Neoadjuvant Platinum Research Articles

A Phase II Trial of a Neoadjuvant Platinum Regimen for Locally Advanced Breast Cancer: Pathologic Response, Long-Term Follow-up, and Correlation With Biomarkers

Purpose The purpose of this study is to determine the response, tolerability, and long-term outcome of a neoadjuvant platinum-containing regimen for locally advanced breast cancer (LABC) and to search for a correlation between pathologic complete response (pCR) and predefined biomarkers in this cohort. Patients and Methods Patients with LABC received 8 cycles of either sequence A or B. Sequence A was doxorubicin 60 mg/m 2 and paclitaxel 175 mg/m 2 (AT) every 3 weeks × 4 followed by cisplatin (C) 60 mg/m 2 and paclitaxel 90 mg/m 2 (CT) every 2 weeks × 4. Sequence B was CT × 4 (with paclitaxel dose escalation) followed by AT × 4. In addition to estrogen receptor (ER) and HER2, immunohistochemistry for MDR-1, MRP-1, topoisomerase IIα (topo IIα), and p53 was performed. Results A total of 88 patients were evaluable for response and toxicity. Median follow-up was 97 months. The overall pCR rate was 21.5%. For subgroups ER+/HER2+, HER2+ and double negative (ER+/HER2+) disease, the pCR rates were 5.9%, 23.3%, and 35%, respectively ( P = .006). Five-year overall survival for the entire cohort was 71.1%. Five-year overall survival was 88.1% (95% CI, 77.1%-99.1%) for the ER+/HER2+ group compared with 68.5% (95% CI, 51.3%-85.7%) and 49.5% (95% CI, 27.4%-71.6%) in the HER2+ and “double-negative” group, respectively ( P = .0077). Overexpression of topo IIα was correlated with pCR ( P < .001). There were no toxic deaths. Conclusion A platinum-containing neoadjuvant regimen was well tolerated and achieved a pCR comparable to other recent studies of multiagent chemotherapy. Further studies tailored for specific breast cancer subtypes are required.

Neoadjuvant chemotherapy for locally advanced squamous cancers of the head and neck: current status and future prospects

To assess the role of neoadjuvant chemotherapy for locally advanced squamous head and neck cancer. Several phase III clinical trials in locally advanced squamous head and neck cancer show promising results for neoadjuvant platinum, taxane, and fluorouracil chemotherapy prior to definitive radiation or concurrent chemoradiation. Clinical trials comparing cisplatin and 5-fluorouracil with or without a taxane followed by radiation or concurrent chemoradiation show that the three-drug induction chemotherapy may improve survival particularly for unresectable tumors. Clinical trials comparing chemoradiation with and without induction three-drug chemotherapy are ongoing. Molecular and clinical considerations for using neoadjuvant chemotherapy in the treatment of locally advanced head and neck cancers are being explored.

Neoadjuvant platinum-based chemotherapy (CT) for triple-negative locally advanced breast cancer (LABC): Retrospective analysis of 125 patients

625 Background: Triple-negative breast cancer (TNBC), defined by lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, accounts for 15–20% of all breast cancers and is associated with poor prognosis. There is no consensus regarding optimal CT for treatment of such patients. Preclinical data suggests TNBC may be sensitive to platinums because of deficiencies in BRCA-associated DNA repair. The aim of this study was to evaluate pathologic complete response (pCR) and overall survival (OS) in patients with TNBC treated with neoadjuvant platinum-based CT. Methods: We identified 674 patients with LABC who received neoadjuvant CT between January 1999 and June 2008 at University of Miami. Of these, 125 (18.5%) had histopathologic confirmation of TNBC. All patients received neoadjuvant platinum salts + docetaxel. 76 (61%) also received neoadjuvant AC, while 42 (34%) received adjuvant AC. pCR was defined as no residual invasive disease in breast and axilla. OS was calculated according to Kaplan-Meier. Results: Demographics: median age 50 (28–86 years). 60% premenopausal. TNM stage distribution: T1 0.9%, T2 5.2%, T3 53.4%, T4 40.5%, N0 25.0%, N1 36.2%, N2 35.4%, N3 3.4%, M0 100%, inflammatory 11%, median tumor size = 9.5 cm. Follow up duration ranged from 0.3 to 8.9 years. pCR was observed in 42 of 125 patients (34%; 95% CI 26–43%). Among patients receiving neoadjuvant AC, 30 of 76 (40%; 95% CI 28–51%) had pCR, while amongst those receiving adjuvant AC, 12 of 42 (29%, 95% CI 16–45%) had pCR at the time of definitive surgery. Patients achieving pCR had significantly higher OS (5-yr rate = 73% in pCR, vs. 49% in non-pCR; p &lt; 0.001). OS in TNBC patients receiving cisplatin/docetaxel was significantly superior to those receiving carboplatin/docetaxel (11 mortality events out of 78 patients receiving cisplatin based CT vs 24 out of 47 receiving carboplatin based CT logrank p = 0.001). Conclusions: To date, this is the largest single institution cohort of locally advanced TNBC uniformly treated with platinum+docetaxel-based CT regimens. Platinum/docetaxel-based neoadjuvant CT provided high rates of pCR and excellent OS for women with locally advanced TNBC. No significant financial relationships to disclose.

A prospective study to evaluate the role of gene expression profiles (GEP) in predicting clinical outcome of patients (pts) receiving preoperative chemotherapy for oesophagogastric (OG) cancer

4501 Background: Whilst preoperative chemotherapy has demonstrated survival benefit for pts with potentially resectable OG cancer it is not possible to predict the benefit for an individual pt. This study was designed to prospectively correlate GEP with clinical outcome. Methods: Eligible pts were deemed to have resectable disease after staging CT, EUS, and laparoscopy as indicated &amp; following discussion at the multidisciplinary team meeting. All pts received neoadjuvant platinum &amp; fluoropyrimidine based chemotherapy &amp; clinical data were entered prospectively onto a study specific database. GEP were produced from total RNA isolated from snap frozen pre treatment tumour biopsies obtained at baseline endoscopy. Labelled cDNA was hybridised versus a universal human reference using an in house c DNA array of 22,000 clones. Results: Of the pts with adequate follow up accrued between 2002–2005, 35 met the quality control measures for the arrays. Median age=66 yrs (47–83); male=32, female=3; tumour subsites: oesophagus=23, oesophago-gastric junction (OGJ)=12; adenocarcinoma=35; T stage: T 2=3, T3=30, T4=2; N stage: N0=12, N1=23; performance status 0=7, 1=28. Median follow up=938 days. Median overall survival (OS) = 570 days. Prognostic groups were designated according to the median OS (days) of the group: good &gt; median and poor &lt; median. Supervised hierarchical clustering of normalised data revealed significantly differentially expressed genes based on OS (p&lt;0.01) with 2 distinct clusters: a poor outcome group: N= 17 (2yr OS 17.6%) [95% CI: 4.3–38.3], a good outcome group: N=18 (2 yr OS 55%) [95% CI: 30.5–74.8]. Of the differentially expressed genes, those involved in receptor tyrosine kinase signalling &amp; cell growth were amongst the most significantly affected pathways. Conclusions: This novel technique using GEP in tumour biopsies has successfully identified groups of tumours with distinct gene expression profiles that correlate with survival. The approach warrants further validation in a larger cohort. It could facilitate the development of tailored treatment according to individual tumour biology in OG cancer. No significant financial relationships to disclose.

Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies.

A Nordic collaborative group assessed the effectiveness of cisplatinum based combination chemotherapy prior to cystectomy in two consecutive trials. We analyzed overall survival in all patients and in prespecified subgroups defined by preoperative T-stage, gender and age. The studies included in 1985-1997 620 patients with clinically T1G3, T2-T4aNXM0 urothelial bladder cancer and WHO performance </=2. Platinum was combined with adriamycin in the first and with methotrexate in the second trial. In the first of the studies, preoperative radiotherapy was used in both arms. Individual patient data were used. No patients were lost to follow-up. The median follow-up was 4.7 years. A fixed effect model was used to combine the results of the two trials. Subgroup analyses were performed for T-stages, gender and age groups. All analyses were done according to intention to treat. The combined study results showed a hazard ratio of 0.80 (95% confidence interval 0.64-0.99) for overall survival in favor of neoadjuvant treatment. Survival was 56% at five years in the experimental group versus 48% in the control group, thus corresponding to an eight percent absolute risk reduction after neoadjuvant chemotherapy. We could not substantiate any differences in effect by subgroup. In a combined analysis of two trials within the same study organization and the same clinical and biological domain, neoadjuvant platinum based combination chemotherapy was associated with a 20% reduction in the relative hazard in probability of death.

Palliative chemotherapy in recurrent carcinoma of the cervix: an audit of the use of ifosfamide and review of the literature.

A review was conducted on 34 patients treated with intravenous ifosfamide for relapsed, inoperable carcinoma of the cervix between 1988 and 1996. The median age of patients was 44 years. Thirty-two patients had squamous cell carcinoma and 2 had adenocarcinoma. Radiotherapy had been used in primary management in 33, neo-adjuvant platinum chemotherapy in 7, and previous palliative chemotherapy in 11. Symptomatic response was assessed with respect to the symptom requiring palliaton. 25 patients failed to complete 6 cycles of chemotherapy: due to progressive disease in 14, lack of symptom response in 2, and toxicity in 11 of whom 7 had encephalopathy sufficient to abandon treatment. 32 patients were evaluable for objective response. Pathologic complete response (CR) was achieved in 1 patient, and partial response (PR) was achieved in 3 patients. The objective response rate was 11.8%. Symptomatic response throughout treatment occurred in 8 patients (24%); objective response was seen in only 3 (1 CR, 2 PR) of them and progressive disease in the remaining 5. Response duration in the 4 objective responders was 25 months in the patient with CR and 4, 6 and 8 weeks in the 3 patients with PR. In conclusion, ifosfamide, as given, is associated with unacceptable toxicity and insufficient symptomatic efficacy for use as a palliative treatment in patients with relapsed carcinoma of the cervix.

Lymph node metastases, cell type, age, HPV status and type, neoadjuvant chemotherapy and treatment failures in cervical cancer

Conflicting evidence on the prognostic influence of some of the clinical and histopathological variables in cervical cancer of the HPV status and type and chemotherapeutic response prompted a number of reviews from nearly 40 years experience in a tertiary referral centre. The collation and analyses of these data with those from recent literature allow some proposals to be made. The disease is more prevalent in the young in women in whom, in many centers, the mortality is also higher; the latter may be related to the reported increase in both small cell types and adeno and adenosquamous carcinoma — a finding more marked in the young. Lymph node metastases, related to increasing grade, size, stage and lymph space invasion, are unequivocally associated with a worse prognosis. Resolution of the exact nature of the intimate association of this disease with the human papilloma virus remains to be resovled as does the influence on prognosis of the tumor HPV status and that of the different oncogenic types. Reports on the efficiency of neoadjuvant platinum based combination chemotherapy are generally promising but vary considerably depending on the regimen used. Its value will not be determined without properly conducted large randomized studies.