The role of total neoadjuvant therapy in locally advanced rectal cancer: a survey of specialists attending the All-Ireland Colorectal Cancer Conference 2022 including lead investigators of OPRA, PRODIGE-23 and RAPIDO.

BACKGROUND: The treatment of locally advanced rectal cancer (LARC) has evolved following recent landmark trials of total neoadjuvant therapy (TNT)-the delivery of preoperative chemotherapy sequenced with radiation. AIM: To assess the preferences of colorectal surgery (CRS), radiation oncology (RO) and medical oncology (MO) specialists attending the All-Ireland Colorectal Cancer Conference (AICCC) 2022 regarding the neoadjuvant management of LARC. METHODS: A live electronic survey explored the preferred treatment approach and TNT regimen for early-, intermediate-, bad-, and advanced-risk categories of rectal cancer according to the European Society of Medical Oncology (ESMO) guidelines. The survey was preceded by an update from lead investigators of TNT trials (OPRA, PRODIGE-23 and RAPIDO), who then participated in a multidisciplinary panel discussion. RESULTS: Ten CRS, 7 RO and 15 MO (32 of 45 specialists) participated fully in the survey resulting in a response rate of 71%. Ninety-four percent, 76% and 53% of specialists preferred a TNT approach for patients with advanced, bad, and intermediate-risk rectal cancer, respectively. A consolidation TNT regimen of long-course chemoradiotherapy followed by chemotherapy was the most preferred regimen. Upfront surgery was preferred by 77% for early-risk disease. CONCLUSION: This survey illustrated the general acceptance of TNT by rectal cancer specialists attending the AICCC as a valuable treatment strategy for higher-risk category LARC. Whilst the treatment of LARC changes, it remains best practice to individualize care, incorporating the selective use of TNT as discussed by an MDT and in keeping with the patient's goals of care.

Consensus statement on the surveillance of patients with gastrointestinal malignancies.

BACKGROUND: Improvements in early detection, screening and treatment of cancer have resulted in a significant improvement in cancer mortality and an increase in the number of cancer survivors globally. Accordingly, a significant rise in the number of cancer survivors in Ireland has been observed. The surveillance of survivors of gastrointestinal malignancies in Ireland is heterogeneous and represents an unmet need for standardisation. AIMS: There are currently no national guidelines in Ireland to guide follow-up practices for these patients. The aim of this study was to establish homogeneity nationally with respect to follow-up of these patients by medical oncologists. METHODS/RESULTS: A consensus group consisting of Irish oncologists with an interest in gastrointestinal malignancies was created to address this issue, and determined that it would be reasonable to adopt the NCCN guidelines for this purpose, but that this recommendation would not be prescriptive, and should be individualised to each patient. CONCLUSION: We hope that this initiative may help to homogenise survivorship practices in this cohort of Irish patients, and may support the implementation of survivorship initiatives by the National Cancer Control Programme (NCCP).

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. METHODS: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. RESULTS: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

North polar trough formation due to in-situ erosion as a source of young ice in mid-latitudinal mantles on Mars.

The clockwise spiral of troughs marking the Martian north polar plateau forms one of the planet's youngest megastructures. One popular hypothesis posits that the spiral pattern resulted as troughs underwent poleward migration. Here, we show that the troughs are extensively segmented into enclosed depressions (or cells). Many cell interiors display concentric layers that connect pole- and equator-facing slopes, demonstrating in-situ trough erosion. The segmentation patterns indicate a history of gradual trough growth transversely to katabatic wind directions, whereby increases in trough intersections generated their spiral arrangement. The erosional event recorded in the truncated strata and trough segmentation may have supplied up to ~25% of the volume of the mid-latitude icy mantles. Topographically subtle undulations transition into troughs and have distributions that mimic and extend the troughs' spiraling pattern, indicating that they probably represent buried trough sections. The retention of the spiral pattern in surface and subsurface troughs is consistent with the megastructure's stabilization before its partial burial. A previously suggested warm paleoclimatic spike indicates that the erosion could have occurred as recently as ~50 Ka. Hence, if the removed ice was redeposited to form the mid-latitude mantles, they could provide a valuable source of near-surface, clean ice for future human exploration.

Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma.

LESSONS LEARNED: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. BACKGROUND: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. METHODS: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study. RESULTS: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076. CONCLUSION: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.

The Chaotic Terrains of Mercury Reveal a History of Planetary Volatile Retention and Loss in the Innermost Solar System.

Mercury's images obtained by the 1974 Mariner 10 flybys show extensive cratered landscapes degraded into vast knob fields, known as chaotic terrain (AKA hilly and lineated terrain). For nearly half a century, it was considered that these terrains formed due to catastrophic quakes and ejecta fallout produced by the antipodal Caloris basin impact. Here, we present the terrains' first geologic examination based on higher spatial resolution MESSENGER (MErcury Surface Space ENvironment GEochemistry and Ranging) imagery and laser altimeter topography. Our surface age determinations indicate that their development persisted until ~1.8 Ga, or ~2 Gyrs after the Caloris basin formed. Furthermore, we identified multiple chaotic terrains with no antipodal impact basins; hence a new geological explanation is needed. Our examination of the Caloris basin's antipodal chaotic terrain reveals multi-kilometer surface elevation losses and widespread landform retention, indicating an origin due to major, gradual collapse of a volatile-rich layer. Crater interior plains, possibly lavas, share the chaotic terrains' age, suggesting a development associated with a geothermal disturbance above intrusive magma bodies, which best explains their regionality and the enormity of the apparent volume losses involved in their development. Furthermore, evidence of localized, surficial collapse, might reflect a complementary, and perhaps longer lasting, devolatilization history by solar heating.

Pilot study of bevacizumab in combination with docetaxel and cyclophosphamide as adjuvant treatment for patients with early stage HER-2 negative breast cancer, including analysis of candidate circulating markers of cardiac toxicity: ICORG 08-10 trial.

BACKGROUND: Combining bevacizumab and chemotherapy produced superior response rates compared with chemotherapy alone in metastatic breast cancer. As bevacizumab may cause hypertension (HTN) and increase the risk of cardiac failure, we performed a pilot study to evaluate the feasibility and toxicity of a non-anthracycline-containing combination of docetaxel with cyclophosphamide and bevacizumab in early stage breast cancer patients. METHODS: Treatment consisted of four 3-weekly cycles of docetaxel and cyclophosphamide (75/600 mg/m2). Bevacizumab was administered 15 mg/kg intravenously on day 1, and then every 3 weeks to a total of 18 cycles of treatment. Serum biomarker concentrations of vascular endothelial growth factor (VEGF), cardiac troponin-I (cTnI), myeloperoxidase (MPO), and placental growth factor (PlGF) were quantified using enzyme-linked immunosorbent assay (ELISA) in 62 patients at baseline and whilst on treatment to determine their utility as biomarkers of cardiotoxicity, indicated by left ventricular ejection fraction (LVEF). RESULTS: A total of 106 patients were accrued in nine sites. Median follow up was 65 months (1-72 months). Seventeen protocol-defined relapse events were observed, accounting for an overall disease-free survival (DFS) rate of 84%. The DFS rates for hormone receptor positive (HR+) and triple-negative (TN) patients were 95% versus 43%, respectively. The median time to relapse was 25 (12-54) months in TN patients versus 38 (22-71) months in HR+ patients. There have been 13 deaths related to breast cancer . The overall survival (OS) rate was 88%. The 5-year OS rate in HR+ versus TN was 95% versus 57%. None of the measured biomarkers predicted the development of cardiotoxicity. CONCLUSIONS: We observed a low relapse rate in node-positive, HR+ patients; however, results in TN breast cancer were less encouraging. Given the negative results of three large phase III trials, it is unlikely that this approach will be investigated further. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00911716.

Multicenter, randomized, double-blind phase 2 trial of FOLFIRI with regorafenib or placebo as second-line therapy for metastatic colorectal cancer.

BACKGROUND: Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer. METHODS: Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1. RESULTS: One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. CONCLUSIONS: The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society.

Early recurrence and progression of a rare rectal squamous cell carcinoma after initial response to primary chemoradiotherapy.

Rectal squamous cell carcinomas represent an extremely rare malignancy which carries a significant morbidity and mortality. Diagnosis requires distinction from squamous cell carcinoma of the anus and colonic adenocarcinoma by endoscopy and histopathological examination of a biopsy. Due to the rarity of the pathology, available evidence is limited and optimum management has yet to be elucidated. Older reports favored radical surgical management, but recent reports in the literature recommend judicious use of primary chemoradiotherapy. We herein report the diagnosis and management of a male patient with an aggressive, locally advanced rectal squamous cell carcinoma treated with good results with primary chemoradiotherapy. Six months after completion of therapy, however, extensive recurrence and metastases were diagnosed. This case highlights the need for stringent clinical and radiological follow-up.

Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity?

Although small cell carcinoma of the gastrointestinal (GI) tract is well-recognized, nonsmall cell type high-grade neuroendocrine carcinoma (HGNEC) of this site remains undefined. At the current time, neither the World Health Organization nor American Joint Committee on Cancer includes this condition in the histologic classifications, and consequently it is being diagnosed and treated inconsistently. In this study, we aimed at delineating the histologic and immunophenotypical spectrum of HGNECs of the GI tract with emphasis on histologic subtypes. Guided primarily by the World Health Organization/International Association for the Study of Lung Cancer criteria for pulmonary neuroendocrine tumors, we were able to classify 87 high-grade GI tract tumors that initially carried a diagnosis of either poorly differentiated carcinoma with or without any neuroendocrine characteristics, small cell carcinoma, or combined adenocarcinoma-neuroendocrine carcinoma into the following 4 categories. The first was small cell carcinoma (n=23), which had features typical of pulmonary small cell carcinoma, although the cells tended to have a more round nuclear contour. The second was large cell neuroendocrine carcinoma (n=31), which had a morphology similar to its pulmonary counterpart and showed positive immunoreactivity for either chromogranin (71%) or synaptophysin (94%) or both. The third was mixed neuroendocrine carcinoma (n=11), which had intermediate histologic features (eg, cells with an increased nuclear/cytoplasmic ratio but with apparent nucleoli), and positive immunoreactivity for at least 1 neuroendocrine marker. The fourth was poorly differentiated adenocarcinoma (n=17). In addition, 5 of the 87 tumors showed either nonsmall cell type neuroendocrine morphology (n=3) or immunohistochemical reactivity for neuroendocrine markers (n=2), but not both. Further analysis showed that most HGNECs arising in the squamous lined parts (esophagus and anal canal) were small cell type (78%), whereas most involving the glandular mucosa were large cell (53%) or mixed (82%) type; associated adenocarcinomas were more frequent in large cell (61%) or mixed (36%) type than in small cell type (26%); and focal intracytoplasmic mucin was seen only in large cell or mixed type. As a group, the 2-year disease-specific survival for patients with HGNEC was 25.4% (median follow-up time, 11.3 mo). No significant survival difference was observed among the different histologic subtypes. In conclusion, our study demonstrates the existence of both small cell and nonsmall cell types of HGNEC in the GI tract, and provides a detailed illustration of their morphologic spectrum. There are differences in certain pathologic features between small cell and nonsmall cell types, whereas the differences between the subtypes of nonsmall cell category (large cell versus mixed) are less distinct. Given the current uncertainty as to whether large cell neuroendocrine carcinoma is as chemosensitive as small cell carcinoma even in the lung, our data provide further evidence in favor of a dichotomous classification scheme (small cell vs. nonsmall cell) for HGNEC of the GI tract. Separation of nonsmall cell type into large cell and mixed subtypes may not be necessary. These tumors are clinically aggressive. Prospective studies using defined diagnostic criteria are needed to determine their biologic characteristics and optimal management.

Cutaneous reactions to chemotherapy and their management.

International data from 2002 report 10.9 million new cases of cancer and 6.7 million cancer deaths. Chemotherapy is an essential component in the multidisciplinary management of most cancers. Cutaneous reactions to chemotherapeutics are common and may contribute significantly to the morbidity, and rarely to the mortality, of patients undergoing such treatments. Recognition and management of these reactions is important to provide optimal care. This article aims to present the most common cutaneous reactions to frequently used chemotherapies and provides management guidelines. A MEDLINE search from 1966 through June 2005 was conducted to identify reports of common cutaneous toxicities with systemic chemotherapy and their appropriate management. An analysis of our literature search is presented in review form outlining common chemotherapy-related cutaneous reactions and their management, as well as the chemotherapeutics responsible for the cutaneous toxicity. Chemotherapy-related cutaneous toxicity includes generalized rashes such as the spectrum between erythema multiforme and toxic epidermal necrolysis, and site-specific toxicity such as mucositis, alopecia, nail changes, extravasation reactions, or hand-foot syndrome. Most of the toxicity is reversible with chemotherapy dose reductions or delays. Certain toxicities can be effectively treated or prevented, allowing optimal delivery of chemotherapy (e.g. premedications to prevent hypersensitivity, prophylactic mouthwashes to prevent mucositis). Newer non-chemotherapeutic targeted therapies such as epidermal growth factor receptor inhibitors (e.g. gefitinib, cetuximab) may also be associated with cutaneous toxicity and can be distressing for patients. Recent data suggest that skin toxicity associated with these agents may correlate with efficacy. Cutaneous toxicity occurs frequently with chemotherapy and non-chemotherapeutic biologic therapies. Early recognition and treatment of the toxicity facilitates good symptom control, prevents treatment-related morbidity, and allows continuation of anti-cancer therapy.

Continued survival of more than ten years, without resection of metastatic disease, in patients with metastatic colorectal cancer treated with biomodulated fluorouracil: report of two cases.

The treatment of metastatic colorectal cancer by chemotherapy alone was considered palliative and without the potential to cure patients unless patients were rendered resectable. We report two patients with metastatic colorectal cancer involving the liver who were considered inoperable and were treated with systemic chemotherapy using biomodulated 5-fluorouracil. Both patients received 5-fluorouracil and N-(phosphonoacetyl)-l-aspartic acid; one also received methotrexate, leucovorin, and triacetyluridine with the N-(phosphonoacetyl)-l-aspartic acid and 5-fluorouracil. Both patients had a complete remission with chemotherapy and are still alive with no evidence of cancer ten years after the diagnosis of unresectable metastatic disease. These patients provide evidence that prolonged survival can be achieved withsystemic chemotherapy without the use of surgery or other forms of local therapy. These patients also confirm the importance of continued investigation of fluorouracil modulating agents, which may further enhance the recent progress made with fluorouracil-based combination chemotherapy for colorectal cancer.

Current strategies using hepatic arterial infusion chemotherapy for the treatment of colorectal cancer.

In recent years, a number of phase III clinical trials have reported median survival times approaching 20 months using modern combination chemotherapy for metastatic colorectal cancer (CRC). Despite the advances in systemic therapy, this approach is still considered palliative because long-term survival or cure is extremely rare. Surgery or the use of ablative techniques may result in prolonged survival for patients with liver metastases, but only a minority of cases are suitable for local therapy. Hepatic arterial infusion (HAI) therapy involves local delivery of drug to liver metastases, resulting in higher intrahepatic drug levels and a consequent doubling in response rates compared with systemic chemotherapy. Despite higher response rates, demonstrating a survival advantage for HAI has been more challenging. Recently, a number of studies have been published that appear to address some of the inadequacies of earlier trials and have demonstrated encouraging results. This review assimilates the current data on HAI for CRC and includes an assessment of new chemotherapeutic agents delivered via HAI, neoadjuvant HAI, HAI combined with systemic chemotherapy, the use of HAI for early-stage colorectal cancer, and future trials. Continued progress in the field of HAI therapy may reduce the morbidity and mortality associated with CRC, so continued research in this area should be encouraged.

Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer.

BACKGROUND: New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity. METHODS: A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity. RESULTS: Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients. CONCLUSION: Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity.

Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days. RESULTS: The MTD for patients in group A was Oxal 100 mg/m(2), CPT-11 150 mg/m(2), and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m(2), LV 400 mg/m(2), and FU 1,400 mg/m(2) by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection. CONCLUSION: Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.

A phase I pharmacologic and pharmacogenetic trial of sequential 24-hour infusion of irinotecan followed by leucovorin and a 48-hour infusion of fluorouracil in adult patients with solid tumors.

PURPOSE: In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions. EXPERIMENTAL DESIGN: CPT-11 was first given at four levels (70-140 mg/m(2)/24 hours), followed by leucovorin 500 mg/m(2)/0.5 hours and 5-FU 2,000 mg/m(2)/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m(2)/48 hours. RESULTS: Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 micromol/L at 3,900 mg/m(2)/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m(2)/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with >/=1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype. CONCLUSIONS: Doses (mg/m(2)) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.