Fractionated Scheme of Oral Vinorelbine as Single-Agent Therapy or in Combination With Cisplatin Concomitantly With Thoracic Radiotherapy in Stage III Non–Small-Cell Lung Cancer: Dose-Escalation Phase I Trial

IntroductionA dose-determination study was conducted in untreated stage III non–small-cell lung cancer to assess continuous exposure to fractionated oral vinorelbine (NVBo), a radiosensitizer, during the radiotherapy period, either alone (first cohort) or in combination with cisplatin (second cohort).Patients and MethodsThree patients with stage IIIAN2/IIIB were expected at each dose level, with 3 additional patients in case of dose-limiting toxicity (DLT). Concomitantly with a 60-Gy total dose of radiotherapy, NVBo was given from 60 mg up to 180 mg total dose per week split on days 1, 3, and 5. Once the maximum tolerated dose (MTD), defined as 2 DLTs in a dose level, was determined and the recommended dose of NVBo alone was established, the trial assessed its recommended dose in combination with cisplatin 80 mg/m² every 3 weeks.ResultsIn the first cohort, 26 patients were enrolled. MTD was 160 mg/wk; there were 3 cases of grade 3 esophagitis and 1 of grade 3 pneumonia as DLT out of 5 patients in this dose level. In the recommended dose level (150 mg/wk), only 1 of 6 patients experienced a DLT. In the second cohort, 11 patients received NVBo weekly doses from 130 mg to 150 mg with cisplatin. Only 2 patients received 150 mg/wk NVBo; the trial closed before MTD was determined. The confirmed response rates were 42% and 55% in the first and second cohort, respectively.ConclusionThe recommended dose of this fractionated NVBo scheme as single-agent therapy concomitantly with radiotherapy for 6 weeks is 50 mg on days 1, 3, and 5 (150 mg/wk); combined with cisplatin 80 mg/m² every 3 weeks, the dose should be 140 to 150 mg/wk adapted on hematology. The response rate is promising.     

The Development of Therapeutic Radiographers in Imaging and Adaptive Radiotherapy Through Clinical Trial Quality Assurance

AimsAdaptive radiotherapy (ART) is an emerging advanced treatment option for bladder cancer patients. Therapeutic radiographers (RTTs) are central to the successful delivery of this treatment. The purpose of this work was to evaluate the image-guided radiotherapy (IGRT) and ART experience of RTTs before participating in the RAIDER trial. A plan of the day (PoD) quality assurance programme was then implemented. Finally, the post-trial experience of RTTs was evaluated, together with the impact of trial quality assurance participation on their routine practice.Materials and methodsA pre-trial questionnaire to assess the experience of the RTT staff group in IGRT and ART in bladder cancer was sent to each centre. Responses were grouped according to experience. The PoD quality assurance programme was implemented, and the RAIDER trial commenced. During stage 1 of the trial, RTTs reported difficulties in delivering PoD and the quality assurance programme was updated accordingly. A follow-up questionnaire was sent assessing experience in IGRT and ART post-trial. Any changes in routine practice were also recorded.ResultsThe experience of RTTs in IGRT and ART pre-trial varied. For centres deemed to have RTTs with more experience, the initial PoD quality assurance programme was streamlined. For RTTs without ART experience, the full quality assurance programme was implemented, of which 508 RTTs completed. The quality assurance programme was updated (as the trial recruited) and it was mandated that at least one representative RTT (regardless of pre-trial experience) participated in the update in real-time. The purpose of the updated quality assurance programme was to provide further support to RTTs in delivering a complex treatment. Engagement with the updated quality assurance programme was high, with RTTs in 24/33 centres participating in the real-time online workshop. All 33 UK centres reported all RTTs reviewed the updated training offline. Post-trial, the RTTs' experience in IGRT and ART was increased.ConclusionOverall, 508 RTTs undertook the PoD quality assurance programme. There was a high engagement of RTTs in the PoD quality assurance programme and trial. RTTs increased their experience in IGRT and ART and subsequently updated their practice for bladder cancer and other treatment sites.     

Durvalumab After Sequential Chemoradiotherapy in Stage III,Unresectable NSCLC: The Phase 2 PACIFIC-6 Trial

IntroductionOn the basis of the findings of the phase 3 PACIFIC trial (NCT02125461), durvalumab is standard of care for patients with stage III, unresectable NSCLC and no disease progression after concurrent chemoradiotherapy (cCRT). Many patients are considered unsuitable for cCRT owing to concerns with tolerability. The phase 2 PACIFIC-6 trial (NCT03693300) evaluates the safety and tolerability of durvalumab after sequential CRT (sCRT).MethodsPatients with stage III, unresectable NSCLC and no progression after platinum-based sCRT were enrolled to receive durvalumab (1500 mg intravenously) every 4 weeks for up to 24 months. The primary end point was the incidence of grade 3 or 4 adverse events possibly related to treatment occurring within 6 months. Secondary end points included investigator-assessed progression-free survival (PFS; Response Evaluation Criteria in Solid Tumors version 1.1) and overall survival.ResultsOverall, 117 patients were enrolled (59.8% with performance status >0, 65.8% aged ≥65 y, and 37.6% with stage IIIA disease). Median treatment duration was 32.0 weeks; 37.6% of patients remained on treatment at data cutoff (July 15, 2021). Grade 3 or 4 AEs occurred in 18.8% of patients. Five patients had grade 3 or 4 possibly related adverse events within 6 months (incidence: 4.3%; 95% confidence interval: 1.4–9.7), including two pneumonitis cases. Two patients (1.7%) had grade 5 AEs of any cause. Survival data maturity was limited. Median PFS was 10.9 months (95% confidence interval: 7.3–15.6), and 12-month PFS and overall survival rates were 49.6% and 84.1%, respectively.ConclusionsDurvalumab after sCRT had a comparable safety profile with that observed with durvalumab after cCRT in PACIFIC and had encouraging preliminary efficacy in a frailer population.     

Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study

IntroductionThe phase 3 PACIFIC trial established consolidation therapy with durvalumab as standard of care for patients with unresectable, stage III NSCLC and no disease progression after definitive chemoradiotherapy (CRT). The observational PACIFIC-R study assesses the real-world effectiveness of durvalumab in patients from an early access program. Here, we report treatment characteristics and a preplanned analysis of real-world progression-free survival (rwPFS).MethodsPACIFIC-R (NCT03798535) is an ongoing, international, retrospective study of patients who started durvalumab (intravenously; 10 mg/kg every 2 wk) within an early access program between September 2017 and December 2018. The primary end points are investigator-assessed rwPFS and overall survival (analyzed by Kaplan–Meier method).ResultsAs of November 30, 2020, the full analysis set comprised 1399 patients from 11 countries (median follow-up duration, 23.5 mo). Patients received durvalumab for a median of 11.0 months. Median rwPFS was 21.7 months (95% confidence interval: 19.1–24.5). RwPFS was numerically longer among patients who received concurrent versus sequential CRT (median, 23.7 versus 19.3 mo) and among patients with programmed cell death-ligand 1 expression greater than or equal to 1% versus less than 1% (22.4 versus 15.6 mo). Overall, 16.5% of the patients had adverse events leading to treatment discontinuation; 9.5% of all patients discontinued because of pneumonitis or interstitial lung disease.ConclusionsConsolidation durvalumab after definitive CRT was well tolerated and effective in this large, real-world cohort study of patients with unresectable, stage III NSCLC. As expected, rwPFS was longer among patients who received concurrent versus sequential CRT and patients with higher programmed cell death-ligand 1 expression. Nevertheless, favorable rwPFS outcomes were observed regardless of these factors.     

Weekly cisplatin or gemcitabine concomitant with radiation in the management of locally advanced carcinoma cervix: results from an observational study

Objective

The use of non-platinum drugs in concurrent chemoradiation in carcinoma cervix has not been well explored and hence a two arm study was planned to compare the outcome of concomitant cisplatin or gemcitabine in locally advanced carcinoma cervix.

Methods

Thirty six patients were evaluated in this study for response rates and complications. These patients were divided into two arms, sixteen patients in the cisplatin arm and twenty patients in the gemcitabine arm. Cisplatin and gemcitabine were given as i.v. infusion at doses of 40 mg/m² and 150 mg/m² respectively for five weeks concomitant with radiotherapy. All patients had received pelvic radiotherapy to a dose of 50 Gy/25 fraction/5 weeks by four field box technique followed by high-dose-rate brachytherapy (3 sessions, each of 7.5 Gy to point A).

Results

Median follow up was of 10.4 months (range, 3 to 36 months) and 10.9 months (range, 2 to 49 months) in the cisplatin and gemcitabine arms, respectively. At first follow up, 68.8% in the cisplatin arm and 70% in the gemcitabine arm had achieved complete response (p=0.93). Similar response rates were noted in different stages in both arms. None of the patients except one developed grade 4 toxicity. Similar toxicity profiles were observed in both arms. Local disease control, distant disease free survival and overall survival was 68.8% vs. 70%, 93.8% vs. 85%, 68.8% vs. 60% in the cisplatin and gemcitabine arms, respectively.

Conclusion

Weekly gemcitabine had similar disease control and tolerable toxicity profile with cisplatin. Gemcitabine may be used as an alternative to cisplatin in patients with compromised renal function.     

周剂量紫杉醇治疗晚期高龄非小细胞肺癌的临床研究

目的：探讨周剂量紫杉醇治疗70岁以上晚期高龄非小细胞肺癌的临床疗效和毒副反应.方法：采用紫杉醇60mg/m2/w.连用2w和（或）3w,每3～4周重复,2～4周期化疗后进行评价.结果：全组32例,总有效率37.5%;其中18例初治有效率为44.4%,CR1例,14例复治病例,有效率为35.7%.毒副反应为Ⅰ～Ⅱ度白细胞下降和周围神经毒性及消化道反应.结论：周剂量紫杉醇可作为治疗70岁以上晚期高龄非小细胞肺癌患者的安全有效的化疗方案之一.     

非小细胞肺癌脑转移铂类化疗同步放疗或序贯放化疗的疗效分析

目的 探讨铂类化疗同步放疗或序贯放化疗对非小细胞肺癌(NSCLC)脑转移患者的临床治疗效果和不良反应情况.方法 回顾性分析103例NSCLC脑转移患者的临床相关资料,根据其治疗方法不同分为A组和B组,A组患者采用铂类化疗同步脑放疗进行治疗,共46例;B组采用铂类化疗序贯脑放疗进行治疗,共57例.结果 A组患者和B组患者的总体ORR分别为19.6％和26.3％,脑转移灶的ORR分别为43.5％和29.8％,差异均无统计学意义(P均＞0.05).A组患者和B组患者的脑转移灶未加量照射总体ORR分别为43.5％和10.5％,差异显著(P＜0.05),A、B两组患者的1年生存率分别是58.5％和52.9％,差异不显著(P＞0.05);2年生存率分别是37.2％和18.9％,A组显著高于B组(P＜0.05).A组无Ⅳ度血小板和白细胞减少情况;B组无Ⅳ度血小板减少情况,但Ⅳ度白细胞减少发生率为15.8％.A组患者和B组患者的白细胞减少发生情况比较差异显著(P＜0.05),血小板和血红蛋白减少的发生情况不存在显著性差异(P＞0.05).结论 全身化疗同步放疗治疗NSCIC脑转移相比序贯放化疗有更好的治疗效果,且安全性更好.     

Skin Toxicity in Early Breast Cancer Patients Treated with Field-In-Field Breast Intensity-Modulated Radiotherapy versus Helical Inverse Breast Intensity-Modulated Radiotherapy: Results of a Phase III Randomised Controlled Trial

AimsSkin toxicity is a common adverse effect of breast radiotherapy. We investigated whether inverse-planned intensity-modulated radiotherapy (IMRT) would reduce the incidence of skin toxicity compared with forward field-in-field breast IMRT (FiF-IMRT) in early stage breast cancer.Materials and methodsThis phase III randomised controlled trial compared whole-breast irradiation with either FiF-IMRT or helical tomotherapy IMRT (HT-IMRT), with skin toxicity as the primary end point. Patients received 50 Gy in 25 fractions and were assessed to compare skin toxicity between treatment arms.ResultsIn total, 177 patients were available for assessment and the median follow-up was 73.1 months. Inverse IMRT achieved more homogeneous coverage than FiF-IMRT; erythema and moist desquamation were higher with FiF-IMRT compared with HT-IMRT (61% versus 34%; P < 0.001; 33% versus 11%; P < 0.001, respectively). Multivariate analysis showed large breast volume, FiF-IMRT and chemotherapy were independent factors associated with worse acute toxicity. There was no difference between treatment arms in the incidence of late toxicities. The 5-year recurrence-free survival was 96.3% for both FiF-IMRT and HT-IMRT and the 5-year overall survival was 96.3% for FiF-IMRT and 97.4% for HT-IMRT.ConclusionsOur study showed significant reduction in acute skin toxicity using HT-IMRT compared with FiF-IMRT, without significant reduction in late skin toxicities. On the basis of these findings, inverse-planned IMRT could be used in routine practice for whole-breast irradiation with careful plan optimisation to achieve the required dose constraints for organs at risk.     

Multimodal Treatment in Operable Stage III NSCLC: A Pooled Analysis on Long-Term Results of Three SAKK trials (SAKK 16/96, 16/00, and 16/01)

Introduction

Long-term data on outcomes of operable stage III NSCLC are scarce.

Adaptive Radiotherapy in the Management of Cervical Cancer: Review of Strategies and Clinical Implementation

The complex and varied motion of the cervix–uterus target during external beam radiotherapy (EBRT) underscores the clinical benefits afforded by adaptive radiotherapy (ART) techniques. These gains have already been realised in the implementation of image-guided adaptive brachytherapy, where adapting to anatomy at each fraction has seen improvements in clinical outcomes and a reduction in treatment toxicity. With regards to EBRT, multiple adaptive strategies have been implemented, including a personalised internal target volume, offline replanning and a plan of the day approach. With technological advances, there is now the ability for real-time online ART using both magnetic resonance imaging and computed tomography-guided imaging. However, multiple challenges remain in the widespread dissemination of ART. This review investigates the ART strategies and their clinical implementation in EBRT delivery for cervical cancer.