局部晚期直肠癌新辅助调强放疗联合卡培他滨化疗67例疗效观察

[目的]评估局部晚期直肠癌新辅助调强放疗联合卡培他滨化疗安全性及疗效.[方法]对临床分期为T25/T4或淋巴结阳性的67例直肠腺癌患者进行新辅助调强放疗联合化疗.调强放疗方案为原发病灶及转移淋巴结外放1cm,放疗剂量55Gy,每次2.2Gy,盆腔放疗剂量为45Gy,每次1.8Gy.卡培他滨1650mg/(m2·d)分2次于放疗d1-14及d22～35口服,手术于放化疗结束后6～8周进行.[结果]除1例因3级腹泻停止放化疗外余均完成同步放化疗.同步放化疗不良反应:3级腹泻4例(6.0％),3级放射性皮炎3例(4.5％),无4级不良反应发生.术后15例(22.4％)达病理完全缓解.术后30d内无死亡病例,3例(4.5％)出现吻合口瘘,2例(3.0％)会阴部切口感染,1例(1.5％)出现肠梗阻.[结论]直肠癌新辅助调强放化疗安全,耐受性好,病理完全缓解率高.     

Phase II Trial of Neoadjuvant Bevacizumab with Modified FOLFOX7 in Patients with Stage II and III Rectal Cancer

Lessons Learned

• Neoadjuvant bevacizumab with modified FOLFOX7 without radiation failed to meet the goal of pathological complete response rate; however, the low number of recurrence and disease‐free survival in this population, with predominantly stage III, is encouraging and worth further exploration.
• The racial distribution of the patient population, as well as a wait time of more than 4 weeks after last chemotherapy, may have contributed to the findings.

BackgroundCombination chemotherapy in lieu of radiation in rectal adenocarcinoma is under exploration in multiple trials. We evaluated the efficacy of neoadjuvant FOLFOX + bevacizumab in patients (pts) with clinical stage II and III disease.MethodsPts received six cycles of bevacizumab (5 mg/kg) and modified FOLFOX7 (oxaliplatin 85 mg/m², leucovorin 20 mg/m², and fluorouracil [5‐FU] 2,400 mg/m²). Surgical resection was performed 6–8 weeks after completion of treatment and upon confirmation of nonmetastatic disease. We employed a Simon two‐stage design and required three pathological complete responses (pCR) in the first 18 pts, with a prespecified pCR rate of 25% before moving to the next stage.ResultsSeventeen pts enrolled; 65% at stage III. Median age was 57 (35–79), 65% were male, 47% were Hispanic, 35% were white, and 18% were Asian. All pts but one completed six cycles of therapy. One pCR was observed (6%), and 11 of 17 (65%) pts had pathological downstaging. One patient experienced systemic recurrence and remains on treatment. Probability of disease‐free survival (DFS) at 5 years is 0.94 (SE, 0.06).ConclusionThe study failed to meet the required three pCRs in the first 18 pts. The DFS in this population is encouraging and supports the hypothesis that select pts with rectal cancer may be spared from radiation.     

卡培他滨联合放疗对直肠癌的疗效评价

目的 探讨术前口服卡培他滨与放疗联合治疗直肠癌的疗效。方法对临床分期属T3／T4、肿块距肛缘3～9cm、无远处转移或侵犯肛管的局部进展期低位直肠癌患者,给予口服卡培他滨1250mg／m^2,2次／日,3周为1个疗程,重复2个疗程;同时给予盆腔常规放疗,总剂量为46～50Gy,2Gy／天。放疗结束后休息3～4周,按TME原则行根治性切除术。结果入组共84例,其中5例患者肿瘤临床完全消退,未手术予于随访。79例患者行根治性手术（RO）,实际保留肛门括约肌功能者80例（95．24％）。13例患者术后病理检查结果显示肿瘤完全消退,加上肿瘤临床完全消退,肿瘤完全消退率（CR）达21．43％,未见疾病进展者（PD）。按DWORAK’S肿瘤消退分级（TRG）,TRGO3例,TRG112例,TRG28例,TRG343例,TRG418例,病理有效率或降期（TRG2＋3＋4）为82．14％。病例均获得随访,随访时间5—25个月,中位随访时间14个月。局部复发1例（1．19％）,肺转移1例,肝转移2例,远处转移率为3．57％,总复发率为4．76％,1年无病生存率（DFS）为86．74％,1年总生存率（OS）为98．51％。3级不良反应有手足综合症2例（2．40％）,3度骨髓抑制1例。结论采用口服卡培他滨辅助放、化疗是高度安全有效的。术前口服卡培他滨与放疗联合治疗,绝大多数患者肿瘤完全消退（TRG4）和中度消退（TRG2＋3）,明显提高了切除率和保肛手术率,疗效确切。     

ShorTrip Trial: A Prospective,Multicentric Phase II Single-Arm Trial of Short-Course Radiotherapy Followed by Intensified Consolidation Chemotherapy With the Triplet FOLFOXIRI as Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer

BackgroundIn patients with locally advanced rectal cancer (LARC) treated with preoperative (chemo) radiotherapy and surgery, adjuvant chemotherapy is poorly feasible and its benefit is questionable. In the last years, several total neoadjuvant treatment (TNT) strategies, moving the adjuvant chemotherapy to the neoadjuvant setting, have been investigated with the aim of improving compliance to systemic chemotherapy, treating micrometastases earlier and then reducing distant recurrence.Patients and MethodsShorTrip (NTC05253846) is a prospective, multicentre, single-arm phase II trial where 63 patients with LARC will be treated with short-course radiotherapy followed by intensified consolidation chemotherapy with FOLFOXIRI regimen and surgery. Primary endpoint is pCR. Among the first 11 patients who started consolidation chemotherapy, a preliminary safety analysis showed a high rate of grade 3 to 4 neutropenia (N = 7, 64%) during the first cycle of FOLFOXIRI. Therefore, the protocol has been emended with the recommendation to omit irinotecan during the first cycle of consolidation chemotherapy. After amendment, in a subsequent safety analysis focused on the first 9 patients treated with FOLFOX as first cycle and then with FOLFOXIRI, grade 3 to 4 neutropenia was reported in only one case during the second cycle.Aim of the studyThe aim of this study is to assess the safety and activity of a TNT strategy including SCRT, intensified consolidation treatment with FOLFOXIRI and delayed surgery. After protocol amendment, the treatment seems feasible without safety concern. Results are expected at the end of 2024.     

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.     

Intensity-Modulated Radiotherapy With a Simultaneous Integrated Boost in Rectal Cancer

AimsDose–response curves suggest that higher doses of radiotherapy improve the complete response rate in rectal cancer. The UK adopted the EXPERT trial dose and fractionation, 45 Gy in 25 fractions to the pelvis with a sequential 9 Gy in five fractions to the gross tumour, in patients where the aim was to maximise the complete response. In the Oxford University Hospital NHS Foundation Trust (Oxford, UK) we deliver a biological equivalent dose (BED5) in selected patients using intensity-modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) in 25 fractions. We carried out a retrospective analysis of our series to: (i) document the toxicity of this protocol; (ii) ascertain whether dose constraints from RTOG 0822 were appropriate; (iii) assess the response.Materials and methodsThe demographics and treatment details for all consecutive patients treated with this protocol were collected using electronic systems. Patients received 45 Gy to the elective nodes and 52 Gy using a SIB to the gross tumour with capecitabine chemotherapy using IMRT or RapidArc plans. Acute toxicity was collected prospectively during weekly reviews. For the purpose of this study, a dedicated gastrointestinal radiologist reviewed all baseline and post-treatment magnetic resonance images and assigned a magnetic resonance tumour regression grade (mrTRG).ResultsSeventy-one patients were identified. Seventy completed radiotherapy with a median overall treatment time of 34 days (range 32–36 days); 67.6% received full-dose chemotherapy, with 21.2% receiving a reduced dose. There was a 4.2% incidence of grade 3+ non-haematological toxicity and 1.5% grade 3 + haematological toxicity. 4.2% were admitted during their radiotherapy, with one death due to a pelvic abscess. The RTOG 0822 constraints were achieved in ≥75% of cases, other than the high-dose bladder constraint. mrTRG 1–2 was seen in 47.8%, with mrTRG 1 seen in 23.9%.ConclusionsWe suggest that our protocol shows acceptable acute toxicity, with promising mrTRG results, and could be adopted by centres as an IMRT equivalent dose for EXPERT dose and fractionation.     

Phase II Trial of Docetaxel/Capecitabine in Hormone-Refractory Prostate Cancer

BackgroundDocetaxel is the most active single agent in the treatment of hormone-refractory prostate cancer (HRPC). Because of the preclinical and clinical evidence of synergy of capecitabine and docetaxel, it was hypothesized that this combination would be active and tolerable in HRPC.Patient and MethodsPatients received docetaxel 60 mg/m² intravenously over 60 minutes on day 1 of each 21-day cycle and capecitabine 1000 mg/m² administered orally twice daily on days 1-14 of each cycle for a maximum of 8 cycles or until disease progression or intolerable toxicity. Seventy-seven patients were enrolled at 43 US Oncology sites. The median age was 69.3 years (range, 48-86 years); 86% were white, and the Eastern Cooperative Oncology Group performance status scores of 0 and 1 were 49% and 51%, respectively. Sixty-nine (90%) patients were evaluable for prostate-specific antigen response.ResultsOverall, 41% of patients had a decreased prostate-specific antigen level ≥ 50%. There were 4 complete responses (6%), 24 partial responses (35%), 29 incidences of stable disease (43%), and 11 incidences of progressive disease (16%). Nine patients had stable disease ≥ 6 months, and the clinical benefit rate was 54%. The median time to response was 1.5 months (range, 1-6 months), and the median duration of response was 5.2 months (range, 1-16.9 months). The estimated survival at 12 and 24 months was 65% and 22%, respectively, with a median survival of 17 months (range, < 1-27 months). There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (50%), leukopenia (22%), hand-foot syndrome (17%), fatigue (11%), and nausea (11%).ConclusionDocetaxel/capecitabine is an active and tolerable combination in HRPC. Toxicity was acceptable and anticipated. Response rate and survival are comparable with other docetaxel combinations.     

The Intensity-Modulated Pelvic Node and Bladder Radiotherapy (IMPART) Trial: A Phase II Single-Centre Prospective Study

AimsNode-positive bladder cancer (NPBC) carries a poor prognosis and has traditionally been treated palliatively. However, surgical series suggest that a subset of NPBC patients can achieve long-term control after cystectomy and lymph node dissection. There is little published data regarding the use of radiotherapy to treat NPBC patients. This is in part due to concerns regarding the toxicity of whole-pelvis radiotherapy using conventional techniques. We hypothesised that, using intensity-modulated radiotherapy (IMRT), the pelvic nodes and bladder could be treated within a radical treatment volume with acceptable toxicity profiles.Materials and methodsThe Intensity-modulated Pelvic Node and Bladder Radiotherapy (IMPART) trial was a phase II single-centre prospective study designed to assess the feasibility of delivering IMRT to treat the bladder and pelvic nodes in patients with node-positive or high-risk node-negative bladder cancer (NNBC). The primary end point was meeting predetermined dose constraints. Secondary end points included acute and late toxicity, pelvic relapse-free survival and overall survival.ResultsIn total, 38 patients were recruited and treated between June 2009 and November 2012; 22/38 (58%) had NPBC; 31/38 (81.6%) received neoadjuvant chemotherapy; 18/38 (47%) received concurrent chemotherapy; 37/38 (97%) patients had radiotherapy planned as per protocol. Grade 3 gastrointestinal and genitourinary acute toxicity rates were 5.4 and 20.6%, respectively. At 1 year, the grade 3 late toxicity rate was 5%; 1-, 2- and 5-year pelvic relapse-free survival rates were 55, 37 and 26%, respectively. The median overall survival was 1.9 years (95% confidence interval 1.1–3.8) with 1-, 2- and 5-year overall survival rates of 68, 50 and 34%, respectively.ConclusionDelivering IMRT to the bladder and pelvic nodes in NPBC and high-risk NNBC is feasible, with low toxicity and low pelvic nodal recurrence rates. Long-term control seems to be achievable in a subset of patients. However, relapse patterns suggest that strategies targeting both local recurrence and the development of distant metastases are required to improve patient outcomes.     

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.