T3+ and T4 rectal cancer patients seem to benefit from the addition of oxaliplatin to the neoadjuvant chemoradiation regimen.

BACKGROUND: To achieve T-downstaging and better resectability in locally advanced rectal cancer, neoadjuvant radiochemotherapy (RCT) has become the current standard of treatment. A variety of schemes have been used. This study investigates which scheme had the best effect on these parameters. METHODS: Our institution is a referral center for locally advanced rectal cancer. Different neoadjuvant radiochemotherapy regimens were administered: long course radiotherapy (RTH), 5-FU and leucovorin (5FUBolus), a combination of capecitabine and oxaliplatin (CORE), and capecitabine only (CAP). Selection of patients for 1 of the regimens was based on hospital policy rather than patient or tumor characteristics. RESULTS: The data of 504 consecutive patients (n = 181 T3+, n = 323 T4) without metastatic disease (cM0) who underwent surgery for advanced rectal carcinoma between 1994 and 2010 were reviewed. The RTH, 5FUBolus, CORE, and CAP scheme were administered to 106, 137, 155, and 106 patients, respectively. Odds ratios for downstaging were less effective for RTH, 5FUBolus, and CAP (0.31, 0.44, and 0.31; P < .0001) when compared with the CORE scheme. Odds ratios for a R1 resection (3.74, 1.94, 1.14; P = .003) or CRM+ resection (3.78, 2.73, 1.34; P = .001) were also in favor of the CORE. Hazard ratios for CSS were significantly better for the CORE scheme. CONCLUSIONS: Downstaging with neoadjuvant treatment results in an increased number of radical resections. In our study, the combination of capecitabine and oxaliplatin appears to be the most effective regimen for locally advanced rectal cancer tumors. However, longer follow-up will be necessary to confirm this conclusion.

Focus on extralevator perineal dissection in supine position for low rectal cancer has led to better quality of surgery and oncologic outcome.

BACKGROUND: After abdominoperineal excision (APE), the presence of tumor cells in the circumferential resection margin (R1) and iatrogenic tumor perforations are still frequent and result in an increased rate of local recurrences. In this study, a standardized supine APE with an increased focus on the perineal dissection (sPPD) is compared to the customary supine APE. METHODS: From 2000 to 2010, a total of 246 patients underwent APE for rectal cancer (sPPD and customary supine APE). All patients were staged with preoperative magnetic resonance imaging (MRI) and received neoadjuvant treatment (n = 203) when margins were involved or threatened (cT3 + and T4). As a result of a quality improvement program in 2006, the surgical technique was modified: it became standardized, emphasis was placed on the perineal dissection, and pelvic dissection was limited to avoid false routes when following the total mesorectal excision planes deep into the pelvis. RESULTS: Overall, the percentage of involved circumferential resection margins (CRMs) was 10%. In the period before introducing sPPD, the R1 percentages for cT0-3 and cT4 tumors were 6.8 and 30.2%, compared to 2.2 and 5.7% after introduction of sPPD (P = 0.001). Risk factors for R1 resection were preoperative T4 tumors (14.9%, P = 0.011), tumor perforation (33.3%, P = 0.002), fistulating tumors (35.7%, P = 0.002), mucus-producing tumors (23.1%, P = 0.006), or bulky tumors (66.7%, P < 0.001). CONCLUSIONS: The objective of surgical treatment of low rectal cancer is to obtain negative resection margins and subsequently reduce the risk of local recurrence. A combination of the appropriate preoperative treatment and standardized surgical technique such as sPPD can achieve this goal.

Impact of preoperative radiotherapy on general and disease-specific health status of rectal cancer survivors: a population-based study.

PURPOSE: To date, few studies have evaluated the impact of preoperative radiotherapy (pRT) on long-term health status of rectal cancer survivors. Using a population-based sample, we assessed the impact of pRT on general and disease-specific health status of rectal cancer survivors up to 10 years post diagnosis. The health status of older (≥75 years old at diagnosis) pRT survivors was also compared with that of younger survivors. METHODS AND MATERIALS: Survivors identified from the Eindhoven Cancer Registry treated with surgery only (SU) or with pRT between 1998 and 2007 were included. Survivors completed the Short Form-36 (SF-36) health survey questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Colorectal 38 (EORTC QLQ-CR38) questionnaire. The SF-36 and EORTC QLQ-CR38 (sexuality subscale) scores of the survivors were compared to an age- and sex-matched Dutch normal population. RESULTS: A total of 340 survivors (response, 85%; pRT survivors, 71%) were analyzed. Overall, survivors had similar general health status. Both short-term (<5 years) and long-term (≥5 years) pRT survivors had significantly poorer body image and more problems with gastrointestinal function, male sexual dysfunction, and defecation than SU survivors. Survivors had comparable general health status but greater sexual dysfunction than the normal population. Older pRT survivors had general and disease-specific health status comparable to that of younger pRT survivors. CONCLUSIONS: For better survivorship care, rectal cancer survivors could benefit from increased clinical and psychological focus on the possible long-term morbidity of treatment and its effects on health status.

Three-dimensional analysis of recurrence patterns in rectal cancer: the cranial border in hypofractionated preoperative radiotherapy can be lowered.

PURPOSE: The aim of this study was to determine whether and where the radiotherapy (RT) clinical target volume (CTV) could be reduced in short-course preoperative treatment of rectal cancer patients. METHODS AND MATERIALS: Patients treated in the Dutch total mesorectal excision trial, with a local recurrence were analyzed. For 94 (25 who underwent radiation therapy 69 who did not) of 114 patients with a local recurrence, the location of the recurrence was placed in a three-dimensionalthree (3D) model. The data in the 3D model were correlated to the clinical trial data to distinguish a group of patients eligible for CTV reduction. Effects of CTV reduction on dose to the small bowel was tested retrospectively in a dataset of 8 patients with three-field conformal plans and intensity-modulated RT (IMRT). RESULTS: The use of preoperative RT mainly reduces anastomotic, lateral, and perineal recurrences. In patients without primary nodal involvement, no recurrences were found cranially of the S2-S3 interspace, irrespective of the delivery of RT. In patients without primary nodal involvement and a negative circumferential resection margin (CRM), only one recurrence was found cranial to the S2-S3 interspace. With a cranially reduced CTV to the S2-S3 interspace, over 60% reduction in absolute small bowel exposure at dose levels from 15 to 35 Gy could be achieved with three-field conventional RT, increasing to 80% when IMRT is also added. CONCLUSIONS: The cranial border of the CTV can safely be lowered for patients without expected nodal or CRM involvement, yielding a significant reduction of dose to the small bowel. Therefore, a significant reduction of acute and late toxicity can be expected.

Trends in colorectal cancer in the south of the Netherlands 1975-2007: rectal cancer survival levels with colon cancer survival.

OBJECTIVE: In the Netherlands over 11 200 patients are yearly diagnosed with colorectal cancer (CRC), of who about 4 700 are expected to die of the disease ultimately. Investigating long-term trends is useful for clinicians and policy makers to evaluate the impact of changes in practice and will help predict future developments. PATIENTS: The 26 826 cases of primary CRC (C18.0-C20.9) diagnosed between 1975 and 2007 in the Dutch population-based Eindhoven Cancer Registry area were included. We analysed trends in incidence, prevalence, stage distribution, treatment, survival, and mortality. RESULTS: The age-standardised incidence of colon carcinoma kept increasing, most markedly in males (up to 39 patients per 100 000 inhabitants) and for tumours of the colon ascendens (subsite-specific incidence doubled). The incidence of rectal carcinoma remained stable. The share of patients aged 80 or older rose from 12 to 19% (p<0.0001). The proportion of patients diagnosed with distant metastases increased up to 25% for colon carcinoma (p<0.0001). Resection rates of the primary tumour remained high except for patients with metastasised disease, showing a decrease since 2000. Recently, the use of adjuvant chemotherapy seemed to level off among patients with stage III colon carcinoma, but the use of neo-adjuvant chemoradiation clearly increased among patients with stage II/III rectal cancer (p<0.0001). Five-year relative survival of colon cancer improved from 51% in 1975-1984 to 58% in 2000-2004, for rectal cancer it improved from 44 to 59%. Two-year relative survival of colon cancer in 2005-2006 was 69%, and 77% for rectal cancer. CONCLUSIONS: The changes in management of rectal cancer led to a superior increase in survival of these patients compared to patients with colon cancer, even surpassing the latter.

Radicality of resection and survival after multimodality treatment is influenced by subsite of locally recurrent rectal cancer.

PURPOSE: To analyze results of multimodality treatment in relation to subsite of locally recurrent rectal cancer (LRRC). METHOD AND MATERIALS: A total of 170 patients with LRRC who underwent treatment between 1994 and 2008 were studied. The basic principle of multimodality treatment was preoperative (chemo)radiotherapy, intended radical surgery, and intraoperative radiotherapy. The subsites of LRRC were classified as presacral, posterolateral, (antero)lateral, anterior, anastomotic, or perineal. Subsites were related to radicality of the resection, local re-recurrence rate, distant metastasis rate, and cancer-specific survival. RESULTS: R0 resections were achieved in 54% of the patients, and 5-year cancer-specific survival was 40.5%. The worst outcomes were seen in presacral LRRC, with only 28% complete resections and 19% 5-year survival (p = 0.03 vs. other subsites). Anastomotic LRRC resulted in the most favorable outcomes, with 77% R0 resections and 60% 5-year survival (p = 0.04). Generally, if a complete resection was achieved, survival improved, except in posterolateral LRRC. Local re-recurrence and metastasis rate were lowest in anastomotic LRRC. CONCLUSIONS: Classification of the subsite of LRRC is a predictor of potentially resectable and consequently curable disease. Treatment of posterior LRRC imposes poor results, whereas anastomotic LRRC location shows superior results.

Patterns of local recurrence in locally advanced rectal cancer after intra-operative radiotherapy containing multimodality treatment.

BACKGROUND AND PURPOSE: The purpose of this study is to analyze the patterns of local recurrence (LR) after intra-operative radiotherapy (IORT) containing multimodality treatment of locally advanced rectal carcinoma (LARC). METHODS AND MATERIALS: Two hundred and ninety patients with LARC who underwent multimodality treatment between 1994 and 2006 were studied. For patients who developed LR, the subsite was classified into presacral, postero-lateral, lateral, anterior, anastomotic or perineal. Patient and treatment characteristics were related to subsite of LR. RESULTS: After 5years, 34 patients (13.2%) developed LR. The most prominent subsite of LR was the presacral subsite. 47% of the local recurrences occurred outside the IORT field. Most recurrences developed when IORT was given dorsally, while least occurred when IORT was given ventrally. Especially after dorsal IORT a high amount of infield recurrences were observed (6 of 8; 75%). In multi-variate analysis tumor distance of more than 5cm from the anal verge and a positive circumferential margin were associated with presacral local recurrence. CONCLUSIONS: Multimodality treatment is effective in the prevention of local recurrence in LARC. IORT application to the area most at risk is feasible and seems effective in the prevention of local recurrence. Dorsal tumor location results in unfavourable oncologic results.

Radical resection after IORT-containing multimodality treatment is the most important determinant for outcome in patients treated for locally recurrent rectal cancer.

BACKGROUND: The optimal treatment for locally recurrent rectal cancer (LRRC) is still a matter of debate. This study assessed the outcome of LRRC patients treated with multimodality treatment, consisting of neoadjuvant radio (chemo-) therapy, extended resection, and intraoperative radiotherapy. METHODS: One hundred and forty-seven consecutive patients with LRRC who underwent treatment between 1994 and 2006 were studied. The prognostic values of patient-, tumor- and treatment-related characteristics were tested with uni- and multivariate analysis. RESULTS: Median overall survival was 28 months (range 0-146 months). Five-year overall, disease-free, and metastasis-free survival and local control (OS, DFS, MFS, and LC respectively) were 31.5%, 34.1%, 49.5% and 54.1% respectively. Radical resection (R0) was obtained in 84 patients (57.2%), microscopically irradical resection (R1) in 34 patients (23.1%), and macroscopically irradical resection (R2) in 29 patients (19.7%). For patients with a radical resection median OS was 59 months and the 5-year OS, DFS, MFS, and LC were 48.4%, 52.3%, 65.5% and 68.9%, respectively. Radical resection was significantly correlated with improved OS, DFS, and LC (P < 0.001). Patients who received re-irradiation or full-course radiotherapy survived significantly longer (P = 0.043) and longer without local recurrence (P = 0.038) or metastasis (P < 0.001) compared to patients who were not re-irradiated. CONCLUSIONS: Radical resection is the most significant predictor of improved survival in patients with LRRC. Neoadjuvant radio (chemo-) therapy is the best option in order to realize a radical resection. Re-irradiation is feasible in patients who already received irradiation as part of the primary rectal cancer treatment.

Circumferential margin involvement is the crucial prognostic factor after multimodality treatment in patients with locally advanced rectal carcinoma.

PURPOSE: After preoperative (radio)chemotherapy, histologic determinants for prognostication have changed. It is unclear which variables, including assessment of tumor regression, are the best indicators for local recurrence and survival. EXPERIMENTAL DESIGN: A series of 201 patients with locally advanced rectal cancer (cT3/T4, M0) presenting with an involved or at least threatened circumferential margin (CRM) on preoperative imaging (<2 mm) were evaluated using standard histopathologic variables and four different histologic regression systems. All patients received neoadjuvant radiochemotherapy or radiotherapy. The prognostic value of all factors was tested with univariate survival analysis of time to local recurrence and overall survival. RESULTS: Local recurrence occurred in only 8% of the patients with a free CRM compared with 43% in case of CRM involvement (P < 0.0001). None of the four regression systems were associated with prognosis, not even when corrected for CRM status. However, we did observe a higher degree of tumor regression after radiochemotherapy compared with radiotherapy (P < 0.001). Absence of tumor regression was associated with increasing invasion depth and a positive CRM (P = 0.02 and 0.03, respectively). CONCLUSIONS: Assessment of CRM involvement is the most important pathologic variable after radiochemotherapy. Although tumor regression increases the chance on a free CRM, in cases with positive resection margins prognosis is poor irrespective of the degree of therapy-induced regression.

Survival of elderly rectal cancer patients not improved: analysis of population based data on the impact of TME surgery.

INTRODUCTION: The incidence of rectal cancer is highest in elderly patients. However, these patients are often underrepresented in randomised studies. Therefore, it is not clear whether results of rectal cancer studies are equally applicable to both elderly and younger patients. In this paper, the Dutch Total Mesorectal Excision (TME) study is revisited, focused on patients aged 75 years and above. The rectal cancer databases of the Comprehensive Cancer Centres (CCC) South and West were combined to analyse the effect of the TME-study in three different periods: before (1990-1995), during (1996-1999) and after (2000-2002) the trial. RESULTS: Implementation of preoperative radiotherapy, as investigated in the TME trial, and the introduction of TME surgery resulted in improved 5 year survival during the subsequent periods, in patients younger than 75 years, of 60% (1990-1995) to 67% (1996-1999) and 70% (2000-2002) (log rank p<0.0001). The older patients did not improve and remained at 41%, 40% and 43% at 5 years in the respective periods. Furthermore, mortality during the first 6-month period after treatment is significantly raised compared to younger patients: 14% in the elderly, compared to 3.9% in the younger TME-study patient (p<0.0001 X2). In the CCC database these figures were confirmed at 16% and 3.9% (p<0.0001 X2). CONCLUSION: Overall survival was not improved in the elderly rectal cancer patient after introduction of preoperative radiotherapy and TME-surgery. Non-cancer related mortality is a significant problem in the first 6 months after surgery.

Which comorbid conditions predict complications after surgery for colorectal cancer?

BACKGROUND: Accurate presurgical assessment is important to anticipate postoperative complications, especially in the growing proportion of elderly cancer patients. We designed a study to define which comorbid conditions at the time of diagnosis predict complications after surgery for colorectal cancer. PATIENTS: A random sample of 431 patients recorded in the population-based Eindhoven Cancer Registry who underwent resection for stage I-III colorectal cancer, newly diagnosed between 1995 and 1999 were entered into this study. METHODS: The influence of specific comorbid conditions on the incidence and type of complications after surgery for colorectal cancer was analyzed. RESULTS: Overall, patients with comorbidity did not develop more surgical complications. However, patients with a tumor located in the colon who suffered from concomitant chronic obstructive pulmonary disease (COPD) more often developed pneumonia (18% versus 2%; P = 0.0002) and hemorrhage (9% versus 1%; P = 0.02). Patients with colon cancer who suffered from deep vein thrombosis (DVT) at the time of cancer diagnosis more often had surgical complications (67% versus 30%; P = 0.04), especially more minor infections (44% versus 11%; P = 0.002) and major infections (56% versus 10%; P < 0.0001), pneumonia (22% versus 2%; P = 0.01), and thromboembolic complications (11% versus 3%; P = 0.02). Patients with a tumor located in the rectum who suffered from COPD more frequently had any surgical complication (73% versus 46%; P = 0.04), and the presence of DVT at the time of cancer diagnosis was predictive of thromboembolic complications (17% versus 4%; P = 0.045). The presence of DVT remained significant after adjustment for relevant patient and tumor characteristics (odds ratio 9.0, 95% confidence interval 1.1-27.9). CONCLUSIONS: Among patients undergoing surgery for colorectal cancer, development of complications was especially predicted by presence of COPD and DVT. In patients with the latter comorbidity, regulation of the pre- and postsurgical hemostatic balance needs full attention.

Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.

BACKGROUND: Few prospective studies have been performed about the impact of preoperative radiotherapy (PRT) or total mesorectal excision (TME) on health-related quality of life (HRQL) and sexual functioning in patients with resectable rectal cancer. This report describes the HRQL and sexual functioning of 990 patients who underwent TME and were randomly assigned to short-term PRT (5 x 5 Gy). PATIENTS AND METHODS: The Rotterdam Symptom Check List supplemented with additional items was used with questionnaires before treatment and at 3, 6, 12, 18, and 24 months after surgery. Patients without a recurrence the first 2 years were analyzed (n = 990). RESULTS: Few differences were found in HRQL between patients treated with or without PRT. Daily activities were significantly less for PRT patients 3 months postoperatively. Irradiated patients recovered slower from defecation problems than TME-only patients (P = .006). PRT had a negative effect on sexual functioning in males (P = .004) and females (P < .001). Irradiated males had more ejaculation disorders (P = .002), and erectile functioning deteriorated over time (P < .001). PRT had similar effects in patients who underwent a low anterior resection (LAR) versus an abdominoperineal resection (APR). Patients with an APR scored better on the physical (P = .004) and psychologic dimension (P = .007) than LAR patients, but worse on voiding (P = .0007). CONCLUSION: Short-term PRT leads to more sexual dysfunction, slower recovery of bowel function, and impaired daily activity postoperatively. However, this does not seriously affect HRQL. The comparison between LAR and APR patients demonstrates that the existence of a permanent stoma is not the only determinant of HRQL.

Treatment of locally advanced rectal cancer.

Historically, locally advanced rectal cancer is known for its dismal prognosis. The treatment of locally advanced rectal cancer is subject to continuous change due to development of new and better diagnostic tools, radiotherapeutic techniques, chemotherapeutic agents and understanding of the subject. It is clear, that a multimodality approach is the only way to achieve satisfactory local recurrence and survival rates in this type of cancer. However, which multimodality strategy is to be used still remains a point of controversy. This review summarises recent developments in imaging, (neo-) adjuvant therapy and surgical techniques in the treatment of primary locally advanced rectal cancer.

Single fraction radiotherapy is efficacious: a further analysis of the Dutch Bone Metastasis Study controlling for the influence of retreatment.

PURPOSE: The Dutch Bone Metastasis Study on the effect on painful bone metastases of 8 Gy single fraction (SF) vs. 24 Gy in multiple fractions (MF) showed 24% retreatment after SF vs. 6% after MF (p < 0.001). The purpose of the present study was to evaluate factors influencing retreatment and its effect on response. METHODS AND MATERIALS: The database on all randomized patients was reanalyzed with separately calculated responses to initial treatment and retreatment. RESULTS: Response to initial treatment was 71% after SF vs. 73% after MF (p = 0.84). Retreatment raised response to 75% for SF; MF remained unaltered (p = 0.54). The response status after initial treatment did not predict occurrence of retreatment: 35% SF vs. 8% MF nonresponders and 22% SF vs. 10% MF patients with progressive pain were retreated. Logistic regression analyses showed the randomization arm and the pain score before retreatment to significantly predict retreatment (p < 0.001). Retreatment for nonresponders was successful in 66% SF vs. 33% MF patients (p = 0.13). Retreatment for progression was successful in 70% SF vs. 57% MF patients (p = 0.24). CONCLUSIONS: With or without the effect of retreatment, SF and MF radiotherapy provided equal palliation for painful bone metastases. Irrespective of response to initial treatment, physicians were more willing to retreat after a single fraction. Overall, retreatment was effective in 63% of retreated patients.

Effects on functional outcome after IORT-containing multimodality treatment for locally advanced primary and locally recurrent rectal cancer.

PURPOSE: In the treatment of patients with locally advanced primary or locally recurrent rectal cancer, much attention is focused on the oncologic outcome. Little is known about the functional outcome. In this study, the functional outcome after a multimodality treatment for locally advanced primary and locally recurrent rectal cancer is analyzed. METHODS AND MATERIALS: Between 1994 and 1999, 55 patients with locally advanced primary and 66 patients with locally recurrent rectal cancer were treated with high-dose preoperative external beam irradiation, followed by extended surgery and intraoperative radiotherapy. To assess long-term functional outcome, all patients still alive (n = 97) were asked to complete a questionnaire regarding ongoing morbidity, as well as functional and social impairment. Seventy-six of the 79 patients (96%) returned the questionnaire. The median follow-up was 14 months (range: 4-60 months). RESULTS: The questionnaire revealed fatigue in 44%, perineal pain in 42%, radiating pain in the leg(s) in 21%, walking difficulties in 36%, and voiding dysfunction in 42% of the patients as symptoms of ongoing morbidity. Functional impairment consisted of requiring help with basic activities in 15% and sexual inactivity in 56% of the respondents. Social handicap was demonstrated by loss of former lifestyle in 44% and loss of professional occupation in 40% of patients. CONCLUSIONS: As a result of multimodality treatment, the majority of these patients have to deal with long-term physical morbidity, the need for help with daily care, and considerable social impairment. These consequences must be weighed against the chance of cure if the patient is treated and the disability eventually caused by uncontrolled tumor progression if the patient is not treated. These potential drawbacks should be discussed with the patient preoperatively and taken into account when designing a treatment strategy.