scholarly journals Challenges and solutions in the design and execution of the PROSPECT Phase II/III neoadjuvant rectal cancer trial (NCCTG N1048/Alliance)

2019 ◽  
Vol 16 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Deborah Schrag ◽  
Martin Weiser ◽  
Leonard Saltz ◽  
Harvey Mamon ◽  
Marc Gollub ◽  
...  
Keyword(s):  
United States ◽  
Rectal Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Phase Ii ◽  
Locally Advanced ◽  
Symptom Burden ◽  
The United States ◽  
Distant Recurrence ◽  
Neoadjuvant Chemoradiation ◽  
Eligibility Criteria

Background More than half of the 40,000 incident rectal cancer patients in the United States each year are diagnosed at clinical stage II and III (locally advanced stage). For this group, high rates of cure can be achieved with the combination of pelvic radiation and sensitizing 5-fluorouracil (chemoradiation), surgery and chemotherapy, but treatment is long, arduous and toxicities are substantial. The PROSPECT trial (N1048, NCT01515787) was designed to determine whether neoadjuvant chemotherapy with 5-fluorouracil and oxaliplatin (FOLFOX) could be used as an alternative to neoadjuvant chemoradiation without compromising treatment outcomes and to spare these patients excess toxicity. The statistical design balanced the twin co-primary goals of achieving low local and distant recurrence rates. Study design features contended with the need for stringent safeguards given limited phase II data, the need for straightforward criteria to facilitate both accrual and protocol fidelity and the importance of patients’ perspectives on symptom burden and treatment toxicity. Methods PROSPECT is an ongoing multi-site two-group seamless phase II/III randomized trial comparing standard neoadjuvant chemoradiation versus neoadjuvant chemotherapy with selective use of chemoradiation for patients with locally advanced rectal cancer. Challenges addressed in the design and conduct of PROSPECT have included the following: (1) setting safety thresholds given limited single-center phase II data, (2) establishing workable eligibility criteria, (3) balancing competing time to local and distant recurrence as co-primary endpoints and (4) obtaining reliable and complete data for patients’ symptom burden. The design and implementation challenges, choices, modifications and their implications for the design of future national cooperative group clinical trials are presented. Results PROSPECT incorporated stringent thresholds for both complete surgical resection (R0) and the time to local recurrence as early stopping rules. When predetermined stopping criteria were not met after evaluation of the first 366 participants in the randomized phase II, the study transitioned seamlessly to phase III with cumulative accrual of over 1000 participants. Eligibility criteria stipulating rectal tumor location based on distance from the anal verge were unworkable, and the protocol was amended to a more pragmatic approach that assigned surgeons with primary responsibility for determining eligibility. Central radiology review was feasible and in some cases prompted discontinuation of protocol treatment. Participation in toxicity reporting using the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events was uniformly high and was well accepted by participants from over 200 sites in the United States, Canada and Switzerland. Conclusion The strategies used to overcome these obstacles may inform the design of other studies that involve multi-modality treatment interventions, particularly trials where implementation of consistent criteria for eligibility and outcomes across hundreds of practice settings is necessary.

INNOVA: A phase II randomized study comparing INterval versus NeOadjuVAnt chemotherapy in magnetic resonance imaging-defined high risk rectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS879-TPS879
Author(s):  
Ramakrishnan Ayloor Seshadri ◽  
Trivadi S. Ganesan ◽  
Arunkumar M N ◽  
Shirley Sundersingh
Keyword(s):  
Rectal Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Neoadjuvant Chemotherapy ◽  
Phase Ii ◽  
Pathological Complete Response ◽  
Locally Advanced ◽  
Complete Response ◽  
Neoadjuvant Chemoradiation ◽  
Rectal Cancers

TPS879 Background: Patients with rectal cancers treated with neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy are not exposed to systemic doses of chemotherapy until very late in the treatment schedule. Preoperative chemotherapy, either in the neoadjuvant or interval setting can lead to early treatment of micrometastasis, improve the tumor response and possibly the overall survival. Phase II studies of neoadjuvant chemotherapy in rectal cancer have shown good response to chemotherapy with no tumor progression and good compliance. A phase II study evaluating the effect of giving chemotherapy in the interval waiting period between chemoradiation and surgery has shown acceptable toxicity and high pathological complete response rates. Methods: This single centre, randomized, open label, phase II trial compares the safety and efficacy of two pre-operative regimens in locally advanced MRI defined high-risk rectal cancers. Based on the Simon optimal two-stage design, 94 patients will be randomised to either Arm A [3 cycles of neoadjuvant chemotherapy (capecitabine and oxaliplatin) followed by chemoradiation (50.4 Gy with capecitabine) and then surgery] or Arm B [neoadjuvant chemoradiation followed by 3 cycles of interval chemotherapy and then surgery]. Patients in both arms receive 3 cycles of adjuvant chemotherapy. The primary end-point is the pathological complete response rate. Secondary end-points include frequency and severity of adverse events, RO resection rates, tumor regression grading and compliance to treatment. The inclusion criteria: age 18 to 70 years; ECOG performance status 0-2; non-metastatic, locally advanced rectal cancer with any one of the following features on high-resolution thin slice MRI: any T3/T4 tumor in the lower rectum, T3c/T3d/T4 tumor in the mid rectum, N2 disease, threatened mesorectal fascia, or extramural vascular invasion. Patients are randomly assigned to one of the two intervention arms in a 1:1 ratio. Prespecified activity goal for the first stage of accrual was met; second stage accrual began in July 2017. Clinical trial information: CTRI/2015/01/005385.

Clinical downstaging and quality of life after neoadjuvant chemotherapy in patients with locally advanced rectal cancer: Interim analysis from a phase II clinical trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15178-e15178
Author(s):  
Ahmed Abdalla ◽  
Amr M. Aref ◽  
Amer Alame ◽  
Danny Ma ◽  
Mohammed Barawi ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Clinical Trial ◽  
Rectal Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Phase Ii ◽  
General Health ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer

e15178 Background: The role of neoadjuvant FOLFOX in achieving clinical downstaging and improvement in quality of life (QOL) in patients with locally advanced rectal cancer (LARC) remains to be established. We are conducting a phase II prospective clinical trial to evaluate the use of six cycles of FOLFOX as neoadjuvant chemotherapy in patients with T2-T3/N0-N+ rectal cancer. We now report tumor clinical downstaging and patient-reported QOL in our first patient cohort. Methods: Eleven Patients enrolled in our phase II prospective trial. Patients received three months of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) administered every two weeks. After three weeks of recovery, each patient was treated with conventional chemo-radiotherapy (5FU or capecitabine) All patients had an MRI and endorectal ultrasound at baseline and after completion of FOLFOX. A compilation of validated QOL questionnaires were also administered before and after FOLFOX. Results: A total of 11 patients completed the chemotherapy regimen. Based on pelvic MRI, complete clinical response (T0N0) was achieved by seven patients (64%), one patient (9%) was clinically downstaged but three (27%) didn’t have any changes following FOLFOX. Importantly, we found no disease progression during the FOLFOX course. QOL assessment after FOLFOX regimen showed trend towards improvement in general health, mobility, bladder control and psychological health. These changes in QOL were not statistically significant due to the small sample size. Patients self-grading of their general health before starting FOLFOX was 50% compared to 75% after. Of the five patients with pain at time of diagnosis, four reported complete pain relief while the fifth reported improvement from extreme to moderate pain. Three patients reported improvement in their anxiety/depression. In terms of bowel function, although there was trend towards improvement in the urgency subscale, other bowel functions subscales were unchanged. In general, scores for mobility, selfcare, and bladder function were slightly better after FOLFOX. Conclusions: This study suggests that adding only six cycles of neoadjuvant FOLFOX before CRT not only resulted in clinical downstaging of (LARC) but showed a trend toward improved QOL. This result provides some reassurance for oncologists that this approach does not diminish QOL with no risk of disease progression during the time of neoadjuvant chemotherapy. These findings need to be validated in a larger phase III trial.

The comparison of mFOLFOXIRI with CAOX/SOX as neoadjuvant chemotherapy for locally advanced rectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 51-51
Author(s):  
Tetsuji Terazawa ◽  
Hiroyuki Kodama ◽  
Hiroki Yukami ◽  
Masahiko Aoki ◽  
Takahiro Miyamoto ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Survival Rate ◽  
Neoadjuvant Chemotherapy ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Distant Recurrence ◽  
Locally Advanced Rectal Cancer ◽  
Pathological Response ◽  
R0 Resection ◽  
Hand Foot Syndrome

51 Background: The standard therapy for the locally advanced rectal cancer (LARC) (Ra or Rb, T2Npsitive, T3/4Nany) is chemoradiotherapy (CRT) followed by surgery. The CRT prevents local recurrence, although problems such as complications or the improvement of distant recurrence still remain. Several studies about the neoadjuvant chemotherapy (NAC) without radiation showed favorable R0 resection rate and outcome, however the best regimen of NAC is unclear. The aim of this study is to investigate the efficacy and safety of mFOLFOXIRI and CAPOX/SOX as NAC. Methods: We examined the patients (pts) with LARC who were planned to receive mFOLFOXIRI (5FU 2400mg/m2/day1-2, leucovorin 200mg/m2, oxaliplatin 85mg/m2, irinotecan 150mg/m2, every 2 weeks) or CAPOX/SOX(capecitabine 2000mg/m2 or S-1 mg/m2 80day1-14, oxaliplatin 130mg/m2, day1, every 3weeks) for 8-12 weeks as NAC, retrospectively. Results: Forty-nine pts received mFOLFOXIRI and thirty-two pts received XELOX/SOX between Jan 2015 and Mar 2019. The characteristics of mFOLFOXIRI and XELOX/SOX were as follows; median age, 64 (37-80) and 65 (33-68); PS 0/1, 46(94%)/3(6%) and 14(44%)/18(56%); Ra/Rb-P, 4(8%)/45(92%) and 0/32; clinical T2/3/4, 4(7%)/27(55%)/19(39%) and 1(3%)/18(56%)/13(41%); clinical N0/1/2, 13(27%)/26(53%)/10(20%) and 7(22%)/17(53%)/8(25%). The pathological response rate which was defined as tumor affected area over one-third were 61.2% in mFOLFOXIRI and 65.6% in CAPOX/SOX including complete remission of 4.1% and 12.5%, respectively. Six of 49 pts withdrew from mFOLFOXIRI due to toxicities, whereas one of 32 pts from CAPOX/SOX. One pt received CRT after SOX because of lack of efficacy. The major grade 3/4 toxicities of mFOLFOXIRI were neutropenia (n = 22, 45%), thrombocytopenia and febrile neutropenia (n = 4, 8%) and anorexia (n = 3, 6%), whereas CAPOX/SOX neutropenia (n = 3. 9%), thrombocytopenia (n = 1, 3%) and hand-foot syndrome (n = 1, 3%). The one year of relapse free survival rate were 85.4% and 83.6%. Conclusions: Although the pathological response of mFOLFOXIRI was comparable with CAPOX/SOX, CAPOX/SOX was less toxic.The further investigation including 5 year overall survival rate rate was needed.

Locally Advanced Rectal Cancer: Time for Precision Therapeutics

2015 ◽  
pp. e192-e196 ◽  
Author(s):  
Martin R. Weiser ◽  
Zhen Zhang ◽  
Deborah Schrag
Keyword(s):  
Rectal Cancer ◽  
Local Recurrence ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Advanced Rectal Cancer ◽  
The United States ◽  
Locally Advanced Rectal Cancer ◽  
Neoadjuvant Chemoradiation ◽  
Current Standard ◽  
Trimodality Therapy

The year 2015 marks the 30th anniversary of the publication of NSABP-R01, a landmark trial demonstrating the benefit of adding pelvic radiation to the treatment regimen for locally advanced rectal cancer with a resultant decrease in local recurrence from 25% to 16%. These results ushered in the era of multimodal therapy for rectal cancer, heralding modern treatment and changing the standard of care in the United States. We have seen many advances over the past 3 decades, including optimization of the administration and timing of radiation, widespread adoption of total mesorectal excision (TME), and the implementation of more effective systemic chemotherapy. The current standard is neoadjuvant chemoradiation with 5-fluorouracil (5-FU) and a radiosensitizer, TME, and adjuvant chemotherapy including 5-FU and oxaliplatin. The results of this regimen have been impressive, with a reported local recurrence rate of less than 10%. However, the rates of distant relapse remain 30% to 40%, indicating room for improvement. In addition, trimodality therapy is arduous and many patients are unable to complete the full course of treatment. In this article we discuss the current standard of care and alternative strategies that have evolved in an attempt to individualize therapy according to risk of recurrence.

A randomized phase II study evaluating efficacy and safety of SOX versus mFOLFOX6 as neoadjuvant chemotherapy for patients with resectable rectal cancer (KSCC1301).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3549-3549
Author(s):  
Kenji Katsumata ◽  
Eiji Oki ◽  
Hiroyuki Kato ◽  
Keisuke Miwa ◽  
Masahiko Sugiyama ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Phase Ii ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
R0 Resection ◽  
Severe Toxicity ◽  
Efficacy And Safety ◽  
Neoadjuvant Radiotherapy ◽  
Randomized Phase Ii

3549 Background: Neoadjuvant radiotherapy is the current standard of care for rectal cancer. However, radiation therapy is sometimes associated with short-term severe toxicity and long-term morbidity. Perioperative introduction of new chemotherapy agents without radiotherapy for locally advanced rectal cancer (LARC) may be a promising option. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) have reported promising efficacy and safety in patients with metastatic colorectal cancer, suggesting a potential replacement for mFOLFOX6. Methods: A randomized phase II trial was undertaken to compare the efficacy and safety of SOX and mFOLFOX6 as neoadjuvant chemotherapy for patients with LARC. Patients were randomly assigned to receive mFOLFOX6 (every 2 weeks; day 1: 400 mg/m2 bolus 5-fluorouracil [5-FU]; days 1 and 2: 2,400 mg/m2 continuous 5-FU; day1: 200mg/m2 l-LV; and day 1: 85 mg/m2 oxaliplatin) or SOX (every 3 weeks; days 1–14: 80 mg/m2 oral S-1; and day 1: 130 mg/m2oxaliplatin). The protocol period for neoadjuvant chemotherapy was 3 months. The primary endpoint was the 3-year disease-free survival rate (3y DFS), and the secondary endpoints included pathological effect, R0 resection rate, survival and safety. Results: Between September 2013 and October 2015, 110 patients were enrolled and randomized (56 received SOX and 54 received mFOLFOX6). Baseline characteristics were balanced between the two arms. The major adverse events were neutropenia, peripheral neuropathy, loss of appetite, and fatigue. The incidence of grade 3 or higher neutropenia based on the CTCAE Vers.4.0was 13.2% in the SOX group and 32.0% in the mFOLFOX6 group. The surgical completion rate was 100% for the SOX group and 96% for the mFOLFOX6 group. The incidence of grade II or more surgical site infection based on Clavien-Dindo classification (CD) was 11.3% and 4.2% for the SOX and mFOLFOX6 groups, respectively. The CD grade III anastomosis-related complications developed in 7 cases in total. Conclusions: The KSCC1301 study suggests that neoadjuvant chemotherapy without radiation is active and safe. The results of pathological response will be provided. Clinical trial information: UMIN000011486.

Early mortality after resection of locally advanced rectal cancer in elderly United States patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11529-11529
Author(s):  
Helmneh M. Sineshaw ◽  
K Robin Yabroff ◽  
Vassiliki Liana Tsikitis ◽  
Ahmedin Jemal ◽  
Timur Mitin
Keyword(s):  
United States ◽  
Rectal Cancer ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
The United States ◽  
Locally Advanced Rectal Cancer ◽  
Early Mortality ◽  
Older Age ◽  
Case Volume ◽  
Comorbidity Score

11529 Background: Early mortality after resection of locally advanced rectal cancer in patients age 75 and older has not been studied in the United States. This information could inform clinical decision-making for patients who achieve complete clinical response after neoadjuvant therapy and consider watchful waiting versus surgical resection. Methods: Using the National Cancer Data Base, we identified patients age 75 years and older who underwent surgery for clinical stage II or III rectal cancer between 2004-2015. We performed multivariable logistic regression analyses to assess associations between patient and facility characteristics and 30-day, 90-day, and 6-month mortality. Results: Among 11,326 patients, 94% underwent resection and the remaining 6% underwent local excision. Overall early mortality rates after surgery were 4%, 7.6% and 11% for 30-day, 90-day and six-month, respectably. Six-month mortality varied by age subgroup (8% in 75-79 years old to 17.7% in 85 years and older), and comorbidity score (9.5% for comorbidity score = 0 to 18.5% for comorbidity score ≥ 2). Between 2004 and 2015, six-month mortality declined significantly from 11.9% in 2004-2007 to 9.8% in 2012-2015 ( P trend = 0.0029), with the decline larger among patients age 85 years and older (from 19.4% in 2004-2007 to 15.3% in 2012-2015, P trend = 0.0377). In the multivariable analysis, older age, higher comorbidity score, and lower facility case volume were significantly associated with higher odds of six-month mortality. Patients treated at National Cancer Institute (NCI) designated centers had 32% lower odds of six-month mortality compared with those treated at non-NCI designated teaching/research centers. Conclusions: Post-operative six-month mortality among patients age 75 years and older with locally advanced rectal cancer in the US declined steadily over the past decade. Older age, high comorbidity score, and low facility case volume were associated with higher six-month mortality after surgery. Additional efforts are needed to guide elderly patients and their physicians in discussing treatment options for locally advanced rectal cancer.

Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer: A single center phase II trial.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 69-69
Author(s):  
Wen Zhang ◽  
Haitao Zhou ◽  
Jun Jiang ◽  
Yuelu Zhu ◽  
Shuangmei Zou ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Folinic Acid ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Venous Invasion ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
R0 Resection

69 Background: Chemoradiotherapy (CRT) remains the standard treatment choice for locally advanced rectal cancer (LARC). Neoadjuvant chemotherapy alone with doublet mFOLFOX6 (folinic acid, 5-fluorouracil, and oxaliplatin) seemed not to influence recurrence free survival with the advantage of less treatment-related complications. This phase II trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in patients with LARC (NCT03443661). Methods: Patients with LARC received up to 5 cycles of mFOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2 were administered on Day 1, fluorouracil 2400 mg/m2 was administered as a continuous intravenous infusion for 48 hours on Day 1, and was repeated every 14 days). Magnetic resonance imaging (MRI) was performed to assess the baseline and post-chemotherapy TN stage. Radical resection was performed within 4–6 weeks of the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX (oxaliplatin and capecitabine) was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2, and positive circumferential resection margin (CRM). The primary endpoint was the pathological complete response (pCR) rate. Results: Between December 2015 to March 2019, a total of 50 patients were enrolled. 48 (96%) of the patients were clinically node-positive, 28 (56.5%) were CRMnvolved, and 39 (78.4%) were extramural venous invasion (EMVI)-positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range, 1–5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients achieved pathological node-negative status. The proportion of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively (table). Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or more toxicities included neutrocytopenia (50%), leukopenia (14%), and diarrhea (12%) during neoadjuvant chemotherapy. Clinical meaningful surgical morbidities included pneumonia (n=1), pelvic infection (n=1), and anastomotic fistula (n=1). With a median follow-up time of 33 months (range, 14–73 months), local recurrences and distant metastases were confirmed in 3 (6.5%) and 8 (17.4%) cases, respectively. Conclusions: Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect with an ordinary pCR rate, and seemed effective in eliminating EMVI and transforming CRM-positive to CRM-negative status in patients with LARC. The preliminary survival results are promising. This regimen could serve as a potential alternative to CRT in selected patients with LARC. Clinical trial information: NCT03443661. [Table: see text]

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