Cisplatin

Low-dose metronomic cisplatin as an antiangiogenic and anti-inflammatory strategy for cancer

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Abstract

Background

Conventional chemotherapy is based on the maximum tolerated dose (MTD) and requires treatment-free intervals to restore normal host cells. MTD chemotherapy may induce angiogenesis or immunosuppressive cell infiltration during treatment-free intervals. Low-dose metronomic (LDM) chemotherapy is defined as frequent administration at lower doses and causes less inflammatory change, whereas MTD chemotherapy induces an inflammatory change. Although several LDM regimens have been applied, LDM cisplatin (CDDP) has been rarely reported. This study addressed the efficacy of LDM CDDP on tumour endothelial cell phenotypic alteration compared to MTD CDDP.

Methods

Tumour growth and metastasis were assessed in bladder cancer-bearing mice treated with LDM or MTD gemcitabine (GEM) and CDDP. To elucidate the therapeutic effects of LDM CDDP, the change of tumour vasculature, tumour-infiltrating immune cells and inflammatory changes were evaluated by histological analysis and mRNA expression in tumour tissues.

Results

Tumour growth and bone metastasis were more suppressed by LDM CDDP + MTD GEM treatment than MTD CDDP + MTD GEM. Myeloid­derived suppressor cell accumulation was reduced by LDM CDDP, whereas inflammatory change was induced in the tumour microenvironment by MTD CDDP.

Conclusion

LDM CDDP does not cause inflammatory change unlike MTD CDDP, suggesting that it is a promising strategy in chemotherapy.

Prevalence and risk factors for ototoxicity after cisplatin-based chemotherapy

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Ototoxicity is a prominent side effect of cisplatin-based chemotherapy. There are few reports, however, estimating its prevalence in well-defined cohorts and associated risk factors.

Methods

Testicular cancer (TC) survivors given first-line cisplatin-based chemotherapy completed validated questionnaires. Descriptive statistics evaluated the prevalence of ototoxicity, defined as self-reported hearing loss and/or tinnitus. We compared patients with and without tinnitus or hearing loss using Chi-square test, two-sided Fisher’s exact test, or two-sided Wilcoxon rank sum test. To evaluate ototoxicity risk factors, a backward selection logistic regression procedure was performed.

Results

Of 145 TC survivors, 74% reported ototoxicity: 68% tinnitus; 59% hearing loss; and 52% reported both. TC survivors with tinnitus were more likely to indicate hypercholesterolemia (P = 0.008), and difficulty hearing (P < .001). Tinnitus was also significantly related to age at survey completion (OR = 1.79; P = 0.003) and cumulative cisplatin dose (OR = 5.17; P < 0.001). TC survivors with hearing loss were more likely to report diabetes (P = 0.042), hypertension (P = 0.007), hypercholesterolemia (P < 0.001), and family history of hearing loss (P = 0.044). Risk factors for hearing loss included age at survey completion (OR = 1.57; P = 0.036), hypercholesterolemia (OR = 3.45; P = 0.007), cumulative cisplatin dose (OR = 1.94; P = 0.049), and family history of hearing loss (OR = 2.87; P = 0.071).

Conclusions

Ototoxicity risk factors included age, cisplatin dose, cardiovascular risk factors, and family history of hearing loss. Three of four TC survivors report some type of ototoxicity; thus, follow-up of cisplatin-treated survivors should include routine assessment for ototoxicity with provision of indicated treatments.

Implications for Cancer Survivors

Survivors should be aware of risk factors associated with ototoxicity. Referrals to audiologists before, during, and after cisplatin treatment is recommended.

Results of Phase III Randomized Trial for Use of Docetaxel as a Radiosensitizer in Patients With Head and Neck Cancer, Unsuitable for Cisplatin-Based Chemoradiation.

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PURPOSE: There is a lack of published literature on systemic therapeutic options in cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) undergoing chemoradiation. Docetaxel was assessed as a radiosensitizer in this situation.

METHODS: This was a randomized phase II/III study. Adult patients (age = 18 years) with LAHNSCC planned for chemoradiation and an Eastern Cooperative Oncology Group performance status of 0-2 and who were cisplatin-ineligible were randomly assigned in 1:1 to either radiation alone or radiation with concurrent docetaxel 15 mg/m2 once weekly for a maximum of seven cycles. The primary end point was 2-year disease-free survival (DFS).

RESULTS: The study recruited 356 patients between July 2017 and May 2021. The 2-year DFS was 30.3% (95% CI, 23.6 to 37.4) versus 42% (95% CI, 34.6 to 49.2) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.673; 95% CI, 0.521 to 0.868; P value = .002). The corresponding median overall survival (OS) was 15.3 months (95% CI, 13.1 to 22.0) and 25.5 months (95% CI, 17.6 to 32.5), respectively (log-rank P value = .035). The 2-year OS was 41.7% (95% CI, 34.1 to 49.1) versus 50.8% (95% CI, 43.1 to 58.1) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.747; 95% CI, 0.569 to 0.980; P value = .035). There was a higher incidence of grade 3 or above mucositis (22.2% v 49.7%; P < .001), odynophagia (33.5% v 52.5%; P < .001), and dysphagia (33% v 49.7%; P = .002) with the addition of docetaxel.

CONCLUSION: The addition of docetaxel to radiation improved DFS and OS in cisplatin-ineligible patients with LAHNSCC.

Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients With Advanced Neuroendocrine Carcinoma of the Digestive System

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Key Points

Question  For patients with advanced neuroendocrine carcinoma of the digestive system, which of the 2 community standard regimens is more effective: etoposide plus cisplatin (EP) or irinotecan plus cisplatin (IP)?

Findings  In this randomized clinical trial of 170 patients who were chemotherapy naive and had recurrent or unresectable neuroendocrine carcinoma of the digestive system, median overall survival was 12.5 months in the EP arm and 10.9 months in the IP arm.

Meaning  Both EP and IP therapy remain standard first-line chemotherapy options.

Abstract

Importance  Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for advanced neuroendocrine carcinoma (NEC).

Objective  To identify whether EP or IP is a more effective regimen in terms of overall survival (OS) in patients with advanced NEC of the digestive system.

Design, Setting, and Participants  This open-label phase 3 randomized clinical trial enrolled chemotherapy-naive patients aged 20 to 75 years who had recurrent or unresectable NEC (according to the 2010 World Health Organization classification system) arising from the gastrointestinal tract, hepatobiliary system, or pancreas. Participants were enrolled across 50 institutions in Japan between August 8, 2014, and March 6, 2020.

Interventions  In the EP arm, etoposide (100 mg/m2/d on days 1, 2, and 3) and cisplatin (80 mg/m2/d on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m2/d on days 1, 8, and 15) and cisplatin (60 mg/m2/d on day 1) were administered every 4 weeks.

Main Outcomes and Measures  The primary end point was OS. In total, data from 170 patients were analyzed to detect a hazard ratio (HR) of 0.67 (median OS of 8 and 12 months in inferior and superior arms, respectively) with a 2-sided α of 10% and power of 80%. The pathologic findings were centrally reviewed following treatment initiation.

Results  Among the 170 patients included (median [range] age, 64 [29-75] years; 117 [68.8%] male), median OS was 12.5 months in the EP arm and 10.9 months in the IP arm (HR, 1.04; 90% CI, 0.79-1.37; P = .80). The median progression-free survival was 5.6 (95% CI, 4.1-6.9) months in the EP arm and 5.1 (95% CI, 3.3-5.7) months in the IP arm (HR, 1.06; 95% CI, 0.78-1.45). A subgroup analysis of OS demonstrated that EP produced more favorable OS in patients with poorly differentiated NEC of pancreatic origin (HR, 4.10; 95% CI, 1.26-13.31). The common grade 3 and 4 adverse events in the EP vs IP arms were neutropenia (75 of 82 [91.5%] patients vs 44 of 82 [53.7%] patients), leukocytopenia (50 of 82 [61.0%] patients vs 25 of 82 [30.5%] patients), and febrile neutropenia (FN) (22 of 82 [26.8%] patients vs 10 of 82 [12.2%] patients). While incidence of FN was initially high in the EP arm, primary prophylactic use of granulocyte colony-stimulating factor effectively reduced the incidence of FN.

Conclusions and Relevance  Results of this randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy options. Although AEs were generally manageable, grade 3 and 4 AEs were more common in the EP arm.

Discussion

Evidence for treatment strategies of advanced NEC is lacking owing to the rarity of the disease. Recently, the results of a randomized phase 2 trial for NEC were reported16; however, enrollment was terminated early in 66 patients owing to the premature analysis, and no definitive conclusion was obtained. The present study represents the final results of a well-designed and, to our knowledge, the first phase 3 trial with high-quality pathological diagnoses and detailed information provided by a CPR.

The primary analysis of OS revealed no statistically significant difference between arms. Therefore, it is reasonable to continue using both regimens as the standard treatment for NEC. We were interested in the effect of pathological findings and primary organs on treatment efficacy. Although the results showed no statistically significant differences in any subgroups, the overall impression had a greater interaction by primary organ than by pathological findings in terms of OS and PFS (Figure 3 and eFigure 5 in Supplement 1). Because platinum regimens have been reported to be less effective in grade 3 NETs,5,8 and the WHO 2017 classification system9 and 2019 classification system10 formally declared grade 3 NETs as a separate entity from NECs,9,10 subgroup analyses of PDNECs only are of relevant clinical interest. Subgroup analysis of OS in PDNECs only indicated weak tendency of preferred results in the EP arm over the IP arm. A subgroup analysis of only PDNECs in each primary tumor indicated that the OS of the EP arm was better than that of the IP arm in the subset of pancreatic PDNEC. Although post hoc subgroup analyses should be interpreted with caution, these results have important implications. The CPR indicated that pancreatic NECs are characterized by a higher proportion of small cell carcinoma and a lower proportion of tumors with non-NEC components (eTable 2 in Supplement 1). Although these characteristics may have influenced the unique results in this subgroup, they cannot fully explain this phenomenon.

In terms of AEs, grade 3 and 4 AEs such as myelosuppression and FN were more common (>2 times) in the EP arm. Although these AEs were generally manageable, the high incidence of FN remains a point of caution. We took note of the high incidence of FN during this trial in the monitoring report; therefore, we revised the protocol to recommend primary prophylaxis with G-CSF32,33 after October 31, 2017. In the exploratory analysis of this study, prophylaxis with G-CSF seemed to effectively decrease the incidence of FN. However, considering higher planned/actual DI and lower relative DI in the EP arm, and higher rate of treatment termination owing to AE or patient’s refusal (third dose reduction owing to neutropenia), lower initial dose of EP therapy may be appropriate.

In addition to the outcome of the clinical trial, this study is very valuable in its provision of information on high-quality pathological diagnoses made by consistent CPR panel members throughout the entire period. Notably, the pathological diagnosis was not consistent with that of the participating institutions in nearly 10% of cases, indicating the difficulty of an accurate pathological diagnosis of NEC. Additionally, detailed information about the pathological findings was obtained for the cross-organ manner, which itself is an important asset in the field of NEC. In the forest plots of OS and PFS, the difference between EP and IP among the CPR subgroups was smaller than that of the primary organs (Figure 3 and eFigure 5 in Supplement 1).

Limitations

This study has some limitations. Although the primary analyses revealed no statistically significant difference in OS between the 2 arms, the study was not designed to assess the equivalence of the 2 regimens. Therefore, the 2 regimens should not be recognized as equivalent, but rather as they do not differ beyond a certain level. In addition, in patients diagnosed via results of biopsy specimens, accurate information of the entire tumor could not be obtained with respect to proliferative activity or the proportion of non-NEC components. In this study, patients diagnosed by biopsy harboring any proportions of non-NEC components, as long as a harboring NEC component was allowed to be enrolled, means that theoretically a certain percentage of patients with mixed adenoneuroendocrine carcinomas were enrolled. These limitations were unavoidable considering the diagnostic procedure, and this is also a universal issue in daily practice. Additionally, because further effects of immune checkpoint inhibitors on platinum regimens has been proven in small cell lung carcinoma,34,35 it is the next important clinical question in NECs.

Conclusions

Results of this phase 3 randomized clinical trial demonstrate that both EP and IP remain the standard first-line chemotherapy regimens for advanced digestive NECs. Post hoc subgroup analyses pointed to the superiority of EP in pancreatic PDNECs, and EP was safely given along with the use of primary prophylactic G-CSF.

Source: JAMA

Dose-intensive cisplatin for hepatoblastoma: have you heard?

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Although survival rates for paediatric cancer have improved greatly during the past four decades, outcomes for children diagnosed with metastatic solid tumours have barely changed. These patients and their families are in desperate need of novel therapeutic approaches. Chemotherapeutic options and approaches might have come to their limit. Surgical resection of metastatic disease is largely unstudied and unproven with the exception of isolated recurrent pulmonary lesions for osteosarcoma, which can sometimes be cured with surgery alone. Radiation therapy is often used with demonstrated benefit to pulmonary metastases, although it is usually given at subtherapeutic doses because of whole lung radiotolerance.

Hepatoblastoma is the most common paediatric liver tumour in the first decade of life and is typically diagnosed in patients younger than 3 years. Surgical resection of the primary tumour is necessary as part of curative therapy whether by primary or delayed resection, including the use of orthotopic liver transplantation. Unfortunately only about a third of newly diagnosed patients are amenable to resection at diagnosis.1 Neoadjuvant chemotherapy can render tumours in many of these patients resectable, but typically a quarter to a third of such patients might never get to resection. About a quarter of newly diagnosed patients present with metastatic disease and typically have had survival rates less than 30%.1 Whether these metastatic patients have better outcomes if their pulmonary disease is eradicated by chemotherapy or by surgical resection has never been formally studied and is not clear or known.

In The Lancet Oncology, József Zsiros and his SIOPEL colleagues2 are to be congratulated for their report of improvement in outcome of patients with high-risk hepatoblastoma, many of whom had pulmonary metastases. 3-year event-free survival was 76% (95% CI 65—87) in the 62 patients studied (77%, 95% CI 63—90, in the 39 patients with metastasis). This finding is perhaps the most substantial improvement in survival that has been described for children with solid tumours and metastatic disease in decades. Because cisplatin is thought to be the most active drug in this disease, the investigators used a novel, well designed therapeutic schema that incorporated weekly dose-dense cisplatin chemotherapy—revisiting an old basic tenet of chemotherapy administration that has never been fully evaluated in paediatric malignancies.3

The use of dose intensification of chemotherapy has had some success in adult malignancies but has been used rarely in paediatric cancers.4 Interval compression of chemotherapy has been shown to be effective in acute myeloid leukemia and Ewing’s sarcoma, although with substantial costs and burden of care, and is now being explored for rhabdomyosarcoma.5, 6Trials in patients with osteosarcoma have shown positive benefits in some trials but no effect in others.7 A previous hepatoblastoma trial from the Children’s Oncology Group (P9645)8 attempted to intensify platinum delivered therapy by alternating cisplatin and carboplatin on an every 2 week schedule. Ultimately, this regimen was inferior to the standard control group, perhaps because of decreased dose intensity of cisplatin.

The SIOPEL-4 trial seems to be a success. 60 (98%) of 61 evaluable patients had at least a partial response from preoperative chemotherapy. 19 of 20 with metastatic disease who had a complete response to chemotherapy alone remain disease-free after surgery, with only one patient having a recurrence. In view of these striking results, these data need to be validated in a large trial. Zsiros and colleagues correctly point out the limitations of this study being a single arm trial that compared outcomes with historical results and therefore needing further study before the approach can be adopted as standard of care. Although the investigators state that their regimen is feasible, the study was not truly designed with parameters to answer this question. The only statistical criterion the study met was that it did not exceed the number of expected serious adverse events, although 18 occurred, which seems quite generous for this sample size. 97% of patients had grade 3 or 4 haematological toxicity. This result is consistent with some studies in adults that have used a similar approach and might be regarded as acceptable.7 However, febrile neutropenia occurred in 71% of patients and four patients had toxic deaths (two from infection, one from surgical bleeding, and one with tumour bleeding). More than 50% of patients had with significant hearing loss. Since ototoxocity is difficult to measure, notoriously under-reported, and can progress over time, the question remains as to what hearing function these very young patients will have in the long run and whether this loss is an acceptable price to pay for the survival rates observed. Lastly, during the three cycles of weekly cisplatin therapy, patients typically had average cumulative delays of 10 days (range −4 to 63 days), which resulted in dose reductions in 9% of the initial chemotherapy block A cycles. Such delays might render a regimen not feasible. Interestingly, irrespective of delays in therapy, all patients did well. This outcome somewhat contradicts the study conclusion that dose intensity was the reason for improvement, since the outstanding results were even seen in patients who had delays and reductions in therapy (unless all patients exceeded the dose-density threshold).

Importantly, the entire international paediatric oncology community, including Europe, Japan, and South and North America, are now working together to create unified approaches to liver tumour classification and treatment and there are plans for a single forthcoming trial. The results here suggest that the SIOPEL-4 regimen should be compared in a randomised trial further evaluating the toxicities of this design. As exciting as these results are, they emphasise the urgent need for new drugs that hold the promise of a cure with acceptable long-term side-effects.

Source: Lancet

Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.

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Background

Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients.

Methods

This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m2 on day 1 of each cycle) and fluorouracil (1000 mg/m2 on days 1—4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265.

Findings

Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8—12·2) in the panitumumab group and 9·0 months (8·1—11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729—1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6—6·6) in the panitumumab group and 4·6 months (4·1—5·4) in the control group (HR 0·780, 95% CI 0·659—0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7—13·7] vs8·6 months [6·9—11·1]; HR 0·73 [95% CI 0·58—0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3—12·9] vs 12·6 months [7·7—17·4]; 1·00 [0·62—1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47—1·04]).

Interpretation

Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings.

Source: Lancet

Combination of Tetrandrine with cisplatin enhances cytotoxicity through growth suppression and apoptosis in ovarian cancer in vitro and in vivo

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Cisplatin, as a first-line drug in the chemotherapy of ovarian cancer, poses significant problems in its toxicity to normal tissue and drug resistance. Here, we report that Tetrandrine, with potent anti-cancer effect, significantly enhances the cytotoxicity of cisplatin in ovarian cancer. The in vitro assay indicates that Tetrandrine can markedly increase growth suppression and apoptosis induced by cisplatin and cause redistribution of the cell cycle. Further assay indicates that modulation of Wnt/cadherin signaling pathway contributes to the chemosensitizing effect of Tetrandrine on the cytotoxicity of cisplatin in ovarian cancer. In vivo, the combination of Tetrandrine and cisplatin exhibits the strongest anti-cancer effect compared with each drug alone, with no obvious additional toxicity. These results provide rational evidence supporting the application of Tetrandrine as an adjunct to cisplatin in improvement of chemotherapy in ovarian cancer.

source: cancer letter