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[Rationalization of adjuvant chemotherapy by induction chemotherapy].

An induction chemotherapy, before any local treatment, allows to precise the chemosensitivity of the primary tumor. These data may help to improve indication and type of a further adjuvant chemotherapy. However there are many biological differences between different sites of the same tumor and along the time, without or after treatment. It is thus impossible to be sure that a chemotherapeutic regimen effective as first treatment on the primary will be equally active on micro-metastases some months later. Many questions in this field will be answered only by controlled studies and careful observations.

Antineoplastic Agents

[Comparative study of 2 chemotherapy induction protocols. Cisplatinum-methotrexate-bleomycin and oncovin-methotrexate-bleomycin].

A prospective randomized study was conducted in 77 patients with stages III and IV epidermoid carcinomas of the buccal cavity, oropharynx, and pharyngolaryngeal regions to compare effects of two induction chemotherapy regimens: cisplatinum, methotrexate, bleomycin, and oncovin, methotrexate, bleomycin. Tumoral response and complications were analyzed as a function of the regimen, the tumoral site, and the stage. Chemotherapy including cisplatinum provided a tumoral response in 58.8 p.cent of stage III pharyngolaryngeal epitheliomas as against 38.4 p.cent with oncovin, methotrexate, bleomycin, but with a higher frequency of complications.

Antineoplastic Combined Chemotherapy Protocols

Adenocarcinoma of the esophagus and gastroesophageal junction. Clinical and pathologic assessment of response to induction chemotherapy.

A preoperative induction chemotherapy regimen consisting of two monthly courses of etoposide, doxorubicin, and cisplatin was given to 13 patients with nonmetastatic adenocarcinoma of the distal esophagus or gastroesophageal junction. Esophageal ultrasound examination was performed both before chemotherapy and again before surgery. Induction chemotherapy was poorly tolerated with 10 of the 13 patients experiencing at least one episode of severe neutropenia. Two of the 13 patients refused the second course of treatment. A symptomatic response to chemotherapy, defined as a reduction in the presenting symptom, was noted in 10 of the 13 patients (77%). Endoscopic improvement occurred in 9 of the 13 patients (69%). Esophageal ultrasound evidence of a reduction in either T or N stage was noted in only 2 of the 13 patients (15%), however, and neither of these responses was confirmed pathologically. Clinical evidence of disease progression was noted in 4 patients during chemotherapy. With a median follow-up of 31 months, the relapse-free and overall survivals are 25% and 31%, respectively. Despite significant toxicity, our chemotherapy regimen would be considered successful if assessed by symptomatic or esophagoscopic improvement. Esophageal ultrasound, careful pathologic staging, and our disappointing survival rates, however, suggest limited, if any, value for this approach.

Adenocarcinoma

Azacitidine-Venetoclax or Induction Chemotherapy for Acute Myeloid Leukemia.

BACKGROUND: Induction chemotherapy has long been a key component of curative therapy for fit patients with acute myeloid leukemia (AML), despite its frequently severe side effects and substantial health care utilization. For patients who are ineligible for induction chemotherapy, hypomethylating therapy plus venetoclax is the standard treatment owing to its efficacy and side-effect profile. METHODS: In this multicenter, phase 2 trial, we randomly assigned, in a 1:1 ratio, previously untreated adults with AML who were eligible for induction chemotherapy to receive either azacitidine plus venetoclax or induction chemotherapy. Patients with core binding factor fusions, mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3), or mutations in the gene encoding nucleophosmin-1 (NPM1; unless the patient was ≥60 years of age) were excluded. The primary end point was event-free survival. RESULTS: A total of 172 patients underwent randomization, with 86 patients assigned to each group. The median age of the patients was 64 years. A total of 72% of the patients had adverse-risk disease according to the European LeukemiaNet 2022 classification. At a median follow-up of 21.9 months, the median event-free survival was 14.5 months (95% confidence interval [CI], 10.4 to 24.4) in the azacitidine-venetoclax group, as compared with 6.2 months (95% CI, 4.1 to 10.1) in the induction chemotherapy group, corresponding to a hazard ratio for event or death of 0.57 (95% CI, 0.39 to 0.84; P = 0.002 by the stratified log-rank test). Infection of grade 3 or higher occurred in 28% of the patients (95% CI, 19 to 39) receiving azacitidine-venetoclax and in 41% of those (95% CI, 30 to 52) receiving induction chemotherapy; hemorrhage of grade 3 or higher occurred in 2% (95% CI, 0.3 to 8) and 12% (95% CI, 6 to 20), respectively. CONCLUSIONS: In this phase 2, randomized trial, azacitidine-venetoclax therapy led to significantly longer event-free survival than induction chemotherapy among induction-eligible patients with AML. (Funded by AbbVie and others; PARADIGM ClinicalTrials.gov number, NCT04801797.).

Adult

[False-positive elevation of alpha-fetoprotein during induction chemotherapy in patients with testicular cancer].

During induction chemotherapy, we experienced the false elevation of the tumor marker alpha-fetoprotein (AFP) in some disseminated testicular cancer patients. We discussed the possibility of the false elevation of the tumor marker AFP and evaluated the relationship between AFP and the markers of liver damage (GOT, GPT, LDH, etc.), the elevation of which were caused by induction chemotherapy of the VAB-6 regimen. We evaluated each variable of the eleven patients with disseminated testicular cancer who had been treated in our hospital between 1979 and 1984. The elevation of each marker of liver damage was induced by the VAB-6 regimen, immediately after the end of each induction chemotherapy but not by other induction chemotherapy regimens. A statistical study confirmed that there was a close correlation between the elevation of AFP and of the markers of liver damage, that is induced frequently by the induction chemotherapy of VAB-6 regimen.

Alanine Transaminase

Chemotherapy induction, consolidation radiotherapy and maintenance alternating chemotherapy in small cell carcinoma of the lung.

Forty-four evaluable, previously untreated patients with small cell lung cancer were treated with two courses of induction chemotherapy consisting of POCC. Subsequently, all limited-disease patients and extensive-disease patients in CR received 4,000 to 5,000 cGy irradiation over 4 to 5 weeks (or the equivalent) to the primary tumor, mediastinum and supraclavicular areas and 3,000 cGy prophylactic cranial irradiation during 2 weeks. All patients received maintenance chemotherapy for a full year after CR or until disease progression. Eleven continued POCC while 33 received vinblastine, cyclophosphamide, and either adriamycin or methotrexate on an alternating schedule (VCMA). For the 20 limited-disease patients, the CR rate was 70% and the PR rate was 20%. Median survival was 22 months, local control was 62%, 2-year DFS was 35% and 3-year DFS was 20%. Of the 24 extensive-disease patients only 21% achieved CR and 54% achieved PR. Median survival was only 8 months and there were no disease-free survivors at 2 years. Toxicity was moderate with nausea and vomiting in all patients, and there were two deaths from myelosuppression in the group that received POCC maintenance therapy; there were no drug-related deaths in the VCMA group. Since these results are similar to those obtained with simpler regimes, we cannot recommend our regimen for the treatment of small cell lung cancer. The optimal treatment for this disease has yet to be elucidated.

Adult

Induction chemotherapy in advanced head and neck cancer.

Induction chemotherapy, followed by definitive treatment, was performed in patients with advanced squamous-cell carcinoma of the head and neck. In this study, carried out between 1984 and 1991, testing the effectiveness of multimodality therapy in patients with previously untreated advanced (stage III and IV) squamous-cell carcinoma of the pharynx, patients received two different induction chemotherapy regimens: cisplatin, vincristine (Oncovin) plus peplomycin (COP), and cisplatin plus continuous 120-hr 5-fluorouracil (5-FU) infusion (CF) for two courses. Overall response rates (complete response plus partial response) to each of the two induction chemotherapy regimens were high: 76 and 82%, respectively. Superior complete response rate in the group receiving CF therapy was 16% versus 10% for COP therapy. Responders to induction chemotherapy had significantly better survival compared with non-responders. The toxicity of these two regimens was tolerable and manageable. It is indispensable to develop the more efficacious chemotherapy regimen with the potential to induce complete disappearance of tumors in patients with advanced head and neck carcinomas.

Adolescent

The value of immunohistochemical detection of P-glycoprotein in breast cancer before and after induction chemotherapy.

We have studied the patterns of P-glycoprotein expression before and after 3 cycles of induction chemotherapy (5-fluorouracil, adriamycin and cyclophosphamide) using immunohistochemically stained paraffin-embedded specimen of 28 patients with locally advanced breast cancer. The frequency of P-glycoprotein expression in untreated breast cancer turned out to be very low: only one out of 28 untreated, biopsy specimen at the time of diagnosis was positive. The frequency of P-glycoprotein expression was markedly increased from 9.1% before chemotherapy to 63.6% after induction chemotherapy (p = 0.006). After 3 cycles of induction chemotherapy, 25 patients had obtained clinical response to chemotherapy (4, CR; 21, PR). Eleven out of 25 tumors (44%) showing clinical response and all three tumors (100%) with minimal response have expressed P-glycoprotein. One out of 6 patients (16.7%) with microscopic residual tumor seen in mastectomy specimen expressed P-glycoprotein, whereas 13 of 22 patients (59.1%) with gross residual tumor showed the presence of P-glycoprotein (p = 0.08). The frequency of intrinsic P-glycoprotein expression in untreated breast cancer was quite low, but approximately half of the patients do acquire P-glycoprotein expression during the cycles of induction chemotherapy. Therefore, the results suggest that the immunohistochemical detection of P-glycoprotein on residual tumor cells after induction chemotherapy can predict acquired drug resistance in breast cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem

Randomized trials of induction chemotherapy. A critical review.

There are nine prospective randomized trials comparing induction chemotherapy with standard therapy published in either final form or as preliminary abstract reports. Only one of the six randomized trials critiqued was designed to account for all known prognostic factors, utilized an effective chemotherapy regimen, and had excellent compliance such that the numbers of patients completing the protocol were adequate to provide a valid statistical interpretation of the data. This was the VA cooperative group trial to preserve the larynx. Although this trial did not show a difference in survival between surgically treated patients and those who received induction chemotherapy, the larynx was preserved in two thirds of patients. The results of the other published trials cannot be considered conclusive owing to the flaws in design and interpretation noted in this review. These trials do confirm the feasibility of administering chemotherapy prior to surgery and RT and do confirm the prognostic importance of various factors suggested by the results of single institution trials. Induction chemotherapy has been tested for almost two decades. During this time we have learned the importance of treating intensively to obtain a high complete response rate. At one primary site, the larynx, it has been shown that 64% of patients can be rendered histologically disease-free after three courses of cisplatin and 5-FU. The results of three randomized trials indicate that induction chemotherapy can change the expected pattern of recurrence by decreasing the rate of distant metastases. This early systemic treatment of micrometastases may also reduce the mutation rate theorized for the development of drug resistance. The goals of future randomized trials should include the use of dose-intensive multidrug regimens to increase complete response rates, improve locoregional control, and decrease distant metastases. Induction chemotherapy trials with cisplatin and 5-FU should explore organ preservation at sites other than the larynx where significant functional impairment results from standard surgical approaches. Randomized trials must be carefully designed and rigorously conducted to ensure that the results and conclusions are valid. New regimens, perhaps incorporating growth factors, need to be identified and tested in this group of patients. Finally, improvement in survival must remain a primary goal of multimodality therapy for advanced head and neck cancer.

Antineoplastic Combined Chemotherapy Protocols

Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy.

The use of interferon for the induction treatment of multiple myeloma has been shown to be effective in about 20 percent of patients. We studied its effects on long-term survival when it was used for maintenance treatment. Between April 1985 and May 1988, 101 patients with symptomatic multiple myeloma who had had a substantial objective response or a lesser objective response with disappearance of symptoms ("disease stabilization") after 12 courses of induction chemotherapy were randomly assigned to receive recombinant interferon alfa-2b as maintenance therapy (n = 50) or to receive no treatment (n = 51). As of December 1989, 66 of the 101 patients have relapsed (25 given interferon and 41 not treated). The median duration of response (from the time of randomization) was 26 months in the patients given interferon and 14 months in the untreated patients (P = 0.0002). A total of 37 patients have died (14 given interferon and 23 not treated). The median duration of survival (from randomization) was 52 months in the interferon group and 39 months in the control group (P = 0.0526). Among the patients who had had a substantial objective response to induction chemotherapy, the difference in survival time was statistically significant (P = 0.03526). Interferon had to be stopped because of toxic effects in 3 of 12 patients initially treated with 10 MU (megaunits) per square meter of body-surface area. After the dose was reduced to 3 MU per square meter, the only toxic effect was a mild influenza-like syndrome lasting two to three weeks. We conclude that maintenance treatment with interferon prolongs response and survival in patients with multiple myeloma who have responded to conventional induction chemotherapy.

Antineoplastic Combined Chemotherapy Protocols

Radiation therapy for chest recurrences following induction chemotherapy in small cell lung cancer.

Once small cell lung cancer fails induction chemotherapy, second line drugs are usually ineffective, accounting for mostly partial responses in the order of 0-20% and a median survival of 6-10 weeks. A review of patients with relapsed small cell lung cancer was carried out at the University of Maryland. Of 51 such patients, 44 received thoracic irradiation at the time of relapse. Excluding 8 patients who received insufficient treatment, the series consists of 36 patients (27 with limited and 9 with extensive disease) and represents the largest experience with relapsed small cell lung cancer subjected to radiation alone. Total radiation doses were 60 Gy in 11, 45-55 Gy in 14, and 38-42 Gy in the remaining 11 patients. No second line chemotherapy was given simultaneously with radiation at time of relapse and it was only given subsequently during the course of the disease to four patients. Responses to radiation were seen in 28 (77%) with 9 (25%) complete and 19 (52%) partial. The median survival was 16-40 weeks varying with disease extent, response, and total dose. Subsequent failures occurred in chest (34%) and distant sites (66%). A dose-response curve was attempted; the higher doses achieved as much as 75% local control. A poor response to induction chemotherapy did not predict a poor radiation response at time of relapse. Nearly 2/3 of patients who had not responded to induction chemotherapy responded to radiation at the time of relapse. The post-recurrence survival after radiation therapy was as long as or longer than the recurrence-free interval after induction chemotherapy, and this clearly demonstrates the value of radiation in achieving excellent palliation and good quality of life in these patients. Thoracic irradiation is recommended as a therapeutic alternative for locally recurrent small cell lung cancer after induction chemotherapy.

Adult

[Inductive chemotherapy of bladder cancer. A critical evaluation].

Cisplatin-based inductive chemotherapy can induce remissions of locally invasive bladder cancer; these can be observed after two cycles of chemotherapy. Non-transitional cell carcinomas of the bladder do not respond to this therapy. The toxicity of inductive chemotherapy is acceptable. The clinical staging after inductive or neo-adjuvant chemotherapy does not correlate with the pathological staging after cystectomy. This discrepancy indicates that bladder preservation after inductive chemotherapy will not be possible until the diagnostic methods are improved enough to correlate exactly with the pathological findings. Many questions remain open with respect to this form of treatment of locally advanced bladder cancer. This is why patients should only be treated with inductive or neo-adjuvant chemotherapy within the context of controlled prospective clinical trials. On the basis of our current knowledge inductive chemotherapy cannot be considered as a definitive form of treatment for locally invasive bladder tumours.

Antineoplastic Combined Chemotherapy Protocols

Advanced primary breast cancer: assessment at mammography of response to induction chemotherapy.

The response to induction chemotherapy is an important prognostic factor in patients with nonmetastatic, locally advanced breast carcinomas. Assessment at mammography of the response of 60 breast cancers in 59 women was performed between 1974 and 1986. Responses were excellent in 13 tumors, moderate in 34, and poor in 13 (excellent moderate = 78%). Assessment of response of discrete masses in a fatty breast was easiest; assessment of response of tumor areas that were poorly defined-such as a focal area of architectural distortion or mass in dense breast parenchyma-was more difficult. Of 17 patients with excellent pathologic responses-that is, minimal or no residual tumor-15 (88%) had complete responses (no residual tumor) as determined with mammography, physical examination, or both. Mammography provides information complementary to physical examination and is essential in the accurate assessment of the response to chemotherapy of locally advanced breast cancer.

Antineoplastic Combined Chemotherapy Protocols

[Experience in combination therapy with amikacin and cephapirin for infections complicated with acute leukemia during induction chemotherapy].

We treated infections accompanied with induction chemotherapy in 9 patients with acute leukemia by the combination of amikacin (AMK) and cephapirin (CEPR). The result was that 1 case was markedly effective, 2 cases were effective, 3 cases were marginally effective, 2 cases showed no effect and 1 case who underwent prophylactic medication had no infection. We recognized no adverse effects by AMK or CEPR. We concluded that the combination of AMK and CEPR was useful as first choice to the treatment of infections during induction chemotherapy of acute leukemia.

Acute Disease

Induction chemotherapy for advanced head and neck cancers: a literature review.

Induction chemotherapy before surgery and/or radiotherapy for previously untreated head and neck carcinoma results in greater response rates than chemotherapy for recurrent head and neck carcinomas. Its theoretical advantages are presented. Most studies using induction chemotherapy are nonrandomized, uncontrolled pilot efforts. Multiple-drug regimens result in greater response rates than single agents, and multiple courses result in greater response rates than single courses. Prognostic factors are discussed. Toxicities are tolerable, except for several reported regimens combining cisplatin, bleomycin, and methotrexate. Induction chemotherapy for head and neck cancer is promising and needs further studies with controlled, randomized trials with long-term follow-up.

Antineoplastic Agents

[Advanced carcinoma of the oropharynx: the value of induction chemotherapy before locoregional treatment. A retrospective study of 138 cases].

Induction chemotherapy in oropharynx carcinomas had demonstrated overall response rates of 80%, but no overall survival benefit have been reported. In order to determine the value of induction chemotherapy for these patients, we conducted a retrospective study: 86 patients were treated with chemotherapy (CT) and RT (group 1) and 52 patients were treated by radiotherapy (RT) alone (group 2). All patients had T3 or T4 tumors. CT used was cisplatinum based associated with bleomycin and vincristine or vindesine and actually with 5 fluoro-uracil. Objective response to the CT was observed for 34% patients. Five years actuarial survival rate was 18% for group 1 and 17% for group 2. Patterns of failure were identical in the 2 groups. A difference was observed only for patients with N3 nodes (24% 5 years survival rate in group 1 versus 6% in group 2) (P = 0.05). According to the histologic differentiation, the tumor site or the type of CT, no difference was observed. We concluded that this study failed to demonstrate an advantage for induction chemotherapy in advanced oropharynx carcinoma excepted for patients with N3 nodes.

Actuarial Analysis

Unexpected hepatotoxicity after priming and treatment with molgramostim (rhGM-CSF) in acute myeloid leukemia during induction chemotherapy.

The effect of supplementing induction chemotherapy with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was studied in a randomized trial of 18 patients with acute myeloid leukemia (AML). Ten patients received rhGM-CSF, starting on day one to three before chemotherapy and continued for a maximum of 21 days after the start of induction treatment. Unexpected adverse effects of rhGM-CSF and chemotherapy combination included a transient decline in plasma coagulation factors II, VII, and X (5 of 5 patients) and an increased transcapillary escape rate of albumin (in 3 of 3 patients tested). The decline in coagulation factors was prevented in subsequent patients by prophylactic treatment with vitamin K. Although the small number of patients studied may not allow a definite conclusion, caution with regard to liver function should be shown in combining rhGM-CSF with intensive chemotherapy.

Adult