Long-term results from a clinical study of xevinapant plus chemoradiotherapy in people with high-risk locally advanced squamous cell carcinoma of the head and neck: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Squamous cell carcinoma of the head and neck (SCCHN) is the most common type of head and neck cancer. About half of the people with locally advanced (LA) SCCHN will have surgery to remove their cancer. For people who do not have surgery, chemoradiotherapy is the standard treatment, with the aim of fully removing the cancer. However, in many people, this treatment does not completely kill the cancer. This summary presents the main results of a phase 2 study of a medicine called xevinapant, which is under investigation as a potential future medicine for people with this type of cancer. WHAT DID THE RESEARCHERS WANT TO FIND OUT?: In this study, researchers wanted to find out whether xevinapant plus chemoradiotherapy could stop the cancer from growing back or getting worse in the years after treatment completion in people with LA SCCHN. They also looked at whether people with this type of cancer had side effects from taking this medicine. Short-term results were collected 18 months after treatment with chemoradiotherapy ended. These results showed that people who received xevinapant plus chemoradiotherapy were less likely to have their cancer grow back, or get worse in the part of the body where it was first found, than people who received liquid placebo-which looked and tasted the same as the active medicine (in this case, xevinapant), but did not contain any medicine-plus chemoradiotherapy. Researchers then continued to collect information for a longer amount of time (at least 3 years). They wanted to see if treatment with xevinapant plus chemoradiotherapy was stopping the cancer from growing back or getting worse and helping people live longer. After this, people were monitored for a further 2 years to see if they were alive 5 years after treatment. WHAT WERE THE MAIN FINDINGS OF THE STUDY?: The results showed that people with this type of cancer who were treated with xevinapant plus chemoradiotherapy were less likely to die, lived longer on average, and were less likely to have their cancer get worse. A phase 3 study, named TrilynX, in a larger group of people, is currently taking place to confirm the results of this study. Clinical Trial Registration: NCT02022098 (Debio 1143-201 Dose-finding and Efficacy Phase I/II Trial) (ClinicalTrials.gov).

Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study.

BACKGROUND: Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck. METHODS: This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18-75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0-3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1-14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting. FINDINGS: Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6-29·4) in the Debio 1143 group and 24·2 months (6·6-26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39-69) of 48 patients in the Debio 1143 group versus 16 (33%; 20-48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13-6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3-4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group. INTERPRETATION: To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients. FUNDING: Debiopharm.

Approach to oligometastatic disease in head and neck cancer, on behalf of the GORTEC.

Median survival for recurrent/metastatic head and neck squamous cell cancer (HNSCC) patients is about 10 months after first-line best systemic treatment. We aimed to assess current approaches of oligometastatic HNSCC patients by the analysis of current concept and published data (1995-2017) in this population. Five-year survival rates are over 20% in selected patients who undergo metastasis-directed therapy by either surgery or stereotactic irradiation. Human papillomavirus(+) HNSCC patients have more disseminated metastases but respond more favorably and also benefit from ablative treatments. Treatments of oligometastases are expanding rapidly. Unmet needs include revised imaging follow-up strategies to detect metastases earlier, identification of predictive noninvasive biomarkers for treatment guidance, assessment and corrections of biases in current studies and randomized clinical trials.

Standard versus fractionated high-dose cisplatin plus radiation for locally advanced head and neck cancer: Results of the CisFRad (GORTEC 2015-02) randomized phase II trial.

BACKGROUND: Chemoradiotherapy with high-dose cisplatin (HD-Cis: 100 mg/m2 q3w for three cycles) is the standard of care (SOC) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Cumulative delivered dose of cisplatin is prognostic of survival, even beyond 200 mg/m2 but high toxicity compromises its delivery. AIM: Cisplatin fractionation may allow, by decreasing the peak serum concentration, to decrease toxicity. To date, no direct comparison was done of HD-Cis versus fractionated high dose cisplatin (FHD-Cis). METHODS: This is a multi-institutional randomized phase II trial, stratified on postoperative or definitive chemoradiotherapy, comparing HD-Cis to FHD-Cis (25 mg/m2/d d1-4 q3w for 3 cycles) in patients with LA-HNSCC. The primary endpoint was the cumulative delivered cisplatin dose. RESULTS: Between December 2015 and April 2018, 124 patients were randomized. Median cisplatin cumulative delivered dose was 291 mg/m2 (IQR: 251;298) in the FHD-Cis arm and 274 mg/m2 (IQR: 198;295) in the HD-Cis arm (P = 0.054). The proportion of patients receiving a third cycle of cisplatin was higher, with a lower proportion of grade 3-4 acute AEs in the FHD-Cis arm compared to the HD-Cis arm: 81 % vs. 64 % (P = 0.04) and 10 % vs. 17 % (P = 0.002), respectively. With a median follow-up of 48 months (IQR: 41;55), locoregional failure rate, PFS and OS were similar between the two arms. CONCLUSION: Although the primary endpoint was not met, FHD-Cis allowed more cycles of cisplatin to be delivered with lower toxicity, when compared to SOC. FHD-Cis concurrently with RT is a treatment option which deserves further consideration.

Extended follow-up of a phase 2 trial of xevinapant plus chemoradiotherapy in high-risk locally advanced squamous cell carcinoma of the head and neck: a randomised clinical trial.

INTRODUCTION: We report long-term efficacy and overall survival (OS) results from a randomised, double-blind, phase 2 study (NCT02022098) investigating xevinapant plus standard-of-care chemoradiotherapy (CRT) vs. placebo plus CRT in 96 patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). METHODS: Patients were randomised 1:1 to xevinapant 200 mg/day (days 1-14 of a 21-day cycle for 3 cycles), or matched placebo, plus CRT (cisplatin 100 mg/m2 every 3 weeks for 3 cycles plus conventional fractionated high-dose intensity-modulated radiotherapy [70 Gy/35 F, 2 Gy/F, 5 days/week for 7 weeks]). Locoregional control, progression-free survival, and duration of response after 3 years, long-term safety, and 5-year OS were assessed. RESULTS: The risk of locoregional failure was reduced by 54% for xevinapant plus CRT vs. placebo plus CRT but did not reach statistical significance (adjusted hazard ratio [HR] 0.46; 95% CI, 0.19-1.13; P = .0893). The risk of death or disease progression was reduced by 67% for xevinapant plus CRT (adjusted HR 0.33; 95% CI, 0.17-0.67; P = .0019). The risk of death was approximately halved in the xevinapant arm compared with placebo (adjusted HR 0.47; 95% CI, 0.27-0.84; P = .0101). OS was prolonged with xevinapant plus CRT vs. placebo plus CRT; median OS not reached (95% CI, 40.3-not evaluable) vs. 36.1 months (95% CI, 21.8-46.7). Incidence of late-onset grade ≥3 toxicities was similar across arms. CONCLUSIONS: In this randomised phase 2 study of 96 patients, xevinapant plus CRT demonstrated superior efficacy benefits, including markedly improved 5-year survival in patients with unresected LA SCCHN.

Impact of Neck Dissection in Head and Neck Squamous Cell Carcinomas of Unknown Primary.

PURPOSE: Management of head and neck cancers of unknown primary (HNCUP) combines neck dissection (ND) and radiotherapy, with or without chemotherapy. The prognostic value of ND has hardly been studied in HNCUP. METHODS: A retrospective multicentric study assessed the impact of ND extent (adenectomy, selective ND, radical/radical-modified ND) on nodal relapse, progression-free survival (PFS) or survival, taking into account nodal stage. RESULTS: 53 patients (16.5%) had no ND, 33 (10.2%) had lymphadenectomy, 116 (36.0%) underwent selective ND and 120 underwent radical/radical-modified ND (37.3%), 15 of which received radical ND (4.7%). With a 34-month median follow-up, the 3-year incidence of nodal relapse was 12.5% and progression-free survival (PFS) 69.1%. In multivariate analysis after adjusting for nodal stage, the risk of nodal relapse or progression was reduced with lymphadenectomy, selective or radical/modified ND, but survival rates were similar. Patients undergoing lymphadenectomy or ND had a better PFS and lowered nodal relapse incidence in the N1 + N2a group, but the improvement was not significant for the N2b or N2 + N3c patients. Severe toxicity rates exceeded 40% with radical ND. CONCLUSION: In HNCUP, ND improves PFS, regardless of nodal stage. The magnitude of the benefit of ND does not appear to depend on ND extent and decreases with a more advanced nodal stage.

Concurrent cisplatin and dose escalation with intensity-modulated radiotherapy (IMRT) versus conventional radiotherapy for locally advanced head and neck squamous cell carcinomas (HNSCC): GORTEC 2004-01 randomized phase III trial.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is the standard of care (SoC) in locally advanced (LA) head and neck squamous cell carcinomas (HNSCC). This trial was designed to test whether dose-escalated IMRT and cisplatin could improve locoregional control without increasing complications over 3D-radiotherapy. METHODS: Patients were randomized between 70 Gy/35F in 7 weeks with 3D-RT (Arm A) versus 75 Gy/35F with IMRT (Arm B). Both arms received 50 Gy in 25 fractions followed by a sequential boost of 20 Gy/10F in Arm A and 25 Gy/10F to gross tumor volume in Arm B, as well as 3 cycles of cisplatin at 100 mg/m2 during RT. The primary endpoint was locoregional progression (LRP). RESULTS: 188 patients were randomized: 85% oropharynx and 73% stage IVa. P16 status was documented for 137 oropharyngeal tumors with P16+ in 53 (39%) patients; and 90% were smokers. Median follow-up was 60.5 months. Xerostomia was markedly decreased in arm B (p < 0.0001). The 1-year grade ≥2 xerostomia (RTOG criteria) was 63% vs 23% and 3-year 45% vs 11% in arms A and B, respectively. Xerostomia LENT-SOMA scale was also reduced in arm B. Dose-escalated IMRT did not reduce LRP with an adjusted HR of 1.13 [95%CI = 0.64-1.98] (p = 0.68). Survival was not different (adjusted HR: 1.19 [95%CI = 0.78-1.81], p = 0.42). No interaction between p16 and treatment effect was found. CONCLUSION: Dose-escalated IMRT did not improve LRC in LA-HNSCC patients treated with concomitant CRT over standard 3D-RT. This trial reinforces the evidence showing IMRT reduces xerostomia in LA-HNSCC treated with radiotherapy. Clinicaltrial.gov: NCT00158678.

10-Year Locoregional Control with Postoperative External Beam Radiotherapy in Patients with Locally Advanced High-Risk Non-Anaplastic Thyroid Carcinoma De Novo or at Relapse, a Propensity Score Analysis.

(1) Background: To assess the role of postoperative external beam radiotherapy (pEBRT) on locoregional failure (LRF) for patients with locally advanced high-risk non-anaplastic thyroid carcinoma (naTC) at primary event or relapse. (2) Methods: Between 1995 and 2015, postoperative naTC patients with a theoretical indication for EBRT were included based on criteria that were common to American-British-French current guidelines, i.e., pT3-4, pN+, gross or microscopic residual disease. Inverse probability of treatment weighting (IPTW) after multiple imputation was used to reduce selection biases. (3) Results: Of 254 naTC patients, 216 patients underwent pEBRT (106 de novo, 110 at relapse, median dose 60 Gy) and 38 underwent surgery only. pEBRT patients had more gross residual disease, a major prognostic factor (p = 0.027) but less perineural invasion (p = 0.008) or lymphovascular emboli (p = 0.009). pEBRT patients more frequently underwent radioiodine therapy (p = 0.026). The 10-year cumulative incidence of LRF was 56% (95% CI, 32-74%) in operated patients, and 23% (95% CI, 17-30%) in pEBRT patients. After IPTW method, pEBRT reduced the risk of LRF (hazard ratio 0.30; 95% CI [0.18-0.49], p < 0.001), but had no impact on OS. In the pEBRT group, non-Intensity Modulated RadioTherapy (IMRT) plans and interruption of the radiotherapy were associated with poorer survival, while extended versus limited field strategy and dose were not. (4) Conclusions: In naTC patients who have pT3-4, pN+ disease or R1-2 resection, pEBRT improved LRF. Limited-field IMRT is preferred.

Unilateral or bilateral irradiation in cervical lymph node metastases of unknown primary? A retrospective cohort study.

INTRODUCTION: Patients with cervical lymphadenopathy of unknown primary carcinoma (CUP) usually undergo neck dissection and irradiation. There is an ongoing controversy regarding the extent of nodal and mucosal volumes to be irradiated. We assessed outcomes after bilateral or unilateral nodal irradiation. METHODS: This retrospective multicentre study included patients with CUP and squamous cellular carcinoma who underwent radiotherapy (RT) between 2000 and 2015. RESULTS: Of 350 patients, 74.5% had unilateral disease and 25.5% had bilateral disease. Of 297 patients with available data on disease and irradiation sides, 61 (20.5%) patients had unilateral disease and unilateral irradiation, 155 (52.2%), unilateral disease and bilateral irradiation and 81 (27.3%), bilateral disease and bilateral irradiation. Thirty-four (9.7%) and 217 (62.0%) patients received neoadjuvant and/or concomitant chemotherapy, respectively. Median follow-up was 37 months. Three-year local, regional, locoregional failure rates and CUP-specific survival were 5.6%, 11.7%, 15.0% and 84.7%, respectively. In patients with unilateral disease, the 3-year cumulative incidence of regional/local relapse was 7.7%/4.3% after bilateral irradiation versus 16.9%/11.1% after unilateral irradiation (hazard ratio = 0.56/0.61, p = 0.17/0.32). The cumulative incidence of CUP-specific deaths was 9.2% after bilateral irradiation and 15.5% after unilateral irradiation (p = 0.92). In multivariate analysis, mucosal irradiation was associated with better local control, whereas no neck dissection, ≥N2b and interruption of RT for more than 4 days were associated with poorer regional control. Toxicity was higher after bilateral irradiation (p < 0.05). No positron-emission tomography-computed tomography, largest node diameter, ≥N2b, neoadjuvant chemotherapy and interruption of RT were associated with poorer cause-specific survival. CONCLUSION: Bilateral nodal irradiation yielded non-significant better nodal and mucosal control rates but was associated with higher rates of severe toxicity.

Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial.

PURPOSE: Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT. PATIENTS AND METHODS: The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05. RESULTS: Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05). CONCLUSION: Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.

Improved Outcome by Adding Concurrent Chemotherapy to Cetuximab and Radiotherapy for Locally Advanced Head and Neck Carcinomas: Results of the GORTEC 2007-01 Phase III Randomized Trial.

Purpose To investigate the effect of adding concurrent chemotherapy (CT) to cetuximab plus radiotherapy (RT; CT-cetux-RT) compared with cetuximab plus RT (cetux-RT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Patients and Methods In this phase III randomized trial, patients with N0-2b, nonoperated, stage III or IV (nonmetastatic) LA-SCCHN were enrolled. Patients received once-daily RT up to 70 Gy with weekly cetuximab or with weekly cetuximab and concurrent carboplatin and fluorouracil (three cycles). To detect a hazard ratio (HR) of 0.64 for progression-free survival (PFS) with 85% power at a two-sided significance level of P = .05, 203 patients needed to be included in each arm. Results Four hundred six patients were randomly assigned to either CT-cetux-RT or cetux-RT. Patient and tumor characteristics were well balanced between arms, including p16 status. With a median follow-up of 4.4 years, the HR for PFS favored the CT-cetux-RT arm (HR, 0.73; 95% CI, 0.57 to 0.94; P = .015), with 3-year PFS rates of 52.3% and 40.5% and median PFS times of 37.9 and 22.4 months in the CT-cetux-RT and cetux-RT arms, respectively. The HR for locoregional control was 0.54 (95% CI, 0.38 to 0.76; P < .001) in favor of CT-cetux-RT. These benefits were observed regardless of p16 status for oropharynx carcinomas. Overall survival (HR, 0.80; P = .11) and distant metastases rates (HR, 1.19; P = .50) were not significantly different between the two arms. The CT-cetux-RT arm, compared with cetux-RT, had a higher incidence of grade 3 or 4 mucositis (73% v 61%, respectively; P = .014) and of hospitalizations for toxicity (42% v 22%, respectively; P < .001). Conclusion The addition of concurrent carboplatin and fluorouracil to cetux-RT improved PFS and locoregional control, with a nonsignificant gain in survival. To our knowledge, this is the first evidence of a clinical benefit for treatment intensification using cetux-RT as a backbone in LA-SCCHN.

Multicenter Randomized Double-Blind, Placebo-Controlled Trial GORTEC (Groupe Oncologie Radiotherapie Tete et Cou) 2009-01 Evaluating the Effect of the Regenerating Agent on Radiodermatitis of Head and Neck Cancer Patients.

PURPOSE: Concomitant cetuximab and radiation therapy (RT) can induce severe radiodermatitis in patients with head and neck cancer (HNC). OTD70DERM, a regenerating agent (RGTA), is a structural and functional analogue of glycosaminoglycans. Preclinical studies have shown that topical RGTA can markedly reduce radiation-induced mucosal and cutaneous toxicities without tumor protection. The present study aimed to evaluate the effect of topical RGTA on radiodermatitis in patients with HNC undergoing RT and cetuximab, for whom RT-induced skin reactions are frequent and/or severe. The primary endpoint was the incidence of grade ≥2 radiodermatitis. METHODS AND MATERIALS: We performed a multicenter, randomized, double-blind, placebo-controlled trial of patients with newly diagnosed HNC undergoing conventionally fractionated RT (70 Gy in 35 fractions) and weekly cetuximab. Patients were randomized 1:1 to receive topical OTD70DERM or placebo on irradiated skin once daily. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, was used to evaluate radiodermatitis (photographs of radiation zone). The Dermatology Life Quality Index score was also evaluated. All the skin reactions seen on the photographs were scored independently by 2 outside experts. RESULTS: Of the 76 randomized patients (38 in each arm), 72 were available for the final radiodermatitis evaluation (37 in the RGTA arm and 35 in the placebo arm). No significant difference was observed concerning the incidence or duration of grade ≥2 radiodermatitis between the 2 arms (81% for RGTA vs 80% for placebo; P=.9). Also, no significant difference was found between the 2 arms regarding grade ≥2 radiodermatitis evaluated by the 2 experts using the photographs of 68 patients (76% vs 74%; P=.78). Finally, no significant difference was found in the Dermatology Life Quality Index score (score >10, 15% vs 20%; P=.45). CONCLUSIONS: Despite the good preclinical rationale, RGTA did not reduce the incidence and severity of radiodermatitis in patients with HNC.

Subcutaneous interleukin-2 and interferon alfa administration in patients with metastatic renal cell carcinoma: final results of SCAPP III, a large, multicenter, phase II, nonrandomized study with sequential analysis design--the Subcutaneous Administration Propeukin Program Cooperative Group.

PURPOSE: This outpatient multicenter trial tested the hypothesis that subcutaneous administration of an interleukin-2 (IL-2)/interferon alfa (IFN alpha) combination produces a response rate greater than 20% in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC received a 12-week induction treatment with subcutaneous IL-2 (5 days/wk, 9 and 18 million U/d)/IFN alpha (3 days/wk, 6 million U/d). After evaluation, patients with objective response or stable disease were randomly assigned to maintenance treatment or short consolidation treatment. RESULTS: Lack of benefit was shown at the 12th sequential analysis, and the trial was closed. At the end of the induction period, 26 (21%) of 122 patients had objective responses (including six complete responses). Thirty-three patients (27%) developed severe toxicity requiring dose reductions, delayed treatment, or treatment termination. Survival rates at one, two, and four years were 63%, 38%, and 17%, respectively. Three-year survival was 20% in patients with two poor prognosis factors and 37% in patients with one or no poor prognosis factors (P =.016). Three-year survival was significantly better (P < 10-3) in patients with erythrocyte sedimentation rate less than 35 mm (43%) compared with those with 1-hour sedimentation rate greater than 35 mm (19%). CONCLUSION: This study confirms the importance of prognostic factors when initiating cytokine immunotherapy in patients with metastatic RCC and underlines the prognostic value of erythrocyte sedimentation rate before treatment initiation. Nonetheless, this subcutaneous IL-2/IFN alpha combination does not improve response rate or survival compared with subcutaneous IL-2 alone, although a definitive conclusion cannot be drawn in the absence of a randomized study comparing the two treatments.

A rationale for chemoradiation (vs radiotherapy) in salivary gland cancers? On behalf of the REFCOR (French rare head and neck cancer network).

BACKGROUND: Salivary gland carcinomas constitute a heterogeneous group of tumors, with over 20 histological subtypes of various prognoses. The mainstay of treatment is surgery, with radiotherapy advocated for unresectable disease or postoperatively in case of poor prognostic factors such as high grade, locally advanced and/or incompletely resected tumors. Concurrent chemotherapy is sometimes advocated in routine practice based on criteria extrapolated from squamous cell carcinomas of the head and neck, on radioresistance of salivary gland tumors and on results obtained in the metastatic setting. The aim of this review was to identify situations where chemotherapy is advocated. MATERIAL AND METHODS: A search of literature was performed with the following key words: parotid, salivary gland, neoplasm, cancer, malignant tumor, chemoradiation, chemotherapy, radiotherapy and treatment. Case report and studies published before 2000 were not included. RESULTS: Platinum-based regimens were the most frequent. Other regimens were reported and seemed dependent on histology. The level of evidence for the concurrent delivery of chemotherapy with radiation therapy is supported by a low level of evidence. Prescribing chemotherapy mostly relies on poor prognostic factors similar to those used to indicate high dose radiotherapy. Protocols vary with histology. CONCLUSION: The rationale for adding chemotherapy to radiotherapy remains to be demonstrated prospectively. Although the type of systemic treatments used may be adapted on histology, the strongest rationale remains in favor of cisplatin.

The rare cancer network: ongoing studies and future strategy.

The Rare Cancer Network (RCN) was formed in the early 1990's to create a global network that could pool knowledge and resources in the studies of rare malignancies whose infrequency prevented both their study with prospective clinical trials. To date, the RCN has initiated 74 studies resulting in 46 peer reviewed publications. The First International Symposium of the Rare Cancer Network took place in Nice in March of 2014. Status updates and proposals for new studies were heard for fifteen topics. Ongoing studies continue for cardiac sarcomas, thyroid cancers, glomus tumors, and adult medulloblastomas. New proposals were presented at the symposium for primary hepatic lymphoma, solitary fibrous tumors, Rosai-Dorfman disease, tumors of the ampulla of Vater, salivary gland tumors, anorectal melanoma, midline nuclear protein in testes carcinoma, pulmonary lymphoepithelioma-like carcinoma, adenoid cystic carcinoma of the trachea, osteosarcomas of the mandible, and extra-cranial hemangiopericytoma. This manuscript presents the abstracts of those proposals and updates on ongoing studies, as well a brief summary of the vision and future of the RCN.

[Treatment of primary thyroid lymphomas]. / Traitement des lymphomes thyroïdiens primitifs de stade localisé

Primary lymphomas of the thyroid (LPT) are a rare entity. LPT represent between 5 and 15% of all thyroid neoplasms. Cytology has limited value; biopsy should be recommended. The differential diagnosis of thyroid carcinoma is differentiated forms indolent or aggressive forms for anaplastic and high grade that may occur by a mass rapidly progressive and compressive. LPT represent a histologically and clinically heterogeneous disease. The most common forms are high-grade LPT (DBLCL) of diffuse large cell type or mucosa-associated lymphoid tissue (MALT). DBLCL receive chemotherapy. The benefit of irradiation is highly debated in view of the data from randomized lymphoma studies (nodal with a minority of extranodal forms) versus those of retrospective studies specifically addressing the case of LPT. Localized MALT lymphomas can be treated with radiation alone. The treatment of other LPT is presented.

Phase I/II and pharmacokinetic study of intravenous vinflunine in combination with cisplatin for the treatment of chemonaive patients with advanced non-small-cell lung cancer.

BACKGROUND: A multicenter phase I/II trial of vinflunine administered in combination with cisplatin at 80 mg/m(2) was conducted in order to determine the dose-limiting toxicities, the maximum tolerated dose, and the recommended dose of the combination. An eventual mutual pharmacokinetic drug-drug interaction when vinflunine and cisplatin were coadministered was also evaluated. The study was also intended to define the response rate of vinflunine in combination with cisplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC) at the recommended dose. PATIENTS AND METHODS: Patients were required to have a histologically confirmed diagnosis of NSCLC not amenable to curable treatment or stage IV disease. Patients may have had previous surgery for NSCLC but were to be chemonaive and have at least 1 bidimensional measurable lesion outside an irradiated area. RESULTS: The recommended dose was established at cisplatin 80 mg/m2 combined with vinflunine 320 mg/m(2). No unexpected adverse events were seen. Pharmacokinetic analysis supported the absence of mutual pharmacokinetic interaction when vinflunine and cisplatin are given in combination. Treatment of 53 patients at this recommended dose demonstrated a tumor response rate of 32.1% in the intent-to-treat population; disease control was achieved in 79.2% of the patients. The median progression-free survival and overall survival were estimated at 5 months and 10.4 months, respectively, and the 1-year survival rate was 43.4%. CONCLUSION: These results place the vinflunine/cisplatin combination among the most active doublets in this treatment setting and warrant further development in phase III trials of first-line treatment of patients with advanced metastatic NSCLC.