scholarly journals Novel Strategies to Effectively De-escalate Curative-Intent Therapy for Patients With HPV-Associated Oropharyngeal Cancer: Current and Future Directions

2020 ◽  
pp. 257-269
Author(s):  
Katharine A. R. Price ◽  
Anthony C. Nichols ◽  
Colette J. Shen ◽  
Almoaidbellah Rammal ◽  
Pencilla Lang ◽  
...  
Keyword(s):  
Oropharyngeal Cancer ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Phase Iii ◽  
Locoregional Therapy ◽  
Transoral Surgery ◽  
Curative Intent ◽  
Definitive Radiotherapy ◽  
Radiotherapy Alone ◽  
Novel Biomarkers

The treatment of patients with HPV-associated oropharyngeal cancer (HPV-OPC) is rapidly evolving and challenging the standard of care of definitive radiotherapy with concurrent cisplatin. There are numerous promising de-escalation strategies under investigation, including deintensified definitive chemoradiotherapy, transoral surgery followed by de-escalated adjuvant therapy, and induction chemotherapy followed by de-escalated locoregional therapy. Definitive radiotherapy alone or with cetuximab is not recommended for curative-intent treatment of patients with locally advanced HPV-OPC. The results of ongoing phase III studies are awaited to help answer key questions and address ongoing controversies to transform the treatment of patients with HPV-OPC. Strategies for de-escalation under investigation include the incorporation of immunotherapy and the use of novel biomarkers for patient selection for de-escalation.

Comparative effectiveness trial of transoral head and neck surgery followed by adjuvant radio(chemo)therapy versus primary radiochemotherapy for oropharyngeal cancer (TopROC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS6093-TPS6093 ◽  
Author(s):  
Chia-Jung Busch ◽  
Simon Laban ◽  
Claus Wittekindt ◽  
Carmen Stromberger ◽  
Silke Tribius ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Oropharyngeal Cancer ◽  
Comparative Effectiveness ◽  
Salvage Surgery ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Standard Of Care ◽  
Transoral Surgery ◽  
Open Label ◽  
Patient Reported

TPS6093 Background: For locally advanced, transorally resectable oropharyngeal cancer (OPSCC), both, surgical resection and risk-adapted adjuvant (chemo)radiotherapy or definite chemoradiotherapy with or without salvage surgery are considered the current standard of care. To date, these two different therapeutic approaches for transorally resectable OPSCC have not been compared head to head in a randomized trial yet. The goal of this study is to compare primary transoral surgery followed by adjuvant treatment with definitive chemoradiation for resectable OPSCC, especially with regards to loco-regional control as well as organ function. Methods: TopROC is a prospective, two-arm, open label, multicenter, randomized controlled comparative effectiveness study. Eligible pts. are ≥18 years old with treatment-naïve, histologically proven OPSCC (T1, N2a-c, M0; T2, N1-2c, M0; T3, N0-2c, M0 TNM 7th ed.) which are amenable to transoral resection, ECOG PS ≤2 and no distant metastasis. p16 immunohistochemistry by local pathology or FFPE tissue must be available for central diagnostic. 280 pts. will be randomly assigned (1:1) to surgical treatment (arm A) or chemoradiation (arm B). Standard of care treatment will be done according to daily clinical practice. Arm A consists of transoral surgical resection with neck dissection followed by risk-adapted adjuvant (chemo)radiation. Pts. treated in arm B receive standard chemoradiation, residual tumor may be subject to salvage surgery. Follow-up visits are planned until three years after treatment. Primary endpoint is time to local or locoregional failure or death from any cause (LRF). Secondary endpoints include overall and disease-free survival, toxicity, patient reported outcomes and cost-effectiveness analysis. Approximately 20 centers will be involved in Germany. This trial is supported by the German Cancer Aid and accompanied by a large scientific support program. Recruitment started in January 2018. Clinical trial information: NCT03691441.

Predictors of swallow function after transoral surgery for locally advanced oropharyngeal cancer

2019 ◽  
Vol 130 (1) ◽  
pp. 94-100 ◽  
Author(s):  
Jennifer H. Gross ◽  
Melanie Townsend ◽  
Helena Y. Hong ◽  
Emily Miller ◽  
Dorina Kallogjeri ◽  
...  
Keyword(s):  
Oropharyngeal Cancer ◽  
Locally Advanced ◽  
Transoral Surgery ◽  
Swallow Function

Preoperative radiotherapy and docetaxel in resectable pancreatic adenocarcinoma: A phase II trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4099-4099 ◽  
Author(s):  
F. Viret ◽  
M. Ychou ◽  
V. Moutardier ◽  
V. Magnin ◽  
P. Rouanet ◽  
...  
Keyword(s):  
Overall Survival ◽  
Pancreatic Adenocarcinoma ◽  
Median Overall Survival ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Pathological Response ◽  
Phase Iii ◽  
Additional Patient ◽  
Curative Intent ◽  
Grade 3

4099 Background: We previously reported results a phase I trial of weekly docetaxel concurrently with radiation therapy in patients (pts) with locally advanced pancreatic adenocarcinoma (Pancreas, Vol 27, N°3, 2003). We prospectively explored this regimen in 34 pts with biopsy proven potentially resectable pancreatic adenocarcinoma. Methods: Treatment consisted of concomitant radiotherapy (45 Gy within 5 weeks directed at the pancreatic tumor and regional lymphatics) with 5 weekly doses of docetaxel (30 mg/m2/week) by 1-hour infusion, followed by a complete staging evaluation 3–4 weeks after chemo-radiation. Pts without disease progression underwent surgery. Results: From May, 2003 to July, 2005, this study enrolled 34 pts (59% men) with median age 62 years (range 45–72). Median tumor size was 3 cm. Pretreatment Endoscopic Ultrasound (EUS) staging was uT1 (7 pts), uT2 (25 pts), uT3 (2pts), uN0 (26 pts) and uN1 (8 pts). Median pretreatment CA 19.9 levels was 114 (range 1–9432). All pts (97%) but one completed radiation and 91% (31 pts) received the 5 weekly doses of docetaxel. Adverse events included grade 3/4 asthenia (28%), grade 3/4 nausea/vomiting (10%), grade 3/4 anemia (7%) and grade 3/4 neutropenia (7%). Median time between diagnosis and surgery was 3.7 months (range 2.8–8.7). Ten pts (29%) presented progressive disease after chemo-radiation and one additional patient (pt) voluntary stopped treatment procedure. Twenty three pts (68%) underwent surgical procedure, which was with curative intent in 17 pts (50%). One pt died within the 30-day post operative period. Pathological response was observed in 7 pts (30%), including 2 complete response. The median Disease Free Survival (DFS) was 11 months and the 2-year DFS was 21%. The median overall survival (OS) was 14 months. The 2-year DFS for the 17 pts resected with a curative intent was 50.4%. In this subgroup, median overall survival was not reached. Conclusions: Pre-operative combination of radiotherapy and docetaxel is feasible with tolerable toxicity and with promising pathological response. A randomized phase III study comparing this regimen (radiotherapy and docetaxel) and surgery versus surgery alone is starting. Supported in part by Sanofi Aventis, France. No significant financial relationships to disclose.

Concurrent chemotherapy practice patterns for head and neck cancer: What is standard of care?

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5542-5542
Author(s):  
S. J. Wong ◽  
Z. Agha ◽  
S. Milligan
Keyword(s):  
Head And Neck ◽  
Initial Dose ◽  
Low Dose ◽  
Single Agent ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Prescribing Patterns ◽  
Phase Iii ◽  
High Dose ◽  
Community Based

5542 Background: The superiority of concurrent high dose cisplatin and radiation (RT) compared to RT alone for pts with locally advanced squamous cell cancer of the head and neck (SCCHN) has been demonstrated in large prospective phase III clinical trials. However, little is known regarding general prescribing patterns for chemotherapy (CT) utilization in combined modality treatment (CMT) for SCCHN. We conducted the present study to gain insight as to whether results from pivotal phase III trials affect utilization of concurrent CT in academic and community centers. Methods: We analyzed individual data from 326 SCCHN pts treated with concurrent CT and RT between 03/2003 and 12/2004 from 53 centers (43 community-based, 7 academic, and 3 VA or military) using electronically captured data from IntelliDose, a chemotherapy order software program. Results: Of 326 total pts, 123 pts (38%) received single agent cisplatin. From this group, 71 (58%) received low dose cisplatin (<74 mg/m2, mean initial dose 67 mg), while 52 patients (42%) received high dose cisplatin (≥ 74 mg/m2, mean initial dose 189 mg). 72 pts (22%) received carboplatin/paclitaxel, 60 pts (18%) received cisplatin /5FU, 18 pts (5.5%) received single agent carboplatin, while 6 pts (1.8%) received cetuximab either alone or in combination with cisplatin. Other infrequently used regimens (each < 5%) cumulatively accounted for 14% of pts treated. Comparison of chemotherapy utilization between academic and community-based practice centers showed no statistical difference with respect to use of high dose cisplatin versus low dose cisplatin, or single agent cisplatin versus non-cisplatin regimens. Conclusions: Despite evidence from phase III studies that concurrent high dose cisplatin is the standard of care for CMT of locally advanced SCCHN, utilization of other regimens, such as weekly low dose cisplatin, are commonly utilized. [Table: see text]

Patterns of locoregional relapses for patients with esophageal cancer for whom exclusive chemoradiotherapy failed: A plea for dose escalation and elective nodal irradiation.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 99-99
Author(s):  
Cedric Chevalier ◽  
Noemie Vulquin ◽  
Mélanie Gauthier ◽  
Aurelie Petitfils ◽  
Etienne Martin ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Primary Tumor ◽  
Standard Of Care ◽  
Complete Response ◽  
Phase Iii ◽  
Curative Intent ◽  
Elective Nodal Irradiation ◽  
Locoregional Failure ◽  
Distant Failure

99 Background: Nearly half of the patients (pts) with an esophageal cancer (EC) have a locoregional failure (LRF) after exclusive chemoradiation (eCRT). eCRT delivering 50Gy remains the standard of care for non operable pts. We aim to evaluate the patterns of LRF with respect to planned dose and/or the incidental (unplanned) dose that covered LRF. Methods: Twenty-two pts with EC who failed locally and/or regionally in their follow-up were exclusively reviewed. All the pts have been initially treated (t0) in a curative intent with eCRT. Co-image registration of CT or PET-CT at time of failure and planning CT at t0 was used for image fusion. Each nodal failure (Nf) and each local failure of the primary tumor (Lf) has been outlined, as well as each nodal station (NS) including Nf according to the RTOG classification. Dosimetric parameters in relation with Lf, Nf and involved NS were derived from the initial dosimetric plan. Results: All the patients underwent eCRT including a 5-FU based chemotherapy regimen. Eighteen patients were treated with elective nodal irradiation (ENI) whereas 4 pts did not. The median dose delivered was 50Gy [50Gy-64Gy]. In the follow-up period, 14 pts were in complete response, 3 pts in partial response, 4 pts had a progressive disease (1pt unknown). The median delay between the start of radiotherapy and LRF was 14.3 months [4.27-48.46]. 13 pts had a Lf (included in “planned-dose”), 9 pts had a Nf, 2 pts had a Lf with Nf and 7 pts had a concomittant distant failure. Among pts with Nf, 8 failures were in-field whereas 3 pts had an out-field relapse. Re-calculated doses for NS delineated on the CT performed at t0 were significantly less important than the planned dose (see Table). Conclusions: Our results suggest that an inadequate dose to both the primary tumor and NS could explain high LRF rates observed in EC. A French randomized phase III trial (NCT 01348217) is currently testing a higher dose to the primary tumor and/or ENI with IMRT in an attempt to improve locoregional control. [Table: see text]

Multicenter randomized controlled phase III study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS6095-TPS6095
Author(s):  
Chia-Jung Busch ◽  
Adrian Muenscher ◽  
Christian Stephan Betz ◽  
Volkan Dogan ◽  
Philippe Schafhausen ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Distant Metastasis ◽  
Tumor Antigens ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Late Toxicity ◽  
Standard Of Care ◽  
Phase Iii ◽  
Free Survival ◽  
Treatment Naïve

TPS6095 Background: Surgically treated locally advanced head and neck squamous cell carcinoma (LA HNSCC) often requires postoperative chemoradiation with high risk of acute and late toxicity. Disease-free survival (DFS) after 2 years is approximately 70%. Combining Nivolumab (N), a PD-1inhibitor, and Ipilimumab, a CTLA4 inhibitor, as maintenance therapy may improve DFS due to anti-tumor effects of immunotherapy by enhancing cross-presentation of tumor antigens. The IMSTAR HN study compares neoadjuvant N and N±I 6 months after adjuvant therapy vs the standard therapy as first-line treatment for LA HNSCC. Methods: Eligible pts are ≥18 years old with treatment-naive LA HNSCC (oral cavity, oropharynx p16-, hypopharynx, and larynx), ECOG PS ≤1, and no distant metastasis. 276 pts will be randomized (2:1) into 2 arms and approximately 10 centers in Germany will be involved. Standard of care (arm II) consists of surgical resection followed by risk-adapted adjuvant (chemo)radiation. The experimental arm I receives neoadjuvant N 3mg/kg. After treatment according to standard arm a second randomization will be performed: In arm Ia N 3mg/kg will be given every 2 weeks until progression or up to 6 months. In arm Ib I 1mg/kg will be applied additionally every 6 weeks also until progression or up to 6 months. Primary endpoints is DFS in arms I and II. Secondary endpoints: Local regional control (LRC), distant metastasis free survival (DMFS), overall survival (OS), quality of life (QoL), survival depending on PD-L1 status, comparison of arm Ia vs arm II and Ib vs. II. AEs, graded per CTCAE v4.03, are evaluated for at least 12 months after randomization. The translational program includes investigations concerning immunmodulation, mutational load in general, but also specific mutations in targets involved in immune function and antigen presentation. Recruitment started in August 2018. Clinical trial information: NCT03700905.

Transoral robotic surgical resection followed by randomization to low- or standard-dose IMRT in resectable p16+ locally advanced oropharynx cancer: A trial of the ECOG-ACRIN Cancer Research Group (E3311).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6500-6500 ◽  
Author(s):  
Robert L. Ferris ◽  
Yael Flamand ◽  
Gregory S. Weinstein ◽  
Shuli Li ◽  
Harry Quon ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Standard Dose ◽  
Locally Advanced ◽  
Operative Therapy ◽  
Phase Iii ◽  
Smoking History ◽  
Transoral Surgery ◽  
Intermediate Risk ◽  
Oropharynx Cancer ◽  
Transoral Resection

6500 Background: ECOG-ACRIN 3311 examines reduced postoperative therapy in patients with “intermediate risk” p16+ oropharynx cancer (OPC) undergoing primary transoral surgical management. We report the primary endpoint of 2-year progression free survival (PFS) for patients randomized to 50Gy vs 60Gy without chemotherapy. Methods: Between December 2013 and July 2017, 82 credentialed surgeons performed transoral resection (TOS) for 519 OPC patients (cT1-2 stage III/IV AJCC7 without matted neck nodes); post-operative management was determined by pathologically assessed risk. Among 353 eligible and treated patients, Arm A enrolled 10% (N=37) for clear margins, 0-1 nodes, no extranodal extension (ENE)), Arms B (50Gy, N=102) or C (60Gy, N=104) randomized 58%, for clear/close margins, 2-4 + nodes, or ENE ≤1mm, while Arm D (N=110, 60-66Gy plus weekly cisplatin, 40 mg/m2, positive margin with any T stage, >4 + nodes, or >1mm ENE) enrolled 31%. Arm D assignment was based on >1mm ENE (76%), > 4 nodes (27%), and/or positive margins (11%). Intermediate-risk patients were stratified by smoking history (>10 pk-yr). Of the 80 pts (15%) deemed ineligible, 28 had scans/labs not done per protocol, however treatment arm distribution for all patients mirrored that for the 353 pts eligible and treated. Results: Median follow-up was 31.8 months. 2 yr PFS for Arms A, B and C were 93.9% (90% CI=87.3%, 100%), 95.0% (90% CI=91.4%, 98.6%) and 95.9% (90% CI=92.6%, 99.3%) respectively, while Arm D was 90.5% (90% CI=85.9%, 95.3%). The regimen of TOS + low-dose radiation is considered worthy of further study, since the primary endpoint of the upper bound of the 90% CI (in the intermediate risk group) exceeding 85% was met. Of 17 progression events, 7 were locoregional. There were 10 distant recurrences: Arm A=1, Arm B=2, Arm C=4, Arm D=3. Grade III/IV treatment-related AE rates were 15%/2% during surgery, 13%/2% for Arm B and 25%/0% for Arm C. There were 2 treatment-related deaths (one surgical and one Arm D). Conclusions: Transoral resection of p16+ OPC is safe and results in good oncologic outcome, presenting a promising deintensification approach. For patients with low-risk disease, 2-yr PFS is favorable without post-operative therapy. For those with uninvolved surgical margins, <5 involved nodes, and minimal (<1mm) ENE, reduced dose postoperative RT without chemotherapy appears sufficient. Transoral surgery plus 50Gy should be compared to optimal non-surgical therapy in a phase III trial. Clinical trial information: NCT01898494 .

scholarly journals KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma

2021 ◽  
Vol 17 (10) ◽  
pp. 1143-1153
Author(s):  
Manish A Shah ◽  
Jaafar Bennouna ◽  
Toshihiko Doi ◽  
Lin Shen ◽  
Ken Kato ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Disease Recurrence ◽  
Phase Iii ◽  
First Line ◽  
Definitive Chemoradiotherapy ◽  
Double Blind ◽  
Clinical Trial Registration ◽  
Curative Intent ◽  
Gastroesophageal Junction Cancer

Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points. Clinical trial registration: NCT04210115 (ClinicalTrials.gov)

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