Different outcomes for relapsed versus refractory neuroblastoma after therapy with 131I-metaiodobenzylguanidine (131I-MIBG)

Background¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) is a targeted radiopharmaceutical with significant activity in high-risk relapsed and chemotherapy-refractory neuroblastoma. Our primary aim was to determine if there are differences in response rates to ¹³¹I-MIBG between patients with relapsed and treatment-refractory neuroblastoma.MethodsThis was a retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with ¹³¹I-MIBG at UCSF between 1996 and 2014. Results were obtained by chart review and database abstraction. Baseline characteristics and response rates between relapsed patients and refractory patients were compared using Fisher exact and Wilcoxon rank sum tests, and differences in overall survival (OS) were compared using the log-rank test.ResultsThe response rate (complete and partial response) to ¹³¹I-MIBG-based therapies for all patients was 27%. There was no difference in response rates between relapsed and refractory patients. However, after ¹³¹I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients (p = 0.02). Among all patients, the 24-month OS was 47.0% (95% confidence interval (CI) 39.9–53.9%). The 24-month OS for refractory patients was significantly higher at 65.3% (95% CI 51.8–75.9%), compared to 38.7% (95% CI 30.4–46.8%) for relapsed patients (p < 0.001).ConclusionsAlthough there was no significant difference in overall response rates to ¹³¹I-MIBG between patients with relapsed versusrefractory neuroblastoma, patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after ¹³¹I-MIBG compared to patients with refractory disease.     

Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with 131I-metaiodobenzylguanidine

Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with ¹³¹I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after ¹³¹I-MIBG have not been defined.This is a multi-institutional retrospective review of patients with neuroblastoma treated with ¹³¹I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to ¹³¹I-MIBG. A competing risk regression was used to identify potential risk factors for SMN.The analytical cohort included 644 patients treated with ¹³¹I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4–13.0%) and 14.3% (95% CI, 8.3–23.9%) at 5 and 10 years from first ¹³¹I-MIBG, respectively. No increase in SMN risk was found with increased number of ¹³¹I-MIBG treatments or higher cumulative activity per kilogram of ¹³¹I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first ¹³¹I-MIBG, bone disease, disease status at time of first ¹³¹I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1–0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma.The cumulative risk of SMN after ¹³¹I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk.     

Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma.

PURPOSE: The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining (131)I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue. PATIENTS AND METHODS: Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received (131)I-MIBG 12 mCi/kg on day -21, followed by carboplatin (1,500 mg/m(2)), etoposide (800 mg/m(2)), and melphalan (210 mg/m(2)) administered from day -7 to day -4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated. RESULTS: The (131)I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil (> or = 0.5 x 10(3)/microL) and platelet (> or = 20 x 10(3)/microL) engraftment were 10 and 28 days, respectively. For the eight patients treated with metastatic disease, three achieved complete response and two had partial responses by day 100 after transplantation. CONCLUSION: Treatment with (131)I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.     

Radio iodized metaiodobenzylguanidine (MIBG) in the treatment of neuroblastoma: modalities and indications

Neuroblastoma is the most common pediatric extracranial solid cancer. Patients with metastatic disease at initial diagnosis who are greater than 18 months of age and patients with MycN amplified locoregional tumors are treated with intensive multimodal therapy. While this intensive approach has been shown to improve outcome, patients with high-risk disease frequently relapse and fewer than 50% of these patients will be long-term survivors necessitating new approaches for therapy. Derived from the sympathetic nervous system, this tumor typically expresses the norepinephrine transporter. This transporter mediates active intracellular uptake of metaiodobenzylguanidine (MIBG) an analogue of norepinephrine in approximately 90% of patients allowing the use of radiolabeled (metaiodobenzylguanidine) MIBG, for targeted radiotherapy. This article will review the clinical experience of using MIBG as targeted radiotherapy in neuroblastoma. The administration guidelines, toxicity, response and survival are discussed. Recent studies have evaluated combinations of (131)I-MIBG with myeloablative regimens such as chemotherapy agents with radiation sensitizing properties, or with biologic agents. Most of them report a response rate of 30-40% with (131)I-MIBG in patients with relapsed or refractory neuroblastoma. Due to this high response rates and low non-hematologic toxicity, (131)I-MIBG seems to be an interesting agent for incorporation into the upfront management of newly diagnosed patients with high-risk neuroblastoma.     

Short topotecan-based induction regimen in newly diagnosed high-risk neuroblastoma

Purpose

Topotecan is an active drug in relapsed neuroblastoma. We investigated the efficacy and toxicity of a topotecan-based induction regimen in newly diagnosed neuroblastoma.

Methods

Patients older than 1 year with either metastatic or localised stage 2-3 MYCN-amplified neuroblastoma received 2 courses of high-dose topotecan (HD-TPT) 6 mg/m² and high-dose cyclophosphamide (HD-CPM) 140 mg/kg, followed by 2 courses of ifosfamide, carboplatin and etoposide (ICE) every 28 days. After surgery on primary tumour, a fifth course with vincristine, doxorubicin and CPM was given, followed by high-dose chemotherapy with stem cell support. Response was assessed in accordance with the International Neuroblastoma Response Criteria.

Results

Of 35 consecutive patients, 33 had metastatic disease. The median length of induction phase was 133 days (range 91-207) and time to high-dose chemotherapy was 208 days (range 156-285). The median tumour volume reduction was 55% after two HD-TPT/HD-CPM courses and 80% after four courses. Radical surgery was performed in 16/27 patients after chemotherapy. After the fifth course, 29/34 patients (85%) had achieved a partial remission (12) or a CR/very good partial remission (17). CR of metastases was achieved in 13/32 (41%) and bone marrow was in complete remission in 16/24 patients (67%). Grade 4 neutropenia and/or thrombocytopenia occurred in 100% of HD-TPT/HD-CPM and in 95% of ICE courses, while non-haematological toxicities were manageable.

Conclusions

These data indicate that our induction regimen is feasible and well tolerated. A major response rate of 85% with 41% complete metastatic response confirms this regimen as effective induction in high-risk neuroblastoma.     

Endocrine late effects from multi-modality treatment of neuroblastoma

Thyroid dysfunction has been reported after 131I-MIBG-treatment for neuroblastoma. In this study, we have evaluated all endocrine functions from patients who were given multi-modality treatment including 131I-MIBG. Twenty-five neuroblastoma survivors who were off therapy for a median period of 6.0 years (range 1.3-11.1) were evaluated and their median age was 8.1 years (range 2.2-14.7). All patients had received 131I-MIBG, 16 chemotherapy, and 16 surgery. Fourteen patients (56%) had permanently elevated thyrotropin levels and 9 received thyroxine. Two patients had a small thyroid volume while 6 had thyroid nodules or cysts. Two boys showed hypergonadotropic hypogonadism. Growth was retarded in 39% of children. Mean Target Height Standard Deviation Score of patients with thyrotropin elevation was lower than those without (P=0.019). Children treated for neuroblastoma with 131I-MIBG, chemotherapy and surgery were seen to be at risk from developing irreversible thyroid function loss, thyroid nodules, hypergonadotropic hypogonadism, and growth retardation. We recommend that during follow-up of neuroblastoma children, special attention should be paid to their endocrine state.     

Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer

BackgroundPalbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole–palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC.Patients and methodsNeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II–III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m², epirubicin 100 mg/m², cyclophosphamide 500 mg/m²)×3 21-day courses followed by docetaxel 100 mg/m²×3 21-day courses. Primary end point was residual cancer burden (RCB 0–I rate). Secondary end points included clinical response, proliferation-based markers, and safety.ResultsOverall, 106 patients were randomised [median Prosigna® ROR Score 71 (22–93)]. RCB 0–I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4–14.9)] and chemotherapy [15.7% (95% CI 5.7–25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm).ConclusionLETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC.Clinical Trial NumberNCT02400567.     

131I-metaiodobenzylguanidine (131I-MIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients

Incomplete response to therapy may compromise the outcome of children with advanced neuroblastoma. In an attempt to improve tumour response we incorporated 131I-metaiodobenzylguanidine (131I-MIBG) in the treatment regimens of selected stage 3 and stage 4 patients. Between 1986 and 1997, 43 neuroblastoma patients older than 1 year at diagnosis, 13 with stage 3 (group A) and 30 with stage 4 disease (group B) who had completed the first-line protocol without achieving complete response entered in this study. 131I-MIBG dose/course ranged from 2.5 to 5.5 Gbq (median, 3.7). The number of courses ranged from 1 to 5 (median 3) depending on the tumour response and toxicity. The most common acute side-effect was thrombocytopenia. Later side-effects included severe interstitial pneumonia in one patient, acute myeloid leukaemia in two, reduced thyroid reserve in 21. Complete response was documented in one stage 4 patient, partial response in 12 (two stage 3, 10 stage 4), mixed or no response in 25 (ten stage 3, 15 stage 4) and disease progression in five (one stage 3, four stage 4) Twenty-four patients (12/13 stage 3, 12/30 stage 4) are alive at 22-153 months (median, 59) from diagnosis. 131I-MIBG therapy may increase the cure rate of stage 3 and improve the response of stage 4 neuroblastoma patients with residual disease after first-line therapy. A larger number of patients should be treated to confirm these results but logistic problems hamper prospective and coordinated studies. Long-term toxicity can be severe.     

Results of Trimodality Therapy in Patients With Stage IIIA (N2-Bulky) and Stage IIIB Non–Small-Cell Lung Cancer

BackgroundThe survival rates for stage IIIA and stage IIIB Non–Small-cell lung cancer (NSCLC) are extremely poor with single-treatment modalities such as radiation therapy or surgery. The purpose of this study is to assess tolerability, response, surgical resectability, and survival of chemotherapy followed by chemoradiation therapy, and then followed by surgery in patients with stage IIIA (N2-bulky) or stage IIIB NSCLC.Patients and MethodsForty-eight patients with stage IIIA (N2-bulky) or stage IIIB (T4 N1-2 M0) NSCLC received 2 cycles of chemotherapy with cisplatin, mitomycin, and vindesine, subsequent radiation therapy (45 Gy, twice-daily 1.5 Gy) with simultaneous low-dose cisplatin and vindesine, followed by surgery.ResultsForty-five patients completed induction chemoradiation therapy. Thirty-three patients (68.8%) had clinical response to induction treatment. Thirty-nine patients underwent a thoracotomy, with a complete resection rate of 62.5% (30/48). The pathologic response rate was 60% (27/45), with complete pathologic response of 8 patients. The median survival time for the total group of 48 patients was 23 months, with 3- and 5-year survival rates of 41.7% and 31.8%, respectively. Multivariate analysis showed that complete resection and pathologic response in surgical specimens were independent predictors of survival (P = .048 and P = .022).ConclusionPreoperative sequence of chemotherapy followed by concurrent chemoradiation therapy is an effective approach in patients with stage IIIA (N2-bulky) and IIIB (T4 N1-2 M0) NSCLC. The operation after induction chemoradiation therapy should be performed in carefully selected patients with surgically resectable diseases. The patients who achieved complete resection and with pathologic response of tumor can benefit from surgery following induction chemoradiation therapy.     

Weekly Cisplatin induction chemotherapy in high-risk cervical-cancer patients with bulky tumor - a phase-ii study

In this study we evaluated efficacy and toxicity of a neoadjuvant chemotherapy regimen before radiation therapy or surgery in high-risk cevical cancer patients. Between January 1988 and July 1993, 37 out of 40 consecutive patients with bulky cervical carcinoma (>40 mm) received chemotherapy consisting of six (range 4-9) weekly courses of cisplatin (1 mg/kg), followed by radical surgery and/or radiotherapy. Thirty-six patients completed the planned sequence of treatment. Overall response rate was 65% after induction chemotherapy (complete 0% and partial 65%) and 73% (complete 57% and partial 16%) after definitive treatment. After a median follow-up of 23 (range 4-61) months the median duration of response was 29, 19 and 11 months for complete partial and non-responders respectively. Toxicities from induction chemotherapy were mild to moderate, reversible and tolerable and did not affect the subsequent application of the definitive treatment. The proposed cisplatin neoadjuvant chemotherapy regimen gave positive results in a good number of cases with low toxicity and without interfering with the definitive radio-surgical treatment of this group of high-risk patients. The number of cisplatin courses for best effect remains to be established.     

Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02)

BackgroundThis multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma.Patients and methodsPatients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m² and docetaxel (Taxotere) 75 mg/m² on days 1 and 22, followed by radiotherapy of 45 Gy (25 × 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m² and docetaxel 20 mg/m² weekly for 5 weeks, followed by surgery.ResultsSixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications.ConclusionsThis neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigation.     

A systematic review of 131I-meta iodobenzylguanidine molecular radiotherapy for neuroblastoma

The optimal use and effectiveness of ¹³¹I-meta iodobenzylguanidine (¹³¹I-mIBG) molecular radiotherapy for neuroblastoma remain unclear despite extensive clinical experience. This systematic review aimed to improve understanding of the current data and define uncertainties for future clinical trials. Bibliographic databases were searched for neuroblastoma and ¹³¹I-mIBG. Clinical trials and non-comparative case series of ¹³¹I-mIBG therapy for neuroblastoma were included. Two reviewers assessed papers for inclusion using the title and abstract with consensus achieved by discussion. Data were extracted by one reviewer and checked by a second. Studies with multiple publications were reported as a single study. The searches yielded 1216 citations, of which 51 publications reporting 30 studies met our inclusion criteria. No randomised controlled trials (RCTs) were identified. In two studies ¹³¹I-mIBG had been used as induction therapy and in one study it had been used as consolidation therapy. Twenty-seven studies for relapsed and refractory disease were identified. Publication dates ranged from 1987 to 2012. Total number of patients was 1121 with study sizes ranging from 10 to 164. There was a large amount of heterogeneity between the studies with regard to patient population, treatment schedule and response assessment. Study quality was highly variable. The objective tumour response rate reported in 25 studies ranged from 0% to 75%, mean 32%. We conclude that ¹³¹I-mIBG is an active treatment for neuroblastoma, but its place in the management of neuroblastoma remains unclear. Prospective randomised trials are essential to strengthen the evidence base.     

Hematologic toxicity of high-dose iodine-131-metaiodobenzylguanidine therapy for advanced neuroblastoma.

PURPOSE: Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) has been shown to be active against refractory neuroblastoma. The primary toxicity of (131)I-MIBG is myelosuppression, which might necessitate autologous hematopoietic stem-cell transplantation (AHSCT). The goal of this study was to determine risk factors for myelosuppression and the need for AHSCT after (131)I-MIBG treatment. PATIENTS AND METHODS: Fifty-three patients with refractory or relapsed neuroblastoma were treated with 18 mCi/kg (131)I-MIBG on a phase I/II protocol. The median whole-body radiation dose was 2.92 Gy. RESULTS: Almost all patients required at least one platelet (96%) or red cell (91%) transfusion and most patients (79%) developed neutropenia (< 0.5 x 10(3)/microL). Patients reached platelet nadir earlier than neutrophil nadir (P <.0001). Earlier platelet nadir correlated with bone marrow tumor, more extensive bone involvement, higher whole-body radiation dose, and longer time from diagnosis to (131)I-MIBG therapy (P 相似文献   

Sequelae and survivorship in patients treated with 131I-MIBG therapy

Background:

¹³¹I-meta-iodobenzylguanidine (¹³¹I-MIBG) has been in therapeutic use since 1980s. Newer treatment modalities are emerging for neuroendocrine tumours (NETs) and chromaffin cell tumours (CCTs), but many of these do not yet have adequate long-term follow-up to determine their longer term efficacy and sequelae.

Methods:

Fifty-eight patients with metastatic NETs and CCTs who had received ¹³¹I-MIBG therapy between 2000 and 2011 were analysed. Survival and any long-term haematological or renal sequelae were investigated.

Results:

In the NET group, the overall median survival and median survival following the diagnosis of metastatic disease was 124 months. The median survival following the commencement of ¹³¹I-MIBG was 66 months. For the CCT group, median survival had not been reached. The 5-year survival from diagnosis and following the diagnosis of metastatic disease was 67% and 67.5% for NETs and CCTs, respectively. The 5-year survival following the commencement of ¹³¹I-MIBG therapy was 68%. Thirty-two patients had long-term haematological sequelae: 5 of these 32 patients developed haematological malignancies. Two patients developed a mild deterioration in renal function.

Conclusion:

Long follow up of ¹³¹I-MIBG therapy reveals a noteable rate of bone marrow toxicities and malignancy and long term review of all patients receiving radionuclide therapies is recommended.     

Comparison of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by radiation vs concurrent chemoradiotherapy with TPF in patients with locally advanced squamous cell carcinoma of the head and neck

AimsTo compare the effectiveness of induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) followed by radiation with that of concurrent chemoradiotherapy with TPF in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).Materials and methodsIn a group of patients receiving induction chemotherapy followed by radiation, 15 patients received two cycles of chemotherapy with docetaxel 60 mg/m², cisplatin 70 mg/m² and 5-day 5-fluorouracil (5-FU) 750 mg/m²/day. Radiotherapy was begun 21 days after completing chemotherapy. In the group receiving concurrent chemoradiotherapy, 19 patients received two cycles of chemotherapy with docetaxel 50 mg/m², cisplatin 60 mg/m², and 5-day 5-FU 600 mg/m²/day. Radiation was begun on the first day of chemotherapy. The total radiation dose was between 63 and 74 Gy.ResultsOverall response rate (partial and complete response — both 100%) and complete response rate (87% and 84%) were similar, but, in overall survival, concurrent chemoradiotherapy with TPF was better than induction chemotherapy with TPF followed by radiation. Mucositis and anaemia were more frequent in the group receiving concurrent chemoradiotherapy, but the group receiving concurrent chemoradiotherapy with TPF improved overall survival.ConclusionsThis is a small non-randomised comparison. The effectiveness of concurrent chemoradiotherapy with TPF was better than that of induction chemotherapy with TPF followed by radiation.     

A phase II study of gemcitabine and cisplatin combination as induction chemotherapy for untreated locally advanced cervical carcinoma

Background:Cisplatin-based chemoradiation for locally advanced cervical carcinoma is now the standard of care for most patients with cervical carcinoma. However, induction chemotherapy followed by surgery, particularly with newer agents or combinations remains to be explored. This study was undertaken to evaluate the antitumor activity and toxicity of gemcitabine in combination with cisplatin for untreated locally advanced cervical carcinoma. Patients and methods:Open-label, single center, phase II, non-randomized study of neoadjuvant gemcitabine plus cisplatin. Forty-one patients with histologic diagnosis of cervical carcinoma, with no previous treatment and staged as IB2 to IIIB, were treated with three 21-day courses of cisplatin 100 mg/m² day 1 and gemcitabine 1000 mg/m² days 1 and 8, followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated before each course and at the end of chemotherapy. Results:All patients were evaluated for toxicity and 40 for response. The overall objective response rate was 95% (95% confidence interval (CI): 88%–100%) being complete in 3 patients (7.5%) and partial in 35 (87.5%). A complete pathological response was found in 6 (26%) of the 23 patients that underwent surgery. Granulocytopenia grades 3–4 occurred in 13.8% and 3.4% of the courses, respectively, whereas non-hematological toxicity was mild. Conclusions:Induction chemotherapy with the combination of gemcitabine and cisplatin is highly active for untreated cervical cancer patients and has an acceptable toxicity profile.     

Induction chemotherapy with docetaxel,cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced squamous cell carcinoma of the head and neck

PurposeTo determine the efficacy and feasibility of induction chemotherapy (ICT) with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab (C) in patients with locally advanced head and neck cancer.Patients and methodsForty-nine previously untreated patients with local advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) received three courses of ICT consisting of docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and infusional 5-fluorouracil 750 mg/m²/day on days 1–5 followed by radiotherapy plus C at 250 mg/m²/week (after an initial loading dose of 400 mg/m²).ResultsAfter completion of ICT 44 of 49 patients received radiotherapy plus C. Three months after therapy completion tumour response was observed in 33 patients and after two years, 25 patients were in complete remission (CR). The most common grade 4 toxicity during the whole treatment period was dermatitis (30%), followed by mucositis (27%) and neutropenia (17%) without fever. One toxic related death was observed during ICT. Two-year progression-free survival (PFS) rate was 59% and two-year overall survival (OS) rate was 63%, respectively.ConclusionConcurrent radiotherapy plus C after three courses of ICT was feasible and was associated with promising CR, PFS and OS rates. Further optimisation of dose and sequence is warranted.     

Platinum-Based Induction Chemotherapy Followed by Radiation as Definitive Treatment for Patients with Locally Advanced Cancer of the Oral Cavity,Oropharynx and Hypopharynx. A Retrospective Analysis of 32 Cases

Summary

Thirty-two patients with locally advanced cancer of oral cavity, oropharynx and hypopharynx were treated with three cycles of platinum-based induction chemotherapy followed by radiation therapy. After completion of the combined treatment 50% of the patients were in complete response (CR) and 28% in partial response (PR). So far, 24 patients have died. Local progression occurred in 20 patients. Survival is 29% at 24 months. Seven (22%) patients remain alive and have been disease-free for 22-59 months.

In conclusion, induction chemotherapy followed by radiation therapy may omit radical surgery, without compromising survival, in some patients with locally advanced cancer of the oral cavity, oropharynx and hypopharynx.     

Lenalidomide Plus Hypomethylating Agent as a Treatment Option in Acute Myeloid Leukemia With Recurrent Genetic Abnormalities—AML With inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

IntroductionAcute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic neoplasm. The cytogenetic changes associated with AML affect the response rate and survival and are one of the most important independent prognostic factors. AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM accounts for 1% to 2% of all forms of AML and has been associated with a younger age at diagnosis, a poor response to standard induction chemotherapy, and very poor long-term prognosis.Patients and MethodsWe performed a single-center, retrospective cohort study comparing the outcomes with hypomethylating agent (HMA) plus lenalidomide to those with standard intensive induction therapies for newly diagnosed and relapsed/refractory AML with inv(3).ResultsOf the 15 patients, 4 (26.7%) had received lenalidomide and HMA as primary therapy. The overall response rate (ORR) was 100% for the 4 patients who had received lenalidomide with HMA as first-line induction therapy. The ORR was 27.3% (3 of 11) for the patients who had received other induction regimens (P = .0256). The duration of response for first induction therapy was an average of 7.4 months after lenalidomide plus an HMA and a mean of 1.5 months after induction with other chemotherapy regimen (P = .057). The ORR for induction and reinduction therapy was also assessed, with an ORR of 21.4% (6 of 28) for alternative chemotherapy regimens and an ORR of 75% (6 of 8) for induction and reinduction with lenalidomide plus HMA (P = .0046).ConclusionsThe high ORR and reasonable duration of response could allow for potentially curative allogeneic hematopoietic cell transplantation for these patients with high-risk AML. Our initial data suggest that lenalidomide plus HMA is a promising approach for patients with AML with inv(3).     

Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5

BackgroundHigh-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5–19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5.MethodsAll children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m²) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1–3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy).ResultsFifty-one patients (median age, 8 y; range, 5–19) were enrolled. The median follow-up was 7.1 years (range: 3.4–9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65–88) and 76% (63–86), and the 3 and 5-year OS were 84% (72–92) and 76% (63–86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated.ConclusionsThis treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.