Kevin S. Hughes

Surgery for Colorectal Cancer Metastatic to the Liver: Optimizing the Results of Treatment

Overall, hepatic resection appears to be an important means of curing patients with metastatic colorectal cancer isolated to the liver. The only absolute contraindication to surgery was the impossibility of a radical removal of tumor: if residual disease will remain after the hepatic resection, this operation is not indicated. A possible second contraindication to surgery is the presence of tumor in the hepatic or celiac lymph nodes. Such metastases from liver metastases signal a biologic grade of tumor that is almost sure to spread to other sites. However, one patient of the 25 in this group did survive long term when positive lymph node groups were dissected. Further clinical experience with this form of the disease along with trials of regional adjuvant therapies such as intraperitoneal chemotherapy may be needed. The presence of extrahepatic metastases at the time of liver resection should be considered a relative contraindication to this surgery, but if the patient can be made clinically disease free, long-term disease-free survival may result. It seems imperative that all patients with hepatic metastases be evaluated by an experienced hepatic surgeon for a curative resection. If the patient has between one and four metastases, a 25 per cent long-term disease-free survival rate can be expected. Patients who have a radical resection of more than four metastases should be considered to be in an experimental group in whom more data are needed. In our current state of knowledge, making such patients clinically disease free is their only chance for long-term survival. Other factors besides the number of metastases that will affect the prognosis of the patient include the disease-free interval between colorectal resection and liver resection, the pathologic margin of resection on the liver specimen, and the presence or absence of mesenteric lymph node metastases from the primary cancer. These factors should be considered when determining the prognosis in a given patient and should be used as stratification variables in prospective trials. However, from our analysis of available data, these factors should not be considered contraindications to hepatic resection.

Germline PTEN mutations in Cowden syndrome-like families.

Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thyroid carcinoma. The diagnosis of CS, as operationally defined by the International Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS gene has recently been identified as PTEN, which maps at 10q23.3 and encodes a dual specificity phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 13-80% of CS families harbouring germline nonsense, missense, and frameshift mutations predicted to disrupt normal PTEN function. To date, only a small number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involvement of PTEN in CS, we postulated that PTEN was a likely candidate to play a role in families with a CS-like phenotype, but not classical CS. To answer these questions, we gathered a series of patients from families who had features reminiscent of CS but did not meet the Consortium Criteria. Using a combination of denaturing gradient gel electrophoresis (DGGE), temporal temperature gel electrophoresis (TTGE), and sequence analysis, we screened 64 unrelated CS-like subjects for germline mutations in PTEN. A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C. This mutation occurred at the last nucleotide of exon 3 and within a region homologous to the cytoskeletal proteins tensin and auxilin. We conclude that germline PTEN mutations play a relatively minor role in CS-like families. In addition, our data would suggest that, for the most part, the strict International Cowden Consortium operational diagnostic criteria for CS are quite robust and should remain in place.

Use of carcinoembryonic antigen radioimmunodetection and computed tomography for predicting the resectability of recurrent colorectal cancer

OBJECTIVEnThe objective was to determine the role of arcitumomab (CEA-Scan; Immunomedics, Morris Plains, NJ), an anticarcinoembryonic antigen (CEA) Fab labeled with technetium-99m, in the presurgical evaluation of patients with recurrent or metastatic colorectal carcinoma.nnnSUMMARY BACKGROUND DATAnSurgical resection is the only method known to cure recurrent or metastatic colorectal carcinoma. The location and extent of disease must be determined before surgery. The role of antibody imaging, a new cancer detection modality, in preoperative evaluation for resection of locally recurrent or metastatic colorectal cancer has not been established, either alone or in combination with standard diagnostic modalities.nnnMETHODSnIn a blinded analysis of 209 patients with known or suspected colorectal cancer, the accuracy of arcitumomab, alone and combined with computed tomography (CT), was compared to that of CT for predicting abdominopelvic tumor resectability by correlating the results with surgical and histopathologic findings.nnnRESULTSnArcitumomab alone or combined with CT was found to be significantly more accurate for predicting surgical outcome than CT alone. When the results of CT and arcitumomab were concordant for abdominopelvic resectability, nonresectability, or absence of disease, the prediction was accurate in 67%, 100%, and 64%, respectively. Thus, the concordance for nonresectability (100% correct) may obviate the need for other diagnostic modalities or exploratory surgery. When the two tests were discordant, arcitumomab was correct substantially more often than CT. Because the liver is the most common site of distant metastasis in colorectal cancer, a subset of patients with hepatic disease was also analyzed; findings were similar to the overall resectability results. The products safety profile was excellent: the incidence of induction of an immune response against arcitumomab was <1% and that of potentially adverse events was 1.2%.nnnCONCLUSIONSnThe accuracy of arcitumomab for assessing resectability status is greater than that of CT, both in all patients undergoing evaluation for curative abdominopelvic resection of colorectal cancer and in the subset of patients with suspected or proven liver metastases. The additional use of arcitumomab with CT potentially doubles the number of patients who could be saved the cost, morbidity, and mortality of unnecessary abdominopelvic surgery and increases those who are potentially resectable for cure by 40%.

Morbidity and mortality of hepatic resection for metastatic colorectal carcinoma.

Hepatic resection is the only curative therapy currently available for colorectal cancer metastases to the liver. However, concern over high morbidity and mortality of the procedure has limited referral of patients for resection. The authors report on 58 patients undergoing hepatic resection for colorectal metastases at the National Cancer Institute between the years 1976 and 1985. Thirty-two patients underwent a major hepatic resection, and 26 patients underwent one or more wedge resections. Mean anesthesia time was 448 minutes, mean estimated blood loss was 3663 ml, and mean hospital stay was 17.5 days. Operative mortality was 3 percent, and morbidity was 62 percent. Using a grading scale for complications, 24 percent of patients had inconsequential complications, 16 percent had moderate complications, and 19 percent had severe complications. Complications were clearly related to extent of procedure. Factors that correlated best with morbidity were high blood loss and trisegmentectomy. The authors conclude that while hepatic resection can carry a high morbidity, much of this morbidity is minor and operative mortality is low. Recent improvements in anesthesia, improved resection technique, and a better understanding of hepatic anatomy have made possible correspondingly lower morbidity and mortality rates. Careful selection of patients can make hepatic resection a safe procedure.

Resection of hepatic metastases from colorectal carcinoma

When liver metastases from colorectal carcinoma are detected, the surgeon must decide whether or not the patient is a candidate for resection. Even though long-term survival after resection is far from optimal, the relegation of patients to nonresective treatment means denying them the only chance for cure currently available. Better understanding of liver anatomy and improvement in resection techniques have decreased the morbidity and mortality. The RHM and the GITSG reports have better defined the prognostic factors for resections of colorectal liver metastases and allowed for a better understanding of the indications for resection. During the last decades, liver resection has been extended to older patients, patients with multiple liver lesions, and patients with larger solitary metastases. At the same time, anatomic rather than wedge resections are more common, and it is preferable to perform the colon and liver resection at different stages. The end result has been a marked increase in the number of hepatic resections performed for colorectal liver metastases during the last two decades.

Management of Recurrent and Metastatic Colorectal Carcinoma

When metastatic or recurrent disease from colorectal carcinoma is detected, the surgeon must decide whether a patient is a candidate for resection. Although long-term survival after resection is not optimal, the relegation of patients to nonresective treatment means denying them the only chance for cure currently available. When isolated disease involving the liver, lung, or region of the primary carcinoma is documented, curative resection must be considered. Symptomatic patients may also obtain maximal palliation from resection, diversion, or a bypass procedure. Chemotherapy for the treatment of recurrent disease is palliative and probably should be considered only within clinical trials. Future alternative methods of treatment or new chemotherapeutic regimens need to be studied to improve survival and quality of life.

MULTIDISCIPLINARY CARE FOR PATIENTS WITH BREAST CANCER

Breast cancer management requires a multidisciplinary approach that is tailored to the patients stage at presentation, desire for breast conservation or reconstruction, estimation of risk of recurrence, and assessment of the benefits and toxicities of potential adjuvant therapies. At the Lahey Clinic Medical Center, breast surgeons, plastic surgeons, radiation oncologists, and medical oncologists staff the Breast Cancer Treatment Clinic, and work closely together to formulate treatment plans that will optimize the likelihood for cure with an acceptable cosmetic result. This involves careful preoperative work-up, surgical axillary staging, breast irradiation in the setting of breast conservation, and selection of chemotherapy or hormonal therapy if appropriate. Newer aspects of breast cancer care, including sentinal lymph node biopsy, postmastectomy radiation therapy, expanded use of hormonal therapy in younger women, new agents and chemotherapy combinations, and autogenous reconstruction techniques, have become an essential part of the multidisciplinary clinic approach.

The Management of Women at High Risk of Experiencing Hereditary Breast and Ovarian Cancer The Lahey Guidelines

Most breast and ovarian cancers occur sporadically, but an estimated 5 to 10% of cases occur in women with hereditary predisposition to these cancers. Two genes, BRCA1 and BRCA2, have been identified, which, when altered, are thought to be responsible for most cases of hereditary breast and ovarian cancer. Testing for mutations in these genes is now available for women who are at risk. At present, only a small percentage of women have been tested, and identification of high risk women is dependent on pedigree analysis and application of empiric models.In the general population, the level of risk of hereditary cancer ranges from nonexistent to highly likely. A disease management approach requires identification of the level of risk of each individual in the population, and the development of a specific management strategy of screening and consideration of chemoprevention and prophylactic surgery commensurate with risk. Therefore, risk identification takes on an important role in the allocation of health resources.This article presents an approach to categorising women who are at increased risk of experiencing hereditary breast or ovarian cancer, whether or not testing is accepted or feasible. An evidence-based approach to screening and measures for prevention are outlined according to level of risk. Occasions when genetic testing would appreciably enhance decisions regarding management are noted.Clinically useful guidelines for risk assessment and management are intended to reduce the incidence of and morbidity associated with hereditary breast and ovarian cancer. Ongoing research with regard to clinical outcomes of carriers of the BRCA1 or BRCA2 mutation will help refine these strategies.

Quality of Life and Cost Effectiveness Issues in the Management of Patients with Hepatic Metastases from Colorectal Cancer

The intent of this chapter is to focus on relevant quality of life and cost effectiveness issues of new treatment strategies for patients who have colorectal cancer that has metastasized to the liver. At the present time, there is no potentially curative treatment except surgical excision of metastatic lesions. There is a danger of rediscovering limitations of old treatments by use of new technologies, unless carefully designed trials are performed. Unless treatment results in prolonged survival, the detrimental effects on quality of life that often accompany these chemotherapeutic regimens argue strongly against their use. It may be that the current strategy for clinical and research efforts in this field should be reexamined. The optimum management of the patient with hepatic metastases may not be part of routine cancer therapy and may still be an important area to investigate. Is it advisable that no more patients with hepatic metastases should be treated by infusion techniques unless they agree to participate in an experimental protocol? Also, should a no treatment control arm be required in all therapeutic trials? Only with a no treatment control arm can the survival, quality of life, and cost of these treatments be assessed properly.

Hepatic Resection for Colorectal Carcinoma Metastases: Present Status and Future Prospects

In reviewing the literature and in updating the experience at the National Cancer Institute, two conclusions become apparent: 1) liver resection offers the only significant chance of cure in patients with colorectal cancer metastases, and 2) 60–80% of patients who undergo liver resection are not cured. The multifactorial nature of the problem makes it difficult to define specific prognostic groups when dealing with small individual series. Therefore, to encourage future collaborative efforts, a discussion of the staging of hepatic metastases and a protocol matrix for uniform data collection and reporting are proposed. If all data can be synthesized into a central data base, it should be possible to define a group of patients who will benefit from surgery alone, a group who will benefit from surgery plus adjuvant treatments, and a group who will not benefit from surgery. This will allow more knowledgeable patient selection for this major surgical procedure.