Chemoradiation Therapy For Rectal Cancer Research Articles

Prevalence and temporal patterns of persistence of symptoms in 165 rectal cancer patients receiving preoperative chemoradiation therapy

19580 Background: The symptom burden during preoperative chemoradiation therapy for rectal cancer (CRT) has not been objectively characterized previously. The severity and temporal patterns of patient self-reported symptoms during CRT were assessed using the MD Anderson Symptom Inventory (MDASI). Methods: 165 consecutive patients with T3/T4/N+ rectal cancer received 45–55 Gy in 25–30 fractions concurrently with capecitabine chemotherapy. No additional intervention beyond standard supportive care was triggered by the MDASI score severity. The mean symptom scores were grouped into three time points; weeks 0–1 (“baseline”), 2–3 (“early treatment”), and 4–6 (“late treatment”) of CRT. Lowess curves were used to demonstrate the severity and pattern of individual symptoms. Linear mixed models were used to assess changes in symptom severity. Repeated measures analyses compared the mean severity of the reported symptoms at the three time points. Results: The median number of data points per patient was 3.0 (range, 1–6), for a total of 533 data points. Lowess curves demonstrated increasing symptom severity during CRT, which was confirmed by the linear mixed models analysis for each symptom (p<0.05). Using repeated measures with the three time points, these symptoms, except fatigue, showed statistically significant differences in mean severity ( Table 1 ). High baseline fatigue levels blunted statistical power to detect differences during CRT. Despite normal hemoglobin levels, fatigue remained the most severe symptom. Placed in context, the mean symptom levels remained mild throughout CRT. Conclusions: CRT was associated with a high prevalence of and progressive increase in symptom burden during therapy although the functional impact was limited. All symptoms followed clinically recognized patterns. The linear mixed model, a more sensitive measure of these trends, is recommended for prospective studies of interventions for symptom control [Table: see text] No significant financial relationships to disclose.

The clinical significance of the circumferential resection margin following preoperative pelvic chemo‐radiotherapy in rectal cancer: why we need a common language

The presence of microscopic tumour cells within 1 mm of the circumferential surgical resection margin (CRM) is the endpoint most strongly associated with local recurrence in rectal cancer and doubles the risk of developing distant metastases. Reporting on the CRM can monitor surgical quality assurance and over the past two decades has driven advances in surgical technique with the increasing use of total mesorectal excision. The aim of this review was to use the evidence from both phase II and phase III randomized trials of preoperative radiotherapy and chemoradiation in rectal cancer, to assess how often CRM involvement is currently documented and examine its utility as an early predictor of both disease-free and overall survival. A literature search identified both randomized and nonrandomized trials of preoperative radiation therapy and chemoradiation therapy in rectal cancer since 1993. The aim was to find those studies, which documented the distance from the periphery of the tumour and the CRM. Small trials treating < 20 patients were excluded. One hundred and eighty-seven phase II and 28 phase III trials of preoperative radiotherapy or chemoradiation were identified. Most trials documented the degree of response but only 10 of 187 phase II/retrospective studies and four of 28 phase III trials presented data on the achievement of a negative CRM. Few defined this early pathological endpoint prospectively with accurate measurements. However, the majority of studies did use the definition of <or= 1 mm as an involved CRM. Discussion Pathological parameters have been used as early endpoints to compare studies of preoperative radiotherapy or chemoradiation. It remains uncertain whether the degree of response to chemoradiation (e.g. complete pathological response, downsizing the primary tumour, sterilizing the regional nodes, tumour regression grades or residual cell density) or the achievement of a curative resection (uninvolved CRM) is the best early clinical endpoint. Retrospective studies in rectal cancer have confirmed a strong association between the presence of microscopic tumour cells within 1 mm of the CRM and increased risks of both local recurrence and distant metastases. However, as yet this early pathological endpoint lacks structured measurement and analysis techniques to control for intra- and inter-observer variation and has not been validated as a potential surrogate for local control and survival. Recommendations are made as to the most appropriate information, which should be documented in future trials. The CRM status predicts outcome after surgery alone, preoperative radiotherapy and preoperative chemoradiation. Yet CRM status and its measurement has been poorly documented in the literature, and rarely as a prospective measure of outcome. The CRM should be measured and documented in all cases, using the definition of <or= 1 mm to denote an involved CRM. This definition should also be incorporated into future rectal cancer studies with the use of a standardized proforma.

Preliminary results of a phase I study of external beam radiation therapy (EBRT), oxaliplatin (OX), bevacizumab (BV), and capecitabine (CAP) for locally advanced or metastatic adenocarcinoma of the rectum

3543 Background: BV, a monoclonal antibody against vascular endothelial growth factor, increases survival when added to first and second line chemotherapy for metastatic colorectal cancer. Preclinical studies suggest BV may enhance tumoral radiation sensitivity. Preliminary studies of OX and 5-FU based chemoradiation therapy for rectal cancer have suggested improved pathologic CR rates compared to 5-FU/ radiation alone. CAP allows fluoropyrimidine treatment without the inconvenience of an infusion pump. We investigated CAP + BV + OX + EBRT for pts with rectal cancer to evaluate for the MTD and preliminary efficacy results. Methods: Pts with adenocarcinoma of the rectum and no prior pelvic irradiation received 5040 cGy EBRT (180 cGy/fx), CAP (625–825 mg/m2 PO BID on EBRT days), BEV (15 mg/kg d1 and 10 mg/kg d8 and d22), and OX (50–75 mg/m2/week during radiation, weeks 1–5) in dose-escalating fashion. DLT was defined as any grade 3 heme tox ≥ 7d, grade 4 heme tox, grade 4 non-heme tox during chemoradiation, or inability to deliver &gt;85% of planned treatment. Pts eligible for surgical resection could have surgery 6–8 wks after treatment completion. After recovery from surgery, patients could be treated with CAP, BV, and OX. Results: 11 patients (5 men/6 women) have been enrolled. All have completed chemoradiation and resection. At dose level 1 (CAP 625 mg/m2 BID, OX 50mg/m2) there were no DLT’s in 3 pts. 1/3 pts had G3 subarachnoid hemorrhage during adjuvant chemotherapy. At dose level 2 (CAP 825 mg/m2, OX 50 mg/m2) 2/2 pts had DLT (1 G4 diarrhea; 1 G2 rectal pain, causing treatment hold for study-defined DLT). 6 more pts were treated at dose level 1. 1pt had DLT of G3 diarrhea. G2 toxicities included diarrhea (3/11), fatigue (2/11), skin changes (2/11), and pain (2/11). 9/11 patients were downstaged. 2/11 patients had pCR at surgery and 2/11 microscopic disease only. Conclusions: CAP + BEV + OX + EBRT is a well-tolerated, active regimen for the treatment of rectal cancer. MTD was determined to be CAP 625 mg/m2 BID + BEV 15 mg/kg d1 + 10 mg/kg d 8 and 22 + OX 50 mg/m2/week. Further study of efficacy at the MTD is warranted. [Table: see text]

Patient's Preferences for Adjuvant Postoperative Chemoradiation Therapy in Rectal Cancer

This study was designed to elicit patient's preferences with regard to adjuvant postoperative chemoradiation therapy in rectal cancer. Forty-seven previously treated colorectal cancer patients underwent a structured interview and were presented with two scenarios involving surgery for rectal cancer: surgery alone, or surgery followed by postoperative chemoradiation therapy. Acute and long-term health states for each options were described. Their willingness to trade-off side-effects for treatment efficacy was evaluated by using the probability trade-off method. The age and gender distribution of the cohort were comparable with the general colon cancer population. Rectal cancer had been diagnosed in 20 individuals. The majority of patients valued their disease-free status in light of the anticipated long-term effects on their quality of life. The median point at which patients switched their preference was 5 percent, a value reflecting the critical local recurrence rate acceptable. The important items that influenced decisions were the effects on bowel function and fear of recurrence. This small study demonstrates a substantial variation in patient's preferences with regard to postoperative chemoradiation for rectal cancer. Further studies in the preoperative setting are warranted.

Advances in chemoradiation therapy in rectal cancer: the impact of imaging

The vast modern speciality of oncology, clinical and medical, was borne out of the more mature parent discipline of radiology and its allied sciences. The infant radiotherapy service rapidly established its value in the care of cancer patients and was quick to adopt medical developments, which provided a systemic approach to complement local management with surgery and radiotherapy. Clinical and medical oncology are now major specialties, critically reliant on modern imaging, itself a much mutated descendant of radiology. The diversity and detail of imaging approaches makes modern diagnostic imaging almost as removed from parent radiology as oncology. Now, the two descendants meet as partners in the management of patients with rectal cancer and this relationship has been hugely facilitated by the establishment of multidisciplinary team meetings (MDTM). Rectal cancer is an excellent example of the contribution of multi-modality therapy [1–3]. The role of the component modalities is now being extended so that whereas before, surgery and radiotherapy were mostly applied to the primary and systemic treatment employed for metastases, all modalities are now contributing to all stages of disease. A particularly obvious example of this is the application of surgery to metastatic disease, most commonly for liver metastases [4, 5], but also in the setting of lung disease [6, 7]. Conversely, chemotherapy is increasingly being used as part of the strategy for downstaging locally advanced primary tumours [8, 9]. Rectal cancer, like gastrointestinal (GI) malignancy in its entirety, was a ‘‘Cinderella’’ subject during the phases of marked oncology development in the 1960s and 1970s. The picture has changed over the past 15–20 years and there is now huge activity in this area. Advances have been adopted from both randomized trial evidence and also from technical work. In the former, most studies have concentrated on the adjuvant setting and investigated chemotherapy, radiotherapy or both, with there also being a large research effort directed at second and subsequent lines of chemotherapy as palliation for patients with relapsed disease. The Scandinavian groups have been particularly productive, in terms of addressing the role of radiotherapy in randomized trials and have put preoperative radiotherapy high up on the international research agenda [10, 11]. This has progressed to a strategy of neoadjuvant treatment, comprising of induction chemotherapy and radiotherapy for locally advanced tumours. Technical advances in surgery and radiotherapy do not lend themselves so easily to assessment in randomized trials. However, there has been meticulous work on developing surgical technique and disseminating this information internationally, so that the standard of surgery has improved dramatically and total mesorectal excision (TME) has become the standard procedure [12, 13]. Radiotherapy advances have gained less prominence, but the gradual increase in sophistication, in terms of radiotherapy planning and exclusion of normal tissues, ought to make the delivery of radiotherapy safer, particularly in this multimodality setting with overlapping toxicities. These advances in management of rectal cancer have been both facilitated and paralleled by developments in imaging. These are covered in another section of this edition, but it needs to be stressed that radiology research has allowed a fresh look at the management of rectal cancer in general, and is key to planning a treatment strategy for individual patients. Despite the ubiquitous influence of imaging on rectal cancer management, there are four main functions in the patient’s pathway where this influence is very clear. These are staging, monitoring response to treatment, treatment precision and surveillance.

The Predictive Value of Clinical Evaluation of Response to Neoadjuvant Chemoradiation Therapy for Rectal Cancer

Multimodality therapy has become the standard treatment for patients with locally advanced (T3 and T4) rectal carcinoma. Accurate preoperative staging of the patients with rectal cancer has increased in importance because the selection of patients with transmural rectal cancer (T3 or T4) or node-positive disease leads to a previous nonsurgical neoadjuvant treatment. The purpose of this study was to evaluate the predictive value of the clinical response to neoadjuvant therapy on the basis of pathological results obtained on rectal cancer patients treated by chemoradiotherapy and surgery. From 1994 to 2003, 58 patients with a primary diagnosis of rectal cancer were studied at our department and enrolled in a neoadjuvant protocol of chemoradiotherapy followed by surgery. All patients were treated by 30 days of chemoradiotherapy. At the end of the chemoradiotherapy, each patient underwent clinical examination, including digital rectal examination, proctoscopy and abdominal-pelvic computerized tomography to define the clinical response to the chemoradiotherapy. Surgical resection was performed in all patients three weeks after the end of chemoradiotherapy, and histological analysis was performed on all resected specimens. The clinical complete response rate corresponded to the pathological complete response rate, whereas the clinical evaluation overestimated partial response and stable disease. The pathologic examination revealed that 3.5% of clinical partial responses and 3.4% of clinical stable disease were really pathological progressive disease. Clinical partial response and clinical stable disease positive predictive values were 92.8% and 90.9%, respectively, whereas the clinical progressive disease negative predictive value was 20%. Then, 6.9% of patients believed to have responded to the therapy, or not to have responded or worsened, actually had worsened by the end of the chemoradiotherapy. Positive and negative predictive values, in particular for partial response and stable disease, of clinical evaluation of the response to chemoradiotherapy were not high enough to consider clinical evaluation accurate enough to make treatment decisions.

Preoperative Chemoradiation Therapy for Rectal Cancer.

The surgeon and the radiation therapist share the primary responsibility for the maintenance of local control in the management of carcinoma of the rectum. Usually, radiation therapy is used to control microscopic disease, while surgery is employed to control macroscopic disease. For ionizing radiation to be effective, targeted tissues must be well oxygenated. Likewise, the risk of local recurrence must be great enough to justify the potential risk of the complications secondary to radiation therapy.

1040 Acute toxicity of chemoradiation therapy (CRT) for rectal cancer: Impact of irradiated volume, type of surgery, sex and sequence of treatment modalities

Materials & Methods: Between 1987 and 1995,120 patients (pts, 73 with primary tumor, 47 with recurrent disease) received CRT for rectal cancer. RT was given by 3-4 field box technique with 6-10 MV-photons. Daily fraction size was 180 cGy, total dose 5040 cGy including 540 cGy local boost. Dose was specified to the ICRU reference point. During the first and fifth week of RT S-FU (1000 mg/m*/24 h) was administered by continuous intitsion for 120 hours. 56 pts received preoperative CRT, 64 pts were treated postoperatively. Toxicity was recorded following (modified) WHO-criteria.