 Recurrent
Rectal Cancer
Surgery for recurrent and metastatic disease in colorectal cancer This paper is based on a book chapter written by Dr McMurrick and Dr Wolff, expressing views on the modern management of stage IV carcinoma of the rectum PJ
McMurrick BG
Wolff Introduction Colorectal carcinoma remains an eminently curable malignancy in approximately one half of all presenting cases. The risk of recurrence remains high, despite demonstrable gains from improvements in surgical technique, the use of adjuvant chemotherapy in node positive colonic carcinoma, and chemoradiation in rectal carcinoma. Considerable progress has been made in the last 20 years in the therapy of recurrent colorectal neoplasia. Surgical therapy of hepatic and pulmonary metastases is well established, and will be discussed briefly. The role of aggressive therapy of locoregional recurrence of colorectal carcinoma is less well established. In selected localised or isolated lesions, surgical resection, often in combination with chemoradiation offers the potential for cure in a significant proportion of patients. The morbidity of these procedures is potentially very significant, and needs to be weighed against potential oncologic gains, which, though well established, are frequently marginal. The majority of patients in whom potentially curable, isolated locoregional recurrence occurs have pelvic recurrence of rectal carcinoma, and hence these patients will be the focus of this review. Risk factors for recurrent colorectal cancer Aside from those factors described in most staging systems for colorectal neoplasia (progressive bowel wall penetration and lymph node involvement), several tumour related factors have now become well established as independent risk factors for aggressive tumour behaviour. High histologic grade, neurovascular invasion, mucin producing lesions, and diminished lymphatic stromal reaction (Feil 1988) are all associated with impoverished outcome. Several surgical factors have long been recognised as being of importance, including presentation with bowel obstruction (Wolmark 1983), surgical perforation (Ranbarger 1982) and direct invasion of adjacent organs (Durdey 1984). Increasingly, the technique of surgical resection of the rectum has been highlighted as a potential risk factor for recurrence. This has been reflected in the dramatic variation in reported levels of local recurrence after curative anterior resection or abdominoperineal resection. Heald (Heald 1986) has reported his own single surgeon series promoting the technique of total mesorectal excision, and reporting local recurrence rates of less than 5%. These figures have been matched in series from acknowledged centres of excellence. Locoregional Recurrence of rectal carcinoma Introduction The risk of locoregional recurrence after resection of primary rectal cancer remains high in the community setting. Figures vary from 5 to 33% (Magrini 1996). Untreated, this process is associated with disabling and distressing morbidity, resulting from failure of function of the pelvic viscera, and severe pain both from direct invasion of pelvic structures and referred pain from involvement of branches of the lumbosacral plexus. Radiation therapy has traditionally been the mainstay of treatment for pelvic recurrence, however recent series have explored the role of potentially curative surgical resection in the setting of isolated locoregional pelvic recurrence. The Mayo Clinic has well established protocols for patient selection and preoperative work up, aimed at excluding non curable cases, and directing aggressive multimodality therapy (combining preoperative chemoradiation, surgical resection and intraoperative radiation therapy) at patients with potentially resectable, isolated pelvic recurrence of rectal adenocarcinoma. Preoperative Assessment Given the physiological impact of pelvic surgery for resection of locoregional recurrence with curative intent, it is mandatory that all patients being considered for this surgery undergo a thorough preoperative work up to exclude distant disease, to assess potential for local resectability, to plan the likely extent of resection and reconstruction, and to exclude underlying general medical conditions that would preclude major surgery. The risks and benefits of this surgery need to be weighed against any potential for oncologic cure. It is the opinion of the authors that high morbidity, radical surgery in this setting is not appropriate if curative potential is excluded either preoperatively or intraoperatively. Clinical assessment Clinical examination remains an important adjunct in the preoperative workup of patients being considered for resection of locoregional recurrence of rectal cancer. Thorough examination should be aimed at excluding extrapelvic disease, and at detecting clinical evidence of locoregional unresectability. In addition, clinical assessment may allow exclusion of patient whose general state of health would preclude major surgery. Clinical examination should include assessment of the liver, lymphatic system, skeletal system and lung fields. Generalised symptoms of carcinomatosis, including weight loss, jaundice, bone pain or excess fatigue should heighten suspicion of widespread disease. In addition, clinical examination may yield critical information regarding the local extent of spread in the pelvis. Pelvic examination is rendered far more effective in women or those patients in whom the rectal stump remains intact, allowing a portal of entry for the examining finger. Posterior fixation and invasion of the prostate or vagina may be assessed on rectal or vaginal examination. Historical evidence of sacral nerve involvement should be sought. In particular, pain radiating down both legs in a sciatic distribution indicates likely unresectability, particularly if this correlates with radiological evidence of sciatic notch involvement. CT scanning CT scanning remains the core investigation in the preoperative assessment of locoregional recurrence of rectal cancer. Specific information to be gained includes : i)
establishing a histologic diagnosis ii)
exclusion of extrapelvic disease iii)
assessment of infiltration of pelvic structures CT
findings indicating unresectable pelvic disease include extensive
lateral pelvic wall invasion, bilateral ureteral obstruction and
invasion of the sacrum above S2. Minimal involvement of the anterior
table of the sacrum at S2 may be dealt with by limited resection
of the anterior table, however formal transection of the sacrum
above this level renders the pelvis unstable. Minimal involvement
of the soft tissues of the lateral pelvic wall may be resectable
at the time of operation, but CT evidence of extensive involvement
represents a contraindication to attempts at curative resection. Miscellaneous investigations It is mandatory that all patients undergo colonoscopy to exclude metachronous colonic neoplasia. A chest xray should be performed to exclude pulmonary metastases, if CT scanning has not already been performed. A number of isotope scans have been proposed in the last decade, with the aim of improving on the sensitivity of CT scanning, and perhaps allowing improved preoperative selection of patients appropriate for surgical exploration. Carcinoembryonic antigen radioimmunodetection using CEA Fab’ labelled with Technitium-99m has been demonstrated as superior to CT scanning for assessing resectability status (Hughes K 1997). The use of a gamma-detecting probe intraoperative to guide surgical resection has been dubbed "RIGS" (radioimmuno guided surgery) (Schneebaum 1997), with claims of significant alteration to the course of surgery for recurrent rectal cancer in a minority of patients. Radiolabelled monoclonal antibody B72.3 has also been used for preoperative scanning in recurrent colorectal cancer, but was found to beneficially alter the course of the operation in only 13% of cases, and to adversely affect the course of surgery in 20%. (Dominguez 1996). A multicentre trial of technitium labelled monoclonal antibody 88BV59 demonstrated superior results to the use of CT scan alone, but again altered the course of surgery in only 20% of patients (Serafini 1998).
Multimodality therapy for locally recurrent rectal cancer Preoperative preparation Informed consent is mandatory in all patients. Full disclosure of the radical nature of the surgery should occur, including discussion of predicted levels of morbidity and mortality, balanced against the relatively low prospect of ultimate cure: approximate one third in patients in whom resection with clear margins is obtained. Specific aspects of the surgery, and multimodality therapy which need to be discussed with the patient include the high likelihood of need for transfusion of blood products, risk to sexual function, the possibility of pelvic exenteration and subsequent urinary conduit formation, and stoma formation. The majority of patients at Mayo who undergo surgery for recurrent rectal carcinoma are offered a preoperative combination of 5-fluorouracil based chemotherapy and external beam radiation to a total of 45 - 60 Gy, depending on their previous therapy. Surgery At the Mayo Medical Centre, Rochester, all patients undergoing exploration and resection of locoregional recurrent rectal carcinoma have their surgery performed in a dedicated intraoperative radiation suite. This operating room is lead shielded, and contains a linear accelerator, specifically modified to suit its purpose of providing directed intraoperative radiation. (picture). After induction of general anaesthesia, the patient is positioned in low Lloyd Davies stirrups, to allow ready access to the perineum. (picture). In the vast majority of patients, cystoscopy and insertion of bilateral ureteric stents is then performed. In addition to providing information regarding possible bladder invasion, this technique greatly improves intraoperative identification of the ureters in the lower abdomen and pelvis, where scarring from previous surgery and radiation often renders positive identification extremely difficult. The abdomen is then prepared and draped in the usual fashion. A generous midline incision is fashioned, and exploratory laparotomy performed. The initial assessment focuses on excluding the presence of extrapelvic disease, or other indications that resection with a view to cure is not possible. Given the fact that previous laparotomy has been performed, adhesiolysis is inevitably required. In many cases, a full assessment of the extent of malignant disease is not possible until extensive adhesiolysis has been performed. In particular, freeing of the small bowel from the pelvic viscera may be necessary prior to making a decision to proceed with pelvic dissection. A careful examination of the liver should be performed. The presence of a single, easily resected liver metastasis does not preclude further resection. In this setting, we would suggest intraoperative ultrasound to exclude further unexpected liver lesions, and proceed with resection of the liver metastasis, followed by pelvic resection as indicated. After fully mobilising the small bowel and carefully examining the abdominal cavity to exclude metastases, pelvic dissection commences. We commence defining the bifurcation of the aorta. In essence, all soft tissue is resected between the common iliac arteries, down to the point where these vessels are crossed by the ureters, and hence all tissue medial to the ureters down to the pelvic brim. At the bifurcation of the aorta, the common iliac veins are individually identified and carefully preserved. All soft tissue anterior to these vessels is resected. Early in this dissection, the ureters are identified and isolated with soft vessel slings. This process is greatly aided by preoperative stenting. Dissection then continues in a caudad fashion to the level of the pelvic brim. If tissue suspicious of tumour is encountered at a level above the pelvic brim, a specimen is sent for frozen section. Peritoneal disease above the pelvic brim is generally a contraindication to continuing resection. On occasions, disease may continue in continuity from the pelvic recurrence to a point above the pelvic brim, and still be deemed resectable, however further peritoneal or soft tissue disease distinct from the pelvic focus renders the process incurable. Pelvic resection As dissection continues into the pelvis, it is frequently noticeable that a substantial amount of mesorectum remains, even in patients who previously have undergone anterior resection or abdomino perineal resection. This tissue is most commonly the seat of the recurrence, and should be fully removed. Hence, a plane is then sought between the sacrum and the tissues anterior to it. The classic presacral plane, dissected in total mesorectal excision, is occasionally apparent, but has often been obliterated by previous surgery and radiation therapy. Hence, a plane needs to be established anterior to the sacrum, allowing dissection of all soft tissue anterior to this point. The large presacral veins, so often the Achilles heel of anterior resection when dissection deviates from the correct plane, are frequently obliterated, but may still cause troublesome bleeding. As distinct from a virgin pelvis, the scar tissue surrounding these veins is well established, and aids in suture ligation of bleeding vessels. Dissection the continues in a plane posterior to the recurrence until the lower limit of the dissection is reached. This level will of course vary according to the structures involved (especially the sacrum) and the intended operation (anterior resection versus abdominoperineal resection. At all times, the principal of en-bloc resection is adhered to. As dissection in the pelvis proceeds, the resection is tailored to the individual requirements of the patient and tumour characteristics, again adhering to the principals of en-bloc resection. Direct involvement of pelvic viscera mandates resection, provided no other contraindication to curative resection exists. Resection may include as necessary, the bladder, prostate, seminal vesicles, or vagina and uterus. The soft tissue of the side wall of the pelvis may resected if it is minimally involved, paying particular attention to the branches of the sacral plexus, which may regularly be encountered. Dissection of these lateral soft tissues may also be accompanied by copious bleeding, particularly in the region of the lateral ligaments of the rectum. Again, suture ligation is aided by the presence of scar tissue, however this site remains one of the main sources of massive blood loss when it occurs during these operations. Sacrectomy Resection of the sacrum is indicated in patients in whom it is directly invaded, where the sacral involvement is the only factor precluding curative resection and where the sacrum can be resected without loss of pelvic stability. In general, this implies direct invasion of the sacrum at or below the level of S3. If the anterior table of S 2 is minimally involved, then this in addition may be "chipped off" without formal resection continuing above the level of S3. In cases where sacrectomy is indicated, the pelvic and abdominal dissection is completed, and stoma formation completed. In those patients in whom sacrectomy at or above the level of S3 is predicted, the internal iliac arteries are ligated during the pelvic dissection. It has become our practice in recent years to repair the perineal defect after sacrectomy with a rectus abdominus myocutaneous flap (Magrini 1996). This has been associated with a modest prolongation of operating time and inpatient hospital stay, but reduced the number of secondary admissions for wound breakdown. Hence, prior to closure of the abdomen, a rectum abdominus myocutaneous flap is raised on a distal neurovascular pedicle. (see figure). A surgical pack is sutured to what will become the distal end of the flap, and the pack is positioned in the presacral space prior to closure of the abdominal wall. This allow ready retrieval of the flap through the perineal wound after sacrectomy. The abdominal wall is closed, and appropriate stomata matured. If bilateral stomata are required (as in the setting of cystectomy and formation of an ileal conduit) an alternative source of myocutaneous flap needs to be considered. The patient is then turned into the prone and flexed position. After preparation and draping, a midline incision is made. The gluteal muscles are dissected free from the sacrum. The sciatic nerve is then clearly identified on each side. The sacrotuberous and sacrospinous ligaments are then dissected free from the sacrum, with particular attention to preservation of the sciatic and pudendal nerves. The endopelvic fascia is then entered, and laminectomy and bony transection performed at the appropriate level. The dural sac is then transfixed and divided. At all times during resection, careful attention is paid to preservation of the lateral pelvic structures, including the ureters and vessels. The specimen is then removed en-bloc and forwarded to pathology. At Mayo, pathologists within the operating room suite then perform frozen section to determine adequacy of margins. Appropriate patients, with involved margins or thought to be at high risk of local recurrence will then undergo IORT. In these patients, a lucite cylinder is then positioned through the perineal defect and directed at the region felt by the surgeon and radiation therapist to be at highest risk of narrow margin. The cylinder is secured by attachment to a ring retractor, and IORT administered (see below). After completion of IORT, the surgical pack attached to the distal end of the flap is retrieved, and the rectus flap sutured into position. Deep pelvic drains are positioned prior to closure. Intraoperative Radiation Therapy (IORT) After resection of the pelvic specimen, histopathology is performed at a dedicated frozen section laboratory which resides with the operating complex. The margins of the resection are thus reported within 30 minutes of resection and are classified as being clear, microsocpically involved or macroscopically involved. Those patients in whom resection is not regarded as being curative are then subjected to IORT. The largest possible lucite cylinder is positioned within the pelvis to allow maximum radiation to the operative field, without irradiating vital structures within the abdomen. Orientation of the cylinder is determined in consultation between the surgeon and radiation therapist, and is influenced by the size of the patients pelvis, and any area which is suggestive of potentially retained disease. The cylinder is fixed in position using a ring retractor, and the patient is then shifted into position beneath the linear accelerator. The equipment is coupled, and IORT administered whilst the surgical personnel are housed in an adjacent room, shielded by a lead wall. Full monitoring is available to the anaesthetist during administration of IORT. Depending upon the total dose of previous external beam irradiation administered to the patient, the total dose of IORT is usually at least 15 Gy. Outcome
Those patients in whom resection with clear margins was not possible can further be subdivided into those in whom involvement was microscopic, versus those with gross residual disease. Surgery with intent to cure The Mayo series of patients on whom surgery was planned for isolated, locally recurrent rectal cancer with intent to cure consists of 176 patients, operated on between 1981 and 1988. (Suzuki 1996). After surgical exploration and consideration of the histopathology, of the total series, 106 operations were deemed to be palliative because of either gross (n=95) or microscopic (n=11) tumour in the pelvic area (Suzuki 1995). Of the remaining 70 patients, the surgery for recurrent disease was undertaken at the Mayo Medical Centre in 65 and hence the results of treatment of these patients was considered for survival calculation. Amongst those 65 patients in whom clear margins were obtained, the median time between operation for primary tumour and initial operation for recurrence was 18.9 months. Local recurrence became apparent within 3 years in 80% of patients. Local recurrences were further classified as assymptomatic (S0) in 35%, symptomatic without pain (S1) in 35%, and symptomatic with pain (S2) in 29%. The preoperative CEA level was elevated in only 45% if patients in whom is was measured. Of the 65 patients, curative operation consisted of abdominoperineal resection (52%), wide local resection (32%), Hartmann’s procedure (5%), low anterior resection (6%) or abdominosacral resection (5%). The surgery was considered as limited (65%) if no adjacent organ was excised, and extended (35%) if other organs or structures were removed. The mean follow up in the series was 6 years. None of the patients died within 30 days of surgery. Major morbidity occurred in 21% of patients, and was more likely in patients undergoing extended than limited resection (30 vs. 17%. p = 0.22). Extended resections also consumed more operating time (4 vs. 2.6 hours) and were associated with an increased requirement for blood transfusions (median 3 vs. 0 units). Five year survival for the series was 34%. This is notably similar to figures obtained for curative resection of liver or pulmonary metastases of colorectal cancer, with clear margins. When results are considered from Mayo series in which palliative procedures are included, survival was improved in those patients in whom resection was regarded as curative, compared with those patients in whom microscopic margins were involved, or gross residual disease was present (3 year survival, 57%, 44% and 26% respectively, and see figure 4 from (Suzuki 1996).). Of the 65 patients with curative resection, local failure in isolation occurred in 11, distant metastases occurred in isolation in 17, and 13 had both distant and local failure. A series of 123 patients in whom pelvic radiation had not occurred after initial resection of the primary cancer were separately considered (Gunderson 1996). As part of therapy for recurrence, these patients all underwent a full course of preoperative external beam radiation to a dose of 50Gy, with or without concurrent 5-fluorouracil based chemotherapy. Maximal surgical resection was then performed, in combination with IORT. Central failure (within the zone of IORT) occurred in only 11% with a 5 year actuarial rate of 26%. 5 year survival overall was 20%. Sacrectomy Those 16 patients at Mayo who required sacrectomy have been separately considered (Magrini 196). There is no doubt that the perioperative morbidity is significantly increased. The median operating time was 12.5 hours, with an average blood loss of 3.35 litres. Length of hospital stay ranged from 11 to 30 days. 50% of patients suffered a severe post operative complication. However, there were no perioperative deaths, and 90 percent of patients felt that their cancer pain was reduced, and that their quality of life was improved. Nearly half of the patients returned to their former work. At a median follow up time of 18 months, 9 of 16 patients were alive, 7 without evidence of disease. Palliative Resection Of those 106 patients at Mayo in whom resection was deemed to be palliative, that is resection margins were involved at histopathologic examination, results have been separately considered (Suzuki 1995). Survival at 5 years was clearly improved in those patients with microscopic margin involvement versus those with gross disease (27% vs. 5%; p=0.32). The addition of IORT appeared to improve outcome in all groups, particularly with regard to reduction in local failure. For those patients in whom gross margin involvement was present, and who underwent IORT, 3 year survival was 44%. The 3 year local relapse rate for those patients receiving IORT was 40%, versus 90% for those who did not. IORT did not significantly affect the rate of formation of distant metastases. Alternative sources of radiation therapy Whilst intraoperative radiation with the use of a linear accelerator is now the preferred method of delivering radiation therapy at Mayo Medical Centre, the cost of establishing a dedicated, shielded suite is expensive, and other alternatives exist. High dose intraoperative brachytherapy is of particular interest, and has produced results similar to those of the use of the linear accelerator. Nag et al. (Nag 1998) report the use of IOHDR (intraoperative high dose rate brachytherapy) in a dose of 10 - 20 Gy, at a depth of 0.5 cm., as an adjunct to palliative treatment. Median survival for patients with microscopic margin involvement was 24 months, and for those with gross residual tumour 17 months. Discussion This series demonstrated that isolated locoregional recurrence can be treated with an aggressive multimodality approach, with negligible mortality, moderate levels of morbidity and with potential for cure in one third of selected patients in whom resection with clear margins is feasible. In addition, it should be noted that those patients in whom microscopic margins are involved with tumour, or in whom gross residual disease is present, still appeared to obtain significant palliative benefit. Indeed, the survival curves for patients with clear margins, and those with microscopic involvement appear to intersect at the five year mark. We feel that it is very likely that IORT has significantly contributed to local control in this situation. In addition, those patients who fail to be cured by aggressive multimodality therapy, but in whom local control is obtained, are spared the most unpleasant outcome of uncontrolled pelvic tumour, with the pain of local neural and visceral involvement. Even those patients in whom extended resection, perhaps involving pelvic exenteration and/or sacrectomy is required, have potential for cure, and appear to gain significant palliative effect even if clear margins can not be obtained.
Locoregional recurrence of colonic carcinoma Isolated locoregional recurrence of colonic carcinoma is rare. This usually occurs in the setting of either i) involved surgical margins at the time of original surgery, or ii) local recurrence of a T4 lesion, where en block resection was not achievable at the time of initial surgery. In either setting, the literature regarding surgery for cure is scant. We advise a similar plan of management as for locally recurrent rectal carcinoma, that is adherence to the principals of preoperative chemoradiation in appropriate cases, en block resection where possible, IORT and reconstruction as appropriate. Distant colorectal metastases Hepatic metastases The liver remains the most common site of distant metastasis for both colon and rectal cancer. 5 year survival in patients with established liver metastases is less than 5 %. Surgery remains the only effective means of cure in this setting. The effect of resection of hepatic metastases with clear margins has been likened to "converting a Dukes D to a Dukes C cancer" (Taylor 1996). Hepatic resection with clear margins, in the absence of extrahepatic metastasis, has traditionally been associated with 5 year survival rates of between 20 and 35%, with a recent multicentre retrospective review of 1568 patients confirming a 5 year survival rate of 25%. (Nordlinger 1996). Perioperative mortality rates of less than 5% in interested units have made the procedure routine clinical practice in the setting of isolated resectable hepatic metastases. Criteria for selection of patients for resection remains controversial. The review by Nordlinger et al (Nordlinger 1996) suggests 7 criteria with a increased relative risk of recurrence post resection of between 1.0 and 2.0 (see Table ) and suggests a scoring system to help identify patients likely to benefit from hepatic resection. Recurrence after hepatic resection is common, and occurs in more than 60% of patients. In approximately 30%, the recurrence will be isolated to the liver. Recent series of patients undergoing repeat hepatic resection have demonstrated morbidity and long term survival figures and prognostic variables comparable to first time resection (Pinson 1996, Adam 1997) and suggest the procedure may be regarded as routine therapy in appropriate candidates. A series of 64 patients (Adam 1997) undergoing 83 repeat hepatectomies, produced overall survival and disease free survival figures at 5 years of 41% and 26% respectively, with no perioperative mortality, and morbidity levels similar to those of first time resections. Increasingly, evidence indicates that recurrence of hepatic metastases may be treated with the same guidelines and efficacy as first time recurrence. The prognosis for repeat surgical resection of hepatic metastases is remarkably similar to that for first time resection (Adam 1997) Repeat hepatic resection may be performed with minimal mortality, and morbidity and survival levels similar to first time resection Miscellaneous metastases Resection of isolated pulmonary metastases in colon cancer is of demonstrated benefit and may produce long term survival. (McAfee 1992). Case reports exist of resection of other isolated metastases of colon and rectal carcinoma exist, claiming curative effect, including incisional metastases, and preaortic metastases.
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Mr PJ McMurrick |
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