Neoadjuvant Methotrexate Research Articles

Chemotherapy-Surgery Interval Effects on Tumor Necrosis and Outcome in Children and Young Adults With Osteosarcoma.

Osteosarcoma treatment incorporates chemotherapy and surgery. Resection of the primary tumor usually occurs after induction chemotherapy. Occasionally, scheduling challenges and medical complications result in delay. The goal of this study is to determine if an increased interval between completion of neoadjuvant therapy and surgical resection correlates with decreased tumor necrosis and inferior outcomes in children and young adults with osteosarcoma. We conducted a retrospective chart review of 121 patients age less than 40years diagnosed with osteosarcoma treated at a single tertiary medical center between 2000 and 2022. Inclusion criteria included receipt of two cycles of neoadjuvant methotrexate, cisplatin, and doxorubicin. Association of the interval from completion of induction chemotherapy to resection with tumor necrosis (Spearman's correlation) and outcomes (multivariable Cox hazard regression) were analyzed. There was no significant correlation between interval length and tumor necrosis. However, patients with an interval greater than 16days had lower 5-year event-free survival (p = 0.019). Multivariable adjusted analysis of patients with initially localized disease revealed that each day increase in interval length corresponds with a 1.1 times greater hazard of having an event (95% CI: 1.0-1.2; p = 0.016). Delays in local control were not associated with tumor necrosis. This is consistent with the hypothesis that tumor necrosis is a biologic marker of a tumor's sensitivity to chemotherapy and may not be affected by minor regimen aberrations. However, surgical delay from completion of induction chemotherapy may confer worse outcomes. Longer intervals generally confer worse outcomes in patients with initially localized disease.

Study of Complete Surgical Response of Stage III Oral Carcinoma Patients in Comparison to Primary Surgery Versus Neoadjuvant Methotrexate With Surgery.

Objective This study aims to compare the efficacy of neoadjuvant methotrexate therapy followed by surgery versus primary surgical management in patients with stage III oral carcinoma. Methods Thirty patients diagnosed with stage III oral carcinoma were enrolled in this prospective study at a tertiary cancer research center. The patients were divided into two groups: 15 patients received neoadjuvant methotrexate therapy followed by surgery, while 15 underwent primary surgical management. Outcomes were evaluated based on tumor downstaging, surgical margins, postoperative complications, and the requirement for adjuvant radiotherapy. Results Patients in the neoadjuvant methotrexate group demonstrated significant tumor downstaging, allowing for less extensive surgical procedures, with 33.3% (n=5) undergoing wide local excision (WLE) compared to 13.3% (n=2) in the primary surgery group. Negative surgical margins were achieved in 93.33% (n=14) of patients in the neoadjuvant group versus 53.33% (n=8) in the surgical group. Additionally, only 13.3% (n=1) of patients in the neoadjuvant group required postoperative radiotherapy, compared to 53.33% (n=8) in the surgical group. The recurrence rate over a six-month follow-up period was comparable between the two groups. Discussion Neoadjuvant methotrexate therapy resulted in better surgical and oncological outcomes by downstaging the tumor, reducing the extent of surgery, and minimizing the need for postoperative radiotherapy. The findings suggest that methotrexate, as a neoadjuvant agent, is effective in improving patient outcomes with fewer side effects compared to standard cisplatin-based regimens. Conclusion Neoadjuvant methotrexate therapy offers a viable treatment option for stage III oral carcinoma, demonstrating improved oncological and surgical outcomes, including less invasive surgery, higher rates of negative surgical margins, and reduced postoperative radiotherapy requirements. Further research with long-term follow-up is necessary to validate these findings and explore the long-term impact on survival and recurrence rates.

Effect of neoadjuvant chemotherapy on health-related quality of life in patients with muscle invasive bladder cancer: Results from JCOG0209, a randomized phase III study.

e17006 Background: Although neoadjuvant chemotherapy (NAC) provides survival benefits in muscle-invasive bladder cancer (MIBC), the impact of NAC on health-related quality of life (HRQoL) has not been investigated by a randomized trial. The purpose of this study is to compare HRQoL in patients with MIBC who received NAC followed by radical cystectomy (RC) or RC alone based on patient-reported outcome data. Methods: Patients were randomized to receive 2 cycles of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) followed by RC or RC alone. HRQoL was measured using the Functional Assessment of Cancer Therapy – Bladder (FACT-BL, version 4) questionnaire before the protocol treatments, after NAC, after RC, and one year after registration. Results: A total of 99 patients were analyzed. No statistically significant differences in postoperative HRQoL were found between the arms. In the NAC arm, the scores after NAC were significantly lower than the baseline scores in physical well-being, functional well-being, FACT-General total, weight loss, diarrhea, appetite, body appearance, embarrassment by ostomy appliance, and total FACT-BL. However, there was no difference in scores for these domains, except for embarrassment by ostomy appliance, between the two arms after RC and one year after registration. Conclusions: Although HRQoL declined during NAC, no negative effect of NAC on HRQoL was apparent after RC. These data support the view that NAC can be considered as a standard of care for patients with MIBC regarding HRQoL. Clinical trial information: C000000093.

Outcomes of patients following dose-dense neoadjuvant chemotherapy for muscle-invasive bladder cancer: Implications for organ-sparing strategies.

426 Background: Locoregional management of muscle-infiltrating bladder cancer (MIBC) after neoadjuvant chemotherapy (NAC) is controversial, because of both the morbidity of radical cystectomy (RC). Bladder preservation may be feasible after complete tumor response. Methods: This single-center retrospective study included 120 MIBC patients (stages ypT2-4aN0-3M0) treated between 2011 and 2017 with up to 6 cycles of neoadjuvant dose-dense Methotrexate, Vinblastin, Doxorubicin and Cisplatin (DD-MVAC). The primary outcome was relapse-free survival (RFS) depending on pathological findings on RC specimens, classified as either pathological complete response (pCR: ypT0N0/x), residual organ-confined disease (yOCD: ypTa/is/1/2N0/x), residual non-organ-confined disease (yNOCD: ypT≥3Nany or ypTanyN1-3). Secondary objectives included the rate of pCR in RC patients, the rate of ypT0 in the intention-to-treat population, and RFS in ypT0 patients according to locoregional management. Results: After a median number of 5 cycles of NAC, RC was performed in 75% of the patients, concurrent radiochemotherapy (CRC) in 11% and cystoscopic surveillance (CS) in 8%. In the intention-to-treat population, the ypT0 rate was 47%. Among 90 patients who underwent RC, 49% achieved pCR, 16% had yOCD and 34% yNOCD. Median follow-up in RC patients alive at last follow-up was 40 months. Three-year RFS was 86% in RC patients with pCR, 69% in patients with yOCD and 21% in patients with yNOCD (p < 0.0001). Outcomes were similar between ypT0 patients treated with either RC or CRC/CS (3-year RFS: 81% vs 100%, p = 0.20). Limitations to this study included its restrospective design and the lower number of patients treated with CRC/CS. Conclusions: Patients reaching ypT0 after dose-dense NAC show improved prognosis regardless of locoregional treatment. Patients with yOCD are frequently cured by RC, as opposed to patients with yNOCD. Prospective trials are needed to compare upfront cystectomy and bladder-sparing management in patients with both pCR or yNOCD.

Systemic Therapy for Invasive Bladder Cancer: The Value Proposition.

Neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy followed by definitive local treatment should be the treatment of choice for otherwise healthy and robust patients with T2b–T4 invasive bladder cancer.

ET-22 * CONVECTION-ENHANCED DELIVERY OF THE AUGER-ELECTRON-EMITTER 125I-UdR: A HIGHLY EFFICIENT THERAPY IN AN ORTHOTOPIC GLIOBLASTOMA XENOGRAFT MODEL

BACKGROUND: Glioblastomas (GBMs), the most common and malignant primary brain tumors, always recur after standard treatment. In order to develop more efficient therapies, we tested a novel therapeutic approach using the radioactive Auger-electron-emitter (AEE) [125I]5-Iodo-2'-deoxyuridine (125I-UdR). This drug incorporates into DNA of dividing cells and upon decay emission of Auger-electrons causes clusters of double strand breaks leading to cell death. METHODS: In vitro, cells from two GBM spheroid cultures (T78 & T87) were exposed to either 125I-UdR or 127I-UdR (non-radioactive analogue) and tumor cell viability and migration were measured. In vivo, nude rats were implanted orthotopically with T87 cells and after tumor formation micro infusion pumps were implanted enabling direct intratumoral convection-enhanced delivery (CED). Animals were divided into three groups (I-III). Group I (n = 8) was treated with 127I-UdR by CED, group II (n = 7) with neoadjuvant methotrexate (MTX) + 125I-UdR by CED and group III with neoadjuvant MTX + 125I-UdR by CED and concomitant systemic temozolomide (TMZ). Rats were followed for 180 days post-treatment with repeated [11C]methylaminoisobutyric acid ([11C]MeAIB) positron emission tomography scans and blood sampling. Single photon emission computed tomography/computed tomography (SPECT/CT) scans were performed to evaluate 125I-UdR distribution. Additionally, post-mortem histological examination of brain, liver, kidneys and thyroid gland was performed. RESULTS: In vitro, 125I-UdR significantly decreased GBM cell viability and migration. In group I, no animals (8/8) survived longer than 23 days after treatment start. In group II, 4/7 animals survived the entire observation period of 180 days. In group III, all animals (8/8) survived the entire observation period. SPECT/CT showed a widespread intracerebral distribution of 125I-UdR, while blood samples and post-mortem histology revealed no signs of dose-limiting adverse effects. CONCLUSIONS: The novel therapeutic approach with CED of MTX and the AEE-compound 125I-UdR in combination with systemic TMZ seemed safe and very efficient in the orthotopic GBM model.

Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209

This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. Patients with MIBC (T2-4aN0M0) were randomised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary end point was overall survival (OS). Secondary end points were progression-free survival, surgery-related complications, adverse events during chemotherapy, proportion with no residual tumour in the cystectomy specimens, and quality of life. To detect an improvement in 5-year OS from 45% in the RC arm to 57% in the NAC arm with 80% power, 176 events were required per arm. Patients (N = 130) were randomly assigned to the RC arm (N = 66) and the NAC arm (N = 64). The patient registration was terminated before reaching the initially planned number of patients because of slow accrual. At the second interim analysis just after the early stoppage of patient accrual, the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion. OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant [hazard ratio 0.65, multiplicity adjusted 99.99% confidence interval 0.19-2.18, one-sided P = 0.07]. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (P < 0.01). In subgroup analyses, OS in almost all subgroups was in favour of NAC. This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC. NAC with MVAC can still be considered promising as a standard treatment. C000000093.

Identification of Distinct Basal and Luminal Subtypes of Muscle-Invasive Bladder Cancer with Different Sensitivities to Frontline Chemotherapy

Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy.

Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS).

4530 Background: Neoadjuvant (NA) ddMVAC in patients (pts) with MI-UC is associated with significant pathologic response (PaR) and radiologic response (RaR). We examined the frequency of PaR and RaR as well as the level of serum and tissue biomarkers in correlation with DFS. Methods: Pts treated on phase II prospective study of NA ddMVAC (4 cycles) in MI-UC were evaluated for RaR (at least &gt;50% decrease in the primary tumor and nodes after chemotherapy, with delayed enhancement of residual disease) and PaR (p&lt;T1N0M0). Elevated serum tumor markers (CA125, C19-9 and ßHCG) at baseline and Day 1 of each cycle were documented. Expression level of baseline DNA ERCC1 protein in tumor biopsy tissues was determined by immunohistochemistry based on H-score &lt;0.1 (negative) vs. &gt;0.1 (positive). Fisher’s Exact test was used to evaluate association with response. Post-surgery DFS was estimated by the Kaplan-Meier method and compared between response and biomarker groups using the logrank test. Results: Of 39 pts (cT2:42%, cT3:42%, cT4:16%, and cN1:45%), 49% (90% CI 35-63) experienced PaR, and 62% (90% CI 47-75) achieved RaR after ddMVAC chemotherapy. Pts who achieved PaR experienced a DFS advantage, with 18-month DFS of 78% (95% CI 47-92) vs. 48% (95% CI 18-74) in those who did not (p=0.146). Those achieving RaR had a significantly longer DFS (p=0.006), with 18-month DFS of 87% (95% CI 57-97) vs. 29% (95% CI 5-60) in those who did not. Among 10 pts with any elevated serum tumor marker at baseline, only 2 pts showed normalization, both without a PaR. ERCC1(+) tumors were not associated with PaR, pT0 or RaR. DFS by ERCC1status was inconclusive due to limited sample size. 18-month DFS was 91% (95% CI 51-99) in ERCC1(+) tumors vs. 63% (95% CI 29-85) in ERCC1(-) tumors. Conclusions: ddMVAC achieves significant PaR and RaR in MI-UC pts that translates into a post-surgery DFS advantage. ERCC1(+) was not associated with response. More effective biomarkers of platinum response are needed to select pts most likely to benefit from NA therapy. Clinical trial information: NCT00808639.

Neoadjuvant Gemcitabine Plus Carboplatin for Locally Advanced Bladder Cancer

Although cisplatin-based neoadjuvant chemotherapy followed by cystectomy was demonstrated to improve the survival among patients with locally advanced bladder cancer, its severe adverse events, including nephrotoxicity, are critical issues. We investigated the safety and activity of carboplatin, a mild nephrotoxic agent, combined with gemcitabine as a neoadjuvant chemotherapy compared with methotrexate, vinblastine, doxorubicin and cisplatin for patients with locally advanced bladder cancer. We retrospectively evaluated 68 patients with locally advanced bladder cancer who received neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (n = 34) or gemcitabine and carboplatin (n = 34) followed by cystectomy at our institute. The adverse events, chemotherapy delivery profile, rate of down-stage and recurrence-free survival were assessed for methotrexate, vinblastine, doxorubicin and cisplatin compared with gemcitabine and carboplatin. The mean cycles of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, were 2.5 and 2.7, respectively. The hematologic adverse events of Grade 3 or 4 neutropenia, anemia and thrombocytopenia for methotrexate, vinblastine, doxorubicin and cisplatin were 15, 18 and 0%, respectively. The occurrences for gemcitabine and carboplatin were 53, 21 and 50%, respectively. Grade 3 or 4 non-hematologic toxicities for methotrexate, vinblastine, doxorubicin and cisplatin were nausea and vomiting in 24%, and were not observed for gemcitabine and carboplatin. The lowest median estimated glomerular filtration rate during methotrexate, vinblastine, doxorubicin, and cisplatin and gemcitabine and carboplatin was 55.8 and 70.6 ml/min/1.73 m(2), respectively (P = 0.002). The rate of down-stage to pT1 or less was 59% for methotrexate, vinblastine, doxorubicin and cisplatin, and 53% for gemcitabine and carboplatin (P = 0.624). The recurrence-free survival of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, at 36 months from the diagnosis was 79 and 75%, respectively (P = 0.85). Neoadjuvant gemcitabine and carboplatin showed less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin, and especially less nephrotoxicity was demonstrated for gemcitabine and carboplatin. Although observed during the short term, the recurrence-free survival for gemcitabine and carboplatin was comparable to that for methotrexate, vinblastine, doxorubicin and cisplatin.

Long-term Results of Two Prospective Bladder-sparing Trimodality Approaches for Invasive Bladder Cancer: Neoadjuvant Chemotherapy and Concurrent Radio-chemotherapy

To report long-term outcomes of selective organ preservation for muscle-invasive bladder cancer (MIBC) using 2 bladder-sparing trimodality approaches. From 1990 to 2010, 80 patients with T2-T4 bladder cancer were prospectively enrolled in 2 successive bladder-sparing protocols. Forty-one patients were treated with neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy followed by radiotherapy (60 Gy) in complete responders (protocol 1 [P1]) and 39 patients were treated with weekly cisplatin concurrent with radiotherapy (64.8 Gy) (protocol 2 [P2]). The median follow-up was 72 months (range, 9-204 months). Five and 10-year cumulative overall survival for all series were 73% and 60% and the corresponding numbers for cancer-specific survival were 82% and 80%, respectively. Of all surviving patients, 83% maintained their own bladder. Although there were no significant differences in overall survival (P = .820), cancer-specific survival (P = .688) and distant metastasis (P = .417) between protocols, complete response rates (P = .003), and disease-free survival (P = .031) were significantly higher in P2 treatment. Trimodality therapy with bladder preservation represents a real alternative to radical cystectomy (RC) in selected patients. Overall survival and cancer-specific survival rates are encouraging with more than 80% of survivors retaining functional bladders.

Retrospective Analysis of Clinical Outcomes With Neoadjuvant Cisplatin-Based Regimens for Muscle-Invasive Bladder Cancer

BackgroundThe benefit of neoadjuvant methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) for muscle-invasive bladder cancer (MIBC) has been prospectively demonstrated in a phase III study. Extrapolating from comparative data in the metastatic setting, platinum doublets such as cisplatin-gemcitabine (CG) have been adopted. We sought to compare clinical outcomes in patients treated for MIBC with neoadjuvant CG and MVAC at our institution. Patients and MethodsPatients with MIBC were identified from a prospectively maintained registry. Clinicopathologic information and clinical outcome data were obtained directly from the registry. When available, pharmacy records were reviewed to ascertain the use of growth factors and chemotherapy dose intensity (DI). Survival was compared in subgroups divided by the regimen of chemotherapy rendered (ie, CG vs. MVAC) using the Kaplan-Meier method. ResultsMedian overall survival (OS) in the overall cohort (N = 61) was 23 months. OS was improved in patients receiving either MVAC or CG chemotherapy compared with patients receiving “other” chemotherapy (35.3 vs. 16.3 months; P = .055). Although the median OS associated with neoadjuvant CG numerically exceeded the survival associated with neoadjuvant MVAC (104.3 and 21.8 months, respectively), this was not statistically significant (P = .73). Pathologic downstaging predicted improved OS with both neoadjuvant CG and MVAC, and the rates of downstaging were similar with both regimens. ConclusionsAlthough warranting prospective validation, our data suggest that CG is a possible alternative neoadjuvant approach to traditional regimens such as MVAC for patients with MIBC.

Carboplatin Based Induction Chemotherapy for Nonorgan Confined Bladder Cancer—A Reasonable Alternative for Cisplatin Unfit Patients?

We investigated induction carboplatin based chemotherapy in patients with nonorgan confined urothelial carcinoma who were considered unfit for cisplatin. A comparison was made with patients who received induction cisplatin based combination chemotherapy. We identified 167 patients with nonorgan confined urothelial carcinoma who received induction cisplatin based combination chemotherapy (126) or gemcitabine and carboplatin (41) at our hospital between 1990 and 2010. Of the patients 124 completed 4 cycles of cisplatin based combination chemotherapy or gemcitabine and carboplatin. Clinical response (ycTNM) was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1. Radical cystectomy and bilateral extended pelvic lymph node dissection were performed in 106 patients. A pathological complete response was defined as no evidence of disease (ypT0N0). Disease specific survival was analyzed using the Kaplan-Meier method. Multivariate analysis was performed. Complete clinical response rates did not differ significantly among the treatment groups. A pathological complete response was seen in 33.7% of specimens in the cisplatin based combination chemotherapy group vs 30.3% in the gemcitabine and carboplatin group (p = 0.808). We found no significant difference in disease specific survival between patients who started cisplatin based combination chemotherapy and those who started gemcitabine and carboplatin. For patients who completed 4 cycles and underwent radical cystectomy there was also no significant difference in disease specific survival between the groups. On multivariate analysis a pathological complete response was the only variable significantly associated with disease specific survival (p <0.045). Induction gemcitabine and carboplatin for nonorgan confined urothelial carcinoma achieves clinical and pathological response rates, and survival outcomes comparable to those of the cisplatin based combination chemotherapy schemes. Our data suggest that a carboplatin based regimen can be considered a reasonable alternative for cisplatin unfit patients in the preoperative setting.

Neoadjuvant Intralesional Methotrexate Before Surgical Treatment of Invasive Squamous Cell Carcinoma of the Lower Lip

Neoadjuvant Intralesional Methotrexate Before Surgical Treatment of Invasive Squamous Cell Carcinoma of the Lower Lip

EURAMOS-1 study: Recruitment, characteristics, and initial treatment of more than 2,000 patients (pts) with high-grade osteosarcoma.

10081 Background: EURAMOS is a transAtlantic collaboration formed to improve survival in osteosarcoma by conducting RCTs in a clinically relevant timeframe. EURAMOS-1, the largest study conducted in this rare cancer, has completed accrual. It includes two randomized comparisons investigating treatment optimization on the basis of histological response to neoadjuvant chemotherapy. Methods: Pts ≤40yrs with resectable, high grade extremity or axial osteosarcoma were eligible for registration. All were planned for 2 cycles of neoadjuvant methotrexate, doxorubicin, cisplatin (MAP) then surgical resection of the primary tumour. Pts with complete macroscopic resection and no disease progression were eligible for randomization: [i] “good responders”, &lt;10% viable tumor, MAP +/- 18m maintenance pegylated interferon; [ii] “poor responders”, ≥10% viable tumor, MAP vs MAPIE (MAP + ifosfamide, etoposide). Target sample size was ~1,260 pts randomized requiring ~2000 pts registered estimating a non-randomization rate of 30-35%. Results: From Apr 2005 to Dec 2011, 2,260 pts were registered and 1,332 randomized from 17 countries, 320 sites: median age 14yrs (IQR 11-17); 59% male; 50% femoral site; 23% definite/possible metastases; 92% conventional osteosarcoma (diagnostic biopsy). At Sep 2011 planned IDMC review, neoadjuvant treatment data were known for 2024 pts; 1926 (95%) completed 2 cycles pre-operative MAP with 3 treatment related deaths. 59% pts were randomized; non-consent was the most frequent reason for non-randomization. Relative to expected age-specific incidence (UK NCIN 1979-2007) there was apparent under recruiting of older pts: females ≥15yrs and all pts &gt;19yrs, with greater under recruitment of females than males &lt;35yrs. Pts 20-29yrs were less likely to be randomized than those aged 5-19 and ≥30 yrs, 52% vs 57-62%. Conclusions: EURAMOS-1 demonstrates that large RCTs are feasible in rare cancers with inter-continental collaboration and is a model for future trials. Neoadjuvant MAP was safe in a geographically diverse cohort. Improving clinical trial access and randomization rates for young people is still required. Multiple funders detailed at bit.ly/ymUR9w.

Neoadjuvant Gemcitabine Plus Cisplatin for Muscle-invasive Bladder Cancer

Downstaging by neoadjuvant chemotherapy improves the survival of patients with muscle-invasive bladder cancer. In salvage setting, gemcitabine plus cisplatin has demonstrated an efficacy similar to that of methotrexate, vinblastine, doxorubicin and cisplatin with less toxicity. Therefore, the application of neoadjuvant gemcitabine plus cisplatin is also being anticipated. Twenty-two patients who received neoadjuvant gemcitabine plus cisplatin were evaluated. The rate of downstaging, chemotherapy delivery profile and toxicity data were assessed. As comparator group, nine patients who were administered with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were evaluated. A mean of 1.9 cycles of neoadjuvant gemcitabine plus cisplatin were performed. Achieved drug intensity for gemcitabine and cisplatin was 83.8 and 95.4%. Downstaging to pT0 and <pT2 was achieved in 50.0 and 63.6%. Grade 3 or 4 neutropenia, anemia, thrombocytopenia and febrile neutropenia appeared in 14.3, 2.4, 21.4 and 2.4%, respectively. Grade 3 or 4 non-hematologic toxicity was not observed. Thrombocytosis developed in 26.2%. A mean of 2.3 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were performed. The achieved drug intensities for methotrexate, vinblastine, doxorubicin and cisplatin were 59.6, 69.8, 100 and 88.6%. In patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin, downstaging to pT0 and <pT2 was achieved in 22.2 and 44.4%. Grade 3 or 4 neutropenia, anemia and thrombocytopenia was present in 19.1, 9.5 and 4.8%. Grade 3 nausea developed in 28.6%. The rate of downstaging by neoadjuvant gemcitabine plus cisplatin was comparable with that by methotrexate, vinblastine, doxorubicin and cisplatin. Gemcitabine plus cisplatin was associated with less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin.

Genoproteomic Mining of Urothelial Cancer Suggests γ-Glutamyl Hydrolase and Diazepam-Binding Inhibitor as Putative Urinary Markers of Outcome after Chemotherapy

Urinary biomarkers for the detection of bladder cancer have been developed, but no similar markers exist for prediction of clinical outcomes after receiving chemotherapy. Here we evaluate an approach that combines genomic, proteomic, and therapeutic outcome datasets to identify novel putative urinary biomarkers of clinical outcome after neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). Using this method, we identified gamma-glutamyl hydrolase (GGH), emmprin, survivin, and diazepam-binding inhibitor (DBI). Interestingly, GGH is a protein associated with methotrexate resistance, whereas emmprin, survivin, and DBI had been previously identified as predictors of outcome after platinum-containing chemotherapeutic regimens when assessed on tumor tissue. Using disease-free survival as a marker for clinical outcome, we evaluated the ability of GGH, emmprin, survivin, and DBI expression in tumor tissue to stratify 27 patients treated with neoadjuvant MVAC. DBI (P = 0.046) but not GGH (P = 0.190), emmprin (P = 0.066), or survivin (P = 0.393) successfully stratified patients. When GGH was used with DBI the significance of stratification improved (P = 0.024), whereas the addition of survivin or emmprin to this latter two-gene model reduced its significance (P = 0.036 and P = 0.040, respectively). Although these predictive results were obtained on tumor tissues, the presence of GGH and DBI in urine serves as a rationale for developing them as urinary markers of clinical outcomes for patients treated with neoadjuvant MVAC.

Concordant Gene Expression Signatures Predict Clinical Outcomes of Cancer Patients Undergoing Systemic Therapy

Conventional development of multivariate gene expression models (GEM) predicting therapeutic response of cancer patients is based on analysis of patients treated with specific regimens, which limits generalization to different or novel drug combinations. We overcome this limitation by developing GEMs based on in vitro drug sensitivities and microarray analyses of the NCI-60 cancer cell line panel. These GEMs were evaluated in blind fashion as predictors of tumor response and/or patient survival in seven independent cohorts of patients with breast (n = 275), bladder (n = 59), and ovarian (n= 143) cancer treated with multiagent chemotherapy, of which 233 patients were from prospectively enrolled clinical trials. In all studies, GEMs effectively stratified tumor response and patient survival independent of established clinical and pathologic tumor variables. In bladder cancer patients treated with neoadjuvant methotrexate, vinblastine, Adriamycin (doxorubicin), and cisplatin, the 3-year overall survival for those with favorable GEM scores was 81% versus 33% for those with less favorable scores (P = 0.002). GEMs for breast cancer patients treated with 5-fluorouracil, Adriamycin (doxorubicin), and cyclophosphamide and ovarian cancer patients treated with platinum-containing regimens also stratified patient survival [5-year overall survival 100% versus 74% (P = 0.05) and 3-year overall survival 68% versus 43% (P = 0.008), respectively]. Importantly, clinical prediction using our in vitro GEM was superior to that of conventionally derived GEMs. We show a facile yet effective approach to GEM derivation that identifies patients most likely to benefit from selected multiagent therapy. Use of such in vitro-based GEMs may provide a robust and generalizable approach to personalized cancer therapy.

Neoadjuvant versus adjuvant chemotherapy for muscle-invasive bladder cancer

Muscle-invasive bladder cancer is a deadly disease that often requires more than radical surgery for optimal management. The best level one evidence supports the use of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) chemotherapy followed by surgery. There remains controversy, however, with some continuing to argue in favor of selective adjuvant chemotherapy only in the highest risk patients. Certain patients and situations argue in favor of a surgery-first approach, with selective chemotherapy in an adjuvant setting. There is a need for better markers for disease risk and progression in advanced bladder cancer to identify those who would benefit the most from aggressive, multimodal therapy. Further studies are needed to address the ongoing questions that remain in the management of this disease.

Bladder cancer

To review the diagnosis and management of all stages of bladder cancer with an emphasis on studies and developments within the last year. Cystoscopy remains the mainstay in the detection and surveillance of bladder cancer, though fluorescent light may enhance detection as well as prolong recurrence-free survival. Urine cytology remains the gold standard for diagnosis and surveillance of bladder cancer; however, there are continued efforts in the development of urinary bladder cancer markers. Transurethral resection and instillation of perioperative chemotherapy remains the treatment of choice for superficial bladder cancer in most patients. Data supports the use of intravesical Bacillus Calmette-Guerin (including a maintenance regimen) for those at high risk for disease progression. Radical cystectomy with thorough pelvic lymphadenectomy remains the gold standard for management of muscle invasive disease. Research on the use of laparoscopy, robot-assisted laparoscopy, the effect on patient's health-related quality of life, and the potential role for bladder preservation strategies is ongoing. The value of neoadjuvant versus adjuvant chemotherapy around the time of cystectomy is still debated, though the best level-one evidence supports the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by cystectomy. Platinum-based chemotherapeutic agents are most commonly used in the community setting. Work is ongoing to develop new regimens, especially in patients who cannot take cisplatin. Research in the development of targeted therapies alone or in combination with chemotherapeutic regimens continues and will hopefully broaden our treatment strategy for patients with advanced/metastatic disease. We are encouraged by the progress in bladder cancer diagnosis and management; however, continued research is needed in order to improve the lives of our patients with this disease.