Neoadjuvant chemotherapy in MRI-staged high-risk rectal cancer in addition to or as an alternative to preoperative chemoradiation?

Background For patients with resectable rectal cancer chemoradiation (CRT) or short-course preoperative radiotherapy (SCPRT) reduces locoregional failure, without extending disease-free survival (DFS) or overall survival (OS). Compliance to postoperative adjuvant chemotherapy is poor. Neoadjuvant chemotherapy (NACT) offers an alternative strategy. Methods A systematic computerised database search identified studies exploring NACT alone or NACT preceding/succeeding radiation. The primary outcome measure was pathological complete response (pCR). Secondary outcome measures included acute toxicity, surgical morbidity, circumferential resection margin, locoregional failure, DFS and OS. Results Four case reports, 12 phase I/II studies, 4 randomised phase II and one randomised phase III study evaluated chemotherapy before CRT. Four prospective studies reviewed chemotherapy after CRT. Three phase II studies investigated chemotherapy using FOLFOX plus bevacizumab without radiotherapy. In 24 studies of 1271 patients, pCR varied from 7% to 36%, but with no impact on metastatic disease. Conclusions NACT before CRT delivers does not compromise CRT but has not increased pCR rates, R0 resection rate, improved DFS or reduced metastases. NACT following CRT is an interesting strategy, and the utility of NACT alone could be explored compared with SCPRT or CRT in selected patients with rectal cancer where the impact of radiotherapy on DFS and OS is marginal.     

Long-course oxaliplatin-based preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study

BackgroundImprovements in local control are required when using preoperative chemoradiation for cT4 or advanced cT3 rectal cancer. There is therefore a need to explore more effective schedules.Patients and methodsPatients with fixed cT3 or cT4 cancer were randomized either to 5 × 5 Gy and three cycles of FOLFOX4 (group A) or to 50.4 Gy in 28 fractions combined with two 5-day cycles of bolus 5-Fu 325 mg/m²/day and leucovorin 20 mg/m²/day during the first and fifth week of irradiation along with five infusions of oxaliplatin 50 mg/m² once weekly (group B). The protocol was amended in 2012 to allow oxaliplatin to be then foregone in both groups.ResultsOf 541 entered patients, 515 were eligible for analysis; 261 in group A and 254 in group B. Preoperative treatment acute toxicity was lower in group A than group B, P = 0.006; any toxicity being, respectively, 75% versus 83%, grade III–IV 23% versus 21% and toxic deaths 1% versus 3%. R0 resection rates (primary end point) and pathological complete response rates in groups A and B were, respectively, 77% versus 71%, P = 0.07, and 16% versus 12%, P = 0.17. The median follow-up was 35 months. At 3 years, the rates of overall survival and disease-free survival in groups A and B were, respectively, 73% versus 65%, P = 0.046, and 53% versus 52%, P = 0.85, together with the cumulative incidence of local failure and distant metastases being, respectively, 22% versus 21%, P = 0.82, and 30% versus 27%, P = 0.26. Postoperative and late complications rates in group A and group B were, respectively, 29% versus 25%, P = 0.18, and 20% versus 22%, P = 0.54.ConclusionsNo differences were observed in local efficacy between 5 × 5 Gy with consolidation chemotherapy and long-course chemoradiation. Nevertheless, an improved overall survival and lower acute toxicity favours the 5 × 5 Gy schedule with consolidation chemotherapy.Clinical trial numberThe trial is registered as ClinicalTrials.gov number NCT00833131.     

Is neoadjuvant chemotherapy with gemcitabine plus cisplatin beneficial in patients with muscle-invasive bladder cancer?

Evaluation of: Weight CJ, Garcia JA, Hansel DE et al. Lack of pathologic down-staging with neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder. Cancer 115, 792–799 (2009).

This study by the Glickman Urological Institute fails to show a beneficial role for neoadjuvant chemotherapy in muscle-invasive bladder cancer. The poor outcomes in the study could be attributed to the use of non-methotrexate, vinblastine, doxorubicin and cisplatin regimens and to excessive delays in performing cystectomy. Randomized trials of neoadjuvant chemotherapy have shown improved survival and increased rates of pathologic complete response when using cisplatin-based combination therapies compared with local therapy alone. A regimen consisting of gemcitabine plus cisplatin has shown similar efficacy and less toxicity in the metastatic setting and further research is warranted before its efficacy can be extrapolated to the neoadjuvant setting.     

Prognostic impact of neoadjuvant chemoradiation in cT3 oesophageal cancer – A propensity score matched analysis

BackgroundThe prognostic effect of neoadjuvant treatment in advanced oesophageal cancer is still debated because most studies included undefined T-stages, different radio/chemotherapies or different types of surgery.ObjectivesTo analyse the prognostic impact of neoadjuvant chemoradiation in patients with clinical T3 oesophageal cancer and oesophagectomy.MethodsIn a retrospective study 768 patients from two centres with cT3/Nx/M0 oesophageal cancer and transthoracic en-bloc oesophagectomy were selected. Clinical staging was based on endoscopy, endosonography and spiral-CT scan. Propensity score matching using histology, location of tumour, age, gender and ASA-classification identified 648 patients (n = 302 adenocarcinoma (AC), n = 346 squamous cell carcinoma (SCC)) for the intention-to-treat analysis comparing group-I (n = 324) patients with planned oesophagectomy and group-II (n = 324) patients with planned neoadjuvant chemoradiation (40 Gy, 5-FU, cisplatin) followed by oesophagectomy. The prognosis was analysed by univariate and multivariate analyses.ResultsIn the intention-to-treat analysis group-I had a 17% and group-II a 28% 5-year survival rate (5-YSR) (p < 0.001). After excluding patients without oesophagectomy the 5-YSR of group-II increased to 30%. The results were more favourable for patients with AC (5y-SR of 38%) compared to SCC (22%) (p = 0.060). In group-II patients with major response (n = 128) had a 41% 5-YSR compared to 20% for those with minor response (n = 155, p < 0,001). In multivariate analysis neoadjuvant chemoradiation was a favourable independent prognostic factor.ConclusionNeoadjuvant chemoradiation followed by oesophagectomy results in 11% higher 5-YSR than surgery alone for patients with cT3/Nx/M0 oesophageal cancer. This effect is due to the substantial prognostic benefit of the major responders.     

Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious?

Neoadjuvant chemotherapy (NACT) is a term originally used to describe the administration of chemotherapy preoperatively before surgery. The original rationale for administering NACT or so-called induction chemotherapy to shrink or downstage a locally advanced tumour, and thereby facilitate more effective local treatment with surgery or radiotherapy, has been extended with the introduction of more effective combinations of chemotherapy to include reducing the risks of metastatic disease. It seems logical that survival could be lengthened, or organ preservation rates increased in resectable tumours by NACT. In rectal cancer NACT is being increasingly used in locally advanced and nonmetastatic unresectable tumours. Randomised studies in advanced colorectal cancer show high response rates to combination cytotoxic therapy. This evidence of efficacy coupled with the introduction of novel molecular targeted therapies (such as Bevacizumab and Cetuximab), and long waiting times for radiotherapy have rekindled an interest in delivering NACT in locally advanced rectal cancer. In contrast, this enthusiasm is currently waning in other sites such as head and neck and nasopharynx cancer where traditionally NACT has been used. So, is NACT in rectal cancer a real advance or just history repeating itself? In this review, we aimed to explore the advantages and disadvantages of the separate approaches of neoadjuvant, concurrent and consolidation chemotherapy in locally advanced rectal cancer, drawing on theoretical principles, preclinical studies and clinical experience both in rectal cancer and other disease sites. Neoadjuvant chemotherapy may improve outcome in terms of disease-free or overall survival in selected groups in some disease sites, but this strategy has not been shown to be associated with better outcomes than postoperative adjuvant chemotherapy. In particular, there is insufficient data in rectal cancer. The evidence for benefit is strongest when NACT is administered before surgical resection. In contrast, the data in favour of NACT before radiation or chemoradiation (CRT) is inconclusive, despite the suggestion that response to induction chemotherapy can predict response to subsequent radiotherapy. The observation that spectacular responses to chemotherapy before radical radiotherapy did not result in improved survival, was noted 25 years ago. However, multiple trials in head and neck cancer, nasopharyngeal cancer, non-small-cell lung cancer, small-cell lung cancer and cervical cancer do not support the routine use of NACT either as an alternative, or as additional benefit to CRT. The addition of NACT does not appear to enhance local control over concurrent CRT or radiotherapy alone. Neoadjuvant chemotherapy before CRT or radiation should be used with caution, and only in the context of clinical trials. The evidence base suggests that concurrent CRT with early positioning of radiotherapy appears the best option for patients with locally advanced rectal cancer and in all disease sites where radiation is the primary local therapy.     

Can shear-wave elastography predict response to neoadjuvant chemotherapy in women with invasive breast cancer?

Background:

Response of invasive breast cancer to neoadjuvant chemotherapy (NAC) is variable, and prediction of response is imperfect. We aimed to ascertain whether tissue stiffness in breast cancers, as assessed by shear-wave elastography (SWE) before treatment, is associated with response.

Methods:

We retrospectively compared pre-treatment tumour mean tissue stiffness, with post-treatment Residual Cancer Burden (RCB) scores and its components in 40 women with breast cancer treated by NAC using Pearson''s correlation coefficient (CC), a general linear model and multiple linear regression. Subgroup analysis was carried out for luminal, HER2-positive and basal immuno-histochemical subtypes.

Results:

Statistically significant correlations were shown between stiffness and RCB scores and between stiffness and percentage tumour cellularity. The correlation between stiffness and percentage cellularity was strongest (CC 0.35 (P<0.0001) compared with CC 0.23 (P=0.004) for the RCB score). The results of a general linear model show that cellularity and RCB score maintain independent relationships with stiffness. By multiple linear regression, only cellularity maintained a significant relationship with stiffness.

Conclusion:

Pre-treatment tumour stiffness measured by SWE, has a statistically significant relationship with pathological response of invasive breast cancer to NAC.     

Is it reasonable to consider second-line chemotherapy in patients with hormone-refractory prostate cancer?

At present, no consensus exists regarding the use of second-line chemotherapy in patients with hormone-refractory prostate cancer (HRPC). A total of 23 patients with evidence of disease progression during or after first-line chemotherapy (epirubicin, etoposide, and dexamethasone) were included in this study. Two second-line treatments were administered throughout the study period (2000-2004) with 15/23 patients receiving carboplatin AUC 3 on day 1 and vinblastine 5 mg/m2 on day 1 of a 21-day cycle and 8/23 patients treated with docetaxel 50 mg/m2 on day 1 of a 21-day cycle. The latter regimen has been used since 2003. The prostate-specific antigen (PSA) level decreased by > or =50% in 3 of 23 patients, corresponding to an overall PSA response rate of 13% (95% confidence interval, 3-34%). The median time to biochemical progression was 9, 24 and 33 weeks, respectively. The median overall survival was 39 weeks (range, 15-73 weeks) with no difference between the two chemotherapy groups (p=0.08). A significant reduction of analgesic use was observed in 2 of 10 patients (20%) who required analgesics for cancer pain upon study entry. The major toxicity was grade 3 thrombocytopenia in 2 of 23 patients (9%). Both second-line treatments, a combination of carboplatin and vinblastine and a monotherapy with docetaxel, showed modest activity at subtoxic doses in patients with HRPC.     

Is guideline adherence the key to increased survival in patients with breast cancer?

Recently, Varga et al. reported in an observational study that guideline adherence could prevent 56.3-78.9% of all deaths in patients with early onset breast cancer [Oncology 2010;78:189-195]. This would mean that nearly all deaths due to breast cancer can be avoided by guideline-adherent treatment. We argue that some methodological issues like immortal time bias or healthy adherer bias may have contributed to these implausible findings. However, the non-transparent reporting of the methods, especially regarding the operationalization of guideline adherence, hampers critical assessment of this study.