Neoadjuvant Cisplatin Research Articles

Neoadjuvant cisplatin (CDDP) chemotherapy (CT) with docetaxel (D) and cetuximab (Cmab) followed by concurrent radiochemotherapy (RTCT) in locally advanced head and neck cancer (LA-HNC).

e16025 Background: Induction CT with D and CDDP followed by concurrent platinum RTCT has emerged as a therapeutic option for LA-HNC. Cmab also challenged the role of CDPP in RTCT. A schedule based on these advances may be valuable in the treatment of LA-HNC. Methods: Patients (pts) with LA-HNC are included in a pilot phase I-II study, having as primary endpoint tolerance and as secondary local progression-free (LPFS), distant metastasis-free (DMFS) and overall survival (OS). Thirteen pts (median age 68 years, median PS 0) with LA-HNC participated. A short course of neoadjuvant CT (two bi-weekly cycles) with D (40mg/m2), CDDP (60mg/m2) and Cmab (400mg/m2) was applied before RTCT with weekly CDDP (40mg/m2) and Cmab (250 mg/m2). Conformal RT was given in 19-21 daily fractions of 2.7Gy supported with high- dose daily amifostine (500-1000mg, using a previously described algorithm). After completion, the same induction regimen was given for 2-4 cycles, depending upon tumor response. The study has completed accrual. Results: Analysis of a minimum of 7 months (m) of follow-up (FU) is presented. Induction CT was well tolerated with only 1 pt experiencing grade (G) 3 leucopenia, 1 pt with G3 anemia and no pt experiencing any thrombopenia. Fatigue of G2 in 3 pts and G3 in 1 pt was noted. Cetuximab was well tolerated with 5 pts experiencing G2 rash and 1 G3. Concurrent RTCT was also well tolerated: 7 pts presented with G1/2 and 1 with G3 mucositis and 1 pt with G1 fungal infection. Amifostine was well tolerated and no pt had any rash. Cetuximab-related rash did not deteriorate during RT. No other toxicities were noted. Minimal/partial response to CT was noted in 11/13 pts. Complete response to RTCT was noted to 11/13 pts. Median LPFS was 9.07m (range: 7-18), with 4 pts experiencing a local recurrence, DMFS was 9.53 m (7-18) with 2 pts having a distant metastasis and OS was 9.61m with all pts alive at the time of the evaluation. Conclusions: The above regimen appears safe and effective for LA-HNC. Although this interim analysis provided no superior results to a previous published study of ours using the RTCT regimen alone, a phase II study is ongoing to extract mature results. No significant financial relationships to disclose.

Clinical outcomes in patients with locally advanced nasopharyngeal cancer treated with neoadjuvant docetaxel and cisplatin followed by radiation treatment and concomitant cisplatin.

e16017 Background: Radiation treatment with concomitant chemotherapy has improved the therapeutic outcome of patients with locally advanced nasopharyngeal carcinoma. However, the importance of neoa...

Neoadjuvant paclitaxel poliglumex (PPX), cisplatin, and radiation (RT) for esophageal cancer.

4085 Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-L-glutamic acid thereby increasing its radiation enhancement factor to 4.0-8.0 compared to 1.5-2.0 for paclitaxel. In previous phase I studies, The Brown University Oncology Group evaluated PPX with concurrent radiation and PPX/cisplatin/RT. A phase II study was subsequently performed to evaluate the pathologic response rate of neoadjuvant PPX, cisplatin and radiation for patients with esophageal cancer. Methods: Eligible patients had pathologically confirmed adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction with no evidence of distant metastasis. Patients received weekly PPX 50 mg/m2 and cisplatin 25 mg/m2 for 6 weeks with concurrent 50.4 Gy of radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. Results: The study completed accrual of 40 patients, 37 with adenocarcinoma and 3 with squamous cell cancer. The median age is 62 years. One of 40 (2%) patients developed a grade 4 hypersensivity reaction. Treatment related grade 3 non-hematologic toxicities included esophagitis (7%), nausea (7%), fatigue (5%). Only one patient required a feeding tube and 1 patient used TPN. There were no grade 4 hematologic toxicities and 2 patients (5%) had grade 3 neutropenia. Three patients with clinical endoscopic complete responses (two with squamous cell cancer) refused surgery. Twelve of 37 patients (32%) had pathologic complete responses. The 12 patients with pathologic CR all had adenocarcinoma. Conclusions: PPX, cisplatin and concurrent radiation is a well tolerated, easily administered regimen for esophageal cancer with a low incidence of significant esophagitis and a high pathologic complete response rate consistent with the preclinical data of PPX and radiation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, Cell Therapeutics

Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer

PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.

Surgical Complications and the Use of Neoadjuvant Bevacizumab.

Abstract Introduction:Neoadjuvant chemotherapy is being increasingly used in operable breast cancer. There are limited data on the safety of bevacizumab (Bev) in combination with chemotherapy in the neoadjuvant setting. We sought to explore the safety and efficacy of neoadjuvant cisplatin/Bev in a protocol for triple negative breast cancer (TNBC), with post operative dose dense AC or AC/Taxol plus Bev. We present our operative experience, including postoperative complications. We also compared this to a smaller single arm neoadjuvant cisplatin alone study.Methods:51 patients with confirmed TNBC provided informed consent and were enrolled in a single arm phase II trial of neoadjuvant cisplatin 75 mg/m2 plus Bev15 mg/kg q 3 weeks x 3 cycles with the 4th cycle cisplatin alone prior to definitive surgery. This design allowed at least 6 weeks between the last dose of Bev and surgery. Research biopsies were obtained before treatment and at surgery. Postoperatively, patients received doxorubicin and cytoxan (AC) plus bevacizumab or AC/Taxol plus Bev. Median age was 50 yrs (range 30-65 yrs); tumors were clinical stage II 48 (94%) and stage III 3 (6%).28 patients with confirmed TNBC were enrolled in our phase II trial of neoadjuvant cisplatin. Single-agent cisplatin 75mg/m2 q3weeks x 4cycles was given prior to definitive surgery. Median age was 50 yrs (range 29-69yrs); tumors were clinical stage II (75%), stage III (25%). Postoperatively, patients received AC or AC/Taxol. Two-sided Fisher exact test were used for comparing the 2 trials.Results:Fifty-one patients received neoadjuvant protocol therapy with cisplatin/Bev (all received at least one cycle of bevacizumab, 7 did not complete all cycles of preop bevacizumab) and underwent definitive local therapy to the breast. Breast conserving therapy was performed in 29 (57%) and mastectomy with or without reconstruction in 22 (43%). Postoperative complications were reported in 22 (43%) of patients: 4 (8%) required wound debridement and explantation of expanders, 8 (16%) wound breakdowns, 5 (10%) developed hematomas requiring operative intervention and 5 (10%) seromas requiring multiple aspirations.Twenty-eight patients completed neoadjuvant cisplatin therapy and underwent definitive local therapy to the breast. Breast conserving therapy was performed in 13 (46%) and mastectomy with or without reconstruction in 16 (54%). Postoperative complications were reported in 11 (39%) of patients: 5 seromas requiring drainage (18%), 2 hematomas (7%), 2 abscesses (7%), and 2 (7%) wound breakdowns. No reconstructions were lost including the 3 expanders and 2 TRAM flaps.We compared all toxicities between the two trials, (p= 0.81 NS), and wound healing related complications between the two trials (p= 0.10 NS).Conclusions:Cisplatin/Bevacizumab and cisplatin alone neoadjuvant therapy resulted in a significant number of postoperative complications. Specifically use of expanders or implants may be problematic for patients treated with Bev with a trend towards more wound related events for this group. However, this was a single arm trial, a randomized controlled studies will be necessary in determine the optimal use of bevacizumab in the timing of breast cancer surgery. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 43.

Primary Intra-Osseous Liposarcoma of the Femur: A Case Report

We report a rare case of an intra-osseous liposarcoma of the proximal femur. A 26-year-old man presented with a 6-month history of left groin pain radiating to the knee and an antalgic gait. Radiology showed a predominantly fatty lesion in the medial aspect of the femoral neck extending toward the lesser trochanter; most of the marrow in the femoral neck had been replaced without evidence of an extra-osseous mass; and the posterior cortex had been destroyed. Histological and immunohistochemical analyses of the tumour after open biopsy were indicative of high-grade liposarcomatous malignancy. After exclusion of any other primary tumour foci or metastases on regional and whole-body magnetic resonance images, the diagnosis of a high-grade intra-osseous primary liposarcoma of the proximal femur was made. The patient received 2 preoperative courses of neoadjuvant doxorubicin, cisplatin and methotrexate. After proximal femoral replacement following en bloc excision of the proximal femur, 4 more cycles of adjuvant ifosfamide and etoposide were given. At the 16-month follow-up, he remained independently ambulatory, with no local or distant recurrence. Tissue diagnosis and multimodal imaging, rather than any single radiological investigation, are important in making the diagnosis.

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 polychemotherapy in locally advanced Merkel cell carcinoma

A 72-year-old man presented with a Merkel cell carcinoma (MCC) of the left cheek with concomitant nodal spread. A 61-year-old man presented with an MCC of the right thigh with rapid nodal recurrence. Skin biopsy samples proved the MCC nature of the neoplasm in both patients. Staging procedure included clinical and radiological investigations. Advanced stage II MCC. Neoadjuvant cisplatin, etoposide and cyclophosphamide (EPC) regimen led to local control in the first patient and allowed curative surgery associated with adjuvant radiation therapy. Complete remission was maintained for 32 months. The second patient was treated by surgery plus radiation therapy. Nodal and cutaneous recurrences were treated with a neoadjuvant EPC regimen leading to a 5-year complete remission.

Bladder Cancer

Bladder cancer is a complex disease of older patients with coexisting medical problems requiring multimodal therapy. For patients with localized bladder cancer, standard management for superficial disease includes transurethral resection with or without intravesical therapy, while muscle-invasive cancer is managed with neoadjuvant cisplatin- based chemotherapy followed by radical cystectomy. Comorbid conditions prevent many older patients from receiving cisplatin-based chemotherapy and/or undergoing surgery. Tri-modality bladder preservation approaches including a complete transurethral resection of the bladder tumor (TURBT) followed by combined chemotherapy and radiation have generally included only those patients who are candidates for a salvage cystectomy. Future research must specifically focus on older adults with bladder cancer including non-cisplatin-based neoadjuvant regimens; bladder preservation strategies using alternative non-cisplatin chemotherapy in noncystectomy candidates; clinical trials evaluating novel targeted agents in older adults; and geriatric assessment tools to assist in decision making.

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.

Neoadjuvant cisplatin and bevacizumab in triple negative breast cancer (TNBC): Safety and efficacy

551 Background: We have previously shown that neoadjuvant cisplatin has activity in TNBC, a subtype of breast cancer for which there is no effective targeted therapy. Bevacizumab adds to the efficacy of chemotherapy in metastatic breast cancer; however, there is limited data on the safety or efficacy of bevacizumab in combination with chemotherapy in the neoadjuvant or adjuvant setting. Thus, we sought to explore the safety and efficacy of the addition of bevacizumab to cisplatin in the treatment of TNBC. Methods: 51 patients (pts) with confirmed TNBC provided informed consent and were enrolled in a single arm phase II trial of neoadjuvant cisplatin 75 mg/m2 q 3 weeks x 4 cycles and bevacizumab 15 mg/kg q 3 weeks x 3 cycles prior to definitive surgery. Only 3 cycles of bevacizumab were delivered to allow 6 weeks between the last dose of bevacizumab and surgery. Research biopsies were obtained and breast MRI performed before treatment and at surgery. Postoperatively, pts received doxorubicin and cytoxan (AC) plus bevacizumab or AC/Taxol plus bevacizumab. Median age was 50 yrs (range 30 to 66 yrs); tumors were clinical T1 (2%), T2 (80%), T3 (18%). Results: Forty-six pts are evaluable for response and 5 pts are still receiving neoadjuvant therapy. Clinical responses to date: 12/46 (26%) clinical complete response (cCR), 24/46 (52%) clinical partial response (cPR), 5/46 (11%) stable disease (SD), and 1/46 (2%) progressive disease (PD). Non-responders included 4/46 (9%) pts who discontinued protocol therapy for toxicity. To date, 7/46 (15%) pts achieved a complete pathological response (Miller-Payne 5) and an additional 10/46 (22%) were Miller-Payne 4. Five pts did not complete neoadjuvant therapy, 2 with tinnitus/hearing loss and 3 with grade 4 toxicities consisting of refractory hypertension in 1 pt and pulmonary embolism (PE) in 2 pts. Tissue-based assays to predict platinum/bevacizumab responses, including BRCA1/2 status, are underway. Conclusions: Cisplatin and bevacizumab has some activity in TNBC as demonstrated by 37% of evaluable pts with a Miller-Payne 4 or 5 pathological response. However, toxicity, including tinnitus/hearing loss, hypertension and PE, limited completion of neoadjuvant therapy in 11% of pts. No significant financial relationships to disclose.

Neoadjuvant docetaxel, cisplatin, and 5-fluorouracil before concurrent chemoradiotherapy or concurrent cetuximab-radiotherapy in locally advanced squamous cell carcinoma of the head and neck

e17045 Background: Encouraging results have recently been reported in patients with locally advanced squamous cell carcinoma of the head and neck. The present study assessed the feasibility of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by concurrent chemoradiotherapy (CHT-RT) or concurrent cetuximab-radiotherapy. Methods: Induction chemotherapy consisted of TPF (docetaxel 75 mg/m(2), cisplatin 75 mg/m(2), 5-fluorouracil 750 mg/m(2)/d continuous infusion for 96 h) every three weeks, followed by CHT-RT regimen (radiotherapy 70 Gy total dose fractionated at 2Gy per day, 5 days a week concurrently with weekly cisplatin 40 mg/m(2) or cetuximab with loading dose of 400 one week before starting radiotherapy and 250 weekly during the radiotherapy) 4–7 weeks later. Percutaneus endoscopic gastrectomy inserted before the combined treatment. The National Cancer Institute Common Toxicity Criteria (version 2) were used for classification of adverse events. Results: Between march 2007 and november 2008, 29 previously untreated patients (19 male and 4 female) with stage III-IV squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx were included to the study. The median age was 60 years (range, 56–75 years). The stage distribution was as follows: stage II, 1 patient; stage III, 14 patients; and stage IV, 14 patients. 16 patients had a performance status of 0 and 11 had a performance status of 1. The response rate (RR) after IC was: complete response (CR) for 10 pts (34%), partial response (PR) for 13 pts (57%) and no response (NR) for 3 pts (13%). Toxicity from IC included neutropenia Gr III,IV 25%,neutropenic fever 9%, mucositis and diarrhrea Gr III, IV 22% . 60% of patients completed 3 cycles, 20% received 2 cycles and 20% received only one cycle of TPF. The toxicity from the concurrent phase included mucositis Gr III-IV in 70% of patients,dermatitis Gr III-IV in 43% and no case of neutropenia Gr III-IV. The combined treatment was interrupted only in 4 patients for one week. Conclusions: TPF was well tolerated with high response rate and low rate of acute toxicity. Three cycles of TPF followed by combined treatment are feasible. No significant financial relationships to disclose.

Phase II pilot study of neoadjuvant docetaxel and cisplatin followed by adjuvant erlotinib in patients with stage I-III non-small cell lung cancer (NSCLC)

7566 Background: Pts with early stage NSCLC, especially with nodal disease, have a poor prognosis despite curative intent therapy. It is unclear which pts may derive the benefit of chemotherapy. The primary endpoint of the study was to assess the tolerability of the regimen. In addition, the clinical response of the chemotherapy regimen as well as tumor biomarkers modulation will be examined. Methods: Pts had previously untreated, potentially surgically resectable, stage I-III NSCLC with ECOG performance status (PS) 0–1 and adequate laboratory parameters. After baseline tissue was obtained, chemotherapy was administered (docetaxel [T] 75 mg/m2 and cisplatin [P] 80 mg/m2 every 3 wks) for 3 cycles. Subsequently, pts underwent restaging, then planned definitive therapy with surgical resection. Pts were then offered treatment for 1 year with erlotinib (E) 150 mg PO daily. Bronchoscopic biopsies were performed at 6 months and 1 year post- surgery. Results: 41 pts were enrolled between 2/07 and 11/08. 3 were not eligible and did not receive treatment. Of the 38 eligible pts: median age was 65 years (42–80); 24 (63.2%) were male; 26 (68%) were PS 1. Stage IB 18% (7), IIB 37% (14), IIIA 39% (15), IIIB 5% (2). 31 pts completed all 3 cycles (35 pts completed at least 2 cycles). 32 pts underwent definitive surgical resection with 1 pt pending for surgery. 5 others did not undergo surgery: pneumonia (1), progressive disease (1), definitive chemo-radiation (3). For pts completing at least 2 cycles of chemotherapy, the radiographic response rate was 57% (20) by RECIST criteria with 40% (14) having stable disease. 1 pt had a complete pathologic response. 16 pts have started adjuvant E, 4 have completed 1 yr of treatment. Grade 3/4 toxicities included neutropenia (6 pts) and hypokalemia (4 pts). Blood and tissue specimens will be analyzed to assess sensitivity to chemotherapy. Conclusions: Neoadjuvant T and P is a tolerable and active regimen with an encouraging response rate in stage I- III resectable NSCLC. In addition to clinical characteristics, determining which patients will benefit from chemotherapy by analyzing their tumor biomarkers may help improve overall outcomes of curative lung cancer pts. Supported by grant DoD# W81XWH-07–1-0306. [Table: see text]

Neoadjuvant paclitaxel poliglumex, cisplatin, and radiation for esophageal cancer: A phase II trial

e15542 Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-L-glutamic acid thereby increasing its radiation enhancement factor to 4.0 to 8.0 compared to 1.5–2.0 for paclitaxel. The Brown University Oncology Group previously performed a phase I study establishing the dose of single agent PPX with radiation, and the combination of PPX, cisplatin and radiation for esophagogastric cancer. A phase II study was therefore initiated to evaluate the pathologic response rate of neoadjuvant PPX, cisplatin and radiation for patients with esophageal cancer. Methods: Eligible patients had pathologically confirmed adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction with no evidence of distant metastasis. Celiac nodal disease was allowed. Patients received weekly PPX 50mg/m2 and cisplatin 25mg/m2 for 6 weeks with concurrent with 50.4Gy of radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. Results: Twenty-three eligible patients have been enrolled. The median age is 63 years. Grade 3/4 treatment related toxicities in the first 15 patients include dehydration (n=5), anorexia (n=5), esophagitis/dysphagia (n=4), electrolyte abnormalities (n=3), nausea (n=2), hypersensitivity (n=2), weight loss (n=1), and anemia (n=1). One patient developed carcinomatous meningitis during treatment. Five of the first 11 patients (45%) undergoing resection had a pathologic complete response. Conclusions: This preliminary data suggests that PPX may provide enhanced radiosensitization as compared to standard paclitaxel, consistent with the preclinical data of PPX and radiation. No significant financial relationships to disclose.

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.

Commentary on A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: A retrospective experience

Neoadjuvant cisplatin-based chemotherapy improves survival in muscle-invasive urothelial cancer, with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) considered the standard regimen. Gemcitabine plus cisplatin (GC) has similar efficacy and less toxicity than MVAC in metastatic disea]se, but is untested as neoadjuvant treatment. The authors retrospectively evaluated patients with muscle-invasive urothelial carcinoma who received neoadjuvant GC before radical cystectomy between November 2000 and December 2006 at Memorial Sloan-Kettering Cancer Center. Post-therapy pathological downstaging to either residual disease at cystectomy (pT0) or no residual muscle-invasion ( Four cycles of neoadjuvant GC were given over 12 weeks ( n = 42). Thirty-nine (93%) of 42 patients received 4 cycles, with a median 91% drug delivery for cisplatin and 90% for gemcitabine. The pT0 proportion was 26% (95% confidence interval [CI], 14–42), and no residual muscle-invasive disease proportion ( Neoadjuvant GC is feasible and allows for timely drug delivery. The proportion of GC-treated patients whose primary tumors were downstaged, with prolonged disease-free survival and minimal or no residual disease, was similar to MVAC-treated patients.

Multicenter Phase II Trial of Neoadjuvant Pemetrexed Plus Cisplatin Followed by Extrapleural Pneumonectomy and Radiation for Malignant Pleural Mesothelioma

Neoadjuvant pemetrexed plus cisplatin was administered, followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT), to assess the feasibility and efficacy of trimodality therapy in stage I to III malignant pleural mesothelioma. Requirements included stage T1-3 N0-2 disease, no prior surgical resection, adequate organ function (including predicted postoperative forced expiratory volume in 1 second > or = 35%), and performance status 0 to 1. Patients received pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) for four cycles. Patients without disease progression underwent EPP followed by RT (54 Gy). The primary end point was pathologic complete response (pCR) rate. Seventy-seven patients received chemotherapy. All four cycles were administered to 83% of patients. The radiologic response rate was 32.5% (95% CI, 22.2 to 44.1). Fifty-seven patients proceeded to EPP, which was completed in 54 patients. Three pCRs were observed (5% of EPP). Forty of 44 patients completed irradiation. Median survival in the overall population was 16.8 months (95% CI, 13.6 to 23.2 months; censorship, 33.8%). Patients completing all therapy had a median survival of 29.1 months and a 2-year survival rate of 61.2%. Radiologic response of complete or partial response was associated with a median survival of 26.0 months compared with 13.9 months for patients with stable disease or progressive disease (P = .05). This multicenter trial showed that trimodality therapy with neoadjuvant pemetrexed plus cisplatin is feasible with a reasonable long-term survival rate, particularly for patients who completed all therapy. Radiologic response to chemotherapy, but not sex, histology, disease stage, or nodal status, was associated with improved survival.

Updated results of bladder-sparing trimodality approach for invasive bladder cancer

Purpose To update long-term results with selective organ preservation in invasive bladder cancer using aggressive transurethral resection of bladder tumor (TURBT) and radiochemotherapy (RCT) and to identify treatment factors that may predict overall survival (OS). Materials and methods Between 1990 and 2007, a total of 74 patients with T2-T4 bladder cancer were enrolled in 2 sequential bladder-sparing protocols including aggressive TURB and RCT. From 1990 to 1999, 41 patients were included in protocol no. 1 (P1) that consisted of three cycles of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy prior to re-evaluation and followed by radiotherapy (RT) 60 Gy in complete responders. Between 2000 and 2007, 33 patients were entered in protocol no. 2 (P2) that consisted of concurrent RCT 64, 8 Gy with weekly cisplatin. In case of invasive residual tumor or recurrence, salvage cystectomy was recommended. Primary endpoints were OS, overall survival with bladder preservation (OSB), and late toxicity. Results The mean follow-up for the whole series was 54 months (range 9–156), 69 months for patients in P1 and 36 months for patients in P2. The actuarial 5-year OS and OSB for all series were 72% and 60%, respectively. Distant metastases were diagnosed in 11 (15%) patients. Grade 3 late genitourinary (GU) and intestinal (GI) complications were 5% and 1.3%, respectively. There were no significant differences in the incidence of superficial recurrences ( P = 0.080), muscle-invasive relapses ( P = 0.722), distant metastasis ( P = 0.744), grade ≥2 late complications ( P = 0.217 for GU and P = 0.400 for GI), and death among the 2 protocols ( P value for OS = 0.643; P value for OSB = 0.532). Conclusion These data confirm that trimodality therapy with bladder preservation represents a real alternative to radical cystectomy in selected patients, resulting in an acceptable rate of the long-term survivors retaining functional bladders.

The Use of Cisplatin to Treat Advanced-Stage Cervical Cancer During Pregnancy Allows Fetal Development and Prevents Cancer Progression: Report of a Case and Review of the Literature

Cervical cancer is one of the most frequently encountered malignancies in pregnancy. For early-stage disease arising in late second/third trimester, treatment may be delayed until delivery. However, in advanced disease, data are lacking. A 26-year-old woman presented at 21 weeks gestation with a stage IIB high-grade clear cell cervical carcinoma. At 25 + 1 weeks gestation, cisplatin 100 mg/m(2) every 21 days was commenced. One month after cycle 3, a healthy infant was delivered. Thereafter, further cisplatin, intracavity cesium, and chemoradiation were administered. Findings from subsequent clinical examination and magnetic resonance imaging were normal. Fifteen months post treatment, both patient and baby remain well. Neoadjuvant cisplatin chemotherapy can be used in stage IIB cervical carcinoma during pregnancy to allow fetal development and prevent disease progression before delivery.