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Biomedical subjects

H Bleiberg

Publications and source records attributed to H Bleiberg.

At least 37 records · Page 2Linked to original sources
PubMed2000

Prognostic factors for tumour response, progression-free survival and toxicity in metastatic colorectal cancer patients given irinotecan (CPT-11) as second-line chemotherapy after 5FU failure. CPT-11 F205, F220, F221 and V222 study groups.

Our purpose was to determine, in patients with metastatic colorectal carcinoma treated with irinotecan single-agent after 5-FU failure, the most significant predictive parameters for tumour response, progression-free survival and toxicity. Between October 1992 and April 1995, 455 patients with 5-FU resistant metastatic colorectal carcinoma entered four consecutive phase II trials. The first two studies assessed tumour response, the other two were randomized studies which assessed the efficacy of racecadotril to prevent irinotecan-induced diarrhoea. Due to homogeneous main eligibility criterias, data from those studies could be pooled for statistical analysis. Potential clinical and biological predictive factors (PF) for toxicity, tumour growth control, e.g. response or stabilization and progression-free survival (PFS), were studied in multivariate analysis. 363 patients were evaluable for response, 432 were evaluable for PFS, 368 for neutropenia and 416 for delayed diarrhoea, respectively. Normal baseline haemoglobin level (Hb), time since diagnosis of colorectal carcinoma, grade 3 or 4 neutropenia or diarrhoea at first cycle and a low number of organs involved were the most PF for tumour growth control (P<0.05). Significant prognostic variables for PFS were WHO Performance Status, liver and lymph-node involvement, time since diagnosis, age and CEA value (P < or =0.02). Six groups of patients based on the number of unfavourable prognostic factors are presented. Baseline bilirubin, haemoglobin level, number of organs involved and time from diagnosis were PF for neutropenia; PS, serum creatinine, leukocyte count, time from 5-FU progression and prior abdominopelvic irradiation were PF for delayed diarrhoea (P< or =0.05). These PF should help clinicians to anticipate for a given patient the probability to observe a response/stabilization or a toxicity. These results should also be prospectively confirmed in ongoing or future trials using irinotecan, both as a single agent and in combination with other drugs.

Adult↗
PubMed2000

A new class of antiemetics: the NK-1 receptor antagonists.

Emesis is one of the most unpleasant and debilitating side effects of anticancer chemotherapy. In acute emesis (vomiting occurring 0-24 hours after chemotherapy administration), the 5-HT3 receptor antagonists and corticosteroids are highly effective, with few significant side effects, and can safely be combined. Delayed emesis (vomiting occurring >24 hours after chemotherapy administration), however, is both not well understood and less well controlled. Studies have yielded conflicting results concerning the use of 5-HT3 receptor antagonists alone in delayed emesis. The data of NK-1 receptor antagonists in the control of acute emesis, although promising, need confirmation in a properly designed study.

Animals↗
PubMed2000

Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group.

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

Adenocarcinoma↗
PubMed2000

A phase I and pharmacokinetic study of docetaxel administered in combination with continuous intravenous infusion of 5-fluorouracil in patients with advanced solid tumors.

Encouraged by preclinical synergism between docetaxel and 5-fluorouracil (5FU), we conducted a Phase I study of docetaxel in combination with continuous i.v. infusion of 5FU in patients with advanced solid tumors to determine the maximum tolerated dose, the recommended dose for Phase II studies, and the safety and pharmacokinetic profiles of this combination. Forty-two patients with advanced solid tumors, most of whom had been previously treated, received docetaxel on day 1 as a 1-h i.v. infusion, immediately followed by a 5-day continuous i.v. infusion of 5FU, every 3 weeks without hematopoietic growth factor support. All patients were premedicated with methylprednisolone. Dose levels of docetaxel/SFU studied were (daily dose, in mg/m2) 60/300, 75/300, 75/500, 75/750, 85/750, 85/1000, and 75/1000. Forty-one patients were assessable for toxicity. The maximum tolerated dose determined during the first cycle was 1000 mg/m2/day for 5 days of 5FU with either 75 or 85 mg/m2 docetaxel. Dose-limiting toxicities at these dose levels were reversible secretory diarrhea (4 of 12 evaluable patients), stomatitis (2 patients), and febrile neutropenia (2 patients). Overall, grade 3/4 neutropenia and febrile neutropenia were seen in 63.4% and 9.8% of the patients, respectively. Four patients experienced grade 3/4 infection, which led to toxic death in one of them. There were five early deaths: (a) one was clearly treatment related; (b) two others were possibly treatment related or remotely treatment related; and (c) two deaths were not related to the study drugs. Partial responses were documented in 5 of 39 evaluable patients. Pharmacokinetic results of both drugs were consistent with those from single-agent studies. The recommended dose of this combination, which showed acceptable toxicity and antitumoral activity at various dose levels, is 85 mg/m2 docetaxel given as a 1-h i.v. infusion on day 1 immediately followed by a 5-day continuous i.v. infusion of 5FU (750 mg/m2/day). This study has been extended by adding cisplatin on day 1 of the combination of docetaxel and 5FU.

Adult↗
PubMed1999

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU).

The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.

Adult↗
PubMed1999

CPT-11 in gastrointestinal cancer.

Colorectal, gastric and pancreatic cancers are major health problems worldwide. Although surgery is a curative option in 50% of patients with colorectal cancer, it is much less effective in gastric cancer (< 20% of patients) and virtually ineffective in pancreatic cancer. These three cancer types also respond poorly to chemotherapy. CPT-11 (irinotecan), a novel cytotoxic drug, is now available in many countries as a single agent for second-line therapy in metastatic colorectal cancer. The response rate in the pivotal European study of metastatic colorectal cancer patients was 14%, with a median duration of response of 8.5 months. There was also a high rate of disease stabilisation (44%), with a median duration of 4.8 months. Median survival time was 10.4 months. The dose-limiting toxicities (DLT) for CPT-11 are delayed diarrhoea and neutropenia, both of which are schedule dependent and non-cumulative. These encouraging data in second-line therapy support the further study of CPT-11 as first-line therapy for colorectal cancer in combination with other agents. Four Japanese trials of CPT-11 as first- and/or second-line single-agent therapy for advanced gastric cancer report response rates of 18-43%. The median durations for response and survival time in the late phase II trial were 2.3 months and 5.8 months, respectively. These results are in the range of those reported for sequential high-dose methotrexate and 5-fluorouracil (5-FU)/doxorubicin (FAMTX), etoposide/leucovorin/5-FU (ELF) or cisplatin/5-FU therapy in gastric cancer. Data are currently available from five phase II studies of CPT-11 in advanced pancreatic cancer: four Japanese and one European. The response rates ranged from 9 to 19%. The median duration of survival for all treated patients in the European study was 5.2 months. CPT-11 in combination with 5-FU is currently being investigated in Japan, the U.S.A. and Europe in patients with gastrointestinal tumours. CPT-11 is also being evaluated in combination with each of the following agents: oxaliplatin, docetaxel, raltitrexed, etoposide and mitomycin C. Japanese studies of CPT-11 plus cisplatin in patients with gastric cancer have produced response rates of 48-59%. These encouraging data highlight the potential for CPT-11 in combination therapy for gastrointestinal tumours.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Oxaliplatin added to 5-fluorouracil-based therapy (5-FU +/- FA) in the treatment of 5-FU-pretreated patients with advanced colorectal carcinoma (ACRC): results from the European compassionate-use program.

PURPOSE: To provide evidence for the therapeutic efficacy of oxaliplatin (Eloxatin) when given as a 2-6-hour i.v. infusion, alone or in combination with 5-fluorouracil/folinic acid (5-FU +/- FA) in patients with advanced colorectal carcinoma (ACRC) who have failed 5-FU-based therapy. To confirm the safety of the drug and its combination in an extended-access context. PATIENTS AND METHODS: Prescribing physicians were supplied oxaliplatin on a nominative compassionate-use basis, after obtaining informed consent. Europe-wide, 206 ACRC patients in 44 centers received 1168 cycles of chemotherapy with oxaliplatin (80-100 mg/m2 q 2 weeks or 100-135 mg/m2 q 3 weeks) delivered as a short (2-6 hours) i.v. infusion, 177 of them (1026 cycles) receiving oxaliplatin + 5-FU +/- FA. RESULTS: Oxaliplatin added to the 5-FU +/- FA regimens of 111 verified 5-FU-refractory patients (imaging and/or clinical proof of progression under prior 5-FU-based regimen), elicited objective responses in 25 of 98 evaluable patients, (ORR: 25.5%, 95% confidence interval (95% CI: 17-35). The median time to progression was 4.1 months (95% CI: 3.3-5.0) and the median overall survival was 9.6 months (95% CI: 8.2-10.9). Differences in the toxicity profile of the oxaliplatin + 5-FU +/- FA combination appear related to administration modality, dose and schedule of the 5-FU-based regimen. CONCLUSIONS: The addition of oxaliplatin (2-6-hour i.v. infusion) to 5-FU +/- FA regimens is active in ACRC patients with clinical resistance to fluoropyrimidines. The therapeutic index of oxaliplatin + 5-FU +/- FA combinations administered as salvage therapy compares favorably with those reported in recent phase II-III trials involving other new agents or combinations active in 5-FU-refractory ACRC patients.

Adult↗
PubMed1999

Marimastat in recurrent colorectal cancer: exploratory evaluation of biological activity by measurement of carcinoembryonic antigen.

Marimastat is a specific inhibitor of matrix metalloproteinases that has been shown to be effective in cancer models. A pilot, escalating-dose study of oral marimastat was performed in patients with recurrent colorectal cancer, in whom evaluation of serological response was made by measurement of carcinoembryonic antigen (CEA) levels. The study assessed the safety and tolerability of 4 weeks administration of marimastat, and determined a dose range producing detectable serological effects. Patients were recruited with a serum CEA level greater than 5 ng ml(-1), and rising by more than 25% over a 4-week screening period. Patients were treated for 28 days and entered into a continuation protocol if a serological response or clinical benefit was observed. Pharmacokinetic and safety data determined that groups of patients were recruited sequentially at 25 mg and 50 mg twice daily, and, thereafter, 10 mg twice daily, 10 mg once daily, 5 mg once daily and 20 mg once daily. A biological effect (BE) was defined as a CEA value on day 28 no greater than on day 0; a partial biological effect (PBE) was defined as a rise in CEA over the 28-day treatment period of less than 25%. Of 70 patients recruited, 63 completed the 28-day treatment period, and 55 were eligible for cancer antigen analysis. Examination of the dose-effect relationships provides evidence for a causal relationship between marimastat and biological effects: the proportion of patients with BE or PBE was higher with twice daily dosing (16 out of 25, 64%) than with once daily dosing (11 out of 30, 37%) (P = 0.043, chi2 test). Furthermore, the median rates of rise of CEA fell markedly during treatment compared with the screening period for patients receiving twice daily marimastat (P<0.0001), but not for patients receiving marimastat once daily (P = 0.25). Musculoskeletal adverse events emerged as the principal drug-related toxicity of marimastat, occurring in a dose- and time-dependent fashion. It was concluded that marimastat was associated with dose-dependent biological effects in cancer patients. The occurrence of musculoskeletal side-effects define 25 mg twice daily as the upper limit of the dose range for continuous use in further studies. Therefore, a dose range of 20 mg once daily to 25 mg twice daily seems appropriate for further studies, which should aim to demonstrate the efficacy of the drug in terms of conventional clinical end points and describe the long-term tolerability of this novel agent.

Administration, Oral↗
PubMed1998

Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer.

BACKGROUND: In phase II trials, irinotecan is active in patients with advanced colorectal cancer, but the survival and clinical benefit of irinotecan compared with second-line fluorouracil by continuous infusion is not known. METHODS: 267 patients who had failed to respond to first-line fluorouracil, or whose disease had progressed after treatment with first-line fluorouracil were randomly allocated irinotecan 300-350 mg/m2 infused once every 3 weeks or fluorouracil by continuous infusion. Treatment was given until disease progression, unacceptable toxic effects, or the patient refused to continue treatment. The primary endpoint was survival, while progression-free survival, response rate, symptom-free survival, adverse events, and quality of life (QoL) were secondary endpoints. FINDINGS: 133 patients were randomly allocated irinotecan and 134 were allocated fluorouracil by continuous infusion. Patients treated with irinotecan lived for significantly longer than patients on fluorouracil (p=0.035). Survival at 1 year was increased from 32% in the fluorouracil group to 45% in the irinotecan group. Median survival was 10.8 months in the irinotecan group and 8.5 months in the fluorouracil group. Median progression-free survival was longer with irinotecan (4.2 vs 2.9 months for irinotecan vs fluorouracil, respectively; p=0.030). The median pain-free survival was 10.3 months and 8.5 months (p=0.06) for irinotecan and fluorouracil, respectively. Both treatments were equally well tolerated. QoL was similar in both groups. INTERPRETATION: Compared with fluorouracil by continuous infusion second-line irinotecan significantly improved survival in patients with advanced colorectal cancer.

Adenocarcinoma↗
PubMed1998

Oxaliplatin (L-OHP): a new reality in colorectal cancer.

Oxaliplatin (trans-/-diaminocyclohexane oxalatoplatinum; L-OHP) is a new platinum derivative for the treatment of advanced colorectal cancer. Preclinical data have shown that oxaliplatin is active in a wide range of human and murine tumour cell lines, and has been found to be non-cross-resistant with cisplatin in various cisplatin-resistant cell lines and tumours. Oxaliplatin in combination with 5-fluorouracil (5-FU) leads to synergistic antiproliferative activity both in vivo and in vitro. Clinical data have shown that oxaliplatin is active and well tolerated both as monotherapy and in combination with 5-FU/folinic acid in first- or second-line treatment of patients with metastatic colorectal cancer. Oxaliplatin has a very good safety profile, and studies have confirmed that peripheral sensory neuropathy is related to the cumulative dose of oxaliplatin administered and that this neuropathy is generally reversible after discontinuation of treatment. High response rates and prolonged survival have been achieved in metastatic colorectal cancer patients, even after 5-FU failure.

Antineoplastic Agents↗
PubMed1998

Continuing the fight against advanced colorectal cancer: new and future treatment options.

The benefit of chemotherapy in the treatment of advanced colorectal cancer has now been clearly demonstrated with several studies reporting advantages in terms of overall survival, quality of life and effective palliation following chemotherapy plus supportive care in comparison to supportive care alone. However, the survival benefit achieved with the current 5-fluorouracil (5-FU)-based regimens is modest and thus investigations are ongoing to identify more effective agents with novel mechanisms of action. The three new agents likely to have the greatest impact in the near future are the thymidylate synthase inhibitor ZD1694 (Tomudex), the topoisomerase I inhibitor irinotecan (Campto) and the new platinum compound, oxaliplatin (L-OHP). Promising response rates of 26 and 20% have been reported with ZD1694 in patients with advanced colorectal cancer in phase II and III studies, respectively. In a European phase II study, irinotecan has achieved response rates of 19% in chemotherapy-naïve patients and 18% in pretreated patients with advanced disease. Oxaliplatin has mainly been investigated in combination with continuous infusion 5-FU, with response rates of 29-58%. Other agents currently in development include monoclonal antibodies (e.g. 17-1A and MN-14), protein synthesis inhibitors (e.g. RA 700) and angiogenesis inhibitors (e.g. PF 4).

Antibodies, Monoclonal↗
PubMed1998

Oxaliplatin combined to 5-fluorouracil and folinic acid: an effective therapy in patients with advanced colorectal cancer.

Patients with colorectal carcinoma progressing after a 5-fluorouracil (5-FU)-containing regimen were eligible. One treatment cycle consisted of repeated administrations of 5-FU combined to folinic acid for six times and to oxaliplatin for three times over 50 days. 5-FU was given at the dose of 2.6 g/m2 as a continuous infusion over 24 h on days 1, 8, 22, 29 and 43 preceded by i.v. folinic acid (FA) at a dose of 500 mg/m2 over 1 h. Oxaliplatin was given 1 h after 5-FU at the dose of 130 mg/m2 over a 2 h infusion on days 1, 22 and 43. A total of 37 patients were treated according to this schedule. The rates of objective responses after the first and second treatment cycles were 28 and 17%, respectively, with rates of tumor growth control, i.e. including the stabilizations, of 55 and 28%. The median duration of response was 10 months and the median duration of stabilizations was 6 months. The median survival time from initiation of oxaliplatin-containing therapy is 10 months (2-28+). The median survival time from the diagnosis of metastatic disease is 24 months (2-40+). The main toxicities were leucopenia, diarrhea, fatigue and paresthesias. The combination of 5-FU/FA/oxaliplatin was well tolerated and appears as a meaningful therapy after failure of a previous 5-FU-containing treatment.

Adult↗
PubMed1998

Tropisetron in the prevention of acute and delayed nausea and vomiting over six courses of emetogenic chemotherapy.

Tropisetron (Navoban") suppresses nausea and vomiting induced by cancer chemotherapy by antagonizing central and peripheral 5-HT3 receptors. In this open-label study, tropisetron was evaluated in 873 patients who were either refractory to antiemetic treatment during previous chemotherapy or at high risk of emesis as a result of current chemotherapy. The most commonly used agents alone or in combination were cyclophosphamide (35%), fluorouracil (30%), carboplatin (24%) and cisplatin (21%). The primary tumors were breast cancer (27%), lung cancer (16%), gynecological cancers (12%) and lymphoma (9%). Tropisetron was administered as a 15 min infusion prior to chemotherapy and an additional oral 5 mg dose was taken by 80% of the patients on subsequent days. During course 1, complete response to tropisetron was obtained in 64% of patients on day 1, 54% on day 2, 63% on day 3, 71% on day 4 and 77% on day 5. Very similar response rates were found for the six chemotherapy courses. There were few failures after complete and partial response, at maximum 3 and 15%, respectively. Moreover, 24-38% of those with partial response and 7-29% of those with failure could achieve a complete response during the following cycle. The treatment was well tolerated, the most frequently reported adverse events being constipation (3.7%) and headache (2.6%).

Acute Disease↗
PubMed1998

Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial.

PURPOSE: The aim of the study was to evaluate the efficacy of antiandrogen therapy on overall survival and response in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 244 patients with unresectable HCC were included in this multicentric double-blind trial. According to a two-by-two factorial design, patients were randomly assigned to receive one of the following treatments: pure antiandrogen plus placebo (A+P group, 60 patients); luteinizing hormone-releasing hormone (LHRH) agonist plus placebo (LHRH+P group, 62 patients); pure antiandrogen plus LHRH agonist (A+LHRH group, 62 patients); or placebo plus placebo (P+P group, 60 patients). Pure antiandrogen consisted of Anandron (Roussel-Uclaf Laboratory, Romainville, France) administered orally (300 mg daily for 1 month, then 150 mg daily). LHRH consisted of goseriline acetate (3.6 mg) or triptoreline (3.75 mg) administered monthly by subcutaneous injection. Treatment was given until death. Response was evaluated every 8 weeks according to World Health Organization (WHO) criteria. RESULTS: Six patients were considered ineligible. One patient had a complete response (A+P arm) and three had a partial response (two in the LHRH+P arm and one in the A+LHRH arm). An overall log-rank test did not demonstrate any significant difference in survival among the four arms. Taking the factorial design into account, comparison of survival showed no significant difference between Anandron-containing regimens and others, or between LHRH-containing regimens and others. No serious side effects occurred for any regimen. CONCLUSION: This controlled study shows clearly the lack of efficacy of androgen treatment in unresectable HCC.

Androgen Antagonists↗
PubMed1998

Oxaliplatin plus 5-fluorouracil: clinical experience in patients with advanced colorectal cancer.

Oxaliplatin was first introduced to the clinical setting as a combination therapy with 5-fluorouracil/folinic acid (5-FU/FA) in an attempt to improve the response rate obtained with 5-FU/FA against colorectal cancer. To dispel the impression that the improvements observed in objective response were somehow due to the chronomodulated regimen used, oxaliplatin was also tested in constant-rate infusion schedules and in regimens using bolus administration followed by 5-FU/FA infusion. The most current data comparing chronomodulated infusion and constant-rate infusion in untreated patients show a lower objective response rate for the latter (51 % v 29%), but comparable median progression-free survival and median survival (9.8 months and 15.9 months v 7.9 months and 16.9 months, respectively). The first trials using constant-rate therapy included pretreated patients with metastatic colorectal cancer, most of whom were refractory to 5-FU. In these studies, conducted using two different regimens or variations of them, objective response rates < or = 46% were obtained. The addition of oxaliplatin to 5-FU/FA in controlled, randomized phase III trials has resulted in a twofold or greater increase in objective response rate and a 3-month gain in time to progression, with survival differences blurred by crossover effect. Compassionate-use programs that included many heavily pretreated relapsing patients reported response rates of 15% to 25%, confirming the value of the oxaliplatin-5-FU/FA regimen and suggesting that oxaliplatin may act synergistically with 5-FU.

Antineoplastic Combined Chemotherapy Protocols↗