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Background Emerging evidence on the optimal use of chemotherapy and biologics in patients with metastatic colorectal cancer should impact management in routine care. Recent studies have demonstrated benefits for initial triplet chemotherapy (5-fluorouracil, oxaliplatin and irinotecan, FOLFOXIRI) and for initial treatment with an epidermal growth factor receptor inhibitor (EGFRi) in patients with a RAS wild-type tumour and a left-sided primary tumour. Aim To explore evolving pattern of metastatic colorectal cancer care over time in Australia. Methods We analysed data from the Treatment of Recurrent and Advanced Colorectal Cancer registry. Results From July 2009 to December 2017, 2552 metastatic colorectal cancer patients were entered into the Treatment of Recurrent and Advanced Colorectal Cancer registry. Of 1585 patients who initially underwent chemotherapy, treatment was with a doublet in 76%. FOLFOXIRI was given to 22 patients (1.4%), mostly young patients and those with potentially resectable disease. Along with first-line chemotherapy, 61% received bevacizumab, while 3.3% received an EGFRi, predominantly over the last 2 years. Within the KRAS wild-type left-sided tumour cohort, EGFRi use increased from 9% in 2015 to 37% in 2017. Across treatment sites, there was a wide variation in the utilisation of FOLFOXIRI and EGFRi therapy; bevacizumab use was more consistent. A clear impact on survival outcomes from these regimens is not evident, potentially due to multiple confounders. Conclusion Doublet chemotherapy + bevacizumab remains the dominant initial strategy, with limited uptake of triplet chemotherapy and of EGFRi. Potential explanations include uncertainty about the significance of post hoc analyses for EGFRi and concerns regarding adverse events for both strategies.

Background The FIRE-3 [5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus cetuximab versus FOLFIRI plus bevacizumab in first line treatment colorectal cancer (CRC)] study reported that first-line FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab resulted in similar progression-free survival (PFS) but improved overall survival (OS). A potential explanation is that the initial biologic agent administered in metastatic CRC (mCRC) affects later line efficacy of the other treatments. We sought to test this hypothesis. Materials and Methods We interrogated our mCRC registry (Treatment of Recurrent and Advanced Colorectal Cancer) regarding treatment and outcome data for RAS wild-type patients receiving epidermal growth factor receptor inhibitors (EGFRIs) in second and subsequent lines. Survival outcomes from the beginning of EGFRI use were determined as a function of previous bevacizumab use and the interval between ceasing bevacizumab and beginning EGFRI use. Results Of 2061 patients, 222 eligible patients were identified, of whom 170 (77%) had received previous bevacizumab and 52 (23%) had not. PFS and OS from the start of EGFRIs did not differ by previous bevacizumab use (3.8 vs. 4.2 months; hazard ratio [HR], 1.12; P = .81; 9.0 vs. 9.2 months; HR, 1.19; P = .48, respectively) for the whole cohort or when analyzed by the primary tumor side (HR for left side, 1.07; P = .57; HR for right side, 1.2; P = .52). PFS was significantly shorter with right-sided primary tumors when the interval between bevacizumab and EGFRI use was 6 months (median, 2.2 vs. 6 months; HR, 2.23; P = .01) but not with left-sided tumors (median, 4.2 vs. 5.5 months; HR, 1.12; P = .26). Conclusion Previous bevacizumab use had no effect on the activity of subsequent EGFRIs. The apparent effect of time between biologic agents in right-sided tumors might reflect patient selection.

Concurrent chemoradiotherapy (CCRT) has become the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). The comparative merits of two widely used regimens: carboplatin/paclitaxel (PC) and cisplatin/etoposide (PE), each with concurrent radiotherapy, remain largely undefined. Records for consecutive patients with stage III NSCLC treated with PC or PE and ≥60 Gy chest radiotherapy between 2000 and 2011 were reviewed for outcomes and toxicity. Survival was estimated using the Kaplan-Meier method and Cox modeling with the Wald test. Comparison across groups was done using the student's t and chi-squared tests. Seventy-five (PC: 44, PE: 31) patients were analyzed. PC patients were older (median 71 vs. 63 years; P = 0.0006). Other characteristics were comparable between groups. With PE, there was significantly increased grade ≥3 neutropenia (39% vs. 14%, P = 0.024) and thrombocytopenia (10% vs. 0%, P = 0.039). Radiation pneumonitis was more common with PC (66% vs. 38%, P = 0.033). Five treatment-related deaths occurred (PC: 3 vs. PE: 2, P = 1.000). With a median follow-up of 51.6 months, there were no significant differences in relapse-free survival (median PC 12.0 vs. PE 11.5 months, P = 0.700) or overall survival (median PC 20.7 vs. PE 13.7 months; P = 0.989). In multivariate analyses, no factors predicted for improved survival for either regimen. PC was more likely to be used in elderly patients. Despite this, PC resulted in significantly less hematological toxicity but achieved similar survival outcomes as PE. PC is an acceptable CCRT regimen, especially in older patients with multiple comorbidities.

With an ever-increasing focus on personalized medicine, all factors known to affect treatment response need to be considered when defining optimal therapy for individual patients. While the prognostic impact of primary tumor site on colorectal cancer (CRC) outcomes is established, emerging data suggest potential differences in response to biologic therapies. We studied the impact of tumor site on bevacizumab efficacy in patients with metastatic CRC.We analyzed data of patients in an Australian prospective multicenter metastatic CRC (mCRC) registry who received first-line chemotherapy. Tumor site was defined as right colon, cecum to transverse; left colon, splenic flexure to rectosigmoid; and rectum. Kaplan-Meier and Cox models were used for survival analyses.Of 926 patients, 297 had right colon, 354 left colon, and 275 rectum primary disease. Median age was 68.6, 65.9, and 63.3 years, respectively (P = .001). Right colon disease was significantly associated with intraperitoneal spread (P .0001), while left colon and rectum disease preferentially metastasized to the liver and lungs, respectively (P .0001 in both settings). A total of 636 patients (68.7%) received bevacizumab. Progression-free survival was superior for bevacizumab-treated patients in all groups but appeared greatest in right colon disease (hazard ratio, 0.46; 95% confidence interval, 0.36-0.60; P ≤ .001). Overall survival was longest in patients with disease of the rectum, followed by left colon and right colon (median, 26.2, 23.6, and 18.2 months, respectively; P = .0004).Tumor site appears to be prognostic in mCRC, with rectum and right colon disease associated with the best and worst outcomes, respectively. Patients who received bevacizumab in addition to chemotherapy had superior outcomes, with the effect appearing greatest in patients with right colon disease.

PURPOSE To compare the efficacy and toxicity profiles of a combination of fluorouracil (5-FU) with recombinant human interferon alfa-2a (Roferon-A; Hoffman La-Roche AG, Basel, Switzerland) versus the combination of 5-FU with leucovorin (LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS A total of 496 previously untreated colorectal cancer patients were randomized to receive either Roferon-A (9 MIU) subcutaneously three times per week, with 5-FU (750 mg/m2/d) by continuous intravenous (i.v.) infusion (CIV) on days 1 to 5, then, after a 9-day hiatus, as a weekly i.v. bolus at the same dose (IFN/5-FU); or LV (200 mg/m2/d) by i.v. infusion plus 5-FU (370 mg/m2/d) by i.v. bolus on days 1 to 5, repeated every 4 weeks (LV/5-FU). RESULTS There were no significant differences between IFN/5-FU and LV/5-FU in the overall response rate (21% v 18%), duration of response (7.3 v 6.2 months), or survival time (median, 11.0 v 11.3 months). Toxicity profiles differed; constitutional symptoms and myelosuppression were more frequent and more severe with IFN/5-FU, and gastrointestinal symptoms with LV/5-FU. More patients interrupted treatment for adverse events (AEs) with IFN/5-FU than with LV/5-FU. Five treatment-related deaths occurred with each regimen. CONCLUSION The combination IFN/5-FU produced response rates, response durations, and survival times similar to those with LV/5-FU. Biochemical modulation of 5-FU by either IFN or LV appears to result in equivalent efficacy; however, fewer patients were able to tolerate the specified IFN/5-FU combination used in this study.

A phase I/II study of the intralesional administration of ricin-labelled monoclonal antibodies was conducted in patients with hepatic metastases of gastrointestinal origin. The anti-carcinoembryonic antigen (CEA) antibody I-1 was conjugated to blocked ricin via a disulphide bridge. After a test dose of antibody, patients were injected with ricin-antibody conjugates under computed tomography (CT) guidance on two occasions 1 week apart. Patients with stable or responding disease would receive a third course. The dose of ricin relative to surface area was increased in a predefined manner in cohorts of 3 patients. A total of 27 patients with hepatic metastases were entered into this study. All patients had metastatic colorectal cancer (26 patients) or adenocarcinoma of unknown primary with elevated CEA levels (1 patient). The presence of malignancy was documented cytologically in 9 of 11 patients tested. Minor responses were seen in 7 patients. However, no major objective responses or changes in the growth rate of injected lesions were observed. Toxicity was generally mild, the most common being hepatic capsular pain 24-48 h after each injection. 6 patients experienced rigors. One patient had anaphylaxis. Human anti-mouse and anti-ricin antibody responses were observed. Although substantial amounts of ricin conjugated to monoclonal antibodies were delivered into single lesions, this therapeutic approach was unsuccessful. Future studies of ricin-labelled antibodies should incorporate the systemic administration of immunoconjugates.

PURPOSE To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.

Two cases of small cell carcinoma of the lung in which flare responses were demonstrated are discussed. Although the primary tumor and extraskeletal metastases responded to first-line chemotherapy, bone scintigraphs performed 3 months after the start of treatment suggested tumor progression. However, following repeat bone imaging and subsequent clinical evaluation, the interim scintigraphs appeared to represent an unusual flare response, in which the activity of pre-existing hot spots increased and new lesions developed.