Health related quality of life in older or frail patients with advanced colorectal cancer treated with dose reduced capecitabine.

OBJECTIVES: Palliative chemotherapy's role is to prolong survival while minimizing treatment toxicities to preserve or improve quality of life. We have recently published a phase II trial of dose reduced capecitabine in older or frail patients with advanced colorectal cancer (aCRC). We herein provide a robust analysis of the health related quality of life (HRQoL) data from our trial. METHODS: A single arm multi-centered phase II trial of dose reduced capecitabine (1500 or 2000 mg/m2 days one-fourteen q21 days) in older or frail patients. Participants (182 patients) were asked to complete Functional Assessment of Cancer Therapy general questionnaire (FACT-G) at enrollment, after each cycle of capecitabine, and once upon completion, if possible. RESULTS: 157 patients completed a baseline questionnaire (86%), and 137 patients (75%) completed at least one subsequent questionnaire. The mean baseline score was 81.6, out of a possible 108. The mean score peaked at 92 after cycle 10. The mean change from baseline was always positive. Patients achieving the minimal clinically important difference (MCID) ranged from 30% to 45% during treatment. Higher baseline FACT-G and Physical Well-being score were independently prognostic for improved survival (p = 0.006 and p < 0.0001, respectively). Time until definitive deterioration (TUDD) was insignificantly longer in patients with a higher baseline FACT-G (p = 0.18). CONCLUSION: Baseline HRQoL scores were independently prognostic for survival, supporting their importance. Compared to full dose, reduced dose capecitabine has previously demonstrated equivalent efficacy and reduced toxicity. We have reported dose reduced capecitabine improves quality of life in older or frail patients with aCRC, further supporting its use in the management of aCRC.

Phase II trial of capecitabine plus erlotinib versus capecitabine alone in patients with advanced colorectal cancer.

Aim & methods: Capecitabine monotherapy as palliation for advanced colorectal cancer (CRC) is generally well tolerated. Adding erlotinib, an EGFR-tyrosine kinase inhibitor, might improve efficacy versus capecitabine alone. 82 patients received capecitabine alone (Arm 1) or capecitabine with erlotinib (Arm 2). RESULTS: Median time-to-progression (TTP) in Arm 1 was 7.9 months versus 9.2 in Arm 2. In KRAS-wild type (WT) patients TTP was 8.4 and 11.7 months in Arms 1 and 2, respectively. In KRAS-mutated patients TTP was 7.4 and 1.9 months in Arms 1 and 2, respectively (p = 0.023). Arm 2 KRAS-WT patients, left-sided primaries, had an overall survival of 16.0 versus 12.1 months in right-sided primaries. CONCLUSION: Adding erlotinib to capecitabine increased TTP by 3.2 months in KRAS-WT patients. This study suggests that erlotinib harms patients with KRAS-mutated advanced CRC while it may provide benefit to those with KRAS-WT CRC. Further study of EGFR-tyrosine kinase inhibitors in patients with left-sided KRAS-WT CRC is warranted.

High-dose-rate interstitial brachytherapy for the treatment of high-volume locally recurrent endometrial carcinoma.

PURPOSE: Limited therapeutic options are available for the treatment of locally recurrent endometrial carcinoma. Our objective was to report an institutional experience using interstitial brachytherapy (IBT) to treat significant recurrent endometrial carcinoma, including previously irradiated disease. METHODS AND MATERIALS: Between December 2004 and September 2012, 40 patients with high-volume locally recurrent endometrial cancer were treated by high-dose-rate IBT (± external beam radiation therapy EBRT). Sixteen patients had prior radiotherapy: EBRT alone (n = 5), intracavitary brachytherapy alone (n = 3), or EBRT with intracavitary brachytherapy boost (n = 8). Actuarial outcome rates were calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Median followup interval was 18 months. Median disease-free interval was 61 months. Actuarial local control, progression-free survival (PFS), and overall survival were 74% and 60%, 70% and 51%, and 83% and 72% at 12 and 24 months, respectively. p-Values for local control, progression-free survival, and overall survival between patient who had prior RT (n = 16) to no prior RT (n = 24) were p = 0.38, 0.32, and 0.90, respectively. Acute toxicities include Grade 1-2 pain (5%), genitourinary (7%), gastrointestinal (12%), soft tissue (5%), and dermatologic (12%). Four patients observed late Grade 3-4 toxicities, including rectal bleeding/fistula and soft tissue necrosis. CONCLUSIONS: High-dose-rate IBT is an effective treatment for locally recurrent endometrial carcinoma with an acceptable toxicity profile. Outcomes are similar between previously irradiated and nonirradiated patients. In women who have received prior radiotherapy and are often considered for palliative treatment, interstitial brachytherapy is a potentially curative option.

Intensity-Modulated Radiation Therapy Versus 3D Conformal Radiotherapy for Postoperative Gynecologic Cancer: Are They Covering the Same Planning Target Volume?

BACKGROUND AND PURPOSE: This study compares dosimetric parameters of planning target volume (PTV) coverage and organs at risk (OAR) sparing when postoperative radiotherapy for gynecologic cancers is delivered using volumetric modulated arc therapy (VMAT) versus a four-field (4FLD) box technique. MATERIAL AND METHODS: From July to December 2012, women requiring postoperative radiation for gynecologic cancers were treated with a standardized VMAT protocol. Two sets of optimized 4FLD plans were retrospectively generated: one based on standard anatomical borders (4FLD) and one based on the clinical target volume (CTV) created for VMAT with a 2 cm expansion guiding field border placement (4FLD+2). Ninety-five percent isodose curves were generated to evaluate PTV coverage. RESULTS: VMAT significantly improved dose conformity compared with 4FLD and 4FLD+2 plans (p < 0.001) and provided additional coverage of the PTV posteriorly and superiorly, corresponding to coverage of the presacral and proximal iliac vessels. There was a significant reduction in dose to all OARs with VMAT, including a 58% reduction in the volume of the small bowel receiving more than 45 Gy (p=0.005). CONCLUSIONS: Despite treating a larger volume, radiotherapy using a 4FLD technique is less homogenous and provides inferior coverage of the PTV compared with VMAT. With meticulous treatment planning and delivery, VMAT effectively encompasses the PTV and minimizes dose to OARs.

ECF chemotherapy for liver metastases due to castration-resistant prostate cancer.

INTRODUCTION: Most men with metastatic castration-resistant prostate cancer (CRPC) have biochemical response to docetaxel, but the objective response rate is low. Liver metastases are uncommon with CRPC and associated with shorter survival. More active treatment might benefit these patients. Epirubicin, cisplatin and flurouracil (ECF) is a standard regimen for gastric cancer and response in CRPC liver metastases has been reported. We reviewed our experience with ECF in CRPC with the primary objective of determining its anti-tumour activity in patients with liver metastatic CRPC. METHODS: Men with CRPC treated with ECF were identified from electronic databases and data were extracted from medical records. Men with tumours showing neuroendocrine features were excluded. RESULTS: In total, we identified 14 CRPC patients treated with ECF were identified, of which 8 had liver metastases. The median age was 56 (range: 42-76) and all had multiple poor prognostic features. A median of 6 cycles of ECF were administered (range: 1-10) and toxicities were similar to previous reports. Of the 8 patients with liver metastases, 5 had partial remission. CONCLUSIONS: ECF was highly active in this small selected group of younger men with liver metastases from CRPC and multiple poor prognostic features. Despite important limitations, this is the third report of high objective response rates with ECF in CRPC. Objective response rates are low with current monotherapies. A higher probability of ORR is preferred for critical organ disease, therefore the anti-tumour activity should encourage testing of ECF in comparison to the most active current therapies.

CT-based interstitial brachytherapy in advanced gynecologic malignancies: outcomes from a single institution experience.

PURPOSE: To evaluate the clinical outcomes of women receiving a "short" course of high-dose-rate gynecologic interstitial brachytherapy (HDR-ISBT) boost with CT-based 3D planning. METHODS AND MATERIALS: Forty-seven women with no prior radiation received HDR-ISBT from August 2004 to February 2012. The mean external beam radiotherapy dose was 45 Gy. A mean HDR-ISBT boost dose of 18.4 Gy was delivered over 2-4 fractions. Dose volume histograms (DVHs) were computed for organs at risk and clinical target volume. RESULTS: With a median followup of 34.8 months, the 3-year local control rate was 68%. Sixteen patients were identified to have tumor recurrence (including eight local). The median time to any recurrence was 26.8 months. Relapse-free survival and overall survival at 3 years was 65% and 73%, respectively. Ten patients experienced Grade 3 late toxicity, mainly vaginal (5) and proctitis (3). The mean prescription volume (V100) was 85 cc and the mean D90 to CTV was 98%. The mean cumulative dose to tumor was 69.9 Gy (equivalent dose in 2 Gy). The mean cumulative equivalent dose in 2 Gy to D2cc of bladder and rectum was 60.9 Gy and 63.0 Gy, respectively. CONCLUSION: A "short" course HDR-ISBT is effective, safe, and convenient with acceptable local control and toxicity. Higher dose per fraction is similar to an external beam radiotherapy stereotactic boost with the inherent advantages of brachytherapy. A shorter overall time for HDR-ISBT means less time that patients are immobilized and in hospital, making it less resource intensive than a longer course.

Adjuvant paclitaxel and carboplatin chemotherapy with involved field radiation in advanced endometrial cancer: a sequential approach.

PURPOSE: To determine the feasibility of adjuvant paclitaxel and carboplatin chemotherapy interposed with involved field radiotherapy for women with advanced endometrial cancer. METHODS AND MATERIALS: This was a prospective cohort study of women with Stage III and IV endometrial cancer. Adjuvant therapy consisted of 4 cycles of paclitaxel (175 mg/m(2)) and carboplatin (350 mg/m(2)) every 3 weeks, followed sequentially by external beam radiotherapy (RT) to the pelvis (45 Gy), followed by an additional two cycles of chemotherapy. Para-aortic RT and/or HDR vault brachytherapy (BT) were added at the discretion of the treating physician. RESULTS: Thirty-three patients (median age, 63 years) received treatment between April 2002 and June 2005. Median follow-up was 21 months. Stage distribution was as follows: IIIA (21%), IIIC (70%), IVB (9%). Combination chemotherapy was successfully administered to 30 patients (91%) and 25 patients (76%), before and after RT respectively. Nine patients (27%) experienced acute Grade 3 or 4 chemotherapy toxicities. All patients completed pelvic RT; 19 (58%) received standard 4-field RT and 14 (42%) received intensity-modulated radiotherapy. Ten (30%) received extended field radiation. Four patients (12%) experienced acute Grade 3 or 4 RT toxicities. Six (18%) patients developed chronic RT toxicity. There were no treatment-related deaths. Two-year disease-free and overall survival rates were both 55%. There was only one pelvic relapse (3%). CONCLUSIONS: Adjuvant treatment with combination chemotherapy interposed with involved field radiation in advanced endometrial cancer was well tolerated. This protocol may be suitable for further evaluation in a clinical trial.

Does sex influence the impact that smoking, treatment interruption and impaired pulmonary function have on outcomes in limited stage small cell lung cancer treatment?

PURPOSE: To look for survival differences between men and women with limited stage small cell lung cancer (LS-SCLC) by examining stratified variables that impair treatment efficacy. METHODS: A retrospective review of 215 LS-SCLC patients treated from 1989 to 1999 with concurrent chemotherapy-radiotherapy modelled on the 'early-start' thoracic radiotherapy arm of a National Cancer Institute of Canada randomized trial. RESULTS: Of 215 LS-SCLC patients, 126 (58.6%) were men and 89 (41.4%) were women. Smoking status during treatment for 186 patients (86.5%) was: 107 (58%) nonsmoking (NS) (76 [71%] male [M]; 31 [29%] female [F]) and 79 (42%) smoking (S) (36 M [46%]; 43 F [54%]) (continuing-to-smoke F versus M, P=0.001). Fifty-six patients (26%) had radiotherapy interruptions (RTI) during chemotherapy-radiotherapy because of toxicity. Radiotherapy breaks were not associated with sex (P=0.95). Survival by sex and smoking status at two years was: F + NS = 38.7%; F + S = 21.6%; M + NS = 22.9%; and M + S = 9.1% (P=0.0046). Survival by sex and RTI status at two years was: F + no RTI = 32.4%; F + RTI = 23.6%; M + no RTI = 23.0%; and M + RTI = 3.8% (P=0.0025). Diffusion capacity for carbon monoxide (DLCO) was recorded for 86 patients (40%) and median survival by sex and DLCO was F = 16.7 months and M = 12.1 months for a DLCO less than 60%; and for a DLCO 60% or more, F = 15.1 months and M = 15.3 months. First relapses were recorded in 132 cases (61%), with chest failure in men (45%) greater than for women (35%) and cranial failure rates similar between sexes (48%). Upon multivariable analysis, continued smoking was the strongest negative factor affecting survival. CONCLUSIONS: In LS-SCLC, women overall do better than men, with or without a negative variable. The largest quantifiable improvement in survival for women came from smoking cessation, and for men from avoidance of breaks during treatment.

Impaired diffusion capacity predicts for decreased treatment tolerance and survival in limited stage small cell lung cancer patients treated with concurrent chemoradiation.

PURPOSE: To determine if stratification of limited stage small cell lung cancer (LSCLC) patients by pre-treatment pulmonary function test (PFT) prognostic indicators predicts for treatment-related toxicity risks and survival following concurrent chemoradiation. MATERIALS AND METHODS: From 1989 to 1999, 215 LSCLC patients received six cycles of alternating cyclophosphamide/doxorubicin/vincristine and etoposide/cisplatin (EP). Thoracic radiation (RT) was initiated only with EP and at cycle 2 or 3. RT dose was: 40 Gy/15 fractions/3 weeks or 50 Gy/25 fractions/5 weeks. RT fields encompassed gross and suspected microscopic disease with a 2 cm margin. Pre-treatment PFT values analyzed included forced expiratory volume in 1s (FEV1) (in liter and as % predicted) and diffusion capacity for carbon monoxide (DLCO) (as % predicted). The "marker" for toxicity during concurrent chemoradiation was the duration of any RT breaks initiated for severe hematologic or locoregional symptomatology. Patient outcomes were analyzed for associations between recognized PFT cut-offs (FEV1 <2l, > or =2l; FEV1 <60%, > or =60% predicted; DLCO <60%, > or =60% predicted), toxicity rates, and survival. RESULTS: For the whole study cohort, median, 2- and 5-year overall survivals were: 14.7 months, 22.7 and 7.2%, respectively. Fifty-six patients (26%) required treatment breaks due to toxicity. FEV1 and DLCO results were available for 96 (45%) and 86 (40%) patients, respectively. Two thirds of FEV1s measured were <2l. On statistical analysis, the incidence of toxicity-related interruptions was significant for DLCO<60% (P=0.043), suggestive for FEV1<2l (P=0.1) and non-significant for FEV1<60%. Patients with simultaneous DLCO<60% and FEV1<2l showed a trend toward increase toxicity risk (P=0.1). For selected PFT measures, median overall survivals were: 12.7 months versus 14.8 months for DLCO<60% versus > or =60%; 13.4 months versus 17.7 months for FEV1<2l versus > or =2l; 15.4 months versus 19.9 months for DLCO<60% + FEV1<2l versus DLCO> or =60% + FEV1> or =2l. Although absolute differences favored all patients with PFT values above the prognostic cut-offs, differences were not statistically significant on this analysis. Patients with both a treatment break and a DLCO<60% had the poorest median survival of all patient subsets, at 11.4 months (P=0.09). CONCLUSIONS: Impaired DLCO (i.e. <60%) is a novel predictor of increased treatment-related toxicity leading to interruptions. The present study suggests a probable role for DLCO and FEV1 (in l) as prognostic factors for predicting survival but larger patient samples are required for confirmation. Patients with impaired DLCOs experiencing treatment interruptions have the poorest survival. Assessment of pre-treatment PFTs contributes to determining optimal management strategies for LSCLC patients receiving definitive chemoradiation.

Toxicity analysis of the 5-day bolus 5-fluorouracil/folinic acid regimen for the treatment of colorectal carcinoma from 2 randomized controlled trials: a concern about dose.

The goal of this study was to ascertain the first cycle intolerability rate of the standard Mayo Clinic regimen, 5-fluorouracil (5-FU) 425 mg/m2 with low-dose folinic acid (FA) 20 mg/m2, as a rapid bolus intravenous injection (5-FU/FA) for 5 days every 4-5 weeks for advanced colorectal cancer chemotherapy. The 5-FU/FA arms of 2 large, randomized, controlled trials of 5-FU/FA versus raltitrexed, performed in Europe and North America, were analyzed for intolerability. Two hundred and twelve European patients and 200 North American patients with locally advanced or distant metastatic colorectal cancer were assigned to the Mayo Clinic regimen. During cycle 1, intolerability of the therapy was assessed. Intolerability was recognized as a protocol-driven, toxicity-mandated dose reduction in cycle 2, the inability to complete 5 days of cycle 1 due to toxicity, or failure to receive cycle 2 at all because of toxicity. After the first cycle of chemotherapy, the intolerability rate for the European trial was 41.0% (95% confidence interval [CI], 34.3-47.6) and 49.0% (95% CI, 42.0-56.0) for the North American trial. For the combined 5-FU/FA populations, the intolerability rate was 44.8% (95% CI, 40.0-49.7). The predominant toxicities were stomatitis, diarrhea, and leukopenia. The standard Mayo Clinic regimen was associated with a higher level of dose-limiting toxicities than the accepted maximum of up to 33% for standard chemotherapy.