Good Performance Status Patients Research Articles

Retrospective review of mitomycin C use as third‐line chemotherapy in metastatic colorectal cancer

AbstractThe aim of this review was to determine the therapeutic value of the combination of mitomycin C with either infusional 5‐fluorouracil or oral capecitabine in metastatic colorectal cancer when used as third‐line treatment or beyond in the setting of routine clinical practice. We retrospectively reviewed 18 patients with advanced colorectal cancer who received this combination at our institution after the failure of two lines of prior treatment. All the patients were assessable for toxicity and survival and 14 for tumor response. The median age of the patients was 61 (range 39–78). Of these, 72% were male and 78% had Eastern Cooperative Oncology Group performance status 0 or 1. Eighty nine percent of the patients had metastatic involvement of the liver and five patients had at least three sites of metastatic involvement. All patients had received at least two lines of chemotherapy and had progressed on an oxaliplatin‐containing regimen. Most of the patients had previously received an irinotecan‐containing regimen, and a third had received prior biological agents. Overall, none of the patients achieved either complete or partial responses. Two patients (11%) achieved stable disease and 12 patients (67%) had progressive disease. The median progression‐free survival was 2.7 months (range 0.5–8.8) and the median overall survival was 5.4 months (range 1.3–31.2). This chemotherapy regimen was well tolerated with an acceptable toxicity profile. The results of our review confirm the low efficacy of combination mitomycin C in heavily pretreated Australian patients with advanced colorectal cancer. This review confirms that it has no role after two lines of modern combination chemotherapy regimens and recommends that focus should be placed on investigating newer agents for good performance status patients progressing after these treatments.

A phase III study of accelerated versus conventional hypofractionated whole brain irradiation in patients of good performance status with brain metastases not suitable for surgical excision

Background and purpose An accelerated prescription for whole brain irradiation (WBI) in the treatment of brain metastases has been reported to provide favourable survival in good performance status patients. Because it was not known whether this outcome represented patient selection or a radiobiologically advantageous regimen, a phase III study to compare overall survival following accelerated and conventional hypofractionated daily WBI was proposed. Materials and methods Ninety patients were randomized between 1996 and 2003 at two centres. The investigational arm received 40 Gy in 20 fractions of 2 Gy twice daily. The control arm received 20 Gy in 5 daily fractions. The study was designed to detect an increase in median survival of 1.75×. Outcome measures included acute side effects (WHO epilation score), neurological function (modified Barthel Index) and late toxicity (LENT/SOMA score for the CNS). Results Both arms of the study were balanced by RPA class. The median survival was 19 weeks in both arms. Subset analysis showed time to retreatment for intracranial relapse was 14 weeks in the control arm and 32 weeks in the accelerated arm ( p = 0.03). Trends for more severe epilation and improved neurological function in the accelerated arm did not reach statistical significance. Overall survival was associated with RPA class and colorectal pathology. Conclusions Although accelerated WBI may improve local control this did not translate into improved overall survival in the patients studied.

Deficits in Japanese word spelling as an initial language symptom of malignant glioma in the left hemisphere

Background A good performance status at diagnosis is a prognostic factor in patients with malignant glioma whose median survival is 24 months. As early diagnosis may improve their poor prognosis, we looked for currently unknown initial symptoms among patients in good performance status. Methods We chose 17 consecutive patients with malignant glioma in the left frontal and/or temporal lobe whose Karnofsky Performance Status was more than 80. At preoperative evaluation, we administered the Japanese version of the Western Aphasia Battery. Results The chief complaint was difficulty in speech (n = 6), headache/nausea (n = 4), seizures (n = 5), and uncinate fits (n = 1); one patient was symptom-free. Of the 17 patients, 14 exhibited no motor deficits. In 15 patients, the aphasia quotient exceeded 80, indicating that the overall language deficits were mild. However, in the reading section, their scores on the “spelled kanji (Japanese ideogram) recognition” test (full score = 10) were selectively low (5.3 ± 1.6 for right-handed individuals with frontal lesions, 6.1 ± 1.0 for right-handed patients with temporal lesions, 7.2 ± 2.0 for left-handed/bimanual individuals with frontal/temporal lesions). Their scores on the “spelling kanji” test were 3.0 ± 1.6, 4.8 ± 1.2, and 9.4 ± 0.6, respectively. Conclusions Our findings point to the importance of recognizing spelling deficits as an initial symptom of left hemisphere glioma in efforts to identify patients in good performance status whose prognosis may be improved. It would be important to determine if the spelling of alphabetic words is also impaired early in the clinical course of left hemisphere glioma.

First-line gefitinib for poor PS patients with EGFR mutations

8070 Background: We had previously reported several phase II studies using good performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations (JCO, 2006:24, 3340, BJC, 2006:95, 998, and 1483). This phase II study was undertaken to investigate the efficacy and feasibility of gefitinib for poor PS pts with EGFR mutations. Methods: The peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method (PNA-LNA PCR clamp) can detect EGFR mutations using cytology specimens such as sputum and pleural effusion (Cancer Res, 2005;65:7276). Chemonaive advanced NSCLC pts with poor PS and EGFR mutations examined by the PNA-LNA PCR clamp were enrolled and received gefitinib (250 mg/day) alone. The response rate, progression-free survival, overall survival, PS improvement rate and toxicity profile were assessed prospectively. Sample size was decided to be > 25 pts to show the lower limit of 90% confidence interval (CI) > ...

A phase II study of concurrent chemoradiotherapy with weekly docetaxel, carboplatin, and radiation therapy followed by consolidation chemotherapy with docetaxel and carboplatin for locally advanced inoperable non-small cell lung cancer

7565 The current standard of care for good performance status patients with locally advanced non-small cell lung carcinoma is concurrent chemoradiation, although a clearly superior regimen has not ...

Final response data of a phase II study of capecitabine and oxaliplatin (CAPOX) in advanced adenocarcinoma of the small bowel or ampulla of Vater

4538 Background: Small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC) are rare tumors. There is limited information regarding chemotherapy in advanced disease and no current standard of care. Methods: Patients with either metastatic or locally advanced unresectable SBA or AAC with adequate organ function, performance status (PS) ≤2 and measurable disease per RECIST were enrolled from 11/04 to 7/07. Prior use of 5-FU either as adjuvant therapy or as a radiosensitizer was allowed. CAPOX was administered as a 21 day cycle with oxaliplatin 130 mg/m2 IV on day 1 and capecitabine 750 mg/m2 PO BID days 1- 14. The planned sample size was 30 and the primary endpoint was overall response rate (ORR). Results: Thirty patients (12 AAC and 18 SBA) have been treated and 29 are evaluable for response. Patients had either locally advanced (5) or metastatic disease (25) and 5 had prior adjuvant 5-FU. The median age was 62 years (41–79); 40% females; 97% PS of 0–1. The median number of cycles administered was 5 (1 to 11); 4 patients remain on treatment. Common grade 3/4 toxicities included fatigue (7), neuropathy (2), granulocytopenia (3), vomiting (3), diarrhea (3), thrombocytopenia (2), and hypokalemia (2). Fifteen patients, 5 AAC and 10 SBA, had a confirmed response with an ORR of 52% (95% CI 33 to 71%); 11 patients had stable disease (SD). Six patients (20%) are currently without evidence of disease. Three patients with metastatic disease are alive in complete remission (CR), two following CAPOX alone and a third following consolidative radiation, at 31, 28, and 21 months, respectively. Three patients with locally advanced disease with SD or PR to CAPOX have since undergone surgery and are alive without evidence of disease at 8, 10, and 20 months. Median PFS is 9.8 m (95% CI 4.7 to 30+m). Twelve patients have died. With a median follow-up of 12.1 months, median overall survival is 20.3 m (95% CI 13 to 30+m). Conclusions: This prospective trial demonstrates that CAPOX delivered to good PS patients with advanced SBA or ACC is well tolerated and leads to the highest response rate and median survival ever reported from prospective trials in these tumor types. We believe, CAPOX should be considered the new standard regimen for advanced SBA and AAC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis

Multimodality management of brain metastases in metastatic melanoma patients

Brain metastases are a frequent complication of advanced melanoma. Neurosurgery (generally followed by radiotherapy) may be useful in managing solitary, superficial brain metastases in good performance status patients, as well as for diagnostic purposes. Since most patients are not felt to be resectable and concurrent extracranial metastases frequently are present, whole-brain radiotherapy (WBRT) has become the de facto treatment standard. WBRT has resulted in disappointing outcomes, resulting in a 3.6–4.1-month median survival. Recent studies have suggested that focal irradiation using linear accelerator-based stereotactic radiosurgery or gamma-knife technologies can result in excellent local control and prolonged survival in some patients. It is possible that more aggressive combined modality treatment strategies, such as addition of systemic therapy, may further improve outcome. Current data suggest that aggressive treatment of patients with up to five brain melanoma brain metastases is capable of producing prolonged survival in many patients, including some long-term complete responses.

Phase I dose escalation study of vinorelbine and topotecan combination chemotherapy in patients with recurrent lung cancer

BackgroundA platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. However, platinum-based treatment may be associated with significant toxicities, therefore alternative platinum-free combinations should be investigated. Topotecan is a topoisomerase I inhibitor that exerts its cytotoxic effect through stabilization of the topoisomerase I-DNA complex. Preclinical data suggests synergy between topoisomerase I inhibitors and mitotic spindle poisons. Considerable hematologic toxicities have been reported with topotecan dosed for 5 consecutive days in combination with vinorelbine. Therefore, the aim of this study was to evaluate the optimal dosage and the maximal tolerated dose (MTD) of topotecan and vinorelbine in patients with relapsed or refractory non-small cell or small cell lung cancer administered on an alternate dosing schedule.MethodsFrom February, 2004 to March, 2007 eighteen patients with advanced or recurrent NSCLC or SCLC previously treated with chemotherapy were enrolled. Patients were heavily pretreated with 22% having received at least 3 prior lines of chemotherapy. Vinorelbine was administered at a fixed dose (20 mg/m2) and topotecan at escalating doses (2, 2.5, 3, 3.5, and 4 mg/m2) on days 1 and 8 every 21 days.ResultsThe MTD was not reached in any of the 5 cohorts, with only one dose limiting toxicity (DLT) occurring in cohort 4. Non-hematological toxicities were manageable. One patient had a partial response with four patients (27%) achieving stable disease. The median progression-free and overall survival for all patients, were 2.7 months (95% CI: 1.6, 9.1) and 10.5 months (95% CI: 4.2, 22.7), respectively.ConclusionVinorelbine and topotecan administered on days 1 and 8 every 21 days is well tolerated without any DLT seen with previously investigated topotecan schedules. This doublet provides a potentially active non-platinum containing doublet for the treatment of patients with advanced SCLC and NSCLC. Vinorelbine and topotecan should therefore be investigated in subsequent phase II studies at a dose of 20 mg/m2 and 4 mg/m2, respectively.Trial Registration NumberNCT00287963.

Neoadjuvant treatment in upper gastrointestinal adenocarcinomas: new paradigms from old concepts?

Despite a decline in the incidence of upper gastrointestinal adenocarcinomas in North America and western Europe during the past century, treatment remains a challenging problem for oncologists. The poor outcome associated with surgical resection with curative intent has generated intensive investigation of combined modality treatment approaches including systemic chemotherapy to prevent recurrences and improve overall mortality. This article reviews data on neoadjuvant and perioperative treatment modalities for upper gastrointestinal adenocarcinomas. Postoperative chemoradiation is favored in the USA for good performance status patients with resected, high-risk gastric or gastroesophageal junction carcinoma (more stage IA). More recently, the UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) and Fédération Nationale des Centres de Lutte Contre le Cancer-Fédération Francophone de Cancérologie Digestive trials results, showing survival benefit with perioperative chemotherapy in operable gastric and lower esophageal cancers, have had an impact on the treatment practice in Europe. Novel strategies, involving induction with chemotherapy followed by preoperative chemoradiation, addition of targeted therapies to perioperative chemotherapy or use of new cytotoxic regimens are under evaluation to improve current standards and try to tailor therapeutic strategies.

Prospective phase II trial of a combination of gemcitabine, cisplatin and UFT as first-line treatment in patients with advanced, unresectable, non-small cell lung carcinoma

18109 Background: Most patients with advanced non-small cell lung cancer (NSCLC) receive either single agents or doublet chemotherapy. For non-elderly patients in good performance status, platinum-based double combinations represent the standard treatment. And oral UFT had the survival advantage in adjuvant setting. Therefore we performed a phase II study using the combination of gemcitabine, cisplatin and UFT as a first line therapy in patients with advanced NSCLC. Methods: Eligible patients had histologically or cytologically confirmed stage IIIB or IV NSCLC with good performance status and were chemotherapy-naive. This study was two-stage design and planned number of patients was forty-seven. Gemcitabine (1,250 mg/m2, 10 mg/kg/min on days 1 and 8) and cisplatin (75 mg/m2 on day 1) were injected intravenously and UFT (400 mg/day) was administered orally on day 1–14. Treatment repeated every 3 weeks. Primary end point was overall response rate and secondary end points were overall survival, time to progression and toxicity. Results: Thirty seven patients with advanced NSCLC were enrolled. The median age of the patients was 60 years (range: 44 to 72). The performance status (WHO) was 0 in 4, 1 in 30 and 2 in 3 patients. Twenty three patients completed six cycles. Complete response was achieved in 1 (3%) patient, partial response in 22 (59%) patients, stable disease in 9 (24%) patients. Overall response rate was 62% on intent to treat basis. Among patients who response evaluation was possible (33 patients), response rate was 70%. The median survival time was 14.5 months (95% CI 6.9, 22.3) and the 1 year survival was 35% and then median time to progression was 3.4 months(95% CI 3, 3.9). Toxicities were moderate and mostly hematological adverse events. Grade 3/4 neutropenia occurred in 37%, 5 patients with febrile neutropenia. Grade 3/4 anemia and thrombocypenia was occurred in 37% and 5%. Nonhematologic toxicities were mild. Conclusion: The combination therapy consisted of gemcitabine, cisplatin and UFT is active and well tolerable first line regimen for NSCLC patients. No significant financial relationships to disclose.

Stage III and stage IV non-small cell carcinoma patients triple chemotherapy combination (carboplatin, paclitaxel, and gemcitabine) in good performance status

18205 Background: Triple drug chemotherapy combinations for nonsmall cell lung cancer (NSCLC) have most recently begun to show promising results in regards to response rate and time to progression (TTP) of disease. This abstract presents data from 99 patients with advanced unresectable disease who were not felt to be candidates for concurrent radiation and chemotherapy for 1999 to 2005 treated with a split dose regimen of paclitaxel 65mg/m2 (d1, 8,15 q29 days), carboplatin AUC 2 (d1, 8,15 q29days), and gemcitabine 650 mb/m2 (d1, 8 or15 q29 days). All patients have completed a minimum of 3 courses of therapy. Methods: 57 males with mean age 72 years, and 42 females, mean age of 69 yrs with performance status of < 1. Stage III A&B-33 patients and Stage IV-56 patients. The regimen was well tolerated with 4% grade 3 to 4 neutropenia, 30% 2-to3 thrombocytopenia. There were no septic deaths, grade 3 to 4 nonhematologic toxicity included alopecia, universally, fatigue at 24% and emesis at 8%. Results: CR-14.4%, PR-31%, minimal/stable-26% with 27.6% progressive/resistant disease with a median survival time of 20.5 months. 37 patients did receive radiation therapy to the primary lesion. Conclusions: This 3-drug regimen administered in split dosing has proven to be highly active and well tolerated in good performance status patients seen in a community practice setting. This cohort of patients was representative and typical for the 85% of patients seen in community oncology practices. No significant financial relationships to disclose.

A phase II study of weekly docetaxel/cisplatin and concurrent radiotherapy followed by surgery in patients with stage III non-small cell lung cancer (NSCLC)

18050 Background: Concurrent chemoradiotherapy treatment is standard of care for patients with stage III NSCLC in good performance. Optimal chemotherapy have yet to be defined and the role of surgery is still unclear. This prospective phase II study analysed the feasibility and efficacy of weekly docetaxel/cisplatin (DC) and concurrent involved-field thoracic radiotherapy (CRT) followed by surgery in good performance status patients with stage IIIA/B NSCLC. Primary endpoint is radiological response of DC and CRT. Secondary endpoints included toxicity, efficacy of surgery, postoperative morbidity and mortality, time to progression and overall survival. Methods: DC consisted of IV docetaxel 20 mg/m2 and cisplatin 20mg/m2 at days 1,8,15,22,29 and 36. CRT was given in once-daily fractions of 1.8 Gy, 5 fractions a week to a total dose of 45 Gy during days 8 to 36. CT-based planning was used to minimise radiation to the contralateral lung. Invasive and non-invasive investigations were performed after induction treatment in order to restage the mediastinum. when mediastinal downstaging was achieved, surgery was performed in order to achieve radical resection. Results: Between January 2005 until August 2006, 45 patients were included, of whom 43 patients were evaluable. Stage IIIB disease was present in 18 patients (cT4N2=9, cT4N0/N1=5 and cN3=4) and 25 had stage IIIA-N2 disease. Radiologic response was seen in 20 patients (47%) and 8 (19%) showed progressive disease. Toxicity was mild. Explorative thoracotomy was performed in 24 (56%) patients. Of these, 14 were initially staged as IIIA and ten as stage IIIB (4 of whom had N3 metastases). Twenty patients (47%) underwent a radical resection without residual mediastinal malignant disease, and ten pneumonectomies (8 left sided) were performed. Three patients showed complete pathological response. The 30 days mortality after operation was 4% (one patient) due to ARDS. Conclusions: Weekly DC and CRT is possible in stage III NSCLC, with limited toxicity and nearly half of the treated patients (47%) could undergo a radical surgical resection (R0) without residual mediastinal malignant disease. This promising tri-modality regimen should be tested in future phase II or III trials. No significant financial relationships to disclose.

Measures of aggressive care in advanced non-small cell lung cancer (NSCLC) patients

9063 Background: Data suggests that cancer care has become more aggressive over the last decade. Patients with advanced NSCLC have a short life expectancy and achieve only a modest survival benefit from chemotherapy. Investigating the aggressiveness of care during and at the end of life (EOL) is a key first step to better understanding quality of care in this patient population. Methods: This exploratory study uses previously defined measures of aggressive care (Earle, JCO 22(2), 2004) to evaluate a small cohort of patients with advanced NSCLC. We performed a pilot study of integrated palliative care in good performance status (PS) patients with newly diagnosed advanced NSCLC, which has been previously reported. This is a retrospective chart review of patients accrued at Massachusetts General Hospital (MGH) using the electronic medical record and case report forms for data collection. Results: 46 patients were enrolled from 10/03 to 6/05 (median age 65.5, 28 female). 43 (93%) patients had stage IV disease and the remainder had stage IIIB with effusions. 45 (98%) of patients had PS 0–1. 39 (85%) patients died at the time of chart review with a median follow up of 29.3 months. Using Earle's data as a benchmark more patients in this study received and began new chemotherapy at the EOL. Patients were also more likely to present to the emergency room (ER) and be admitted to the hospital. While more patients were admitted to hospice before death, the length of stay (LOS) in hospice was shorter and many patients still died in acute care hospitals. Conclusions: This study supports the finding that current cancer care is aggressive with many patients receiving chemotherapy at the EOL and having a short LOS in hospice. [Table: see text] No significant financial relationships to disclose.

Triplets vs. doublets in the management of advanced non-small cell lung cancer (NSCLC) using third generation chemotherapeutic agents: A meta-analysis

7580 Background: A platinum-based doublet is the current standard of care in the management of NSCLC. Addition of a third agent to the doublet has not shown to improve outcomes in a previous meta-analysis. Since one of the reasons for this may have been the inclusion of trials utilizing agents inferior to the currently used, we conducted a meta-analysis to evaluate the benefit of adding a third generation cytotoxic chemotherapeutic agent to a platinum doublet in terms of response rate, survival, and toxicity in patients with advanced NSCLC. Methods: Randomized controlled trials for advanced NSCLC, published as full papers in English, comparing doublets to triplets restricted to platinum salts and third-generation cytotoxic chemotherapeutic agents (vinorelbine, gemcitabine, docetaxel, paclitaxel) were analyzed. A Medline search was performed using the search terms “lung cancer” and “randomized trials”. Manual searches were also performed in the Journal of Clinical Oncology and Annals of Oncology. Pooled odds ratios (ORs) for the objective response and toxicity rates were calculated using the Mantel-Haenszel estimate. Pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios of individual study. Results: Eight trials (2,107 patients) published between 2000 and 2006 were eligible. Patients receiving triplet therapy had a significantly increased response rate (OR 1.86; 95% CI, 1.53 –2.26; P<0.001) and median survival (41.9 weeks vs. 37.05 weeks; OR: 1.14, 95% CI: 1.00–1.31; P=0.047), at the expense of higher grade III/IV hematological and neurological toxicity (P<0.001) ( Table ). Conclusions: The addition of a third-generation cytotoxic agent to a platinum-based doublet was associated with improved response rate and survival, but with increased hematological and neurological toxicity. Thus, triplet therapy may be considered in selected good performance status patients with advanced NSCLC. No significant financial relationships to disclose. [Table: see text]

Multimodale Therapie des kleinzelligen und nichtkleinzelligen Lungenkarzinoms

Lung cancer is divided into two types: non-small cell and small cell lung cancer. Small-cell lung cancer is a very aggressive rapid growing tumour type treated primarily with chemotherapy and, in the minority of patients with limited disease, with radiotherapy. Non-small cell lung cancer is treated in a multidisciplinary way with surgery, radiotherapy and chemotherapy depending on stage. Surgery is the mainstay of treatment for early stage non-small cell lung cancer patients. Adjuvant therapy has become state of the art in stage II and IIIA patients and must be considered in stage IB. Stage III patients should be treated in a multimodal way with radiotherapy and chemotherapy, and, if possible, with surgery. Treatment for every stage III patient should be discussed in a multidisciplinary team. Stage IV patients in good performance status will benefit from a combination chemotherapy, preferably platinum-based. Second line therapy has become standard and targeted therapies are under evaluation and are common in second line chemotherapy.

Pemetrexed disodium in combination with cisplatin versus other cytotoxic agents or supportive care for the treatment of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy whose incidence is expected to increase in the United Kingdom, Western Europe, and Australia over the next 20 years as a result of occupational exposure to asbestos fibres. Surgery is feasible in only a small proportion of cases, and radiotherapy and cytotoxic chemotherapy are used in palliation. Pemetrexed is the first and only chemotherapy agent that has been granted a marketing approval for use in combination with cisplatin for the treatment of chemo-naïve patients with unresectable MPM. To examine evidence on the clinical effectiveness of pemetrexed disodium used in combination with cisplatin for the treatment of unresectable malignant pleural mesothelioma in chemotherapy naïve patients compared with other cytotoxic agents used alone or in combination, or supportive care. CENTRAL (Issue 2, 2005), EMBASE (1980-2005), MEDLINE (1980-2005), HTA database (1990-2005), Web of Knowledge (1990-2005) and handsearching (including reference lists of retrieved articles and the pharmaceutical company submission to to NICE), up to October 2005. Randomised Controlled Trials (RCTs) where the use of pemetrexed disodium in combination with cisplatin is compared with other cytotoxic agents, or supportive care for the treatment of malignant pleural mesothelioma (or non-RCTs, in the absence of RCT data ). Outcomes included overall survival, tumour response, progression-free survival, toxicity and quality of life. Data extraction and quality assessment of included trials was completed independently. Trial data and quality assessment were tabulated and presented narratively. One RCT involving 448 patients and comparing pemetrexed plus cisplatin versus cisplatin alone for the treatment of unresectable malignant mesothelioma was included in the review. In the intention-to-treat study population, the median survival was statistically significantly longer in the combination arm of pemetrexed plus cisplatin when compared with the cisplatin alone arm. (12.1 and 9.3 months, respectively, p=0.002). The incidence of grade 3/4 toxicities was higher in the combination arm compared with the cisplatin alone arm. Pemetrexed disodium in combination with cisplatin and with folic acid and vitamin B(12 )supplementation may improve survival when used in combination with cisplatin in good performance status patients. Further studies including patients with poor performance status are needed in order to generalise the treatment findings. Further studies are also needed into the optimum chemotherapy, and a clear definition of what constitutes best supportive care.

A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma

Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody-drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Le(y)) antigen, conjugated to doxorubicin. Le(y) is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Le(y)-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients. Sixty-two patients with recurrent or metastatic NSCLC expressing Le(y), one or two prior chemotherapy regimens, and PS< or =2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life. Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A. SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.

Relationship between VHL mutation status, tumor VEGF expression and plasma VEGF measurement in sporadic renal cell carcinoma

4602 Background: The relationship between VHL mutation status and prognosis in renal cell carcinoma (RCC) remains controversial. The aim of this study was to evaluate prospectively the association between VHL status, tumor VEGF expression, plasma VEGF levels and usual prognostic parameters in RCC. Methods: 70 patients with clear cell RCCs were included in this study. Genomic DNA was extracted using the QIAmp DNA mini kit (Qiagen) from frozen tumor samples. Four amplimers covering the whole coding sequence and exon/intron junctions of the VHL gene were synthetized by PCR followed by Big Dye sequencing (Applied Biosystems). Mutation bearing sequences were confirmed in a second round of PCR and sequencing reactions. Tumor VEGF expression was determined by immunohistochemistry and plasma VEGF was measured by enzyme-linked immunosorbent assay (Quantikine immunoassay, R&amp;D systems). Results were expressed in pg/ml. Qualitative and quantitative variables were compared by using Chi-square (Fischer exact test) and Student t tests, respectively. Results: A VHL mutation was found in 46 cases (65.7%). VHL mutations were localized in exon 1, 2 and 3 in 23, 16 and 7 cases respectively. Median tumor VEGF expression was 45% (5–100). Median plasma VEGF was 104 pg/ml (13–1430). A significant association was found between VHL mutation and N stage (p: 0.01), Fuhrman grade, symptoms at presentation (p: 0.02) or tumor size (p: 0.007). A VHL mutation was found in 83.5% of low grade (G1–2) and 80% of incidental tumors respectively. A trend towards more frequent VHL mutations was observed in T1 tumors (87% mutation rate, p: 0.07) and in good performance status patients. Interestingly, VEGF tumor expression and plasma VEGF levels were not significantly different among patients with tumors having or not mutated VHL (p: 0.7). Conclusion: VHL mutations are more frequent in small incidental low stage or low grade tumors. Although VHL inactivation was not specifically determined in this study, we failed to show any association between VHL mutational status and VEGF tumor or plasma expression suggesting that other pathways than the VHL/HIF axis are required for explaining the angiogenic phenotype of RCC. No significant financial relationships to disclose.

Carboplatin-based chemotherapy in patients with advanced non-small cell lung cancer and a poor performance status

Poor performance status patients with advanced non-small cell lung cancer (NSCLC) have frequently been excluded from clinical trials due to the perception that they would have excessive treatment-related toxicity and a limited life expectancy. A retrospective review of two multicenter trials centered at the University of North Carolina of patients who were treated with platinum-based chemotherapy for advanced NSCLC was conducted. Patients were divided into two subgroups based on Karnofsky performance status (KPS). Patients with a KPS = 70 were considered to have poor performance status, while patients with a KPS > or =80 were considered to have good performance status. Of the 387 patients, 19% (n = 73) had a poor performance status. The response rate (complete and partial responses) was similar between the two sub-groups (26% versus 28%); however, there was a difference in survival (p = 0.0004, log-rank test) between the groups. The median survival and 1-year survival rate for the poor performance status patients was 4.9 months and 21%, while the good performance status patients had a median survival of 8.4 months and a 1-year survival rate of 31%. The rate of National Cancer Institute (NCI) Common Toxicity Criteria (CTC) toxicities was similar between the two groups (p = 0.33). The percentage of patients receiving <4 cycles of therapy in the poor and good performance status was 55 and 39%, respectively (p = 0.012). Patients with poor performance status treated with platinum based chemotherapy have a similar rate of toxicity compared to good performance status patients. Their overall survival was lower despite a similar response to chemotherapy.

Low-dose Prophylactic Cranial Irradiation in Patients with Poor Prognosis Small-cell Lung Cancer

In small-cell lung cancer (SCLC), prophylactic cranial irradiation (PCI) provides a survival advantage in good performance status patients with limited disease. Its role in those with poor performance status limited disease or extensive disease is unclear. A low-dose PCI schedule has been used in these groups, and outcomes have been analysed. Retrospective analyses of brain metastasis-free survival and overall survival of patients receiving low-dose PCI over a 2-year period. Fifty-six patients were treated, with 55 evaluable due to missing notes for one. No major treatment-related toxicity was observed. Median brain metastasis-free survival and overall survival for the group were 44 and 46 weeks, respectively. The median brain metastasis-free survival were 32 and 50 weeks, and median overall survival were 39 and 57 weeks, in those with extensive and limited disease, respectively. A total of 10 patients developed clinical or radiological evidence of brain metastases, four (16%) with limited disease and six (21%) with extensive disease. Thirteen (52%) with limited disease and 10 (36%) with extensive disease survived 1 year. Symptomatic brain metastases occurred less frequently than would be expected, with most patients developing widespread metastatic disease. Low-dose PCI may benefit these groups, and the results of an ongoing EORTC randomised-controlled trial in extensive disease should provide more information.