A systematic review and network meta-analysis of randomised controlled trials comparing neoadjuvant treatment strategies for stage II and III rectal cancer.

AIM: Multiple neoadjuvant therapy strategies have been used and compared for rectal cancer and there has been no true consensus as to the optimal neoadjuvant therapy regimen. The aim is to identify and compare the neoadjuvant therapies available for stage II and III rectal cancer. DESIGN: A systematic literature review was performed, from inception to August 2022, of the following databases: MEDLINE, EMBASE, Science Citation Index Expanded, Cochrane Library. Only randomized controlled trials comparing neoadjuvant therapies for stage II and III rectal cancer were considered. Stata was used to draw network plots, and a Bayesian network meta-analysis was conducted through models utilizing the Markov Chain Monte Carlo method in WinBUGS. RESULTS: A total of 58 articles were included based on 41 randomised controlled trials, reporting on 12,404 participants that underwent 15 neoadjuvant treatment regimens. No significant difference was identified between treatments for major or total postoperative complications, anastomotic leak rates, or sphincter-saving surgery. Straight to surgery (STS) ranked as best treatment for preoperative toxicity but ranked worst treatment for positive resection margins and complete response. STS had significantly increased positive resection margins compared to long-course chemoradiotherapy with short-wait (LCCRT-SW) or long-wait (LCCRT-LW) to surgery, or short-course radiotherapy with short-wait (SCRT-SW) or immediate surgery (SCRT-IS). LCCRT-SW or LCCRT-LW resulted in significantly increased complete response rates compared to STS. LCCRT-LW significantly improved 2-year overall survival compared to STS, SCRT-IS, SCRT-SW. Total neoadjuvant therapy regimes with short-course radiotherapy followed by consolidation chemotherapy (SCRT-CT-SW), induction chemotherapy followed by long-course chemoradiotherapy (CT-LCCRT-S), long-course chemoradiotherapy followed by consolidation chemotherapy (LCCRT-CT-S), significantly improved positive resection margins, complete response, and disease-free survival compared to STS. Chemotherapy with monoclonal antibodies followed by long-course chemoradiotherapy (CT+MAB-LCCRT+MAB-S) significantly improved complete response and positive resection margins compared to STS, and 2-year disease-free survival compared to STS, SCRT-IS, SCRT-SW, SCRT-CT-SW, LCCRT-SW, LCCRT-LW. CT+MAB-LCCRT+MAB-S ranked as best treatment for disease-free survival and overall survival. CONCLUSIONS: Conventional neoadjuvant therapies with short-course radiation or long-course chemoradiotherapy have oncological benefits compared to no neoadjuvant therapy without increasing perioperative complication rates. Prolonged wait to surgery may improve oncological outcomes. Total neoadjuvant therapies provide additional benefits in terms of complete response, positive resection margins, and disease-free survival. Monoclonal antibody therapy may further improve oncological outcomes but currently is only applicable to a small subgroup of patients and requires further validation.

Neoadjuvant Long-Course Chemoradiotherapy for Rectal Cancer: Does Time to Surgery Matter?

The objective of this paper was to evaluate whether delaying surgery following long-course chemoradiotherapy for rectal cancer correlates with pathologic complete response. Pre-operative chemoradiotherapy (CRT) is standard practice in the UK for the management of locally advanced rectal cancer. Optimal timing of surgery following CRT is still not clearly defined. All patients with a diagnosis of rectal cancer who had undergone long-course CRT prior to surgery between January 2008 and December 2011 were included. Statistical analysis was performed using Stata 11. Fifty-nine patients received long-course CRT prior to surgery in the selected period. Twenty-seven percent (16/59) of patients showed a complete histopathologic response and 59.3% (35/59) of patients had tumor down-staging from radiologically-assessed node positive to histologically-proven node negative disease. There was no statistically significant delay to surgery after completion of CRT in the 16 patients with complete response (CR) compared with the rest of the group [IR: incomplete response; CR group median: 74.5 days (IQR: 70-87.5) and IR group median: 72 days (IQR: 57-83), P = 0.470]. Although no statistically significant predictors of either complete response or tumor nodal status down-staging were identified in logistic regression analyses, a trend toward complete response was seen with longer delay to surgery following completion of long-course CRT.

Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial.

BACKGROUND: In the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer. METHODS: In this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m(2) on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m(2) twice daily on days 1-21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0-1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m(2) once per week) or capecitabine (830 mg/m(2) twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987. FINDINGS: 114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6-73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4-63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9-19·2) in the capecitabine group and 13·4 months (95% CI 11·0-15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18-0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1-89·5) in the capecitabine group and 64·2 (95% CI 46·4-77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2-14·6) in the capecitabine group and 10·4 months (95% CI 8·9-12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32-1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3-4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups. INTERPRETATION: Our results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small. FUNDING: Cancer Research UK.

Regional radiotherapy to axilla and supraclavicular fossa for adjuvant breast treatment: a comparison of four techniques.

PURPOSE: The three techniques commonly used to treat the axilla and supraclavicular nodes in adjuvant radiotherapy all have significant disadvantages, including underdosing the deeper nodes, excessively irradiating normal tissues, or producing undesirable hot spots. We assessed whether an anterior field with posterior boost field to the axilla with customized compensation of the anterior beam (APcomp-PAboost) would minimize these drawbacks. METHODS AND MATERIALS: The axillary and supraclavicular nodal volumes, planning target volume (PTV), irradiated volume, and brachial plexus were contoured for 10 patients. The plans for each technique-single anterior field (AP); anterior to posterior parallel pair (AP-PA); anterior field with posterior boost (AP-PAboost); and APcomp-PAboost-were then generated for each patient using CadPlan and compared. RESULTS: The AP plan gave poor PTV coverage in 60% of cases. The AP-PA provided good PTV coverage and minimal hot spots, but resulted in consistent unnecessary RT to the medial posterior neck. The skin and tissue of the medial posterior neck and chest wall (i.e., the tissue overlying the posterior half of the ribs and posterior to the latissimus dorsi muscle, which forms the posterior wall of the axilla) was incidentally included in the radiation fields of the AP-PA and the exit of the AP beam. No nodal tissue is present in this region, and, therefore, this tissue was unnecessarily irradiated to higher doses with the AP-PA technique. The AP-PAboost provided adequate PTV coverage and a limited dose to the medial posterior neck, but produced hot spots in excess of 120% in 90% of cases. The APcomp-PAboost provided good PTV coverage, a limited dose to the medial posterior neck, and hot spots to <120% in all cases. CONCLUSION: In most cases, the APcomp-PAboost technique offered the best compromise, but the AP-PA technique may be preferred if a less intense hot spot is sought.