Severe Non-haematological Toxicity Research Articles

Predictive significance of FGFR4 p.G388R polymorphism in metastatic colorectal cancer patients receiving trifluridine/tipiracil (TAS-102) treatment

BackgroundTAS-102 (Lonsurf®) is an oral fluoropyrimidine consisting of a combination of trifluridine (a thymidine analog) and tipiracil (a thymidine phosphorylation inhibitor). The drug is effective in metastatic colorectal cancer (mCRC) patients refractory to fluorouracil, irinotecan and oxaliplatin. This study is a real-world analysis, investigating the interplay of genotype/phenotype in relation to TAS-102 sensitivity.MethodsForty-seven consecutive mCRC patients were treated with TAS-102 at the National Cancer Institute of Naples from March 2019 to March 2021, at a dosage of 35 mg/m2, twice a day, in cycles of 28 days (from day 1 to 5 and from day 8 to 12). Clinical-pathological parameters were described. Activity was evaluated with RECIST criteria (v1.1) and toxicity with NCI-CTC (v5.0). Survival was depicted through the Kaplan-Meyer curves. Genetic features of patients were evaluated with Next Generation Sequencing (NGS) through the Illumina NovaSeq 6000 platform and TruSigt™Oncology 500 kit.ResultsMedian age of patients was 65 years (range: 46–77). Forty-one patients had 2 or more metastatic sites and 38 patients underwent to more than 2 previous lines of therapies. ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) was 2 in 19 patients. The median number of TAS-102 cycles was 4 (range: 2–12). The most frequent toxic event was neutropenia (G3/G4 in 16 patients). There were no severe (> 3) non-haematological toxicities or treatment-related deaths. Twenty-six patients experienced progressive disease (PD), 21 stable disease (SD). Three patients with long-lasting disease control (DC: complete, partial responses or stable disease) shared an FGFR4 (p.Gly388Arg) mutation. Patients experiencing DC had more frequently a low tumour growth rate (P = 0.0306) and an FGFR4 p.G388R variant (P < 0.0001). The FGFR4 Arg388 genotype was associated with better survival (median: 6.4 months) compared to the Gly388 genotype (median: 4 months); the HR was 0.25 (95% CI 0.12- 0.51; P = 0.0001 at Log-Rank test).ConclusionsThis phenotype/genotype investigation suggests that the FGFR4 p.G388R variant may serve as a new marker for identifying patients who are responsive to TAS-102. A mechanistic hypothesis is proposed to interpret these findings.Graphical

Neutropenia as a prognostic factor and safety of second-line therapy with S-1 for advanced or recurrent pancreatic cancer.

The aim of this retrospective study was to investigate the safety of S-1 as second-line therapy and to evaluate the association between neutropenia occurring during first-line gemcitabine (GEM) therapy and survival for advanced or recurrent pancreatic cancer (APC). Between January, 2010 and December, 2014, 123 APC patients received chemotherapy at the Ogaki Municipal Hospital (Ogaki, Japan). Of those, 37 received GEM as first-line and S-1 as a second-line therapy (GEM→S-1 group). A further 60 patients received GEM as first-line therapy, but did not receive second-line therapy (GEM group). The median overall survival in the GEM→S-1 (n=37) and GEM (n=60) groups was 323 days [95% confidence interval (CI): 138-218.9 days] and 172 days (95% CI: 105-184.4 days), respectively (P=0.0004). The median overall survival in the mild (grade ≤2; n=63) and severe (grade ≥3; n=34) neutropenia groups was 178 days (95% CI: 182-275 days) and 330 days (95% CI: 297-514 days), respectively (log-rank test, P=0.0023). The severe non-haematological toxicities associated with S-1 as second-line therapy were nausea (2.7%) and hand-foot syndrome (2.7%). Second-line S-1 treatment was discontinued due to adverse events in 5.4% (2/37) of the cases. In conclusion, neutropenia occurring during GEM therapy administered as first-line treatment to APC patients was strongly associated with a better prognosis. S-1 therapy as second-line treatment was associated with a low incidence of severe adverse events and the patients were able to successfully continue treatment.

Chemotherapy with gemcitabine, cisplatin, and docetaxel in the treatment for patients with muscle-invasive bladder cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG)

To assess the antitumor activity and toxicity of gemcitabine, cisplatin, and docetaxel (GCD) regimen in patients with locally advanced or metastatic urothelial cancer. Chemotherapy-naïve patients, aged ≤70years with measurable or evaluable disease and a performance status (PS) of 0-2 were treated with sequential cisplatin 80mg/m(2) (d1), gemcitabine 1,100mg/m(2) (d1 and d14), and docetaxel 80mg/m(2) (d14) every 28days. Sixty patients with an ECOG PS of 0-2 were enroled. Most (71.7%) patients had stage IV disease. A median number of 4 chemotherapy cycles per patient (range, 1-9) was administered. Eight (13.3%) patients achieved a CR and 16 (26.7%) a partial response (PR) (intention-to-treat: ORR 40%; 95% CI 27.6-52.4%). Thirteen (21.7%) and 23 (38.3%) patients experienced stable and progressive disease, respectively. The median time to progression (TTP) was 7.7months (range, 0.7-43.4), and the median overall survival 21.4months (range, 0.7-68.6). Grade 3 and 4 neutropenia occurred in 27 (45%) patients and grade 3 and 4 thrombocytopenia in five (8.3%). Three (5%) patients developed febrile neutropenia. There were no treatment-related deaths. Severe non-haematological toxicity was infrequent. The GCD combination is an active and well-tolerated regimen in patients with chemotherapy-naive locally advanced or metastatic TCC and merits to be further investigated.

Combined Low-Dose Homoharringtonine, Cytarabine and Granulocyte Colony-Stimulating Factor for Patients with Advanced Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia Transformed From MDS

AbstractAbstract 4004A pilot study of the efficacy and toxicity of the low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF) (CHG protocol) in patients with advanced myelodysplastic syndromes (MDS) or MDS-transformed acute myeloid leukaemia (t-AML) was conducted. A total of 50 patients (31, advanced MDS; 19, t-AML) were enrolled in this study. All patients were administered the CHG regimen comprising low-dose cytarabine (25 mg/d, intravenous continuous infusion, days 1 C14), homoharringtonine (1 mg/d, intravenous continuous infusion, days 1 C14) and G-CSF (300 μg/d, subcutaneous injection, days 0 C14, intermitted when the peripheral WBC count reached >20 °Á 109/L). This regimen was followed by conventional chemotherapy as post-remission therapy when complete remission (CR) was achieved. The overall response rate was 68.0% after one course of the CHG regimen was applied. Of the total 50 patients, 24 (48.0%) achieved CR and 9 (18.0%) achieved partial remission (PR). The median overall survival (OS) was 14.1 months. Among the patients aged ≥ 70 years, the response rate was 81.0% (71.4% CR and 9.6% PR), while in patients aged < 70 years, the response rate was 55.2% (31.0% CR and 24.1% PR) (P < 0.01). There were no statistically significant differences for CR, PR and OS when the patients were grouped by blast percentage in bone marrow and karyotypes, respectively. 8 of the 24 CR patients who just received post-remission regimens of HA (homoharringtonine and cytarabine) and DA (daunorubicin and cytarabine) relapsed rapidly and just kept a mean CR of 4.3 months. Otherwise, the other 14 CR patients alternatively received succeeded chemotherapy, which combined mitoxantrone, idarubicin, pirarubicin or aclarubicin with cytarabine or decitabine. The mean CR duration of these 14 patients reached 15.5 months with 4 still maintaining continuous CR. No treatment-related deaths were observed. Myelosuppression was mild to moderate, and no severe non-haematological toxicity was observed. Thus, CHG priming regimen as an induction therapy is well tolerated and effective in advanced MDS or t-AML patients. Disclosures:No relevant conflicts of interest to declare.

Phase II study of dose-dense doxorubicin and docetaxel as neoadjuvant chemotherapy with G-CSF support in patients with large or locally advanced breast cancer

To evaluate the efficacy and safety profile of the concomitant dose-dense administration of doxorubicin and docetaxel as primary chemotherapy for patients with large or locally advanced breast cancer. Forty-seven patients were included and received 50 mg/m(2) of doxorubicin and 75 mg/m(2) of docetaxel every two weeks for four cycles. Primary prophylaxis with granulocyte colony stimulating factor was administered. Patients included had mainly stage III disease (66%). Efficacy and toxicity analyses were carried out on an intention-to-treat basis. After study treatment, the rate of clinical responses was 85% (95% CI: 75-95) with 6% judged as clinical complete responses. Surgery was performed on 94% patients for whom the breast was conserved in 27%. Only one patient obtained a pathological complete response (with no evidence of invasive or non-invasive tumour in the breast and the lymph nodes). In three additional patients, malignant cells were detected only in one lymph node. The single severe haematological toxicity was neutropenia, occurring in one patient (2%) and two cycles (1%), being grade 3 in one and grade 4 in the other. Severe non-haematological toxicities were grade 3, and the most common was asthenia (8% of patients), followed by cutaneous toxicity, arthromyalgia and stomatitis, which occurred in fewer than 4% of patients in each case. The concomitant dose-dense administration of doxorubicin and docetaxel as neoadjuvant chemotherapy with granulocyte colony stimulating factor support is a feasible and effective schedule with a safe toxicity profile for women with large or locally advanced breast cancer.

A two-month cisplatin-epirubicin-paclitaxel (PET) weekly administration is highly effective in large operable breast cancer. Final analysis of a SICOG phase II study

566 Background: The present study was aimed at defining the antitumor activity of 8 cisplatin-epirubicin-paclitaxel (PET) weekly cycles with granulocyte-colony stimulating factor (G-CSF) support in patients with large operable breast cancer. Methods: Operable breast cancer (T2-T3 N0–1; T>3 cm) patients received 8 preoperative weekly cycles of cisplatin 30 mg/m2, epirubicin 50 mg/m2, paclitaxel 120 mg/m2, with G-CSF (5 microgr./kg days 3–5) support. Results: Sixty-three patients (T2/T3=30/33; N0/N+=8/55) were enrolled. Thirty-one clinical complete (49%), and 30 partial (48%) responses, were recorded, giving a 97% response rate [95% confidence interval, 89–100%]. Breast-sparing surgery was performed in 32/63(51%) patients. At pathological assessment, 28 patients (45%) showed absence of invasive residual disease in breast and 34 (55%) had negative axilla. In 20 women (32%) both breast and axilla were found disease-free. The absence of Estrogen receptors was associated with a higher probability of pCR achievement (ER- vs. ER+= 66% vs. 14%; p=0.00005). A significantly higher pCR probability was also observed in HER2 3+ patients (60% vs. 23%; p=0.01). At a 23-month median follow-up (range; 4–63), only 8 relapses, and 2 deaths have occurred, 5-year projected RFS and OS being 59% and 95%, respectively. Grade 3–4 neutropenia, and anaemia occurred in 24% and 5% of patients, respectively. Emesis, diarrhoea, and mucositis were the main non-haematological toxicities; however, only 9(14%) patients experienced one or more episodes of severe non-haematological toxicity. Peripheral neuropathy was frequent, but never severe. Conclusions: A two-month weekly treatment with PET represents a well tolerated and highly effective approach in large operable breast cancer patients. A randomized study comparing weekly PET with triweekly epirubicin-paclitaxel is underway. No significant financial relationships to disclose.

Carboplatin and paclitaxol (Taxol) as an induction regimen for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer: an EORTC phase II study (EORTC 08958)

The aim of this study was to document the activity and toxicity of paclitaxel (Taxol)/carboplatin when used as induction chemotherapy in patients with stage IIIA N2 non-small cell lung cancer (NSCLC) prior to definitive local treatment within a large, ongoing comparative study (EORTC 08941). 52 eligible, consenting, chemotherapy-naı̈ve patients with NSCLC, median age of 60 years, stage IIIA N2 disease and the ability to tolerate a pneumonectomy received paclitaxel 200 mg/m2 as a 3-h infusion followed by carboplatin at an area under the concentration curve (AUC) of 6 every 3 weeks for three courses. Most patients received three courses. No grade 3/4 anaemia or thrombocytopenia was documented. Over all of the cycles, 6% (3 patients) experienced grade 3 leucopenia while 63% (32/51 patients) experienced grade 3-4 neutropenia. There was 1 patient (2%) with febrile neutropenia, no early or toxic deaths and no hypersensitivity reactions. Severe non-haematological toxicity was uncommon, with the exception of grade 3 alopecia in 39%, lethargy in 8% and myalgia in 6%. Of the eligible patients (n=52), there was one complete response (CR) and 32 partial responses (PR), resulting in a response rate of 64% (95% Confidence Interval (CI) 49%–76%). Of the 15 eligible patients randomised to surgery after induction chemotherapy, 3 patients did not receive surgery and 2 patients (n=12) had no tumour in the mediastinal nodes (17%). Resections were considered complete in 2 of the 12. Median survival for all eligible patients (n=52) was 20.5 months (95% CI 16.1–31.2), with an estimated 1-year survival rate of 68.5% (95% CI 55.2–81.7). In patients with N2 stage IIIA NSCLC, paclitaxel/carboplatin is an active and very well-tolerated induction regimen.

Results of randomised phase II studies comparing S16020 with methotrexate in patients with recurrent head and neck cancer

The purpose of this study was to carry out two randomised phase II trials of S16020, a new olivacine derivative, tested as a single agent in patients with recurrent head and neck cancer, using methotrexate as the control arm to validate the results. S16020 at either 80 or 100 mg/m2 was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50 mg/m2, was given by bolus injection, weekly for a minimum of 6 weeks. In total, 36 patients were entered in the randomised studies (25 in an initial study, 11 in a confirmatory study) of whom 24 received S16020 and 12 received methotrexate. A scheduled interim analysis showed one patient having a non-confirmed objective response with S16020 and three patients having a confirmed objective response with methotrexate. In the methotrexate group, there were no patients with severe non-haematological toxicity. With S16020, there was a high incidence of severe non-haematological toxicities, including asthenia, oedema of the face, oedema and pain at the tumour sites and erythematous rash; consequently, both studies were stopped. Both studies were stopped due to the poor anticipated benefit/risk ratio for S16020, although time to progression and overall survival time were similar in both treatment arms.

Gemcitabine, cisplatin and vinorelbine as induction chemotherapy followed by radical therapy in stage III non-small-cell lung cancer: a multicentre study of galician-lung-cancer-group

Purpose: To determine the effectiveness of a gemcitabine–cisplatin–vinorelbine combination in patients with stage III non-small-cell lung cancer (NSCLC). Patients and methods: Patients ( n=46) with stage III NSCLC and naive of therapy were recruited into the trial to receive gemcitabine (G, 1000 mg/m 2) on days 1 and 8, cisplatin (C, 100 mg/m 2) on day 1 and vinorelbine (V, 25 mg/m 2) on days 1 and 8 every 21 days for three cycles. Results: Two patients achieved complete response (CR) and 23 partial response (PR), overall response 52%. Subsequent radical surgery included nine patients of whom four were non-resectable and five were resected and with 1 CR. Radiotherapy was administered to 31 patients, and two achieved CR. The median time to progression and overall survival were 37 and 50 weeks, respectively. Grade 3–4 neutropenia and thrombocytopenia occurred in 35% of cycles, with two toxic deaths. Severe non-haematological toxicity was uncommon. Conclusions: This GCV combination is effective in patients with stage III NSCLC, and with an acceptable toxicity.

Cisplatin, doxorubicin and ifosfamide in carcinosarcoma of the female genital tract. A phase II study of the European Organization for Research and Treatment of Cancer Gynaecological Cancer Group (EORTC 55923)

Carcinosarcomas of the female genital tract are highly malignant tumours composed of carcinomatous and sarcomatous elements. In the past, these tumours were frequently treated as sarcomas. However, a number of arguments, including the sensitivity of these tumours to platinum-based chemotherapy, suggest that these tumours behave more like poorly differentiated carcinomas. The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group therefore decided to perform a prospective phase II study in patients with advanced or metastatic carcinosarcoma with an approach such as that used in gynaecological carcinomas. Eligible patients could have primary or recurrent disease, but prior radiotherapy or chemotherapy was not allowed. The treatment plan recommended upfront debulking, followed by chemotherapy with cisplatin, ifosfamide and doxorubicin. Patients who could be debulked to non-measurable disease remained eligible for the study, but the response assessment was restricted to patients who had measurable disease before the start of chemotherapy. A total of 48 patients (39 primary disease, 9 recurrent disease) were registered, 41 of them being eligible. In 9 patients, all macroscopic lesions could be removed, 32 patients were left with residual disease and were assessable for response. The overall response rate was 56%: a complete response (CR) was observed in 11 (34%) patients and partial response (PR) in 7 (22%) patients. No change occurred in 5 patients and progression in 2 patients. In 7 patients, response could not be assessed. Median survival for all of the 41 eligible patients was 26 months. Severe leucopenia and thrombocytopenia were common and necessitated dose reductions or delays in 60% of patients. From a clinical point of view, the most severe non-haematological toxicity was renal dysfunction, and one patient died of this complication in the absence of disease progression. The results of this study are in-line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. The treatment also included upfront cytoreduction when feasible. Considering the observed toxicities, alternative platinum-based regimens with more favourable toxicity profiles should be explored.

Severe non-haematological toxicity after treatment with gemcitabine.

The authors report that 4 out of a series of 56 patients (7.1%) treated with gemcitabine developed an unexplained non-cardiogenic pulmonary distress syndrome most likely related to gemcitabine. One further patient developed ventricular arrhythmia immediately after gemcitabine exposure, leading to cardiac arrest. Between 1995 and 1998 56 patients with locally advanced or metastatic carcinoma were treated with gemcitabine. The patients suffered from breast cancer (n = 17), pancreatic cancer (n = 17), lung cancer (n = 12), cancer of unknown primary (n = 5), ovarian cancer (n = 2), oral cavity cancer (n = 2) and cancer of the bladder (n = 1). Their median age was 55 years, and there were 33 female and 23 male patients. Fifteen patients had been pretreated with radiation therapy: 2 had received radiation therapy involving the mediastinum as treatment for non-small-cell lung cancer and cancer of unknown origin respectively, 11 patients had had prior neoadjuvant or adjuvant radiation therapy of the chest wall for breast cancer and 2 patients had received radiation therapy for head/neck cancer. All patients received gemcitabine on days 1, 8 and 15 and this was repeated on day 29 at a dose of 1000 mg/m(2) as a 30-min infusion in 250 ml isotonic NaCl. In 4 patients gemcitabine treatment was combined with cisplatinum, in 7 patients with a somatostatin analogue and in 1 patient with epirubicin. All other patients received gemcitabine as a single agent. We assume that the pulmonary or cardiac toxicity of 5 patients was related to gemcitabine. In 3 patients re-exposure resulted in repeated toxicity. One patient did not receive gemcitabine again because of the life-threatening nature of the primary response. Two patients had received prior radiation to the mediastinum with 62 Gy and 50 Gy respectively, 3 years and 1 year before gemcitabine application. In our experience pulmonary toxicity after gemcitabine treatment is more common than initially anticipated. Gemcitabine should be used with caution in patients who have received prior radiation to the mediastinum.

Optimal use of docetaxel (Taxotere®)

The safety of docetaxel (Taxotere) has been evaluated in the safety overview population consisting of 1070 patients recruited to phase II trials. These patients received a total of 4989 cycles of therapy (median four cycles per patient). Since docetaxel is known to be metabolized in the liver, hepatic impairment was predicted to be a risk factor for increased toxicity and was studied prospectively, comparing the 42 patients in the overview population with moderate hepatic impairment with the 1028 patients with liver function within normal limits. Hepatic dysfunction was associated with an increase in the percentage of cycles of therapy during which febrile neutropenia occurred and the number of patients suffering documented infection and severe (grade 3/4) stomatitis. The incidence of toxic death was also increased in patients with moderate hepatic impairment. The severity of fluid retention, a cumulative toxicity of docetaxel, was found to be reduced, and its onset delayed, by prophylactic treatment with corticosteroids for 5 days, starting 1 day before docetaxel administration. Treatment with corticosteroids was also recommended to reduce the incidence and severity of hypersensitivity reactions and cutaneous toxicities. The most frequent severe non-haematological toxicity of docetaxel was asthenia. Other non-haematological toxicities were generally mild or moderate.