Unresectable Recurrent Rectal Cancer Research Articles

Prognostic impact of local recurrence and timing of palliative radiotherapy in patients with unresectable recurrent rectal cancer.

132 Background: The standard treatment for unresectable recurrent rectal cancer (URRC) is chemotherapy (CTx) regardless of local recurrence (LR). Approximately 80% of patients with LR experience LR-related pain, making these patients difficult to treat, especially the timing of radiotherapy (RT). However, the impact of LR and the appropriate timing of palliative RT on prognosis in patients with URRC remains unclear. Methods: This retrospective study included patients with URRC who had an ECOG Performance Status (PS) of 0–2 and received fluoropyrimidines plus oxaliplatin and/or irinotecan as first-line CTx between September 2006 and December 2020 at a single institution. Patients were divided into two groups: patients with LR (LR+) and patients without LR (LR−). Progression-free survival (PFS), overall survival (OS), and post-progression survival (PPS) after first-line CTx were compared between the two groups. The association between receiving palliative RT for LR-related symptoms until disease progression after first-line CTx and the proportion of patients receiving subsequent second-line CTx was also evaluated in the LR+ group. Multivariate Cox analysis, including variables with p < 0.10 in univariate analyses, was performed for PPS. Results: The LR+ and LR− groups included 49 and 99 patients, respectively. No significant differences in the baseline characteristics were detected between the two groups, except liver metastasis, which occurred less frequently in the LR+ group. OS and PPS were shorter in the LR+ group compared with the LR- group (median OS, 33.4 vs. 48.2 months; hazard ratio [HR], 1.52; p = 0.05; median PPS, 17.2 vs. 23.5 months; HR, 1.77; p = 0.01). PFS was similar between the two groups (median PFS, 13.0 vs. 15.8 months; HR, 1.18; p = 0.39). Fewer patients in the LR+ group received second-line CTx compared with the LR- group (68 vs. 83%, p = 0.06). The proportions of patients with PS ≥ 1 (78 vs. 52%, p = 0.007) and PS deterioration at progression after first-line CTx (59 vs. 27 %, p = 0.002) were higher in the LR+ group compared with the LR group-. The most common cause of PS deterioration in the LR+ group was LR-related pain (77%). Among patients with LR-related pain, the proportion of patients receiving subsequent second-line CTx was numerically lower in patients who did not receive palliative RT than in patients who did receive palliative RT until disease progression after first-line CTx (75 vs. 54%, p = 0.23). Multivariate analysis revealed that receiving subsequent second-line CTx was an independent prognostic factor for PPS in LR+ patients (adjusted HR, 4.77; p = 0.006). Conclusions: The presence of LR is associated with poor prognosis in URRC, which may be due to worsening PS caused by LR-related symptoms and the lower proportion of subsequent CTx. Thus, palliative RT should be recommended more actively when LR becomes symptomatic.

Circulating tumour cell gene expression and chemosensitivity analyses: predictive accuracy for response to multidisciplinary treatment of patients with unresectable refractory recurrent rectal cancer or unresectable refractory colorectal cancer liver metastases

BackgroundPatients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs).MethodsIn this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected.ResultsOur analyses resulted in evaluations of 94.12% (95% CI 0.71–0.99) for sensitivity, 5.26% (95% CI 0.01–0.26) for specificity, a predictive value of 47.06% (95% CI 0.29–0.65) for a positive response, a predictive value of 50% (95% CI 0.01–0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30–0.64).ConclusionsThis is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.

Precision oncotherapy based on liquid biopsies in multidisciplinary treatment of unresectable recurrent rectal cancer: a retrospective cohort study

BackgroundThird line innovative systemic treatments and loco-regional chemotherapy by hypoxic pelvic perfusion (HPP) have both been proposed for the treatment of unresectable not responsive recurrent rectal cancer (URRC). In the present study, we have compared the safety and efficacy of HPP/target therapy, using drug regimens selected by liquid biopsy precision oncotherapy, to third-line systemic therapy based on tissue specimens precision oncotherapy.MethodsHPP/target therapy regimens were selected based on precision oncotherapy, including assays for chemosensitivity and viability, and qRT-PCR for tumor-related gene expression. In the control group, systemic third-line and further lines of therapy were defined according to clinical and biological parameters.ResultsFrom 2007 to 2019, 62 URRC patients were enrolled, comprised of 43 patients in the HPP/target-therapy group and 19 patients in the systemic therapy control group. No HPP related complications were reported and the most common adverse events were skin and bone marrow toxicity. In the HPP/target-therapy group, the ORR was 41.8% whereas in the systemic therapy control group was 15.8%. DCR of the HPP/target-therapy group was significantly improved over the systemic therapy group (P = 0.001), associated with a PFS of 8 vs 4 months (P = 0.009), and OS of 20 vs 8 months (P = 0.046).ConclusionsThe present data indicate that in URCC patients, the integration of HPP/target-therapy and precision oncotherapy based upon liquid biopsy is as effective and efficacious as third-line treatment in local disease control and, therefore, deserves to be further assessed and compared to conventional systemic treatments in future prospective randomized trials.

Multidisciplinary palliation for unresectable recurrent rectal cancer: hypoxic pelvic perfusion with mitomycin C and oxaliplatin in patients progressing after systemic chemotherapy and radiotherapy, a retrospective cohort study

BackgroundInnovative systemic treatments and loco-regional chemotherapy by hypoxic pelvic perfusion (HPP) have been proposed for unresectable recurrent rectal cancer (URRC). Regorafenib and trifluridine-tipiracil reported significantly increased PFS 1.9-2.0 months, OS 6.4-7.1 months vs placebo, respectively. Present study evaluated safety and efficacy of mitomycin/oxaliplatin HPP associated to intravenous cetuximab, and of third line systemic therapy in clinical practice.MethodsHPP consisted of: isolation, perfusion, chemofiltration. Patients received mitomycin 25 mg/m2 and oxaliplatin 80 mg/m2 during HPP; from days 21 to 28, cetuximab 250 mg/m2/week. In case of partial response or stable disease, HPPs were repeated every 8 weeks. In control group, systemic third and further lines of therapy were defined in clinical practice according to clinical (age, comorbidities, performance status), biological parameters (KRAS, NRAS, BRAF genotype).ResultsFrom 2005 to 2018, 49 URRC patients were enrolled; 33 in HPP/target-therapy, 16 in systemic therapy control group. No HPP related complications were reported. Most common adverse events were skin, bone marrow toxicities. In HPP/target-therapy group, ORR and DCR were 36.4 and 100%; in systemic therapy control group, 18.7 and 31.25%, respectively. In HPP/target-therapy compared with systemic therapy group, respectively, DCR seemed significantly favourable (P = 0.001), as PFS 8 vs 4 months (P = 0.018), and OS 15 vs 8 months (P = 0.044).ConclusionsPresent data showed that integration of HPP/target-therapy may be effective in local control, and efficacy as third line treatment of URCC patients. This therapeutic strategy deserves further prospective randomized trials to be compared to conventional systemic treatments.

Hypoxic pelvic perfusion with cisplatin and mitomycin C in multidisciplinary palliative treatment of patients with unresectable recurrent rectal cancer: a retrospective study.

Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy may be candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. Thirty-seven patients with unresectable recurrent rectal cancer in progression after standard treatments underwent repeated HPP with mitomycin C (25 mg/m2) and cisplatin (70 mg/m2). Twenty patients, exhibiting epidermal growth factor receptor (EGFR) overexpression, also received cetuximab targeted-therapy, following the ultimate HPP treatment. Following initial HPP treatment, median progression-free survival was 7 months (range: 5-19 months), median time-to-death or termination of follow-up was 13 months (range: 9-18 months), one-year survival-rate was 59.45%, two-year survival rate was 10.81%, and three-year survival rate was 2.7%. Survival was significantly influenced by cetuximab targeted-therapy post-HPP and the presence of additional metastatic sites (P<0.03). Repeated HPP treatments with mitomycin C plus cisplatin, followed by cetuximab targeted-therapy, may represent a safe and efficacious palliative therapy in patients with unresectable recurrent rectal cancer, in progression following standard systemic chemo- and radio-therapy, and thus warrants confirmation in a larger phase III study.

Palliation with a multimodality treatment including hypoxic pelvic perfusion for unresectable recurrent rectal cancer: outcomes based on a retrospective study.

Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy are candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. From a cohort of 77 patients with unresectable recurrent rectal cancer in progression after standard treatments and submitted to HPP, 21 patients underwent repeat HPP using mitomycin C (MMC) at the dose of 25mg/m2. After the last HPP, 7 patients received a targeted-therapy with cetuximab according to overexpression of epidermal growth factor receptor in recurrence cancer cells. The median overall survival of these 21 patients from the diagnosis of unresectable recurrent rectal cancer was 23months (iqr 18-24). After the first HPP, the median survival of the 21 patients until death or end of follow-up was 10months (iqr 9-13). The 1-year and 2-year survival rates were 71.4%, and 4.8%, respectively. From the first HPP, age > 60years, a recurrence shrinkage of at least 30% (partial response), and the addition of a post-HPP targeted-therapy with cetuximab significantly affected survival (P < 0.04). In conclusion, repeated MMC-HPP followed by targeted-therapy seems to be an effective palliative treatment for patients with unresectable recurrent rectal cancer in progression after systemic chemotherapy and radiation but the results of this study have to be confirmed by a larger phase III trial.

Mitomycin C hypoxic pelvic perfusion for unresectable recurrent rectal cancer: pharmacokinetic comparison of surgical and percutaneous techniques

Patients with unresectable recurrent rectal cancer that progresses after standard and multi-modular treatments are candidates for hypoxic pelvic perfusion. Hypoxic pelvic perfusion can be performed using a surgical or percutaneous approach. The aim of this study was to examine whether the surgical and percutaneous approaches are comparable with respect to tumor drug exposure in the pelvis. A pharmacokinetic study was performed in 18 patients. Both the surgical and percutaneous procedures were performed using mitomycin C (MMC) at a dose of 25 mg/m2. The main parameter that was used to evaluate pelvic tumor drug exposure was the ratio of the areas under the MMC plasma concentration curves in the pelvis and the systemic compartment during the perfusion time (AUC0–20). The mean values ± SD for the ratios between the MMC AUC0–20 in the pelvic and systemic compartments were 14.38 ± 4.31 and 13.15 ± 4.26 for the surgical and percutaneous techniques, respectively (p = 0.53). This pharmacokinetic study demonstrated that the percutaneous approach for hypoxic pelvic perfusion did not statistically differ from the surgical approach. When perfusion must be repeated several times in the same patient, the percutaneous and surgical methods may be adopted interchangeably.ClinicalTrials.gov IdentifierNCT01891552.

Radiofrequency Ablation as Salvage Therapy for Unresectable Locally Recurrent Rectal Cancer

Despite total mesorectal resection, often with accompanying chemoradiation therapy, local recurrence continues to cause significant morbidity and mortality in cases of rectal cancer. Recurrent rectal cancers are often inoperable as a result of pelvic sidewall and sacral invasion. The authors describe the use of radiofrequency (RF) ablation to manage an unresectable multiply recurrent rectal cancer in which complete ablation with durable long-term control was achieved despite the large size of the tumor. RF ablation is a viable option for patients who are poor surgical candidates or whose disease is not amenable to conventional surgical approaches.

Three-dimensional conformal radiotherapy combined with FOLFOX4 chemotherapy for unresectable recurrent rectal cancer

To investigate the effect of three-dimensional conformal radiotherapy (3-DCRT) in combination with FOLFOX4 chemotherapy for unresectable recurrent rectal cancer. Forty-eight patients with unresectable recurrent rectal cancer were randomized and treated by 3-DCRT or 3-DCRT combined with FOLFOX4 chemotherapy between September 2001 and October 2003. For the patients without prior radiation history, the initial radiation was given to the whole pelvis by traditional methods with tumor dose of 40 Gy, followed by 3-DCRT for the recurrent lesions to the median total cumulative tumor dose of 60 Gy (range 56-66 Gy); for the post-radiation recurrent patients, 3-DCRT was directly given for the recurrent lesions to the median tumor dose of 40 Gy (36-46 Gy). For patients in the study group, two cycles chemotherapy with FOLFOX4 regimen were given concurrently with radiotherapy, with the first cycle given simultaneously with the initiation of radiation and the second cycle given in the fifth week for patients receiving conventional pelvis radiation or given in the last week of 3-DCRT for patients receiving 3-DCRT directly. Another 2-4 cycles (average 3.6 cycles) sequential FOLFOX4 regimen chemotherapy were given to the patients in the study group, beginning at 2-3 wk after chemoradiation. The outcomes of symptoms relieve, tumor response, survival and toxicity were recorded and compared between the study group and the control group. For the study group and the control group, the pain-alleviation rates were 95.2% and 91.3% (P > 0.05); the overall response rates were 56.5% and 40.0% (P > 0.05); the 1-year and 2-year survival rates were 86.9%, 50.2% and 80.0%, 23.9%, with median survival time of 25 mo and 16 mo (P < 0.05); the 2-year distant metastasis rates were 39.1% and 56.0% (P = 0.054), respectively. The side effects, except peripheral neuropathy which was relatively severer in the study group, were similar in the the two groups and well tolerated. Three-dimensional conformal radio-therapy combined with FOLFOX4 chemotherapy for unresectable recurrent rectal cancer is a feasible and effective therapeutic approach, and can reduce distant metastasis rate and improve the survival rate.

171 Workshop Clinical application of IMRT in the treatment of patients with unresectable T4 or recurrent rectal or rectosigmoid cancer: feasibility and toxicity data

171 Workshop Clinical application of IMRT in the treatment of patients with unresectable T4 or recurrent rectal or rectosigmoid cancer: feasibility and toxicity data