The present invention broadly relates to the staging of cancer and more particularly to the biostaging of adenocarcinomas typified by colorectal adenocarcinomas (colorectal cancer) utilizing radiolabeled TAG antibodies. While the present invention has applicability to a adenocarcinoma in general, the invention will be particularly illustrated by description of colorectal cancer. Such illustrative description is by no means a limitation on the present invention.
Cancer of the large bowel, i.e., the colon or rectum, affects about one person in 20 in the United States and in most Westernized countries. With more than 155,000 new cases diagnosed in the United States each year, representing 15% of all cancers, this disease constitutes a major public health problem. Efforts at earlier diagnosis and the control of metastatic disease have reduced somewhat the overall death rate from colorectal cancer in recent years. The 5-year relative survival rate from colon cancer increased from 41% in the 1950's to 54% in the 1980's, and the rate for rectal cancer increased from 40% to 51.5% during the same period.
The major histologic type of large bowel cancer is adenocarcinoma, which accounts for 90% to 95% of all large bowel tumors. It is the only histologic type further classified by grade. Grade 1 tumors are the most differentiated, with well-formed tubules and the least nuclear polymorphism and mitoses. Grade 3 tumors are the least differentiated, with only occasional glandular structures, pleomorpehic cells, and a high incidence of mitoses. Grade 2 is intermediate between Grades 1 and 3.
If diagnosed early enough, large bowel adenocarcinoma is highly curable by surgical treatment with minimal morbidity and mortality. In fact, in its initial stage such cancer is virtually 100% curable by surgery. The fact that this common malignancy remains such a deadly killer can be attributed to a number of factors, particularly to diagnostic shortcomings, both in detecting micrometastatic lesions at surgery and in staging colorectal cancer so that appropriate post-surgical adjuvant therapy may be selected.
Colorectal cancer may spread by local invasion, lymphatic extension, hematogenous spread, or implantation. After the initial mucosal growth, a tumor may progress locally in several directions, but usually it protrudes first into the lumen. Mural penetration may result in local failure or peritoneal seeding.
Colorectal cancer first metastasizes to the perirectal nodes at the level of the primary tumor or immediately above it. Next the chain accompanying the superior hemorrhoidal vessels is involved. In later stages of disease, when the hemorrhoidal lymphatics are blocked, there is lateral or downward spread. In colon carcinoma, the normal lymphatic flow is through the lymphatic channels along the major arteries, with three echelons of lymph nodes: pericolic, intermediate, and principal. If tumors lie between two major vascular pedicles, lymphatic flow may drain in either or both directions. If the central lymph nodes are blocked by tumor, lymphatic flow can become retrograde along the marginal arcades proximally and distally. The risk for lymph node metastases increases with increasing tumor grade, as does the number of lymph nodes affected.
The liver is the primary site of hematogenous metastases, followed by the lung. Involvement of other sites in the absence of liver or lung involvement is rare.
Implantation refers to the release of tumor cells from the primary tumor and their deposition on another surface. Implantation has been reported with tumor cells shed intraluminally, from the serosal surface through the peritoneum, and by surgical manipulation and resultant deposition on wound surfaces.
Many variables affect the curability of colorectal cancer. Multivariate analysis indicates the surgical-pathologic stage is the most important. Recurrence patterns are described as local (direct extension), regional (lymphatic and nodal), and peritoneal seeding. The major risk for recurrence in patients with colon cancer remains disseminated disease. The liver is involved in as many as two-thirds of patients who experience recurrence. The risk for locoregional failure varies with the pathologic stage of the primary tumor.
The staging of colorectal carcinoma has been complicated by the fact that it evolved over half a century. Most investigators agree that the most important independent pathologic factor for survival or recurrence after potentially curative surgery is the stage of cancer, which is determined by the depth of penetration through the bowel wall and the presence and number of positive lymph nodes. Other independent factors for survival have included gross appearance, lymphatic vessel invasion, blood vessel invasion, nucleolar organizer regions, character of invasive margin and tumor type, number of mast cells, nuclear shape, sedimentation rate and leukocytosis, lymphocytic infiltration, obstruction, perforation, and rectal bleeding, filtration, infiltrating border (lateral margins), age, grade, venous invasion, gender, obstruction, ploidy, and preoperative carcinoembryonic antigen.
The first practical staging system was the Dukes classification, named after a British pathologist who conducted extensive studies, in the 1930's, on the local invasion and lymphatic spread of rectal cancer. Dukes originally classified rectal tumors from A to C, with stage A indicating penetration into but not through the bowel wall, stage B indicating penetration through the bowel wall, and stage C indicating involvement of lymph nodes, regardless of bowel wall penetration. This system had the virtue of being simple and predictive of prognosis. It has since been modified many times, to reflect finer levels of penetration and nodal metastases, and has been extended to include both colon and rectum. Stage C was further subdivided into C1 (locally positive nodes) and C2 (positive nodes at the point of ligature). Stage A was split into a new stage A (mucosa only) and B1 (into but not through the muscularis propria), and original stage B then became B2. A fourth stage, D, was added to designate disease beyond the limit of surgical resection.
The TNM classification system ranks the primary tumor (T), the regional lymph nodes (N), and distant metastases (M). For example, a T1 tumor invades the submucosa, a T2 tumor the muscularis propria, etc.; N0 indicates an absence of regional node metastases, whereas N1 correlates with 1-3 positive nodes and N2 correlates with 4 or more positive nodes, etc.; and M0 indicates an absence of distant metastases, while M1 indicates that such metastases are present. Any given case of colorectal cancer can thus be described in terms of its TNM status, i.e., T.sub.x N.sub.x M.sub.x.
Another staging system, called Astler-Coller, allowed separation of wall penetration and nodal status. The Gunderson-Sosin modification of the Astler-Coller staging system subdivided T3 tumors into those with microscopic (B2.sub.m or C2.sub.m) and gross (B2.sub.m+g or C2.sub.m+g) penetration of tumor through the bowel wall. In all pathologic staging systems, particularly those applied to rectal cancer, the abbreviations (m) and (g) may be used: (m) to denote microscopic transmural penetration; (g) or (m+g) to denote transmural penetration visible on gross inspection and confirmed microscopically.
In 1988, the American Joint Committee on Cancer (AJCC) and the Union Internationale Contra le Cancer (UICC) adopted a joint TNM classification scheme taking into account the number of positive nodes and also free mesothelial penetration.
Yet another classification system was introduced in 1987 by Jass and colleagues. Using a Cox regression analysis, they found that the number of positive nodes, whether the invasive border was pushing or infiltrative, the presence of a conspicuous lymphocytic infiltrate, and the absence or presence of transmural penetration were independent prognostic factors. Because the Jass staging system is far more complicated than the modified Dukes and TNM systems, it has not been formally accepted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) or other major clinical groups. The Gastrointestinal Tumor Study Group (GITSG) has also developed a classification system, which shares some of the features of the Jass system.
Not surprisingly, then, the issue of which staging system to use remains a matter of great controversy. The UICC and AJCC TNM staging systems incorporate information regarding the number of positive nodes. In contrast to the Jass and GITSG systems, which stratify by 1 to 4 compared with 5 or more positive nodes, the UICC and AJCC staging systems stratify by 1 to 3 versus 4 or more positive nodes. Further, in contrast to the modified Astler-Coller staging system, the UICC, AJCC, GITSG, and Jass staging systems do not incorporate information regarding the difference between microscopic and gross extension of tumor through the bowel wall. The ongoing controversy over the merits of each of these systems, and their continuing modifications, attests to the fact that no satisfactory system of staging colorectal cancer yet exists. A summary of these staging systems for colorectal carcinoma appears below:
__________________________________________________________________________ STAGING FOR COLORECTAL CARCINOMA Distant Confined to Penetrates Metastatic Staging System Bowel Wall Bowel Wall Lymph Nodes Site* Comments __________________________________________________________________________ Dukes A B C Not Included Rectum Astler-Coller A, B1 B2 C1 or C2 D Colon and Rectum Gunderson Sosin A, B1 B2, m + g C2, C2, m + g D Colon and Rectum TNM T1, 2 NoMo T3, 4 NoMo Any T N1, 2, 3 Mo M/M1 Colon and Rectum AJCC T1, 2 NoMo T3, 4 NoMo N0 = No Positive Nodes M1 Colon and Rectum N1 = 1-3 Positive Nodes N2 = 4 or more Positive Nodes UICC T1, 2 NoMo T3, 4 NoMo N0 = No Positive Nodes M1 Mesothelial N1 = 1-3 Positive Nodes Penetration N2 = 4 or more Positive Nodes JASS T1, 2 NoMo T3, 4 NoMo N0 = No Positive Nodes M1 Lymphocytic N1 = 1-3 Positive Nodes Infiltrative Invasive N2 = 4 or more Positive Nodes Border (Pushing/Infiltrative) 1 GITSG T1, 2 NoMo T3, 4 NoMo N1 = 1-4 Positive Nodes M1 Colon and Rectum N2 = 5 or more Positive Nodes TNM T1, 2 NoMo T3, 4 NoMo N0 = No Positive Nodes M1 Current System (American N1 = Regional Close Positive Nodes Cancer Society) N2 = Regional Distant Positive Nodes N3 = Distant Nodes Around a Major __________________________________________________________________________ Vessel *Including nodes outside regional resection.
Thus, a reliable and accurate system for the staging of colorectal cancer is urgently needed, whereby available health-care resources may be utilized to their fullest advantage by appropriately identifying those patients whose condition will be improved by the administration of adjuvant chemotherapy, and whereby realistic prognoses may be provided to patients immediately following surgery for primary or recurrent colorectal cancer.