2-year Locoregional Progression-free Survival Research Articles

Impact and optimal timing of local therapy addition in borderline resectable or locally advanced pancreatic cancer after FOLFIRINOX chemotherapy

BackgroundTo evaluate the efficacy and optimal timing of local treatment in patients with borderline resectable (BR) or locally advanced pancreatic cancer (LAPC) treated with upfront FOLFIRINOX. MethodBetween 2015 and 2020, 258 patients with pancreatic ductal adenocarcinoma (PDAC) were analysed. Treatment outcomes were compared between systemic treatment group (ST) and multimodality treatment groups (MT) using Kaplan–Meier curves and log-rank test. The MT were stratified as follows: FOLFIRINOX + radiation therapy (RT) (MT1), FOLFIRINOX + surgical resection (MT2), and FOLFIRINOX + RT + surgical resection (MT3). ResultsWith median follow-up period of 18 months, the 2-year overall survival (OS) for the ST was 22.0%, and it was significantly worse than MT (MT1, 46.3%; MT2, 65.7% and MT3; 90.2%; P < .001). The 2-year locoregional progression free survival (LRPFS) and overall PFS in ST were 10.7% and 7.0%, which were also significantly lower than those of MT (2-year LRPFS: MT1, 31.8%; MT2, 45.3%; MT3, 81.0%; 2-year overall PFS: MT1, 23.3%; MT2, 35.0%; MT3, 66.3%; P < .001). In time-varying multivariate Cox proportional hazard model, local treatment contributed to better treatment outcomes, with adjusted hazard ratios of 0.568 (95% confidence interval [CI], 0.398-0.811), 0.490 (95% CI, 0.331-0.726), and 0.656 (95% CI, 0.458–0.940) for OS, LRPFS, and overall PFS, respectively. The time window of 11–17 months after FOLFIRINOX appeared to demonstrate the maximal efficacy of local treatments in OS. ConclusionsAdding local treatment in BR/LAPC patients treated with upfront FOLFIRINOX seemed to contribute in improved treatment outcomes, and it showed maximal efficacy in OS when applied 11-17 months after the initiation of FOLFIRINOX. We suggest that administration of sufficient period of upfront FOLFIRINOX may intensify the efficacy of local treatments, and well controlled prospective trials are expected.

Safety and Efficacy of Concurrent or Sequential Radiotherapy Plus (PD-1) Inhibitors in Oligometastatic Esophageal Cancer.

We assess real-world outcomes, including safety and efficacy, of concurrent or sequential treatment with radiotherapy plus programmed cell death protein 1 (PD-1) inhibitors in patients with oligometastatic esophageal cancer (OMEC). This cohort study retrospectively collected clinical data of patients with synchronous or metachronous OMEC. All patients underwent concurrent or sequential treatment with radiotherapy plus PD-1 inhibitors. Each patient had up to five measurable metastatic lesions and up to three organs involved. Study endpoints were progression-free survival (PFS), treatment-related toxicities, locoregional progression-free survival (LRPFS), objective response rate (ORR), and disease control rate (DCR). Description statistics and Kaplan-Meier models were used for statistical analysis. A total of 86 patients were included, most of whom were diagnosed with squamous cell carcinoma histology (98%) and presented with synchronous OMEC (64%). The median follow-up period was 17 months (range: 6-32 months), the median PFS was 15.2 months (95% confidence interval: 12.1-18.2 months); and the 1- and 2-year PFS rates were 61.4% and 26.7%, respectively. The 1- and 2-year LRPFS were 91.3% and 57.3%, respectively. The ORR and DCR were 46.5% and 91.8%, respectively. Forty-two patients (48.8%) experienced grade 3 or higher treatment-related adverse events (TRAEs); a grade 5 treatment-related adverse event was observed in one patient (1.2%) who died of immune-related pneumonitis. Combining radiotherapy with PD-1 inhibitors is a safe and effective treatment option for patients with OMEC. No new safety concerns were identified in this study. However, due to the potential risk of cumulative toxicity, an individual risk-benefit assessment for each patient is required prior to treatment initiation.

Comparing the outcomes of MR-based versus CT-based tumor delineation in locally advanced non-small cell lung cancer treated with hypo-fractionated radiotherapy and concurrent chemotherapy.

Delineating gross tumor volume (GTV) using computed tomography (CT) imaging is the standard for lung cancer contouring, but discrepancies among observers compromise accuracy and reliability. Magnetic resonance imaging (MRI) provides superior soft-tissue resolution compared to CT, thus, we design this retrospective study to compare the treatment outcomes of magnetic resonance-based (MR-based) and CT-based tumor delineation in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with hypo-fractionated concurrent chemoradiotherapy (hypo-CCRT). A total of 293 LA-NSCLC patients treated with hypo-CCRT from three trials between October 2015 and October 2020 were screened. Ninety patients with each MR-based delineation and CT-based delineation of the primary tumor were selected for analysis. In the MR-based delineation group, T1-enhanced MR images was rigidly registered with 10 respiratory phases of planning CT images, respectively. The primary tumors were contoured on each respiratory phase based on co-registered MRI. The locoregional progression-free survival (LPFS), progression-free survival (PFS), overall survival (OS) and toxicities in both groups were analyzed. The 2-year LPFS rate was 69.2% [95% confidence interval (CI): 59.6-80.2%] in the MR-based delineation group and 61.0% (95% CI: 50.9-73.0%) in the CT-based delineation group (P=0.37). There was no significant difference in median PFS (P=0.45) or OS (P=0.69) between the two groups. The MR-based delineation group had smaller planning target volume (186.1 vs. 315.3 cm3, P<0.001), lower incidences of ≥G2 pneumonitis (10% vs. 24.4%, P=0.001) and ≥G3 esophagitis (2.2% vs. 15.6%, P<0.001). In evaluating the patterns of recurrence, in-field recurrences were the dominant type in both groups (21 out of 27 patients in MR-based delineation group, 24 out of 32 patients in CT-based delineation group). MR-based delineation in hypo-CCRT was feasible and achieved similar treatment efficacy to CT-based delineation. The use of MR imaging to reduce the target volume resulted in promising local control and lower incidence of radiation-induced toxicities.

Exclusive Chemoradiotherapy With or Without Radiation Dose Escalation in Esophageal Cancer: Multicenter Phase 2/3 Randomized Trial CONCORDE (PRODIGE-26)

Increasing dose of chemoradiotherapy in locally advanced esophageal cancer unsuitable for surgery has been a matter of debate in the last 2 decades. Advances in tumor staging and radiation targeting with modern imaging and IMRT should allow further testing exclusive radiation dose escalation in esophageal cancer.We performed a multicenter, randomized, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 28 centers in France between 07/06/2011 and 11/10/2019. Eligible participants had confirmed stage I-III biopsy proven esophageal carcinoma, ECOG 0-2 and sufficient caloric intake. Patients were randomly assigned (1:1) to receive 50Gy in 25 fractions over 5 weeks (standard arm) or 66Gy in 33 fractions over 6.5 weeks (experimental arm). Elective nodal irradiation (40Gy) was delivered in both groups. Concomitant chemotherapy was FOLFOX-4 for 3 courses followed by 3 adjuvant courses. Random allocation to treatment groups was done by a central computerized randomization procedure by minimization, stratified by center, histology, weight loss, and technique of radiotherapy. The primary endpoint was 2-year locoregional progression-free survival (LRPFS).109 participants were randomly allocated to the 50Gy arm and 108 to the 66Gy group (intention-to-treat population). 177 men (81.6%) and 40 women (18.4%) were included with a mean age of 62.6 years (± 7.8). 191 patients (88.4%) had squamous cell cancer and 25 (11.6%) has adenocarcinoma. Most of the patients had stage III tumors (74% vs 26% for stage I-II). IMRT was delivered in 169 patients (80.1%) and 3D conformal in 42 patients (19.9%). 59 patients (54.1%) have died in the 50Gy group and 65 patients (60.2%) in the 66Gy group with a median follow up 35.3 months (range: 2.0-65.7) and 35.5 months (range: 1.3-60.7), respectively. Median overall survival was 25.2 months (95% CI 17.8-NR) in the 50Gy group and 23.5 months (14.5-32.2) in the 66Gy group (HR 1.14, 95% CI 0.82-1.59; P = 0.44). Median LRPFS was 16.2 months (95% CI 10.9-26.0) in the 50Gy group and 18.4 months (12.2-25.7) in the 66Gy group (HR 1.03, 95% CI 0.75-1.40; P = 0.88). The 2-year LRPFS rates were 42.7% (95% CI 33.2%-51.8%) and 43.8% (95% CI 34.1%-54.1%). No significant differences were recorded in the rates of late adverse events between the treatment groups (P = 0.14). The rates of grade 3/4 toxicities in the 50Gy group were 29.5%/0% and 24.0%/5.3% in the 66Gy group. 5 toxic deaths (4.6%) occurred in the 50Gy group and 7 (6.7%) in the 66Gy group. One and 2 toxic deaths out of the 5 in the 50Gy were related to radiotherapy or chemotherapy, respectively. Two and 3 out of the 7 toxic deaths in the 66Gy were related to radiotherapy or chemotherapy, respectively.Dose escalated chemoradiotherapy delivering 66Gy is not more toxic than 50Gy but did not improve locoregional progression-free survival. Chemoradiotherapy delivering 50Gy should be definitely admitted as a standard dose.

Prognostic value of neutrophil-to-lymphocyte ratio in locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy.

PurposeThis study aimed to investigate neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors in patients with locally advanced non-small cell lung cancer (NSCLC) who received concurrent chemoradiotherapy (CCRT).Materials and MethodsWe retrospectively analyzed 66 patients with locally advanced NSCLC treated with definitive CCRT. Among these patients, 95% received paclitaxel/carboplatin or docetaxel/cisplatin. The median radiation dose was 66 Gy in 33 fractions. The NLR and PLR before/after CCRT were evaluated. The maximally selected log-rank test was used to obtain the cutoff values related to the overall survival (OS).ResultsPatients with high post-CCRT NLR (>3.12) showed worse OS, locoregional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS) than those with low NLR (2-year OS: 25.8% vs. 68.2%, p < 0.001; 2-year LRPFS: 12.9% vs. 33.8%, p = 0.010; 2-year DMFS: 22.6% vs. 38.2%, p = 0.030). Patients with high post-CCRT PLR (>141) showed worse OS and LRPFS than those with low PLR (2-year OS: 37.5% vs. 71.1%, p = 0.004; 2-year LRPFS: 16.5% vs. 40.3%, p = 0.040). Patients with high NLR change (>1.61) showed worse OS and LRPFS than those with low NLR change (2-year OS: 26.0% vs. 59.0%, p < 0.001; 2-year LRPFS: 6.8% vs. 31.8%, p = 0.004). The planning target volume (hazard ration [HR] = 2.05, p = 0.028) and NLR change (HR = 3.17, p = 0.025) were the significant factors for OS in the multivariate analysis.ConclusionNLR change after CCRT was associated with poor prognosis of survival in patients with locally advanced NSCLC. An elevated NLR after CCRT might be an indicator of an increased treatment failure risk.

Locally advanced inoperable primary or recurrent non-small cell lung cancer treated with 4-week hypofractionated radiation therapy (3Gy/fraction).

The prognosis of locally advanced non-small cell lung cancer (NSCLC) treated with conventional radiotherapy remains poor. Hypofractionation reduces overall treatment time increasing biological effect in patients not suitable for concurrent chemo-radiotherapy. From January 2009 to October 2016, 76 inoperable locally advanced primary or recurrent NSCLC patients were treated with 60Gy in 20 fractions of 3Gy/each for 4weeks as exclusive or post-chemotherapy treatment. Fifty-eight patients (76.3%) had stage III and 18 (23.7%) stage IV (≤ 2 metastases) disease: 63 primary (82.9%) and 13 recurrent (17.1%). Median and 2-year overall survival were 17months and 38.9%, respectively. Median and 2-year loco-regional progression free survival were 27months and 55.3%, respectively. Univariate and multivariate analyses demonstrated that patients with complete response presented better outcomes, whereas no statistically relevant difference was evidenced in terms of previous chemotherapy, recurrent vs primary disease, volume and stage. Thirty patients (39.5%) presented acute esophagitis (1-grade 3) and 19 (25.0%) acute pneumonitis (2-grade 3). Six patients (7.9%) developed grade 2-3 late pneumonitis and 3 patients (3.9%) grade 1 late esophagitis. In patients not suitable of concurrent radio-chemotherapy, exclusive or sequential hypofractionated schedule using 60Gy in 20 fractions was well tolerated and presented promising results. Complete local response was a predictor of better outcomes, and any efforts will be made to perform prospective clinical trials to further evaluate hypofractionated regimens with increased lesional BED.

Inoperable early-stage primary and early recurrent non-small cell lung cancer: outcomes of a mono-institutional experience using a moderate hypofractionated schedule

Patients with medically inoperable early-stage non-small cell lung cancer (NSCLC) may beneficiate of a hypofractionated radiation therapy in order to intensificate the treatment and to reduce the number of hospital access. From 2007 to 2015, 27 patients with early-stage primary or limited loco-regional recurrent (T2a > 4cm, T2b N0 or T1-2 N1M0) NSCLC were treated. All patients were medically inoperable or refused surgery and were treated with 60Gy in 20 fractions, 5 times per week. Thirteen (48.1%) presented limited recurrence after surgery and 14 (51.9%) primary disease. Median follow-up was 34months. Twelve patients achieved a CR (44.4%) and 8 a PR (29.6%) with a tumour response rate of 74%. Median overall survival (OS) and 2-year OS were 34months and 63.0%, respectively. Median and 2-year loco-regional progression-free survival (LR-PFS) were 31months and 51.4%, respectively. Survival outcomes were statistically favourable in patients with partial or complete response with respect to patients with stable or progressive disease, whereas stage (N0 vs N1) and primary or relapse/recurrent disease not. No cases of acute toxicity > grade 2 were observed. Seven patients (25.9%) presented grade 2 late toxicities. Sixty Gy in 20 fractions is well tolerated and achieves good clinical outcomes in early primary or recurrent NSCLC patients. A greater number of patients and a longer follow-up are necessary to confirm the results obtained with our treatment.

Phase 2 Trial of Intensity-Modulated Radiation Therapy +/- Concurrent Doxorubicin for Patients With Locally Advanced or Recurrent Non-anaplastic Thyroid Cancer

Given a lack of prospective studies, the use of radiotherapy in the treatment of advanced non-anaplastic thyroid remains controversial. The addition of radiotherapy can potentially limit the associated morbidity with uncontrolled locoregional disease. The purpose of this study was to evaluate the efficacy and tolerability of radiation therapy with or without concurrent chemotherapy in patients with locally advanced non-anaplastic thyroid carcinoma. This was a single-institution non-randomized phase II study for patients with gross residual or unresectable non-anaplastic thyroid carcinoma treated with intensity-modulated radiotherapy (IMRT) with or without concurrent doxorubicin (10mg/m2) (NCT01882816). The primary endpoint was 2-year locoregional progression free survival. Secondary endpoints included overall survival, safety and tolerability. Among 27 evaluable patients enrolled in this study, there were 11 (40.7%) females and 16 (59.3%) males with a median age of 63.9 years (range, 30-83.2 years). Twelve patients (44.4%) had unresectable disease and 15 (55.6%) had gross residual disease. The median number of prior surgeries was 1.0 (range, 0-3). Sixteen (59.3%) patients received prior radioactive iodine therapy. The median IMRT dose was 70Gy. Twenty-six of 27 patients (92.5%) completed the full planned treatment course. One patient was switched to a palliative regimen after 10 fractions (21.2Gy) secondary to rapid tumor progression. A second patient elected to abort therapy against medical advice after 29 fractions (58Gy). Acute treatment related toxicity, regardless of attribution, included dermatitis, mucositis, and dysphagia with limited grade ≥3 toxicity with rates of 22.2%, 7.4%, and 7.4%, respectively. No elective tracheostomy or feeding tubes were placed. Three patients required a tracheostomy, 1 of which was placed for disease progression while the remaining 2 were placed for laryngeal edema, and 2 patients required a feeding tube during or within 90 days of IMRT completion. The incidence of late toxicity was low. With a median follow-up of 23.2 months among surviving patients, the 2-year Kaplan-Meier estimate of locoregional progression free survival and overall survival was 84.1% and 73.1%, respectively. Intensity modulated radiation therapy +/- concurrent doxorubicin was well tolerated and associated with favorable efficacy outcomes in patients with locally advanced non-anaplastic thyroid carcinoma.

Early treatment volume reduction rate as a prognostic factor in patients treated with chemoradiotherapy for limited stage small cell lung cancer.

PurposeTo investigate the relationship between early treatment response to definitive chemoradiotherapy (CRT) and survival outcome in patients with limited stage small cell lung cancer (LS-SCLC).Materials and MethodsWe retrospectively reviewed 47 patients with LS-SCLC who received definitive CRT between January 2009 and December 2012. Patients were treated with systemic chemotherapy regimen of etoposide/carboplatin (n = 15) or etoposide/cisplatin (n = 32) and concurrent thoracic radiotherapy at a median dose of 54 Gy (range, 46 to 64 Gy). Early treatment volume reduction rate (ETVRR) was defined as the percentage change in gross tumor volume between diagnostic computed tomography (CT) and simulation CT for adaptive RT planning and was used as a parameter for early treatment response. The median dose at adaptive RT planning was 36 Gy (range, 30 to 43 Gy), and adaptive CT was performed in 30 patients (63.8%).ResultsWith a median follow-up of 27.7 months (range, 5.9 to 75.8 months), the 2-year locoregional progression-free survival (LRPFS) and overall survival (OS) rates were 74.2% and 56.5%, respectively. The mean diagnostic and adaptive gross tumor volumes were 117.9 mL (range, 5.9 to 447 mL) and 36.8 mL (range, 0.3 to 230.6 mL), respectively. The median ETVRR was 71.4% (range, 30 to 97.6%) and the ETVRR >45% group showed significantly better OS (p < 0.0001) and LRPFS (p = 0.009) than the other group.ConclusionETVRR as a parameter for early treatment response may be a useful prognostic factor to predict treatment outcome in LS-SCLC patients treated with CRT.

Salvage Re-Irradiation for Recurrent Head and Neck Cancer

To present a retrospective review of treatment outcomes for recurrent head and neck (HN) cancer patients treated with re-irradiation (re-RT) at a single medical center. From July 1996-September 2005, 105 patients with recurrent HN cancer underwent re-RT at our institution. Sites included were: the neck (n = 21), nasopharynx (n = 21), paranasal sinus (n = 18), oropharynx (n = 16), oral cavity (n = 9), larynx (n = 10), parotid (n = 6), and hypopharynx (n = 4). The median prior RT dose was 62 Gy. Seventy-five patients received chemotherapy with their re-RT (platinum-based in the majority of cases). The median re-RT dose was 59.4 Gy. In 74 (70%), re-RT utilized intensity-modulated radiation therapy (IMRT). With a median follow-up of 35 months, 18 patients were alive with no evidence of disease. The 2-year loco-regional progression-free survival (LRPFS) and overall survival rates were 42% and 37%, respectively. Patients who underwent IMRT, compared to those who did not, had a better 2-year LRPF (52% vs. 20%, p < 0.001). On multivariate analysis, non-nasopharynx and non-IMRT were associated with an increased risk of loco-regional (LR) failure. Patients with LR progression-free disease had better 2-year overall survival vs. those with LR failure (56% vs. 21%, p < 0.001). Acute and late Grade 3-4 toxicities were reported in 23% and 15% of patients. Severe Grade 3-4 late complications were observed in 12 patients, with a median time to development of 6 months after re-RT. Based on our data, achieving LR control is crucial for improved overall survival in this patient population. The use of IMRT predicted better LR tumor control. Future aggressive efforts in maximizing tumor control in the recurrent setting, including dose escalation with IMRT and improved chemotherapy, are warranted.