Total Clinical Response Rate Research Articles

Acupuncture and moxibustion treatment for myasthenia gravis: A systematic review and meta-analysis.

Myasthenia gravis (MG) is a common autoimmune disease that often involves the skeletal muscle of the whole body and seriously affects patients' quality of life. Acupuncture and moxibustion treatment of MG has unique advantages, the aim is to evaluate the clinical effect of acupuncture and moxibustion on MG. The literature on acupuncture and moxibustion treating MG in PubMed, CochraneLibrary, EMBASE, SCI, China Academic Journals full-text database, China Biology Medicine disc, VIP and Wanfang database were searched through computers from the establishment of the database to December 2022. A total of 11 studies were included, involving 658 patients, where 330 in the treatment group and 328 in the control group. The results of the meta-analysis showed that the treatment group performed better than the control group in improving the total clinical response rate (OR = 3.26, 95%[2.04,5.21], P < .01). Additionally, the treatment group outperformed the control group in raising the absolute clinical score (MD = -3.48, 95%CI[-5.17, -1.78], P < .01). However, there was no significant difference between the treatment group and the control group in improving the level of serum interleukin-6 receptor (MD = -1.45,95%CI[-6.85,3.95], P > .05) and OMG quantitative score (MD = -2.16,95%CI[-4.85,0.52], P > .05). The total clinical effective rate was tested for publication bias, which showed that the 2 sides of the funnel plot were asymmetrical, suggesting the possible existence of publication bias. Acupuncture and moxibustion has a good effect on MG, which is better than conventional Western medicine in improving the total clinical effective rate and absolute clinical score.

Adjuvant treatment with yupingfeng granules for recurrent respiratory tract infections in children: Asystematic review and meta-analysis.

Yupingfeng granules (YPFG) contribute to various chronic respiratory infections. Several clinical studies have evaluated its efficacy and safety in treating recurrent respiratory tract infections (RRTIs) in children. However, the evidence for its use has not been conclusively proven. The aim of this study was to demonstrate the efficacy and safety of YPFG in the adjuvant treatment of RRTIs in children. We searched PubMed, Embase, Web of Science, Cochrane Library, Clinical Trials, Chinese Clinical Trial Registry, Sinomad, China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chinese Scientific Journals Database (VIP) for randomized controlled trials (RCTs) of YPFG adjuvant therapy for children with RRTIs as of September 1, 2022. We screened the literature for inclusion and exclusion criteria, assessed the quality of each included literature, and then extracted data from each study for this systematic review and meta-analysis. A total of 17 RCTs were included. Data analysis showed that the total clinical response rate in the YPFG group was significantly higher than that in the control group [risk ratio (RR) = 1.18, 95%CI (1.12, 1.24), I 2 = 39%, P < 0.00001]. Compared with the control group, three serum immunoglobulin levels were significantly increased in the YPFG group: IgA level [standardized mean difference (SMD) = 1.23, 95%CI (0.68, 1.78), I 2 = 95%, P < 0.0001]; IgM level [SMD = 0.85, 95%CI (0.35, 1.35), I 2 = 93%, P = 0.0009]; IgG level [SMD = 1.06, 95%CI (0.65, 1.47), I 2 = 91%, P < 0.00001]. The TNF-α level was significantly lower in the YPFG group [SMD = -1.03, 95%CI (-1.55, -0.51), I 2 = 84%, P = 0.0001] compared with the control group. In summary, adjuvant YPFG therapy improves clinical efficacy and immunity in children with RRTIs. However, the effectiveness and safety of YPFG remain to be further verified. [https://inplasy.com/inplasy-2022-3-0150/], identifier [INPLASY202230150].

The Efficacy and Safety of Zhengqing Fengtongning for Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Background Zhengqing Fengtongning release tablet (ZQFTN) is a proprietary Chinese medicine preparation of sinomenine, the main active component of the traditional Chinese medicine (TCM) Sinomenium acutum. It is used in China as a complementary and alternative medicine (CAM) for knee osteoarthritis (KOA). The objective of this study was to evaluate the clinical efficacy and safety of ZQFTN in KOA treatment. Method Randomized controlled trials of ZQFTN in KOA treatment were searched in PubMed, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journals Database, and Wanfang database. Two reviewers independently conducted the screening, extracted the data, and assessed the methodological quality. Statistical analysis was performed using RevMan 5.3 software. Results Eighteen studies were assessed that included 1512 participants (757 in the treatment group and 755 in the control group). The results showed that compared with the control group, the Visual Analogue Scale (standardized mean difference (SMD) = −0.87, 95% confidence interval (CI): [−1.08, −0.66], P < 0.001), Western Ontario and Mc Master University (WOMAC) Osteoarthritis Index pain score (SMD = −0.67, 95% CI: [−0.88, −0.46], P < 0.001), WOMAC stiffness score (SMD = −0.53, 95% CI: [−0.86, −0.20], P=0.001), WOMAC function score (SMD = −0.76, 95% CI: [−0.97, −0.55], P < 0.001), serum interleukin-1β level (SMD = −4.36, 95% CI: [−6.41, −2.31], P < 0.001), and serum tumor necrosis factor-α level (SMD = −8.45, 95% CI: [−11.20, −5.69], P < 0.001) of the ZQFTN treatment group were lower, and the total effective rate was higher relative risk (RR = 1.15, 95% CI [1.07, 1.23], P < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups (RR = 0.96, 95% CI: [0.69, 1.35], P=0.82). Conclusion ZQFTN can effectively relieve knee pain, morning stiffness, and daily activity function disorders, reduce the expression of inflammatory factors in serum, and improve the total clinical response rate without increasing the incidence of adverse reactions. Therefore, ZQFTN has considerable potential as a CAM for KOA. However, due to the limitation of the quality of the included studies, the strength of this conclusion is affected. In the next step, multicenter, large sample, high-quality randomized controlled studies are needed to further confirm the present conclusion.

Short-Term Efficacy of Tislelizumab with Carboplatin/Cisplatin Pemetrexed in Advanced Lung Adenocarcinoma and its Effect on Tumor Markers

We attempt to study the short-term efficacy of tislelizumab+carboplatin/cisplatin+pemetrexed in advanced lung adenocarcinoma and its effect on tumor markers. Retrospectively analyzed the clinical data of 68 advanced lung adenocarcinoma patients admitted to our hospital from May 2019 to June 2021 and divided them into control group (n=34) and study group (n=34). Treated control group with carboplatin or cisplatin+pemetrexed, while treated study group with tislelizumab+carboplatin or cisplatin+pemetrexed. Compared both groups on total clinical response rate, serum tumor marker levels and immune function indexes before treatment and after 6 mo treatment. Study group had higher total effective rate than control group (p<0.05); after 6 mo treatment, study group had lower serum carbohydrate antigen 125, carbohydrate antigen 199 and carcinoembryonic antigen levels than control group (p<0.05). Meanwhile, study group had higher cluster of differentiation 3, cluster of differentiation 4 and cluster of differentiation 4/cluster of differentiation 8 than control group, while lower cluster of differentiation 8 than control group (p<0.05). Tislelizumab plus carboplatin or cisplatin plus pemetrexed therapy in advanced lung adenocarcinoma can improve short-term efficacy, reduce serum tumor marker levels and improve immune function.

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell...

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort

BackgroundWe report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β)RII receptor (a TGF-β...

The Safety and Efficacy of Intra-Arterial versus Intravenous Neoadjuvant Chemotherapy in Patients with Locally Advanced Cervical Cancer: A Meta-Analysis.

Objective The aim of this study was to evaluate the safety and efficacy of intra-arterial versus intravenous neoadjuvant chemotherapy for the management of patients with locally advanced cervical cancer. Methods The PubMed, EMBASE, PMC, Web of Science, and Cochrane databases were searched to identify correlational studies published in English. Prospective controlled studies that evaluated the treatment effect of intra-arterial neoadjuvant chemotherapy or intravenous neoadjuvant chemotherapy in patients with locally advanced cervical cancer were pooled for a meta-analysis. Results A total of three eligible studies with 112 patients with locally advanced cervical cancer were eventually included in this analysis. The baseline regimen of neoadjuvant chemotherapy was platinum-based chemotherapy. The total clinical response rate was 71.4%, and the overall pathological complete response (CR) rate was 11.5%. The grade 3/4 toxicity rate was 27.2%. In the intra-arterial group, the response rate was 83.1% (CR, 22.0%; partial response (PR), 61.0%), which was significantly higher than 58.5% (CR, 11.3%; PR, 47.2%) in the intravenous group (P=0.01). The pathological CR rate was 15.5% in the intra-arterial group, which was higher than 6.5% in the intravenous group. The grade 3/4 toxicity rate was 17.2% in the intra-arterial group, which was higher than the rate of 13.8% in the intravenous group. Conclusion Platinum-based neoadjuvant chemotherapy was well tolerated in patients with locally advanced cervical cancer and showed moderate response activity. Compared to intravenous neoadjuvant chemotherapy, intra-arterial neoadjuvant chemotherapy had an evident advantage in terms of the clinical response while maintaining a similar toxicity rate. The clinical efficacy of intra-arterial neoadjuvant chemotherapy deserves further evaluation.

1354 The Safety and Efficacy Of Intra-Arterial Versus Intra-Venous Neoadjuvant Chemotherapy in Patients with Locally Advanced Cervical Cancer: A Meta-Analysis

Study Objective The aim of this study was to evaluate the safety and efficacy of intra-arterial (NCIA) versus intravenous (NCIV) neoadjuvant chemotherapy in managing patients with locally advanced cervical cancer (LACC). Design The PubMed, EMBASE, PMC, Web of Science and Cochrane databases were searched to identify correlational studies published in English. Prospective controlled studies that evaluated the treatment effect of NCIA or NCIV in patients with LACC were pooled for a meta-analysis. Setting N/A Patients or Participants N/A Interventions N/A Measurements and Main Results A total of three eligible studies with 112 LACC patients were eventually included in this analysis. The baseline regimen of neoadjuvant chemotherapy (NACT) was platinum-based chemotherapy. The total clinical response rate (RR) was 71.4%, and the pathological complete response (PCR) was 11.5% overall. The grade 3/ 4 toxicity rate was 27.2%. In the NCIA group, the RR was 83.1% (complete response [CR], 22.0%; partial response [PR], 61.0%), which was significantly higher than the 58.5% RR (CR, 11.3%; PR, 47.2%) in the NCIV group (P=0.005). The PCR was 15.5% in the NCIA group, which was slightly higher than 6.5% PCR in the NCIV group (P=0.43). The grade 3/4 toxicity rate was 17.2% in the NCIA group, which was slightly higher than the 13.8% toxicity rate in the NCIV group (P=0.38). Conclusion Platinum-based NACT was well tolerated in patients with LACC and showed moderate response activity. Compared to NCIV, NCIA showed an evident advantage in the clinical response with a similar toxicity rate. The clinical efficacy of NCIA deserves further evaluation.

Abstract CT075: Phase I evaluation of M7824, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus (HPV)-associated malignancies

Abstract Background: TGF-β pathway dysregulation may play a critical role in carcinogenesis and immune evasion in HPV-associated cancers (HACs), including anal, cervical, and p16+ squamous cell carcinoma of the head and neck (SCCHN). Targeting this pathway may also enhance clinical response to PD-(L)1 antibodies. M7824 is an innovative first-in-class bifunctional fusion protein composed of two extracellular domains of TGF-βRII (a TGF-β “trap”) fused with a human IgG1 monoclonal antibody against PD-L1. In the dose-escalation cohort of the ongoing Phase I trial of M7824 (NCT02517398), patients with HACs who developed an HPV-specific immune response on M7824 had improved clinical responses. Here we report efficacy and safety data from patients with HPV-positive malignancies from the dose-escalation cohort pooled with data from HAC expansion cohorts for patients with HPV-positive disease. Methods: Patients received M7824 Q2W at 1-30 mg/kg in the dose-escalation phase or at the recommended phase 2 dose of 1200 mg in the expansion cohorts. Treatment continued until progressive disease (PD), unacceptable toxicity, or trial withdrawal; treatment past PD was allowed if clinically justified. Safety and best overall response by RECIST v1.1 were the primary endpoints of the dose-escalation and expansion phases, respectively. Results: As of August 24, 2018, 36 patients with pretreated HPV-positive HACs (4 anal; 18 cervical; 14 SCCHN) had received M7824 for a median duration of 19.0 weeks (range, 2.0-96.0). 10 patients had a response per investigator (2 complete response [CR]; 8 partial response [PR]; ORR 27.8%). 1 additional patient developed a PR after data cutoff; 3 additional patients had a delayed PR after initial PD (total clinical response rate 38.9%). Both patients with CR and 5 patients with PR have an ongoing response. The median duration of response was not reached (range, 4-22+ months). 9 patients (25%) had grade 3 treatment-related adverse events (TRAE): anemia, cystitis, diabetic ketoacidosis, increased γ-glutamyltransferase, gastroparesis, hyperkeratosis, hypokalemia, keratoacanthoma, macular rash, pleural effusion, pneumonitis, and skin SCC. The patient with gastroparesis had asymptomatic grade 3→4 hypokalemia (1 grade 4 TRAE, 2.7%). No treatment-related deaths occurred. 6 patients (16.7%) permanently discontinued M7824 due to TRAEs (gastroparesis, infusion-related reaction, cystitis, pneumonitis, and acneiform and psoriasiform dermatitis). Conclusions: M7824 has a manageable safety profile and shows encouraging clinical efficacy in patients with HPV-positive HACs (total clinical response rate 38.9%). M7824 is a promising therapeutic agent for these patients and is under further evaluation in phase 1b and 2 trials. Updated survival results will be reported. Citation Format: Julius Strauss, Margaret E. Gatti-Mays, Byoung Cho, Sébastien Salas, Edward McClay, Jason Redman, Houssein Abdul Sater, Renee N. Donahue, Elizabeth Lamping, Andrea Burmeister, Jennifer L. Marté, Lisa Cordes, Laureen S. Ojalvo, Christoph Helwig, Alex Rolfe, Christian S. Hinrichs, Ravi A. Madan, Jeffrey Schlom, James Gulley. Phase I evaluation of M7824, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus (HPV)-associated malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT075.

Expression of VEGF and HIF-1α in locally advanced cervical cancer: potential biomarkers for predicting preoperative radiochemotherapy sensitivity and prognosis.

Locally advanced cervical cancer (LACC) is an early-stage cervical cancer characterized by a local tumor diameter of ≥4 cm. Patients with LACC have a relatively poor prognosis. Although preoperative radiochemotherapy (PRCT) might offer a valuable opportunity for subsequent radical surgery, surgeons should also consider the nonresponsive rate, the adverse effects of PRCT, and the surgical complications before designing a treatment plan. Therefore, biomarkers for predicting PRCT sensitivity and prognosis in patients with LACC are of high importance. We investigated the prognostic significance of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α) in patients with LACC. A total of 43 patients with LACC who underwent PRCT (one course each of intravenous chemotherapy and after-loading intracavitary brachytherapy followed by a radical hysterectomy) during the period 2009–2014 were included in this study. VEGF and HIF-1α expression levels were evaluated by immunohistochemistry in LACC lesions before and after PRCT. In addition, we analyzed the association of these proteins with the clinical response and pathological findings of pelvic lymph node metastasis (PLNM) after the subsequent surgery. The total clinical response rate was 81.39% after PRCT, including five complete responses and 30 partial responses. VEGF and HIF-1α expression before PRCT was significantly higher than after PRCT (VEGF: 85.71% vs 66.67%; HIF-1α: 83.33% vs 59.52%, P<0.05). In addition, the same trend was found in patients with PLNM compared to those without PLNM (VEGF: 100% vs 77.78%; HIF-1α: 100% vs 74.07%, P<0.05). The areas under the receiver operating characteristic curves were 0.896 and 0.835 when using pre-PRCT VEGF and HIF-1α expression levels, respectively, to diagnose PLNM in patients with LACC. Serial detection of VEGF and HIF-1α demonstrated a sensitivity of 66.67% and specificity of 88.89%. These findings suggest that VEGF and HIF-1α expressions are potential biomarkers for PRCT and have great clinical significance for the prediction of PRCT response and prognosis in patients with LACC.

Efficacy and Safety of Docetaxel Combined With Oxaliplatin as a Neoadjuvant Chemotherapy Regimen for Chinese Triple-Negative Local Advanced Breast Cancer Patients

To determine the efficacy and toxicity of an oxaliplatin-based regimen as a neoadjuvant chemotherapy setting in triple-negative local advanced breast cancer (TNLABC) patients. Patients with stage IIIb or IIIc, chemotherapy-naive TNLABC receive docetaxel 75 mg/m day 1 and oxaliplatin 130 mg/m day 2, every 21 days for up to 4 cycles. The primary end point is pathologic complete response (CR), and the secondary end points are clinical response (including CR and partial response), disease-free survival, overall survival, and safety. Twenty-nine TNLABC patients were treated: 17(58.62%) had stage IIIB disease and 12 (41.38%) had stage IIIC disease. After neoadjuvant chemotherapy, there were 10 patients (34.48%) with pathologic CR (95% confidence interval, 21.51%-48.70%). Twenty patients responded (7 CR and 13 partial response) with a 68.97% total clinical response rate (95% confidence interval 57.51%-88.02%). Nearly 27.59% patients (8 patients) had disease progression after at least 2 cycles of chemotherapy, and only 1 patient (3.45%) had the disease stable, respectively. In the 29 treated patients, there were no unusual or unexpected adverse events in a total of 91 cycles for the chemotherapy setting. Common grade 3 or 4 hematologic toxicities were leukocytopenia, which occurred in 4 TNLABC patients (13.79%), and thrombocytopenia in 1 patient (3.45%). Grade 3 or 4 transaminase elevation occurred in 5 (17.24%) patients and grade 3 vomiting occurred in 1(3.45%) patient. One patient experienced grade 3 neurosensory toxicities. There are 5 reports (17.24%) of grade 3 fatigue. The results of this phase II clinical study suggest that docetaxel combined with oxaliplatin as a neoadjuvant chemotherapy regimen in TNLABC patients is active and well tolerated, and should be further investigated as a favorable treatment alternative for TNLABC patients. A large randomized prospective clinical study is warranted to confirm the results.

Combined chemotherapy with domestic gemcitabine plus carboplatin in the treatment of advanced non-small cell lung cancer

Chemotherapy is very important in the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy, clinical benefit and toxicity of combined chemotherapy with domestic gemcitabine (ZEFEI) plus carboplatin in the treatment of advanced NSCLC. Thirty-four previously untreated patients with advanced NSCLC (stage III-IV) received domestic gemcitabine of 1000mg/m² on days 1, 8, and carboplatin of AUC 5 on day 1, with 21 days as a cycle. Each patient received at least three cycles. The total clinical response rate (complete and partial response) was 44% (15/34). Overall clinical benefit rate was 53% (18/34). The main toxicities were hematological toxicities. The rate of grade III-IV leukopenia and thrombocytopenia was 47% and 24% respectively. Combined chemotherapy with domestic gemcitabine plus carboplatin is an effective and feasible regimen for advanced NSCLC.

Do clinical trials of neoadjuvant chemotherapy for locally advanced breast cancer (LABC) overestimate the actual response rates observed in clinical practice?

890 Background: Neoadjvuant chemotherapy (NAC) is an established standard of care for LABC. Evidence shows that both clinical (cCR) and pathologic (pCR) complete response predicts for locoregional recurrence, disease free and overall survival. However, the definition of pCR is not universal and there exists variation as to the inclusion of residual intraductal and microinvasive disease. Phase II and III trials with different NAC regimens report cCR rates of 60–80% with corresponding pCR rates of 10–39%. Purpose: To compare response rates of cCR and pCR in a prospectively collected patient cohort to those reported in the literature for women with LABC. Methods: Patients with clinical stage III and primary tumors greater than 5cm were defined as having LABC. 49 pts were treated between Sept 2003 & Nov 2004 and were eligible for the study. Two pts were excluded as one discontinued therapy secondary to mitral valve disease and the second moved out of the country to pursue alternative therapies. Results: Median pt age was 50 (range 27 to 76). Clinical staging at diagnosis showed 12% IIB, 48% IIIA, 34% IIIB and 6% IIIC. Eighty-eight percent were clinical stage III at presentation and of these, seven (15%) had T4d inflammatory breast cancers. Eighty three percent had clinical axillary node involvement, 51% of tumours were hormone receptor positive & 38% overexpressed her2neu. Thirty four pts (72%) received an anthracycline based regimen & thirteen pts (28%) received both a taxane and anthracycline based regimen. Following neoadjuvant chemotherapy, 32% of pts had a cCR and 26% had a cPR, for a total clinical response rate of 58%. pCR was seen in 4 (9%) pts. Conclusions: The cCR and pCR response rates in this study were 28% and 9% respectively. This is clearly lower than reported in clinical trials and may reflect the advanced nature of patients selected for neoadjuvant therapy in actual practice. Depending on the definition of pCR used in this study, the range of pCR varied from 4.2% to 10.6% (using definitions form Chevallier et al and NSABP-27 respectively). Thus, it is essential that the pathologic response definition used in each trial be considered when interpreting study outcomes. No significant financial relationships to disclose.

Concurrent paclitaxel, carboplatin and radiotherapy (CMT) with subcutaneous amifostine in advanced squamous cell head and neck cancer (SCCHN): Preliminary results of a phase II study

5564 Background: CRT for stage III/IV SCCHN improves tumor control at the cost of increased toxicity. Radioprotector, amifostine, administered intravenously (iv) significantly reduced the incidence of ≥ grade 2 acute xerostomia. This interim analysis reports efficacy and subcutaneous (sc) amifostine effects on the incidence of acute treatment toxicities. Methods: Eligibility included previously untreated TNM stage III, IV SCCHN, ECOG PS 0–1, adequate organ function, and informed consent. All patients received a percutaneous endoscopic gastrostomy, and vigorous dental and nutritional support during therapy. Paclitaxel (40mg/m2) and Carboplatin (100mg/m2) were administered iv weekly for six weeks. Patients received amifostine as two, 250mg sc injection (2.5ml total) 30 minutes prior to daily radiotherapy (1.8 to 2.0 Gy/day). Radiotherapy was given daily five times a week to a total dose of 70–72 Gy. Diphenhydramine 25mg, dexamethasone 4mg, odanestron 8mg, and acetaminophen 1000mg were given 30mins prior to amifostine. Results: Of eighteen patients entered to date, thirteen have completed treatment and were evaluable. Mean age was 54 years. Primary sites are oropharynx (12), oral cavity (1). Grade 3 hematologic toxicities: neutropenia (0%), thrombocytopenia (8%), anemia (0%). Grade 3 non-hematologic toxicities: nausea (1%), mucositis (10%). The incidence of ≥ grade 2 xerostomia was 53%. Median accumulated radiotherapy dose to onset of xerostomia was 58 Gy. There was no grade 3 amifostine-associated cutaneous toxicity. All patients completed radiotherapy without treatment breaks. Eight patients (62%) had a complete clinical response (CR) and 5 (38%) had a partial response (PR). Total clinical response rate was 100%. Conclusions: Concurrent chemoradiation with daily sc amifostine proves feasible with high response rate. This approach is a well-tolerated outpatient treatment program. Subcutaneous amifostine offers convenience of administration and reduces the severity of acute radiotherapy and chemotherapy associated toxicities. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Medimmune Pharmaceutical Company

Expression of LRP and MDR1 in locally advanced breast cancer predicts axillary node invasion at the time of rescue mastectomy after induction chemotherapy.

Axillary node status after induction chemotherapy for locally advanced breast cancer has been shown on multivariate analysis to be an independent predictor of relapse. However, it has been postulated that responders to induction chemotherapy with a clinically negative axilla could be spared the burden of lymphadenectomy, because most of them will not show histological nodal invasion. P-glycoprotein expression in the rescue mastectomy specimen has finally been identified as a significant predictor of patient survival. We studied the expression of the genes encoding multidrug resistance associated protein (MDR1) and lung cancer associated resistance protein (LRP) in formalin-fixed, paraffin-embedded tumor samples from 52 patients treated for locally advanced breast cancer by means of induction chemotherapy followed by rescue mastectomy. P-glycoprotein expression was assessed by means of immunohistochemistry before treatment in 23 cases, and by means of reverse-transcriptase-mediated polymerase chain reaction (RT-PCR) after treatment in 46 (6 failed). LRP expression was detected by means of immunohistochemistry, with the LRP-56 monoclonal antibody, in 31 cases before treatment. Immunohistochemistry for detecting the expression of c-erb-B2, p53, Ki67, estrogen receptor and progesterone receptor are routinely performed in our laboratory in every case, and the results obtained were included in the study. All patients had received between two and six cycles of standard 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) chemotherapy, with two exceptions [one patient received four cycles of a docetaxel-adriamycin combination, and the other four cycles of standard cyclophosphamide-methotrexate-5-fluorouracil (CMF) polychemotherapy]. Response was assessed in accordance with the Response Evaluation Criteria In Solid Tumors (RECIST). By these, 2 patients achieved a complete clinical response, 37 a partial response, and the remaining 13 showed stable disease. This makes a total clinical response rate of 75.0%. None achieved a complete pathological response. MDR1 mRNA expression detected by RT-PCR was associated with the presence of invaded axillary nodes at surgery in 18/22 cases (81.8%), compared with 13/24 (54.2%) in the group with undetectable MDR1 expression. This difference was statistically significant (P < 0.05). LRP expression in more than 20% of tumor cells before any treatment was associated with axillary nodal metastasis after chemotherapy and rescue mastectomy in 17/23 cases, compared with 3/8 in nonexpressors. Again, this difference was highly significant (P < 0.01). LRP expression before treatment and MDR1 mRNA expression after treatment were significantly interrelated (P < 0.001), which might reflect the presence of chemoresistant clones liable to metastasize to the regional nodes. Persistence of previously detected MDR1-positivity after treatment (7/9 compared with 0/2 cases) was significantly associated with axillary node metastasis (P < 0.05). Finally, in a logistic regression multivariate model, histology other than ductal, a Ki67 labeling index of at least 20% and the combination of LRP and MDR1 positivity emerged as independent predictors of axillary node invasion at the time of rescue mastectomy. The expression of different genes involved in resistance to chemotherapy, both before and after treatment with neoadjuvant, is associated with the presence of axillary node invasion at rescue surgery in locally advanced breast cancer. This might reflect the presence of intrinsically resistant clones before any form of therapy, which persist after it, and could be helpful both for prognosis and for the choice of individual treatment.

Preoperative chemoradiation coupled with aggressive resection as needed ensures near total control in advanced head and neck cancer

Preoperative chemotherapy or chemoradiation protocols are generally associated with high clinical response rates, but limited pathologic responses for large primary tumors. We have initiated a prospective phase II study of weekly paclitaxel 60 mg/M2, and carboplatin (AUC of 1) plus concurrent fractionated external beam radiation (45 Gy) followed by organ-preserving (or function restorative) surgery when applicable to maximize local-regional tumor control. Operable patients staged by triple endoscopy received a percutaneous endoscopic gastrostomy and vigorous dental and nutritional support during therapy. Weekly paclitaxel 60 mg/M2, carboplatin (AUC of 1), and radiation 45 Gy were given with rebiopsy of the primary site at 5 weeks. Patients with positive biopsy had definitive surgery in 4 to 5 weeks. Patients with negative biopsy-results received 3 additional weeks of radiation, to a total dose of 72 Gy plus carboplatin and paclitaxel. The 35 patients were 29 men and 6 women, aged 40 to 71 years, with stage III (12) or stage IV (23) cancer. The site of the cancer was oral cavity, 10; base of tongue, 3; oropharynx, 3; hypopharynx, 4; larynx, 12 (glottic, 6; supraglottic, 6), unknown primary, 2; other, nasal cavity, 1. Of 34 evaluable patients, 16 (47%) had a complete clinical response (CR) and 18 (53%) had a partial response (PR); total clinical response rate was 100%. A pathologic CR at the primary site occurred in 23 of 34 patients (68%; 2 had an unknown primary) who went on to completion radiation at 67 to 72 Gy. After induction chemoradiation 21 patients with N1-3 nodes had neck dissection; 6 (31%) had positive nodes. Twelve patients had residual cancer at the primary site at time of rebiopsy: mandible, 4; maxilla, 1; base of tongue, 2; larynx, 4; floor of mouth, 1; and nasal cavity, 1. All were resected with function-preserving reconstruction. At median follow-up of >12 months, progression-free and overall survivals were 71% and 83%, respectively. Preoperative treatment with paclitaxel, carboplatin, and radiation is associated with high CR at the primary site and a high level of organ preservation or functional restoration if ablation is done.

Ovarian malignant mixed müllerian tumors treated with platinum-based chemotherapy

To characterize the clinical course of patients diagnosed with ovarian malignant mixed müllerian tumors treated with platinum-based chemotherapy. Thirty-six patients received this treatment at The University of Texas M. D. Anderson Cancer Center in the period 1979-1993. The mean age was 59 years. Stage distribution was as follows: stage IA, one (3%) patient; stage IIIB, two (5.5%); stage IIIC, 21 (58%); and stage IV, two (5.5%). Ten (28%) patients were unstaged. Chemotherapy regimens included cisplatin, doxorubicin, and cyclophosphamide in 16 patients; cisplatin-ifosfamide in five; cisplatin-cyclophosphamide in four; carboplatinum in three; cisplatin-doxorubicin in three; and various other combinations in the remaining five. Of 16 patients evaluated for clinical response, seven (44%) had a complete response and four (25%) had a partial response, for a total clinical response rate of 69%. Nine patients were evaluated for surgical response: five (56%) had a complete response and one (11%) had a partial response, for a total surgical response rate of 67%. The median survival for the cohort was 18 months. At the time of this analysis, five (14%) patients were alive and disease-free, 25 (69%) had died of disease, five (14%) were alive with disease, and one had been lost to follow-up. This study suggests that the clinical course of patients with ovarian malignant mixed müllerian tumors treated with platinum-based chemotherapy is similar to the clinical course experienced by patients with high-grade epithelial carcinoma of the ovary.

Preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for rectal cancer

A Phase I trial was performed to determine the maximum tolerated dose of concurrent preoperative radiation therapy (5040 cGy) and 2 cycles (bolus daily times 5) of 5-fluorouracil (5-FU) and low-dose leucovorin (LV) (20 mg/m2), followed by surgery and 10 cycles of postoperative 5-FU/LV in patients with primary or recurrent rectal cancer. Twenty-four patients were entered into the study. Preoperatively, the initial dose of 5-FU was 325 mg/m2. 5-FU was escalated 50 mg/m2, while the dose of LV and radiation therapy remained constant. Chemotherapy and radiation began concurrently on day 1. The postoperative chemotherapy was not dose escalated; 5-FU, 425 mg/m2, and LV, 20 mg/m2. The median follow-up was 10 months (range, 4-19 months). The resectability rate with negative margins in the 23 patients who underwent surgery was 100%. One patient refused surgery. The pathologic complete response rate was 13% (3 of 23). An additional four patients had negative nodes and a microscopic foci of tumor in the bowel wall. Therefore, the total clinical complete response rate was 30% (7 of 23). The maximum tolerated dose of 5-FU for the preoperative combined modality segment was 375 mg/m2; therefore, the recommended Phase II dose level is 325 mg/m2. The incidence of Grade 3+ toxicity for the 22 patients treated at the recommended 5-FU dose level (325 mg/m2) during the preoperative combined modality segment was as follows: diarrhea, 14%; erythema, 5%; hematologic, 10%; and total, 18%. The median nadir counts were leukocyte count, 3.7 (range, 1.5-5.9); hemoglobin count, 12.2 (range, 10.2-14.3); and platelet count (times 1000), 165 (range, 92-237). With this regimen, the recommended doses of chemotherapy in the combined modality segment are slightly higher than those recommended in arm 2 of the Intergroup postoperative adjuvant rectal trial 0114. This regimen will serve both as the preoperative arm of the Intergroup randomized trial of preoperative versus postoperative combined modality therapy for resectable rectal cancer (INT R9401) as well as the basis for the combined modality segment of NSABP RO-3.

First line combination chemotherapy with cisplatin and etoposide in advanced ovarian cancer.

Thirty-one consecutive patients with advanced epithelial ovarian cancer entered a phase II study with cisplatin and etoposide combination chemotherapy. None of them had received prior chemotherapy or radiotherapy. Most patients had advanced (88%) or far advanced (61%) disease. All 31 patients are evaluable for toxicity which was significant and led to removal of five (16%) patients from the study. Of the 23 patients evaluable for response there were four clinical complete (CR) and eight partial (PR) responders for a total clinical response rate of 52% of evaluable patients and 39% of all patients. Eight patients (four clinical CR and four good PR) have undergone second look laparotomy with pathological CR in one of the clinical CR patients. Median survival time for responders and non-responders is 19 and 8 months respectively. The results obtained appear to be inferior to other cisplatin based combinations. Although this could be attributed to the unusually high proportion of patients with bulky disease and stage IV patients, we feel that the study suggests that etoposide did not add any benefits for this patient population to cisplatin as a single agent.

Netilmicin in Gram-Negative Bacterial Infections

Netilmicin, a new semisynthetic aminoglycoside, was used in the treatment of 42 patients with serious gram-negative bacterial infections. Of the 40 evaluable patients, 24 (60%) were cured, and 8 (20%) had a favorable clinical response, for a total clinical response rate of 80%. Eight patients failed to respond; of these, three had undrained abscesses and two had severe granulocytopenia. Three of the patients who failed had organisms in which resistance to netilmicin developed during therapy, and in two of these three netilmicin was the only aminoglycoside to which resistance developed. Of the 37 patients evaluable for toxicity, 8 (22%) developed renal insufficiency. Two patients had mild but persistant elevation in serum creatinine. Three patients had nephrotoxicity while on gentamicin in the past. Pre- and posttherapy audiograms were done on 26 patients; none had hearing loss. Four patients had mild, transient asymptomatic elevations in alkaline phosphatase. The pretreatment clinical isolates were tested for in vitro susceptibility. The median minimal inhibitory concentration of netilmicin, gentamicin, and tobramycin ranged between 0.5 and 2 mug/ml. The median minimal inhibitory concentration of amikacin was approximately twofold higher. No clear in vitro superiority of one aminoglycoside over another was observed.