Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer: A Randomized Trial Comparing Two Radiation Doses (original) (raw)
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Preoperative chemoradiation of locally advanced T3 rectal cancer combined with an endorectal boost
International Journal of Radiation Oncology*Biology*Physics, 2006
Purpose: To investigate the effect and feasibility of concurrent radiation and chemotherapy combined with endorectal brachytherapy in T3 rectal cancer with complete pathologic remission as end point. Methods and Materials: The study included 50 patients with rectal adenocarcinoma. All patients had T3 tumor with a circumferential margin 0 -5 mm on a magnetic resonance imaging scan. The radiotherapy was delivered by a technique including two planning target volumes. Clinical target volume 1 (CTV1) received 60 Gy/30 fractions, and CTV2 received 48.6 Gy/27 fractions. The tumor dose was raised to 65 Gy with endorectal brachytherapy 5 Gy/1 fraction to the tumor bed. On treatment days, the patients received uracil and tegafur 300 mg/m2 concurrently with radiotherapy. Results: Forty-eight patients underwent operation. Histopathologic tumor regression was assessed by the Tumor Regression Grade (TRG) system. TRG1 was recorded in 27% of the patients, and a further 27% were classified as TRG2. TRG3 was found in 40%, and 6% had TRG4. The toxicity was low. Conclusion: The results indicate that high-dose radiation with concurrent chemotherapy and endorectal brachytherapy is feasible with a high rate of complete response, but further trials are needed to define its possible role as treatment option.
Clinical and Translational Oncology, 2016
Background To assess the role of radiation dose intensification with simultaneous integrated boost guided by 18-FDG-PET/CT in pre-operative chemo-radiotherapy (ChT-RT) for locally advanced rectal cancer. Methods A prospective study was approved by the Internal Review Board. Inclusion criteria were: age [18 years old, World Health Organization performance status of 0-1, locally advanced histologically proven adenocarcinoma of the rectum within 10 cm of the anal verge, signed specific informed consent. High-dose volumes were defined including the hyper-metabolic areas of 18-FDG-PET/CT of primary tumor and the corresponding mesorectum and/or pelvic nodes with at least a standardized uptake values (SUV) of 5. A dose of 60 Gy/30 fractions was delivered. A total dose of 54 Gy/30 fractions was delivered to prophylactic areas. Capecitabine was administered concomitantly with RT for a dose of 825 mg/mq twice daily for 5 days/ every week. Results Between September 2011 and July 2015 fortypatients were recruited. At the time of the analysis, median follow up was 20 months (range 5-51). The median interval from the end of ChT-RT to surgery was 9 weeks (range 8-12). Thirty-seven patients (92.5 %) were submitted to sphincter preservation. Tumor Regression Grade (Mandard scale) was recorded as follows: grade 1 in 7 (17.5 %), grade 2 in 17 (42.5 %), grade 3 in 15 (37.5 %) and grade 4 in 1 (2.5 %). Post-surgical circumferential resection margin was negative in all patients. A tumor downstaging was reported in 62.5 % (95 % CI: 0.78-0.47). A nodes downstaging was registered in 85 % (95 % CI: 0.55-0.25). 18-FDG-PET/CT was not able to predict pCR. No correlation was found between pre-treatment SUV-max values and pCR. A metabolic tumor volume [127 cc was related to ypT C2 (p 0.01). Patients with TRG [2 had higher tumor lesion glycolysis values (p 0.05). Conclusion Preliminary results did not confirm some advantages in terms of primary tumor downstaging/downsizing compared to conventional schedules reported in historical series. The role of 18-FDG-PET/CT in neoadjuvant rectal cancer management needs to be confirmed in further investigations. Long terms results are necessary.
International Journal of Radiation Oncology*Biology*Physics, 2013
This study compared radiation dose and tumor regression at the time of operation in 222 rectal cancer patients. A significant correlation between dose and tumor regression was found when dose levels in the range of 50.4-70 Gy were considered, and dose-response relationships for different levels of tumot regression were established. Tumor size and N category both had an influence on the dose response. This may prove of interest for dose escalation studies and watch-and-wait protocols.
Where next with preoperative radiation therapy for rectal cancer?
International Journal of Radiation Oncology*Biology*Physics, 2004
Purpose: The basic question for radiation oncologists is what we hope to achieve from treatments that are adjuvant to surgery: better local (pelvic) control and, hopefully, because of that, fewer metastases. Chemotherapy could add to the local effect of irradiation and may also decrease distant metastases directly. Selection criteria for individual treatment could enhance the therapeutic index. Local Control: Total mesorectal excision reduces the incidence of local recurrence, but preoperative (chemo) radiation is still indicated for more advanced tumors (T3-T4) and for lymph node involvement. Pelvic recurrences arise from tumor clonogens residual beyond the surgical margins. Thus, the practice of shrinking fields to boost the dose to the primary tumor makes no sense, except for tumors that invade residual structures, such as the sacrum.Subclinical disease beyond the future surgical margins grows more quickly than the primary tumor, and hence treatment should be as intense as tolerable. A short treatment course (e.g. 5 ؋ 5 Gy) is desirable, but this regimen, which is currently the gold standard, should be compared (as in the recently closed randomized Polish trial) with higher-dose, longer-duration chemoradiotherapy regimens. The recently closed EORTC trial 22921 examines the benefit of pre-and postoperative chemotherapy combined with a long schedule of radiation. Likewise, continuous infusion of a cycle-active agent rather than bolus administration is a logical addition to radiation therapy in the treatment of fast-growing subclinical tumor extensions. Systemic Disease: The reduction in distant metastasis rates attributable to adjuvant chemotherapy varies greatly among reports. If the reduction is of the order of 10 -25%, the efficacy of chemotherapy equates to as little as about 5 to 12.5 Gy and not more than 20 Gy of total body irradiation. Interval Between Radiation Therapy and Postradiation Surgery: Early excision after preoperative irradiation would be desirable if the primary tumor were still disseminating viable metastatic clonogens. Most tumors do not metastasize until they contain enough viable clonogens to render them clinically detectable. A dose of 10 Gy in 2 Gy fractions reduces at least 30-fold the absolute number of viable clonogens in the primary tumor, to levels that do not yield metastases from the untreated tumor. After a dose of 44 -50 Gy in 2 Gy fractions, there is little chance that the surviving tumor clonogens could regrow to a metastasis-yielding volume in any reasonable radiation-surgery interval. Thus there is no tumor-related necessity for early postradiation surgery. The importance of the interval between radiation and surgery is currently being addressed in a Swedish randomized trial. Prognostic and Predictive Characterization: Tumor volume should be included in the staging system. There are many tumor-and host-related characteristics that can be used to fingerprint the tumor to help select appropriate individual treatment.
Background: To retrospectively evaluate the difference in terms of pathologic complete response (pCR) according to time elapsed between chemoradiation (CRT) and total mesorectal excision (TME) on a large unselected real-life dataset of locally advanced rectal cancer (LARC) patients. Methods: A multicentre retrospective cohort study of LARC patients from 21 Italian Radiotherapy Institutions was performed. Patients were stratified into 3 different time intervals from CRT. The 1st group included 300 patients who underwent TME within 6 weeks, the 2nd 1598 patients (TME within 7–12 weeks) and the 3rd 196 patients (TME within 13 or more weeks after CRT), respectively. Results: Data on 2094 LARC patients treated between 1997 and 2016 were considered suitable for analysis. Overall, 578 patients had stage II while 1516 had stage III histological proven invasive rectal adeno-carcinoma. A CRT schedule of one agent (N = 1585) or 2-drugs (N = 509) was administered. Overall, pCR was 22.3% (N = 468 patients). The proportion of patients achieving pCR with respect to time interval was, as follows: 12.6% (1st group), 23% (2nd group) and 31.1% (3rd group) (p < 0.001), respectively. The pCR relative risk comparison of 2nd to 1st group was 1.8, while 3rd to 2nd group was 1.3. Moreover, between the 3rd and 1st group, a pCR relative risk of 2.4 (p < 0.01) was noted. At univariate analysis, clinical stage III (p < 0.001), radiotherapy dose >5040 cGy (p = 0.002) and longer interval (p < 0.001) were significantly
BMJ Open, 2022
Introduction The standard of care for patients with localised rectal cancer is radical surgery, often combined with preoperative neoadjuvant (chemo)radiotherapy. While oncologically effective, this treatment strategy is associated with operative mortality risks, significant morbidity and stoma formation. An alternative approach is chemoradiotherapy to try to achieve a sustained clinical complete response (cCR). This non-surgical management can be attractive, particularly for patients at high risk of surgical complications. Modern radiotherapy techniques allow increased treatment conformality, enabling increased radiation dose to the tumour while reducing dose to normal tissue. The objective of this trial is to assess if radiotherapy dose escalation increases the cCR rate, with acceptable toxicity, for treatment of patients with early rectal cancer unsuitable for radical surgery. Methods and analysis APHRODITE (A Phase II trial of Higher RadiOtherapy Dose In The Eradication of early rectal cancer) is a multicentre, open-label randomised controlled phase II trial aiming to recruit 104 participants from 10 to 12 UK sites. Participants will be allocated with a 2:1 ratio of intervention:control. The intervention is escalated dose radiotherapy (62 Gy to primary tumour, 50.4 Gy to surrounding mesorectum in 28 fractions) using simultaneous integrated boost. The control arm will receive 50.4 Gy to the primary tumour and surrounding mesorectum. Both arms will use intensity-modulated radiotherapy and daily image guidance, combined with concurrent chemotherapy (capecitabine, 5-fluorouracil/ leucovorin or omitted). The primary endpoint is the proportion of participants with cCR at 6 months after start of treatment. Secondary outcomes include early and late toxicities, time to stoma formation, overall survival and patient-reported outcomes (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CR29, low anterior resection syndrome (LARS) questionnaire). Ethics and dissemination The trial obtained ethical approval from North West Greater Manchester East Research Ethics Committee (reference number 19/ NW/0565) and is funded by Yorkshire Cancer Research. The final trial results will be published in peer-reviewed journals and adhere to International Committee of Medical Journal Editors guidelines. Trial registration number ISRCTN16158514.