Intensified Total Neoadjuvant Therapy in Patients With Locally Advanced Rectal Cancer: A Phase II Trial

AimsWe assessed the efficacy and safety of total neoadjuvant therapy, including targeted agent plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by intensified chemoradiotherapy (CRT) and surgical resection, in patients with locally advanced rectal cancer.Materials and methodsThis was a single-arm, single-centre phase II trial. Eligible patients had non-metastatic locally advanced rectal adenocarcinoma. Based on Ras-BRAF status, patients were treated with bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) plus FOLFOXIRI regimen followed by oxaliplatin–5-fluorouracil-based CRT and surgery. The primary end point was pathological complete response rate. Secondary end points were toxicity, compliance, tumour downstaging, complete resection, surgical complications, local and distant failures and overall survival. The sample size was planned to expect an absolute 20% improvement in pathological complete response rate over historical literature data with an α error of 0.05 and a power of 80%.ResultsBetween October 2015 and September 2019, 28 patients (median age 66 years) were enrolled. All patients had regional lymph node involvement at diagnosis. FOLFOXIRI plus bevacizumab was administered in 11 mutated Ras-BRAF patients, whereas the 17 wild-type Ras-BRAF patients received FOLFOXIRI plus panitumumab/cetuximab. Overall, total neoadjuvant therapy was well tolerated and 26 patients (92.9%) completed the programmed strategy. A complete response was achieved in nine cases (32.1%) and a nearly pathological complete response (ypT1 ypN0) in two patients (7.2%). There was no evidence of febrile neutropenia and no grade 4 adverse events were recorded. Radical resection was achieved in all cases.ConclusionFOLFOXIRI plus targeted agent-based induction chemotherapy and intensified CRT before surgery showed promising clinical activity and was well tolerated in locally advanced rectal cancer patients. This phase II trial provides a strong rationale for phase III studies.     

Neoadjuvant Chemotherapy With mFOLFOXIRI Without Routine Use of Radiotherapy for Locally Advanced Rectal Cancer

IntroductionAlthough neoadjuvant chemo-radiotherapy (CRT) achieves low local recurrence rates in locally advanced rectal cancer (LARC), it raises a lot of concerns about long-term anal and sexual functions. We explored the efficacy of preoperative chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in patients with LARC.Patients and MethodsPatients with LARC evaluated by pelvic magnetic resonance imaging (MRI) were enrolled in this trial. All received 4 to 6 cycles of mFOLFOXIRI. MRI was performed to assess clinical response after chemotherapy. Patients with mesorectal fascia-positive or ycT4a/b after re-evaluation would receive radiation before surgery, whereas responders would have immediate total mesorectal excision (TME). Adjuvant chemotherapy with mFOLFOX6 (folinic acid, 5-fluorouracil, and oxaliplatin) was recommended. The primary endpoint was the proportion of tumor downstaging to ypT_0-2N₀M₀. The secondary endpoints were pathologic complete response rate (pCR), 3-year disease-free survival rate, and safety.ResultsOverall, 106 patients were enrolled and received neoadjuvant mFOLFOXIRI chemotherapy. A total of 103 participants underwent TME surgery. Among 103 patients who completed at least 4 cycles of preoperative chemotherapy, 2 received short-term radiation before TME, and 12 underwent long-term CRT after MRI evaluation. The pCR rate was 20.4%, and the tumor downstaging rate was 42.7%. Among patients without preoperative long-term radiotherapy, the pCR rate and tumor downstaging rate were 17.4% and 41.3%, respectively. Among the per-protocol population, the tumor downstaging rate was 48.1%, and the pCR rate was 20.3%. The chemotherapy-related toxicity was well-tolerated.ConclusionNeoadjuvant chemotherapy with mFOLFOXIRI and selective radiation does not seem to compromise outcomes in LARC. It could be a reasonable alternative to CRT in previously untreated patients with LARC.     

Nonoperative Rectal Cancer Management With Short-Course Radiation Followed by Chemotherapy: A Nonrandomized Control Trial

PurposeShort-course radiation therapy (SCRT) and nonoperative management are emerging paradigms for rectal cancer treatment. This clinical trial is the first to evaluate SCRT followed by chemotherapy as a nonoperative treatment modality.MethodsPatients with nonmetastatic rectal adenocarcinoma were treated on the single-arm, Nonoperative Radiation Management of Adenocarcinoma of the Lower Rectum study of SCRT followed by chemotherapy. Patients received 25 Gy in 5 fractions to the pelvis followed by FOLFOX ×8 or CAPOX ×5 cycles. Patients with clinical complete response (cCR) underwent nonoperative surveillance. The primary end point was cCR at 1 year. Secondary end points included safety profile and anorectal function.ResultsFrom June 2016 to March 2019, 19 patients were treated (21% stage I, 32% stage II, and 47% stage III disease). At a median follow-up of 27.7 months for living patients, the 1-year cCR rate was 68%. Eighteen of 19 patients are alive without evidence of disease. Patients with cCR versus without had improved 2-year disease-free survival (93% vs 67%; P = .006), distant metastasis-free survival (100% vs 67%; P = .03), and overall survival (100% vs 67%; P = .03). Involved versus uninvolved circumferential resection margin on magnetic resonance imaging was associated with less initial cCR (40% vs 93%; P = .04). Anorectal function by Functional Assessment of Cancer Therapy-Colorectal cancer score at 1 year was not different than baseline. There were no severe late effects.ConclusionsTreatment with SCRT and chemotherapy resulted in high cCR rate, intact anorectal function, and no severe late effects.NCT02641691.     

Neoadjuvant Chemotherapy Followed by Radiotherapy Should Not Be A Standard Approach for Locally Advanced Cervical Cancer

Purpose: To investigate the role of neoadjuvant chemotherapy followed by radiotherapy in locally advanced cervical cancer.Methods and Materials: This study cites all known literature on the subject in the English language. Articles were selected for analysis by MEDLINE and CANCERLINE computer searches. In Phase II trials, the response rates of some selective series were analyzed. However, This article will specially emphasize the result of all Phase III randomized trials.Results: Several investigators did obtain promising results from Phase II trials of neoadjuvant chemotherapy, mostly cisplatin-based combinations, followed by radiotherapy. However, most Phase III trials failed to demonstrate any benefit in terms of loco-regional relapse and/or survival by up-front chemotherapy.Conclusion: The role of neoadjuvant chemotherapy remains to be defined, and the search for more active new agents must be continued. The neoadjuvant setting is still experimental and could not be recommended as a standard treatment at the present.     

Comparative Effectiveness of Total Neoadjuvant Therapy Versus Standard Adjuvant Chemotherapy for Locally Advanced Rectal Cancer

IntroductionThe use of total neoadjuvant therapy (TNT) for locally advanced rectal cancer has been increasing in recent years, but the long-term overall survival characteristics of this approach is currently unknown.MethodsWe performed a retrospective study of patients with clinical stage II/III rectal cancer within the National Cancer Database. Patients who received TNT (defined as chemotherapy, followed by CRT, followed by surgery) were propensity score matched to patients who received adjuvant therapy (defined as CRT, followed by surgery, followed by chemotherapy). We compared overall survival (OS) and rates of pathologic complete response (pCR) between the 2 arms.ResultsOf the 4300 patients in our cohort, 3502 (81%) received adjuvant therapy and 798 (19%) received TNT. At baseline, patients who received TNT were more likely to have higher clinical T and N stages (P< .001). The 5-year OS was 77% for both TNT and adjuvant therapy patients (hazard ratio [HR] 1.06, 95% confidence interval [CI], 0.88-1.28, P = .57). After propensity score matching and adjusting for potential confounders, there were no significant differences in OS (HR_adj 1.00, 95% CI, 0.71-1.40, P = .99). After propensity score matching, there were higher pCR rates among TNT patients (16.1%) compared to adjuvant therapy patients (12.0%) (P = .037).ConclusionIn this observational study, we found TNT was not associated with a lower OS compared to standard adjuvant chemotherapy. This finding potentially reassures clinicians choosing TNT as an alternative to adjuvant chemotherapy. However, future prospective data are needed to confirm these findings.     

Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management

Colorectal carcinoma is the second leading cause of cancer-related deaths in the United States, with rectal cancer accounting for approximately one-third of newly diagnosed cases, thus representing a major socioeconomic health burden. Although minimally invasive procedures (ie, transanal excision) may be appropriate for a subset of patients with small, superficially invasive tumors, a more comprehensive trimodality approach with neoadjuvant chemoradiotherapy, total mesorectal excision, and systemic chemotherapy is recommended for medically operable patients with nonmetastatic, locally advanced rectal cancer (LARC). Although such multimodality therapy has markedly reduced local recurrence rates, there remains an estimated 5-year distant relapse rate of 35%, representing the leading cause of death in this population. This review critically assesses the literature regarding neoadjuvant therapy for LARC, as well as the available evidence to support selective exclusion of individual modalities from the contemporary therapeutic paradigm, including controversies of nonoperative management, selective radiation sparing, and neoadjuvant systemic therapy. Through the review of existing data and the anticipated results of ongoing clinical trials, we outline the pragmatic opportunities for future investigation into questions of efficacy, safety, and ultimate improvements to the current status quo.     

The Feasibility and Safety of Induction Chemotherapy Followed by Definitive Chemoradiation in Patients with Locally Advanced Cervical Cancer: A Single-Arm Phase II Clinical Trial

Background: The present study aimed at investigating the feasibility and safety of induction chemotherapy followed by definitive chemoradiation (dCRT) in patients with locally advanced cervical cancer. Materials and Methods: In this single-arm clinical trial, patients with cervical cancer (stages IB3-IVA) received a median four cycles of induction chemotherapy (paclitaxel and carboplatin, every three weeks) followed by dCRT (which consisted of the whole pelvis at the dose of 45-50 Gy along with weekly cisplatin (40 mg/m2) followed by intracavitary brachytherapy at the total dose of 80-90 Gy). Primary end point was local control at three months, which was assessed by gynecologic examination and pelvic MRI. The secondary outcome of the study was treatment-related toxicity. Results: Seventy-four patients with the mean age of 51.6 ± 9.5 years were included. The most frequent (51.4%) disease stage was IIB. Complete and partial clinical responses were observed in 60.8% and 14.9% of patients, respectively. The frequency of progressive disease and stable disease were 14.9% and 9.5%, respectively. Grade II and III neutropenia (during neoadjuvant chemotherapy were 13.5% and 2.7%, respectively; these figures during chemoradiation were 29.7% and 13.5%, respectively. A treatment interruption was observed for 60.8% (45 cases) of patients during chemoradiation and 31.1% during  induction chemotherapy. Discussion and conclusion: Induction chemotherapy followed by chemoradiation is feasible in patients with locally advanced cervical cancer; however, the toxicity should be managed properly to avoid delayed e treatment. More than three quarters of the patients achieved complete or partial clinical response within a three-month follow-up.     

Intensified Neoadjuvant Chemotherapy with Nab-Paclitaxel plus Gemcitabine Followed by FOLFIRINOX in a Patient with Locally Advanced Unresectable Pancreatic Cancer

The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose (¹⁸F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial.Key Words: Pancreatic cancer, Locally advanced disease, Neoadjuvant chemotherapy, Nab-paclitaxel, Gemcitabine, 5-Fluorouracil, Folinic acid, Oxaliplatin, Irinotecan     

Paclitaxel and Carboplatin as Neoadjuvant Chemotherapy in Patients With Locally Advanced Breast Cancer: A Phase II Trial of the Hellenic Cooperative Oncology Group

PurposeThis phase II study sought to evaluate the efficacy of the paclitaxel-carboplatin combination as neoadjuvant chemotherapy in patients with locally advanced breast cancer (LABC).Patients and MethodsA total of 46 patients with LABC and inflammatory breast cancer (IBC) received 6 cycles of paclitaxel 175 mg/m², followed by carboplatin, at an area under the curve of 6, before mastectomy. The primary endpoint constituted response to chemotherapy. We studied ERCC1 protein, microtubule-associated protein-τ, estrogen receptor, progesterone receptor, epidermal growth factor receptor (EGFR), HER2, and Ki-67 immunohistochemically in tissue microarray and whole-tissue sections. In addition, EGFR and HER2 gene status was assessed by fluorescence in situ hybridization. Predictive and prognostic molecular markers were retrospectively investigated.ResultsA total of 42 female patients were considered eligible. Forty percent had IBC. Twenty-five patients (60%) experienced a clinical response, and 4 patients (9.5%) experienced a pathologic complete response. Chemotherapy was well tolerated. After a median follow-up of 45 months (range, 8.8-64.8 months), the estimated 3-year progression-free survival (PFS) was 54%, and the 3-year overall survival (OS) was 66%. The overexpression of EGFR protein was associated with a lower response rate (0 vs. 67%; P = .023), whereas high Ki-67 expression, high-grade tumors, tumor stage T4, and triple-negative tumors were associated with poorer PFS. Only high-grade tumors were associated with a significantly shorter OS (P = .004).ConclusionThe combination of paclitaxel and carboplatin is an effective and well-tolerated regimen in female patients with LABC.     

A Phase II Neoadjuvant Trial of Sequential Nanoparticle Albumin-Bound Paclitaxel Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide in Locally Advanced Breast Cancer

BackgroundNeoadjuvant chemotherapy has become standard treatment for women with locally advanced breast cancer (LABC). Various regimens have explored the addition of newer agents to determine safety and efficacy. The aim of this phase II study was to incorporate albumin-bound paclitaxel with sequential anthracycline-based therapy.Patients and MethodsSixty-six women with LABC but without prior treatment and regardless of hormone receptor or HER2 status were enrolled. All patients were to receive albumin-bound paclitaxel weekly for 12 weeks followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) every 3 weeks for 4 cycles. Trastuzumab was allowed in HER2-positive (HER2⁺) patients. Primary endpoint was pathologic complete response (pCR; CR) in breast. Secondary endpoints included pCR in breast and nodes, clinical CR, 2-year progression-free survival, and overall survival.ResultsSixty-five patients received at least 1 dose of chemotherapy and were included in this analysis. Sixty-three patients completed 4 cycles of albumin-bound paclitaxel. Sixty-two patients received at least 1 dose of FEC, and 58 completed 4 cycles. Seventeen of 19 HER2⁺ women received trastuzumab. The pCR in breast was 29% (19 of 65). For the HER2⁺ subset, the pCR was 58% (11 of 19). Both albumin-bound paclitaxel and FEC were well tolerated. The most significant toxicities were grade 2/3 neuropathy (16%) with albumin-bound paclitaxel and grade 3/4 febrile neutropenia (7%) with FEC.ConclusionAlbumin-bound paclitaxel given over 12 weeks is well tolerated. Albumin-bound paclitaxel should be further evaluated in a randomized setting in both adjuvant and neoadjuvant trials.     

Neoadjuvant Intra-arterial Chemotherapy in Locally Advanced Breast Cancer: A Prospective Randomized Study

A prospective randomized study of neoadjuvant chemotherapy wascarried out on 73 patients with locally advanced breast cancer.Group A (n 26) received no neoadjuvant therapy, group B (n 22)received intra-arterial infusions of epirubicin and group C(n 25) received intravenous epirubicin. The regression of theprimary tumor was significantly higher in group B than in groupC (68.2 vs 36.0%, P<0.05). The post-operative survival ofresponders to neoadjuvant therapy was better than that of non-responders.Side effects were milder in group B than in group C. There was,however, no difference among the three groups in terms of overalland disease-free survivals. Thus, neoadjuvant intra-arterialchemotherapy was effective for achieving loco-regional controlof locally advanced breast cancer with a low toxicity, but couldnot improve survival.     

Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

BackgroundNeoadjuvant chemoradiotherapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients have disease that will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity using next-generation sequencing assays.Patients and MethodsDNA was extracted from formalin-fixed, paraffin-embedded biopsy samples from a cohort of patients with locally advanced rectal adenocarcinoma (T3/4 or N1/2 disease) who received nCRT. High read-depth sequencing of > 400 cancer-relevant genes was performed. Tumor mutations and variant allele frequencies were used to calculate mutant-allele tumor heterogeneity (MATH) scores as measures of intratumoral heterogeneity. Response to nCRT was pathologically scored after surgical resection.ResultsBiopsy samples from 21 patient tumors were analyzed. Eight patients had disease noted to have complete response, 2 moderate, 4 minimal, and 7 poor. Higher MATH scores correlated with poorer response to treatment, demonstrating significantly increased tumor heterogeneity compared to complete response (P = .039).ConclusionThe application of MATH scores as a measure of tumor heterogeneity may provide a useful biomarker for treatment response in locally advanced rectal cancer.