Intraoperative radiotherapy for locally advanced or locally recurrent rectal cancer: Does it work at all?

BACKGROUND: Intraoperative radiotherapy (IORT) has been given for primary and locally recurrent rectal cancer for 30 years. Still, its effect is not clear. MATERIAL AND METHODS: PubMed and EMBASE search for papers after 1989 on surgical treatment and external beam radiotherapy (EBRT) for primary advanced and locally recurrent rectal cancer, with and without IORT. From each center the most recent paper was generally selected. Survival and local recurrence at five years was tabulated for the total groups and separate R-stages. Also, the technique for IORT, use of EBRT and chemotherapy as well as surgical approach was registered. RESULTS: In primary cancer 18 papers from 14 centers were tabulated, including one randomized and five internally comparing studies, as well as seven studies without IORT. In locally recurrent cancer 18 papers from 13 centers were tabulated, including four internally comparing studies and also five without IORT. Overall survival (OS) and local recurrence rate (LRR) were higher for primary cancer compared to recurrent cancer. Patients with R0 resections had better outcome than patients with R1 or R2 resections. For primary cancer OS and LR rate of the total groups and R0 stages was not influenced by IORT. An effect on R1/R2 stages cannot be excluded. The only randomized study (primary cancer) did not show any effect of IORT. CONCLUSION: IORT does not convincingly improve OS and LR rate for primary and locally recurrent rectal cancer. If there is an effect of IORT, it is small and cannot be shown outside randomized studies analyzing the separate R stages.

Long-Term Outcome in a Phase II Study of Regional Hyperthermia Added to Preoperative Radiochemotherapy in Locally Advanced and Recurrent Rectal Adenocarcinomas.

Hyperthermia was added to standard preoperative chemoradiation for rectal adenocarcinomas in a phase II study. Patients with T3-4 N0-2 M0 rectal cancer or local recurrences were included. Radiation dose was 54 Gy combined with capecitabine 825 mg/m2 × 2 daily and once weekly oxaliplatin 55 mg/m2. Regional hyperthermia aimed at 41.5-42.5 °C for 60 min combined with oxaliplatin infusion. Radical surgery with total or extended TME technique, was scheduled at 6-8 weeks after radiation. From April 2003 to April 2008, a total of 49 eligible patients were recruited. Median number of hyperthermia sessions were 5.4. A total of 47 out of 49 patients (96%) had the scheduled surgery, which was clinically radical in 44 patients. Complete tumour regression occurred in 29.8% of the patients who also exhibited statistically significantly better RFS and CSS. Rate of local recurrence alone at 10 years was 9.1%, distant metastases alone occurred in 25.6%, including local recurrences 40.4%. RFS for all patients was 54.8% after 5 years and CSS was 73.5%. Patients with T50 temperatures in tumours above median 39.9 °C had better RFS, 66.7% vs. 31.3%, p = 0.047, indicating a role of hyperthermia. Toxicity was acceptable.

Radical treatment for oesophageal cancer patients unfit for surgery and chemotherapy. A 10-year experience from the Norwegian Radium Hospital.

BACKGROUND: Over a 10-year period from 1990, 445 patients with carcinoma of the oesophagus were admitted to the Norwegian Radium Hospital and 184 of these patients received treatment with curative intent. Even though surgery is the treatment of choice for these patients, many of them suffer from medical conditions that increase the risk for postoperative mortality and morbidity. In a retrospective study, the effect of the curative treatment offered to patients was explored with a particular focus on patients unfit for surgery. METHODS: Medical data of the 184 patients treated with curative intent were reviewed and additional clinical information was retrieved from local hospitals and general practitioners. Preoperative radiotherapy followed by surgery was the standard curative treatment for operable patients. Medically inoperable patients were offered radical split-course hyperfractionated radiotherapy followed by a brachytherapy boost. RESULTS: More than 50% (103/184) received non-surgical treatment only. Patients who received radical surgery (n = 81) were younger, had better performance status, less weight loss and dysphagia compared to patients treated with radical radiotherapy (n = 102). One patient received only photodynamic therapy. The 3-year survival was 29% for patients treated with radical surgery, and 8% for patients who received radical radiotherapy. The overall median crude survival for the two groups of patients were 20 months and seven months respectively. CONCLUSION: The hyperfractionated radiotherapy provided symptom relief without extensive toxicity and with a possibility for cure for patients with oesophageal cancer who are unfit for surgery and chemoradiotherapy. The literature supports the curative potential of high dose accelerated hyperfractionated radiotherapy even though the optimal radiotherapy regimen still needs to be explored.

Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group.

BACKGROUND: The recommendation of adjuvant chemotherapy for colon cancer with lymph node metastases, based on two studies from USA, was reluctantly accepted by Norwegian medical doctors. It was therefore decided to assess the role of adjuvant therapy with 5fluorouracil (5-FU) combined with levamisole (Lev) in a confirmatory randomised study. MATERIAL AND METHODS: Four hundred and twenty five patients with operable colon and rectum cancer, Stage II and III (Dukes' stage B and C), were from January 1993 to October 1996, included in a randomised multicentre trial in Norway. The age limits were 18-75 years. Therapy started with a loading course of bolus i.v. 5-FU (450 mg/m(2)) daily for 5 days and p.o. doses of Lev (50 mg x 3) for 3 days. From day 28 a weekly i.v. 5-FU dose (450 mg/m(2)) were administered for 48 weeks. From day 28 also p.o. doses of Lev (50 mg x 3) for 3 days were given every 14 days. In total 214 patients were randomised to 5FU/Lev and 211 were included in the control group with surgery alone. Some did not comply with the inclusion and exclusion criteria, thus leaving 206 evaluable patients in each group. RESULTS: There was no significant survival difference between the two groups at 5 years: Disease-free survival (DFS) was 73% after chemotherapy, 68% (p=0.24) in the control group, and corresponding cancer specific survival (CSS) 75% and 71%, respectively (p=0.69). There was no difference between the two groups when analysed for colon and rectum separately. However, the subgroup of colon cancer with stage III exhibited a statistically significant difference both for DFS, 58% vs. 37% (p=0.012) and CSS, 65% vs. 47% (p=0.032) in favour of adjuvant chemotherapy. The benefit was further statistically significant for women but not for men. Toxicity was generally mild and acceptable with no drug related fatalities. CONCLUSIONS: Colon cancer patients with lymph node metastases benefit from adjuvant chemotherapy with 5-FU/Lev with acceptable toxicity. In a subgroup analysis females did better than males. Rectal cancer does not benefit from this regimen.

Molecular detection (k-ras) of exfoliated tumour cells in the pelvis is a prognostic factor after resection of rectal cancer?

BACKGROUND: After total mesorectal excision (TME) for rectal cancer around 10% of patients develops local recurrences within the pelvis. One reason for recurrence might be spillage of cancer cells during surgery. This pilot study was conducted to investigate the incidence of remnant cancer cells in pelvic lavage after resection of rectal cancer. DNA from cells obtained by lavage, were analysed by denaturing capillary electrophoresis with respect to mutations in hotspots of the k-ras gene, which are frequently mutated in colorectal cancer. RESULTS: Of the 237 rectal cancer patients analyzed, 19 had positive lavage fluid. There was a significant survival difference (p = 0.006) between patients with k-ras positive and negative lavage fluid. CONCLUSION: Patients with k-ras mutated cells in the lavage immediately after surgery have a reduced life expectation. Detection of exfoliated cells in the abdominal cavity may be a useful diagnostic tool to improve the staging and eventually characterize patients who may benefit from aggressive multimodal treatment of rectal cancer.

Pseudomyxoma peritonei--two novel orthotopic mouse models portray the PMCA-I histopathologic subtype.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease, most commonly originating from appendiceal lesions and characterized by accumulation of mucinous tumor tissue in the peritoneal cavity. Since the disease is infrequent, the task of carrying out studies of treatment efficacy and disease biology in the clinical setting is challenging, warranting the development of relevant in vitro and in vivo PMP models. METHODS: Human tumor tissue was implanted in the peritoneal cavity of nude mice to establish two orthotopic models exhibiting noninvasive intraperitoneal growth without metastasis development. RESULTS: Xenograft tissues have retained essential properties of the original human tumors, such as macro- and microscopic growth patterns, mucin production as well as expression of carcinoembryonal antigen, cytokeratins 20 and 7 and the proliferation marker pKi67. Upon microscopic examination, the human tumors were categorized as the PMCA-I (peritoneal mucinous carcinomatosis of intermediate features) subtype, which was conserved through 14 examined passages in mice, for the first time modeling this particular histopathologic category. CONCLUSION: In conclusion, two novel orthotopic models of human PMP have been established that consistently portray a distinct histopathologic subtype and reflect essential human tumor properties. Xenografts can easily and reproducibly be transferred to new generations of mice with acceptable passage periods, rendering the models as attractive tools for further studies of PMP biology and treatment.

[Treatment of locally recurrent rectal cancer]. / Behandling av lokalt residiv ved endetarmskreft.

BACKGROUND: It has not been common practice to operate local recurrence after rectal cancer and the treatment has received little attention in the J Norw Medical Ass. MATERIAL AND METHODS: This overview is based on literature retrieved from PubMed and own experience during 16 years. RESULTS AND INTERPRETATIONS: Type of local recurrence and the treatment related to it are classified and described. Most recurrences will benefit from preoperative irradiation. The difficulties caused by the confusion of postoperative fibrosis and recurrent cancer with regard to diagnosis, operability, the demand for multivisceral resection and the operative technique are discussed. The operations will often require cooperation between rectal surgeons, urologists, orthopaedists as well as plastic surgeons and gynaecologists. Our hospital has one of the largest published series, most other materials are small (< 70 patients). The results vary considerably regarding both survival and re-recurrences. This may be caused by differences in patient selection, oncological treatment and surgical aggressiveness. The surgical radicality is the most important prognostic factor. After a microscopic radical resection (R0 resection) the survival is similar to that for resection of Dukes C-grade primary colorectal cancer. The prognosis can probably be improved by improving the preoperative chemoradiation. This treatment should only be offered in a few centres in Norway because of the specific requirements.

[Recurrence of rectal cancer--treatment in Norwegian hospitals]. / Residiv av endetarmskreft--synspunkter på behandling.

BACKGROUND: The aim of this study was to examine if Norwegian surgeons had a passive attitude to treatment of patients with local recurrence of rectal cancer after primary treatment and if attitudes to treatment differed between hospitals. MATERIAL AND METHODS: All 46 departments for gastrointestinal surgery in Norway answered a questionnaire detailing their policy for workup, referral and treatment of patients with pelvic recurrence after surgery for rectal cancer. RESULTS: All hospitals used MRI for evaluation of the pelvis. Most clinics initially considered the patients potentially curable. Many wished to refer the patients to hospitals with more competence. Most patients in Norway are treated in eight different departments. Most of the surgeons give preoperative chemoradiotherapy before surgical resection of the local recurrence. INTERPRETATION: There seems to be a reasonable consensus among Norwegian surgeons about treatment of recurrent rectal cancer. The doctors themselves have to a certain degree centralized the treatment. Patients with recurrent rectal cancer should be discussed in multidisciplinary teams.

[Protective silicone prosthesis prior to radiotherapy of recurrent colonic cancer]. / Skjermende silikonprotese ved bestråling for residiv av coloncancer.

Radiation therapy for abdominal recurrence of colon cancer is rarely an option due to subsequent bowel injury. Our case is a woman who underwent resection for a large retroperitoneal recurrence of caecal cancer. Tumour deposits encasing the iliac vessels had to be left behind. A silicone breast prosthesis for displacement of the abdominal content was implanted, allowing postoperative irradiation with 50 Gy. The prosthesis was removed once radiotherapy was accomplished; tumour regression was then complete. Complications are described, so are indications for surgical management of local recurrences of colonic origin as well as technical aspects of abdominal implantation of displacing prostheses. At follow-up after eighteen months the patient has no signs of enteropathy, she enjoys a good quality of life, and she is free of disease. Still, her prognosis is considered uncertain.

Operative treatment of locally recurrent rectal cancer.

Few centres with varying regimens have published studies including more than 100 patients on the treatment of locally recurrent rectal cancer. The results vary considerably. Thus there seems to be a need for more studies to establish the potential benefit of a more widespread treatment of these cancers. In total, 193 patients had surgery for locally recurrent rectal cancers after preoperative irradiation 46-50 Gy in 2 Gy fractions. The patients were followed up and the data prospectively entered in a database. In 88 patients with primary low anterior resection, 3% had lower end of tumour located more than 2 cm above the anastomosis, 5% more than 2 cm below the anastomosis; 13% had exploratory laparotomy, 8% low anterior resections, the rest equally frequent abdomino-perineal resections, Hartmann's operations, and tumour resections. Nearly half had resection of part of the pelvic wall. Hysterectomy was performed in 15% and cystoprostatectomy in 9%. Three patients had en bloc prostatectomy. R0 resections were achieved in 39%, R1 in 36%, and R2 or no resection in 25%. R0 stage was twice as often achieved after a primary low anterior resection as after abdomino-perineal resections. The 30-days postoperative mortality was 1%. Postoperative morbidity was 48%, most frequently pelvic abscesses. Estimated 5-year survival was 18% for the total group. There was a statistically significant difference in survival and local re-recurrences between R0 / R1 and R2 stages. The results are discussed relative to recent studies. Patients in whom R0 resections can be achieved will benefit from the treatment, and probably patients with R1 resections would also benefit. Such operations should possibly be performed in specialised centres as joint ventures between various surgical subspecialities.

Hydronephrosis as a prognostic factor in pelvic recurrence from rectal and colon carcinomas.

BACKGROUND: After multimodal treatment estimated 5-year survival of locally recurrent rectal cancer is about 25%. Hydronephrosis secondary to pelvic recurrence of colorectal cancer is a condition claimed to represent a contraindication to surgery due to a dismal prognosis. METHODS: Prospective registration of 193 consecutive patients operated for pelvic recurrence in rectal or colon cancer from January 1991 until March 2002 at a tertiary referral hospital, 121 men and 72 women, median age 67 years, all given irradiation preoperatively. Twenty-three of 193 had hydronephrosis prior to preoperative irradiation for recurrent disease. RESULTS: R-0 stage resection was obtained in 22% of patients with hydronephrosis and in 41% without. The median survival times in patients without metastasis were 27 and 32 months, respectively, and 5-year survival rates were 11% and 25%. CONCLUSIONS: An aggressive surgical approach offers patients with pelvic recurrence from rectal and colon cancer the best potential for survival. The presence of hydronephrosis probably indicates a lower chance for complete surgical resection of the recurrence, but local control and improved survival may still be achieved, and about two thirds of patients may benefit from the operation.

Genome characteristics of primary carcinomas, local recurrences, carcinomatoses, and liver metastases from colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths in the Western world, and despite the fact that metastases are usually the ultimate cause of deaths, the knowledge of the genetics of advanced stages of this disease is limited. In order to identify potential genetic abnormalities underlying the development of local and distant metastases in CRC patients, we have, by comparative genomic hybridization, compared the DNA copy number profiles of 10 primary carcinomas, 14 local recurrences, 7 peritoneal carcinomatoses, and 42 liver metastases from 61 CRC patients. RESULTS: The median number of aberrations among the primary carcinomas, local recurrences, carcinomatoses, and liver metastases was 10, 6, 13, and 14, respectively. Several genetic imbalances, such as gains of 7, 8q, 13q, and 20, and losses of 4q, 8p, 17p, and 18, were common in all groups. In contrast, gains of 5p and 12p were more common in the carcinomatoses than in other stages of the disease. With hierarchical cluster analysis, liver metastases could be divided into two main subgroups according to clusters of chromosome changes. CONCLUSIONS: Each stage of CRC progression is characterized by a particular genetic profile, and both carcinomatoses and liver metastases are more genetically complex than local recurrences and primary carcinomas. This is the first genome profiling of local recurrences and carcinomatoses, and gains of 5p and 12p seem to be particularly important for the spread of the CRC cells within the peritoneal cavity.

Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer.

PURPOSE: Preoperative chemoradiotherapy is considered standard treatment for locally advanced rectal cancer, although the scientific evidence for the chemotherapy addition is limited. This trial investigated whether chemotherapy as part of a multidisciplinary treatment approach would improve downstaging, survival, and relapse rate. PATIENTS AND METHODS: The randomized study included 207 patients with locally nonresectable T4 primary rectal carcinoma or local recurrence from rectal carcinoma in the period 1996 to 2003. The patients received either chemotherapy (fluorouracil/leucovorin) administered concurrently with radiotherapy (50 Gy) and adjuvant for 16 weeks after surgery (CRT group, n = 98) or radiotherapy alone (50 Gy; RT group, n = 109). RESULTS: The two groups were well balanced according to pretreatment characteristics. An R0 resection was performed in 82 patients (84%) in the CRT group and in 74 patients (68%) in the RT group (P = .009). Pathologic complete response was seen in 16% and 7%, respectively. After an R0 + R1 resection, local recurrence was found in 5% and 7%, and distant metastases in 26% and 39%, respectively. Local control (82% v 67% at 5 years; log-rank P = .03), time to treatment failure (63% v 44%; P = .003), cancer-specific survival (72% v 55%; P = .02), and overall survival (66% v 53%; P = .09) all favored the CRT group. Grade 3 or 4 toxicity, mainly GI, was seen in 28 (29%) of 98 and six (6%) of 109, respectively (P = .001). There was no difference in late toxicity. CONCLUSION: CRT improved local control, time to treatment failure, and cancer-specific survival compared with RT alone in patients with nonresectable rectal cancer. The treatments were well tolerated.

Prognostic groups in 1,676 patients with T3 rectal cancer treated without preoperative radiotherapy.

PURPOSE: The use of preoperative radiotherapy in patients with T3 tumors shows considerable variation among countries and institutions. The Norwegian guidelines have been very restrictive, limiting the indication to T4. This study was designed to identify subgroups of patients with T3 tumors with presumed high risks on adverse outcome and to use these results to reevaluate the national guidelines for preoperative radiotherapy. METHODS: This was a national cohort study of 2,460 patients with pT3 rectal adenocarcinoma, undergoing major surgery without preoperative radiotherapy from November 1993 to December 2002. Circumferential resection margin in millimeters was given for 1,676 patients. RESULTS: Multivariate analyses identified circumferential resection margin and nodal status as independent prognostic factors for local recurrence, metastases, and overall mortality. Analyses based on 12 combinations of N stage and circumferential resection margin showed that the estimated five-year rate of local recurrence increased from 11.1 percent (circumferential resection margin >3 mm; N0) to 36.5 percent (circumferential resection margin < or =1 mm; N2). The rate of distant metastases increased from 18.5 to 77.7 percent and the five-year survival decreased from 68.6 to 25.7 percent, respectively. CONCLUSIONS: There is great variation in outcome for patients with T3 cancers, and the outcome is not acceptable for the groups of patients with circumferential resection margin <3 mm or involved lymph nodes. These groups should be considered for neoadjuvant therapy.

Clinical outcome in patients with complete pathologic response (pT0) to preoperative irradiation/chemo-irradiation operated for locally advanced or locally recurrent rectal cancer.

BACKGROUND: The importance of pT0 stage after preoperative radiation/chemoradiation is unclear. METHODS: Four hundred and nineteen patients had preoperative irradiation (46-50 Gy/2 Gy fractions) for primary locally advanced (PLA) or locally recurrent (LR) rectal cancer. 141 PLA and 65 LR cases with R0 resections/M0 stage are studied. Two of the pT0 PLA patients had also been given sensitizing chemotherapy and two pT0 in the LR group had received pelvic hyperthermia as well. RESULTS: pT0 was achieved in 7% of 229 PLA and 8% of 190 LR patients. For the PLA group, actuarial 5-year survival of pT0 was 90% versus 53% for the pT > 0 group. The difference was statistically significant. At five years local recurrence was zero in pT0 patients versus 23% in pT > 0 (not significant). For the LR groups 5-year-survival was 62% for pT0 versus 45% for the other pT-stages, local recurrence was 17 and 35% respectively (not significant). The seemingly better results for pT0 cases of PLA cancers versus the LR ones did not reach statistical significance. CONCLUSION: pT0 after preoperative irradiation is associated with improved survival for pT0 cases of PLA. Our studies on pT0 LR was suggestive of an improvement in this group as well.

Total pelvic exenteration with preoperative irradiation for advanced primary and recurrent rectal cancer.

OBJECTIVE: To study the complication rate, local recurrence rate, and survival after total pelvic exenteration for primary advanced and recurrent rectal cancer. DESIGN: Prospective study. SETTING: Tertiary referral university hospital, Norway. SUBJECTS: 25 patients who were operated on for primary advanced and 22 for recurrent rectal cancer since 1991; 42 men and 5 women, mean age 64 years (range 44-78). All had preoperative irradiation of 46-50 Gy. MAIN OUTCOME MEASURES: Incidence of major complications, and actuarial 5-year survival and local recurrence rate. RESULTS: Twenty patients had RO resection in the primary group versus seven in the recurrent group. No R2 resections were done in the primary group compared with four in the recurrent group. Half the primary cases (n = 13) had abdominoperineal resections. Hartmann's procedures were common in both groups (n = 8 in each). Postoperative mortality at 30 days was 4% (n = 2) and in-hospital 13% (n = 6). 18 patients had major complications and 12 were reoperated on. Overall 5-year actuarial survival for 43 patients without distant metastases was 28%-those with primary tumours 36%, and those with recurrent tumours 18%-similar to the figures for RO and R1 resections. Actuarial local recurrence at 5 years for primary cancers was 18% compared with 68% for recurrent cancers, again nearly identical to the figures for R0/R1 operations (p = 0.008 and p = 0.03). CONCLUSION: Some patients with advanced rectal cancer either primary or recurrent may benefit from simultaneous en-bloc cystectomy. The higher postoperative morbidity and mortality indicate the need for well-defined indications for this procedure and the necessity for thorough preoperative staging.

A national strategic change in treatment policy for rectal cancer--implementation of total mesorectal excision as routine treatment in Norway. A national audit.

INTRODUCTION: Rectal cancer surgery has been characterized by a high incidence of local recurrence, an occurrence which influences survival negatively. In Norway there was a growing recognition that local recurrence rates were related to surgeon performance and that surgeons applying a standardized surgical technique in the form of total mesorectal excision could achieve better results. This contrasts with the prevailing argument voiced by many opinion leaders that local recurrence rates and possibly survival rates can only be improved by adjuvant or neoadjuvant treatment strategies. The Norwegian Rectal Cancer Project-initiated in 1993-aimed at improving the outcome of patients with rectal cancer by implementing total mesorectal excision as the standard rectal resection technique. METHODS: This observational national cohort study covers all new patients (3,319) with rectal cancer from a population of 4.5 million treated between November 1993 and August 1997. The main outcome measures were local recurrence, survival, and postoperative mortality and morbidity rates. The technique of total mesorectal excision was compared with conventional surgery. RESULTS: The proportion of patients undergoing total mesorectal excision was 78 percent in 1994, increasing to 92 percent in 1997. The observed local recurrence rate for patients undergoing a curative resection was 6 percent in the group treated by total mesorectal excision and 12 percent in the conventional surgery group. Four-year survival rate was 73 percent after total mesorectal excision and 60 percent after conventional surgery. Postoperative mortality rate was 3 percent and the anastomotic dehiscence rate was 10 percent. Radiotherapy was given to 5 percent and chemotherapy to 3 percent of the patients in the curative resection group. CONCLUSION: A refinement of the surgical resection technique for rectal cancer can be achieved on a national level, the technique of total mesorectal excision can be widely distributed, and surgery alone can give good results.