Francis Lévi

Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen–specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer

PURPOSE To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS Grade 3 to 4 toxicity from 5-FU-LV occurred in </= 5% of the patients (</= 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU-LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P <. 001). The median progression-free survival time was 6.1 months with 5-FU-LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU-LV (P =.048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION By chronomodulating 5-FU-LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.

Rescue Surgery for Unresectable Colorectal Liver Metastases Downstaged by Chemotherapy: A Model to Predict Long-term Survival

Objective:To evaluate the long-term survival of patients resected for primarily unresectable colorectal liver metastases (CRLM) downstaged by systemic chemotherapy and to use prognostic factors of outcome for a model predictive of survival on a preoperative setting. Summary Background Data:Surgery of primarily unresectable CRLM after downstaging chemotherapy is still questioned, and prognostic factors of outcome are lacking. Methods:From a consecutive series of 1439 patients with CRLM managed in a single institution during an 11-year period (1988–1999), 1104 (77%) initially unresectable (NR) patients were treated by chemotherapy and 335 (23%) resectable were treated by primary liver resection. Chemotherapy mainly consisted of 5-fluorouracil and leucovorin combined to oxaliplatin (70%), irinotecan (7%), or both (4%) given as chronomodulated infusion (87%). NR patients were routinely reassessed every 4 courses. Surgery was reconsidered every time a documented response to chemotherapy was observed. Among 1104 NR patients, 138 “good responders” (12.5%) underwent secondary hepatic resection after an average of 10 courses of chemotherapy. At time of diagnosis, mean number of metastases was 4.4 (1–14) and mean maximum size was 5.2 cm (1–25). Extrahepatic tumor was present in 52 patients (38%). Multinodularity or extrahepatic tumor was the main cause of initial unresectability. All factors likely to be predictive of survival after liver resection were evaluated by uni- and multivariate analysis. Estimation of survival was adjusted on risk factors available preoperatively. Results:Seventy-five percent of procedures were major hepatectomies (≥3 segments) and 93% were potentially curative. Liver surgery was combined to portal embolization, to ablative treatment, or to a second-stage hepatectomy in 42 patients (30%) and to resection of extrahepatic tumor in 41 patients (30%). Operative mortality within 2 months was 0.7%, and postoperative morbidity was 28%. After a mean follow-up of 48.7 months, 111 of the 138 patients (80%) developed tumor recurrence, 40 of which were hepatic (29%), 12 extrahepatic (9%), and 59 both hepatic and extrahepatic (43%). Recurrence was treated in 52 patients by repeat hepatectomy (71 procedures) and in 42 patients by extrahepatic resection (77 procedures). Survival was 33% and 23% at 5 and 10 years with a disease-free survival of 22% and 17%, respectively. It was decreased as compared with that of patients primarily resected within the same period (48% and 30% respectively, P = 0.01). At the last follow-up, 99 patients had died (72%) and 39 (28%) were alive; 25 were disease free (18%) and 14 had recurrence (10%). At multivariate analysis, 4 preoperative factors were independently associated to decreased survival: rectal primary, ≥3 metastases, maximum tumor size >10 cm, and CA 19–9 >100 UI/L. Mean adjusted 5-year survival according to the presence of 0, 1, 2, 3, or 4 factors was 59%, 30%, 7%, 0%, and 0%. Conclusions:Modern chemotherapy allows 12.5% of patients with unresectable CRLM to be rescued by liver surgery. Despite a high rate of recurrence, 5-year survival is 33% overall, with a wide use of repeat hepatectomies and extrahepatic resections. Four preoperative risk factors could select the patients most likely to benefit from this strategy.

Tumor Progression While on Chemotherapy: A Contraindication to Liver Resection for Multiple Colorectal Metastases?

Objective:To evaluate the influence of the response to preoperative chemotherapy, especially tumor progression, on the outcome following resection of multiple colorectal liver metastases (CRM). Summary Background Data:Hepatic resection is the only treatment that currently offers a chance of long-term survival, although it is associated with a poor outcome in patients with multinodular CRM. Because of its better efficacy, chemotherapy is increasingly proposed as neoadjuvant treatment in such patients to allow or to facilitate the radicality of resection. However, little is known of the efficacy of such a strategy and the influence of the response to chemotherapy on the outcome of hepatic resection. Methods:We retrospectively analyzed the course of 131 consecutive patients who underwent liver resection for multiple (≥4) CRM after systemic chemotherapy between 1993 and 2000, representing 30% of all liver resections performed for CRM in our institution during that period. Chemotherapy included mainly 5-fluorouracil, leucovorin, and either oxaliplatin or irinotecan for a mean of 9.8 courses (median, 9 courses). Patients were divided into 3 groups according to the type of response obtained to preoperative chemotherapy. All liver resections were performed with curative intent. We analyzed patient outcome in relation to response to preoperative chemotherapy. Results:There were 58 patients (44%) who underwent hepatectomy after an objective tumor response (group 1), 39 (30%) after tumor stabilization (group 2), and 34 (26%) after tumor progression (group 3). At the time of diagnosis, mean tumor size and number of metastases were similar in the 3 groups. No differences were observed regarding patient demographics, characteristics of the primary tumor, type of liver resection, and postoperative course. First line treatments were different between groups with a higher proportion of oxaliplatin- and/or irinotecan-based treatments in group 1 (P < 0.01). A higher number of lines of chemotherapy were used in group 2 (P = 0.002). Overall survival was 86%, 41%, and 28% at 1, 3, and 5 years, respectively. Five-year survival was much lower in group 3 compared with groups 1 and 2 (8% vs. 37% and 30%, respectively at 5 years, P < 0.0001). Disease-free survival was 3% compared with 21% and 20%, respectively (P = 0.02). In a multivariate analysis, tumor progression on chemotherapy (P < 0.0001), elevated preoperative serum CA 19–9 (P < 0.0001), number of resected metastases (P < 0.001), and the number of lines of chemotherapy (P < 0.04), but not the type of first line treatment, were independently associated with decreased survival. Conclusions:Liver resection is able to offer long-term survival to patients with multiple colorectal metastases provided that the metastatic disease is controlled by chemotherapy prior to surgery. Tumor progression before surgery is associated with a poor outcome, even after potentially curative hepatectomy. Tumor control before surgery is crucial to offer a chance of prolonged remission in patients with multiple metastases.

Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy.

OBJECTIVE The authors discuss the technique and evaluate the results of an aggressive surgical approach in patients with primarily unresectable colorectal liver metastases that were downstaged by chronomodulated chemotherapy. BACKGROUND Resection is the best treatment of colorectal liver metastases, but it may be achieved in only 10% of patients. In the remaining 90%, survival is poor, even after partial response to chemotherapy. Little is known about the results of curative hepatectomy in patients whose metastases are downstaged by chemotherapy. PATIENTS AND METHODS Fifty-three patients with colorectal liver metastases initially unresectable because of ill located (8), large (8), multinodular (24) lesions, or because of extrahepatic disease (13) were downstaged by a systemic chronomodulated chemotherapy associating 5-fluorouracil, folinic acid and Oxaliplatin to the point that operation could be performed. This consisted of a major hepatectomy in 37 patients and a minor resection in 16. Associated procedures (including 5 two-stage hepatectomies and 3 pulmonary resections) were performed in 25 patients. RESULTS There was no operative mortality. Complications occurred in 14 patients. The cumulative 3- and 5-year survival rates were 54% and 40% (according to the type of lesions: ill-located, 75% and 48%; large, 62% and 62%; multinodular, 54% and 40%; extrahepatic, 43% and 14%). Hepatic recurrence (34 patients, 64%) was amenable to repeat surgery in 15 cases. CONCLUSIONS Liver resection may be achieved in some previously unresectable patients with the help of an effective chemotherapy. The benefit in survival seems comparable to that obtained with primary liver resection (40% at 5 years). This therapeutic strategy involves a multimodal approach, including repeat hepatectomies and extrahepatic surgery.

Five-Year Survival Following Hepatic Resection After Neoadjuvant Therapy for Nonresectable Colorectal [Liver] Metastases

Background: Surgical resection is the most effective treatment for colorectal liver metastases but only a minority of patients are candidates for a potentially curative resection. Our experience with neoadjuvant chemotherapy followed by resection and five years survival analysis of the patients treated is presented.Methods: Between February of 1988 and September of 1996, 701 patients with unresectable colorectal liver metastases were treated with neoadjuvant chemotherapy. Four categories of nonresectable disease were defined: large size, ill location, multinodularity, and extrahepatic disease. Liver resection was performed in those patients whose disease became resectable. After resection, the patients were followed up every 3 months. A 5-year survival analysis by the different categories described was performed.Results: Ninety-five patients (13.5%) were found to be resectable on reevaluation and underwent a potentially curative resection. There was no perioperative mortality, and the complication rate was 23%. As of December of 1999, 87 patients have completed 5 years of follow-up. The overall 5-year survival is 35% from the time of resection and 39% from the onset of chemotherapy. Respective 5-year survival rates are 60% for large tumors, 49% for ill-located lesions, 34% for multinodular disease, and 18% for liver metastases with extrahepatic disease. In this latter category, however, a 35% 5-year survival was found when all the patients with extrahepatic disease were analyzed rather than only those for whom extrahepatic disease was the main cause of nonresectability.Conclusions: Neoadjuvant chemotherapy enables liver resection in some patients with initially unresectable colorectal metastases. Long-term survival is similar to that reported for a priori surgical candidates.

Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery

CONTEXT Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy. OBJECTIVE We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible. PATIENTS AND METHODS From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size (> 5 cm), multinodular (> 4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team. RESULTS In 151 patients, the size of liver metastases decreased by > 50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19-28 months), with 28% surviving at five years (20%-35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25-71), with a five-year survival rate of 50% (38-61). CONCLUSION This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.

Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer

BACKGROUND The efficacy of chemotherapy may be affected by circadian rhythms. Therefore, we tested chronomodulated infusion (administered to coincide with relevant circadian rhythms) of oxaliplatin, fluorouracil, and folinic acid compared with a constant-rate infusion method. The combination of three drugs was delivered for 5-day courses with 16-day intervals. METHODS We expected chronotherapy to increase objective response rate by 20% compared with constant-rate infusion. We tested this effect in a randomised multicentre trial involving patients with previously untreated metastases from colorectal cancer who were enrolled at nine institutions in three countries. 93 patients were assigned chronotherapy and 93 were assigned constant-rate infusion via multichannel programmable ambulatory pumps. The trial was interrupted when a significant difference in main outcome was reached. All data were analysed by intention to treat. FINDINGS On enrollment, we found significant imbalances in two characteristics-abdominal gland or bone metastases (constant-rate infusion two patients, chronotherapy ten patients) and relapse from surgically treated metastases (constant-rate infusion seven patients, chronotherapy 22 patients). An objective response was obtained in 47 (51%) of the chronotherapy group, and in 27 (29%) of the constant-rate group (difference 21.5% [95% CI 13.7-31.2], p = 0.003). Chronotherapy reduced five-fold the rate of severe mucosal toxicity (14% vs 76%, p < 0.0001) and halved that of functional impairment from peripheral sensitive neuropathy (16% vs 31%, difference 15.0% [9.5-25.7], p < 0.01). Median time to treatment failure was 6.4 months on chronotherapy and 4.9 months on constant-rate infusion (p = 0.006), and 24% of the patients from the constant-rate infusion group received chronotherapy after failure. With a minimum follow-up of 3 years, median survival times and 3-year survival were similar in both groups (15.9 vs 16.9 months and 22% vs 21%, respectively). INTERPRETATION Chronotherapy was significantly less toxic and more effective than constant-rate infusion. The results support the concept of temporal selectivity of cancer chemotherapy.

A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer

A significant increase in the dose intensity of chemotherapy with fluoropyrimidines and platinum complexes has resulted from selective circadian timing and/or circadian modulation of the infusion rate. The relevance of such chronopharmacologic strategy for improving the outcome of metastatic colorectal cancer was evaluated in an extended Phase II clinical trial involving 93 patients. Cancer 1992; 69:893–899.

Circadian Timing in Cancer Treatments

The circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.