboplatin with a cumulative dose of 1500 mg/m2, six revealed a significant hearing impairment. Although ototoxicity caused by platinum compounds is considered irreversible, we identified hearing improvements over time in 11 children (9.8%) and 3 adults (17.6%). None of these patients received irradiation to the head. We conclude that hearing loss is frequent in children treated with protocols containing platinum compounds and recommend prospective testing via audiometry.
doi:10.3892/ol.2012.997
PMCID: PMC3525486  PMID: 23255940
hearing; child; cancer; late effects; platinum compounds
24.  Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries 
Neuro-Oncology  2012;14(9):1194-1200.
Intracranial germ cell tumors (GCTs) are relatively rare. Their incidence has been considered to be higher in East Asia than in the United States. This study estimates the incidence of CNS GCTs in Japan and the United States, investigates gender discrepancies in each country, and describes treatment outcomes. Data on primary CNS GCTs from 4 databases were utilized: population-based malignant incidence data from (1) the Japan Cancer Surveillance Research Group (2004–2006; 14 registries), malignant and nonmalignant incidence data from (2) the Surveillance, Epidemiology, and End Results Program (2004–2008; 17 registries), and hospital-based observed survival data from (3) the Brain Tumor Registry of Japan (1984–2000) and (4) the US National Cancer Data Base (1990–2003). Incidence rates per 100 000 for malignant GCTs were not statistically significantly different between Japan (males = 0.143, females = 0.046) and the United States (males = 0.118, females = 0.030). The malignant incidence-rate ratio was higher for pineal GCTs versus nonpineal (ie, the rest of the brain) GCTs in Japan (11.5:1 vs 1.9:1, respectively) and the United States (16.0:1 vs 1.7:1, respectively). In general, 5-year survival estimates were high: over 75% for all GCTs, and over 81% for germinomas, regardless of the type of treatment in either Japan or the United States. The incidence of primary GCTs is similar between Japan and the United States and has the same gender-based patterns by location. High rates of survival were observed in both countries.
doi:10.1093/neuonc/nos155
PMCID: PMC3424216  PMID: 22869621
brain tumor; epidemiology; germ cell tumors; germinoma; mixed germ cell tumors; pineal gland; teratoma; tumor registry
25.  Consolidative high-dose chemotherapy after conventional-dose chemotherapy as first salvage treatment for male patients with metastatic germ cell tumours 
Introduction:
Some men with metastatic germ cell tumours that have progressed after response to initial cisplatin-based combination chemotherapy are cured with conventional dose first salvage chemotherapy (CDCT) – however, many are not. High-dose chemotherapy with autologous stem cell rescue (HDCT) may be of value in these patients. Prognosis has recently been better defined by International Prognostic Factor Study Group (IPFSG) prognostic factors. HDCT after response to CDCT has been offered at our institution over the past two decades. We retrospectively assessed the validity of the IPFSG prognostic factors in our patients and evaluated the value of HDCT.
Methods:
We identified eligible men with metastatic germ cell tumour progressed after at least 3 cycles of cisplatin-based chemotherapy and treated with cisplatin-based CDCT alone or with carboplatin-based HDCT. We also collected their clinical data. Patients were classified into risk groups using IPFSG factors, and progression-free and overall survival factors were analyzed and compared in patients treated with CDCT alone and with HDCT.
Results:
We identified 38 eligible first salvage patients who had received a median of 4 cycles (range, 1 to 7 cycles) of CDCT. Twenty patients received CDCT alone and 18 patients received CDCT plus HDCT. The overall median progression- free survival was 24.6 months (95%CI, 7.3 to 28.7 months) and overall median overall survival was 34.6 months (95%CI, 17.2 to 51.3 months). Distribution by IPFSG category and 2-year progression- free survival and 3-year overall survival rates within each risk category were very similar to the IPFSG results. There were two toxic deaths with CDCT and none with HDCT. Overall, patients treated with CDCT plus HDCT had improved progression- free survival and overall survival.
Conclusions:
The IPFSG prognostic risk factors appeared valid in our patient population. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved progression- free survival and overall survival outcomes, consistent with observations of the IPFSG group. Ideally, the value of optimal HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic germ cell tumour with a randomized trial.
doi:10.5489/cuaj.11233
PMCID: PMC3328550  PMID: 22511417

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