5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m2), modulated by MTX (24 h earlier, 200 mg/m2) were alternated with a 3-week continuous infusion of FU (200 mg/m2daily), modulated by LV (20 mg/m2weekly bolus). Mito, 7 mg/m2, was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28–46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III–IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents. © 2001 Cancer Research Campaign http://www.bjcancer.co

Curative immune checkpoint inhibitors therapy in patients with mismatch repair-deficient locally advanced rectal cancer: a real-world observational study

Background: Sustained clinical complete remissions were reported in all of 23 mismatch repair deficient/microsatellite instable (dMMR/MSI) locally advanced rectal cancer (LARC) patients treated with dostarlimab alone in a recent phase II study. These results led to off-label use of dostarlimab or other immune checkpoint inhibitors (ICIs) in dMMR/MSI-LARC even before regulatory approval. The present study [STAR(t)-IT-REDUCE] describes the outcome of dMMR/MSI-LARC patients treated with ICI in Italy. Materials and methods: Investigator-initiated, observational, retrospective-cohort, multicentric study of ICI treatment in dMMR/MSI-LARC. Patients were eligible if treated with ≥1 ICI dose from July 2022 to December 2023 (date of approval of dostarlimab for this indication in Italy). Results: Seventeen dMMR/MSI-LARC patients (13 of 17 treatment-naïve) were eligible. Fourteen patients completed 6 months of treatment, two discontinued after four doses and one after five doses because of immune-related pneumonia, social constraints, or non-oncological bowel obstruction, respectively. Overall, 16 of 17 assessable patients [94.1%; 95% confidence interval (CI) 69.24% to 99.69%, 'ITT analysis'] achieved complete clinical response (cCR). Ten of 11 treatment-naïve patients completing 6 months of treatment had cCR (90.9%; 95% CI 57.12% to 99.52%, 'per-protocol analysis'). One patient with near-CR underwent rectal surgery and minimal residual intramucosal tumor was found. With a median follow-up of 9.5 months, no local relapse occurred. One patient developed unconfirmed lung metastases. Two grade 3 and no grade 4 adverse events were reported. Conclusion: The present STAR(t)-IT-REDUCE study documents the immunoablative and curative activity of ICI monotherapy in dMMR/MSI-LARC. Toxicity and compliance issues inherent to real-world practice are limited and do not affect achievement of initial complete tumor response but may limit response duration

Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy

We analysed the expression of microsatellite instability, p53, p21, vascular endothelial growth factor and thymidylate synthase (TS) in pretreatment biopsy specimens from 57 locally advanced rectal cancers. The aim of the study was to correlate the expression of these markers with pathological response. Nineteen patients were treated with preoperative concomitant radiotherapy (RT) and fluorouracil/oxaliplatin-based chemotherapy (RCT), while 38 had RT alone. Pathological complete remission (pCR) and microfoci residual tumour (micR) occurred more frequently in patients treated with RCT (P=0.002) and in N0 tumours (P=0.004). Among patients treated with RCT, high TS levels were associated with a higher response rate (pCR+micR; P=0.015). No such correlation was found in the RT group. The other molecular factors were of no predictive value. Multivariate analysis confirmed a significant interaction between nodal status and the probability of achieving a pathological response (P=0.023) and between TS expression and treatment, indicating that a high TS level is predictive of a higher pathological response in the RCT subset (P=0.007). This study shows that lymph node status is the most important predictive factor of tumour response to preoperative treatment. Thymidylate synthase expression assessed immunohistochemically from pretreatment tumour biopsies may be a useful predictive marker of rectal tumour response to preoperative RCT

Recent advances in gastrointestinal oncology - updates and insights from the 2009 annual meeting of the American Society of Clinical Oncology

We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site

Thymidylate synthetase mRNA levels are increased in liver metastases of colorectal cancer patients resistant to fluoropyrimidine-based chemotherapy

BACKGROUND: Fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluoro-2'deoxyuridine (FUDR) are among the most effective chemotherapeutic agents for treatment of metastatic colorectal cancer (CRC). Increased expression of thymidylate synthetase (TS) in CRC metastases has been proposed to be an important mechanism of resistance to fluoropyrimidine-based chemotherapy. METHODS: The present study investigated whether TS mRNA levels in liver metastases of 20 CRC patients before treatment with FUDR by hepatic arterial infusion (HAI) correlated with frequency of clinical response or survival duration. RESULTS: Median survival duration of patients with TS mRNA levels above and below the median was 15 and 18 months, respectively (p > 0.05). Clinical response was achieved in 40% of patients with low TS mRNA levels, but in only 20% of patients with high TS mRNA levels (p = 0.01). TS mRNA levels were also measured for liver metastases of 7 of the patients that did not achieve a clinical response. A statistically significant increase in expression of TS mRNA was observed for liver metastases resistant to chemotherapy (21 ± 14) in comparison to liver metastases of the same patients before chemotherapy (8 ± 4) (p = 0.03). CONCLUSION: This is the first report to demonstrate increased TS expression in liver metastases from CRC patients resistant to fluoropyrimidine based chemotherapy. These findings are consistent with previous studies indicating that increased TS expression is associated with resistance to fluoropyrimidine-based chemotherapy

ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel

<p>Abstract</p> <p>Background</p> <p>One of the major challenges in currently chemotherapeutic theme is lacking effective biomarkers for drug response and sensitivity. Our current study focus on two promising biomarkers, ERCC1 (excision repair cross-complementing group 1) and BRCA1 (breast cancer susceptibility gene 1). To investigate their potential role in serving as biomarkers for drug sensitivity in cancer patients with metastases, we statistically measure the mRNA expression level of ERCC1 and BRCA1 in tumor cells isolated from malignant effusions and correlate them with cisplatin and/or docetaxel chemosensitivity.</p> <p>Methods</p> <p>Real-time quantitative PCR is used to analysis related genes expression in forty-six malignant effusions prospectively collected from non-small cell lung cancer (NSCLC), gastric and gynecology cancer patients. Viable tumor cells obtained from malignant effusions are tested for their sensitivity to cisplatin and docetaxel using ATP-TCA assay.</p> <p>Results</p> <p>ERCC1 expression level is negatively correlated with the sensitivity to cisplatin in NSCLC patients (P = 0.001). In NSCLC and gastric group, BRCA1 expression level is negatively correlated with the sensitivity to cisplatin (NSCLC: P = 0.014; gastric: P = 0.002) while positively correlated with sensitivity to docetaxel (NSCLC: P = 0.008; gastric: P = 0.032). A significant interaction is found between ERCC1 and BRCA1 mRNA expressions on sensitivity to cisplatin (P = 0.010, n = 45).</p> <p>Conclusion</p> <p>Our results demonstrate that ERCC1 and BRCA1 mRNA expression levels are correlated with <it>in vitro </it>chemosensitivity to cisplatin and/or docetaxel in malignant effusions of NSCLC and gastric cancer patients. And combination of ERCC1 and BRCA1 may have a better role on predicting the sensitivity to cisplatin than the single one is considered.</p

Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial

Oxaliplatin and 5-fluorouracil have a significant activity in locally advanced oesophageal squamous cell cancer (OSCC). However, their optimal dosage and efficacy when combined with concurrent radiotherapy as neoadjuvant treatment are unknown. This non-randomised, phase I/II study aimed to define the maximum tolerated dose (MTD) and assessed the histopathological tumour response rate to neoadjuvant oxaliplatin in weekly escalating doses (40, 45, 50 mg m−2) and continuous infusional 5-fluorouracil (CI-5FU; 225 mg m−2) plus concurrent radiotherapy. Patients had resectable OSCC. Resection was scheduled for 4–6 weeks after chemoradiotherapy. During phase I (dose escalation; n=19), weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 was established as the MTD and was the recommended dosage for phase II. Oesophageal mucositis was the dose-limiting toxicity at higher doses. During phase II, histopathological responses (<10% residual tumour cells within the specimen) were observed in 10 of 16 patients (63%; 95% confidence interval: 39–82%). Overall, 16 of the 25 patients (64%) who underwent resection had a histopathological response; tumour-free resection (R0) was achieved in 80%. Neoadjuvant weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 with concurrent radiotherapy provides promising histological response rates and R0 resection rates in locally advanced OSCC

Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study

<p>Abstract</p> <p>Background</p> <p>Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to capecitabine and concurrent radiotherapy for LARC.</p> <p>Methods</p> <p>Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/m²twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR).</p> <p>Results</p> <p>61 patients were enrolled (median age 60 years [range 31-80], 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively.</p> <p>Conclusions</p> <p>This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower.</p

Irinotecan+5-fluorouracil with concomitant pre-operative radiotherapy in locally advanced non-resectable rectal cancer: a phase I/II study

In the UK, 10% of patients diagnosed with rectal cancer have inoperable disease at presentation. This study ascertained whether the resectability rate of inoperable locally advanced rectal cancer was improved by administration of intravenous irinotecan, 5-fluorouracil (5-FU) and pelvic radiotherapy. During phase I of the trial (n=12), the dose of irinotecan was escalated in three-patient cohorts from 50 mg m−2 to 60 mg m−2 to 70 mg m−2 to identify the maximum tolerated dose (60 mg m−2). In phase II, 31 patients with non-resectable disease received 45 Gy radiotherapy and 5-FU infusions (200 mg m−2 per day) for 5 weeks. Irinotecan (60 mg m−2) was given on days 1, 8, 15 and 22. After treatment, patients were operated on if possible. Thirty patients completed the protocol, 28 underwent surgery. Before surgery, MRI restaging of 24 patients showed that 19 (79%) had a reduction in tumour stage after treatment (seven complete clinical response and 12 partial). Of 27 patients followed up after surgery, 22 (81%) had clear circumferential resection margins. Disease-free and overall survival estimates at 3 years were 65 and 90%, respectively. The regimen was well tolerated. Irinotecan, 5-FU and radiotherapy results in tumour downgrading, allowing resection of previously inoperable tumour with acceptable toxicity