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Surgery_Schwartz. staging (cTNM or TNM) is based on informa-tion gained up until the initial definitive treatment. Pathologic staging (pTNM) includes clinical information and information obtained from pathologic examination of the resected primary tumor and regional lymph nodes. Tumor size following neo-adjuvant chemotherapy is designated as ypT, and should be based on the largest single focus of residual invasive cancer. Other classifications, such as staging at the time of retreatment for recurrence (rTNM) or autopsy staging (aTNM), should be clearly identified as such.The clinical measurement of tumor size (T) is the one judged to be the most accurate for each individual case based on physical examination and imaging studies. For example, in breast cancer the size of the tumor could be obtained from a physical examination, mammogram, or ultrasound, and the tumor size is based only on the invasive component.If even one lymph node is involved by tumor, the N com-ponent is at least N1. For many solid


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Surgery_Schwartz. physical examination, mammogram, or ultrasound, and the tumor size is based only on the invasive component.If even one lymph node is involved by tumor, the N com-ponent is at least N1. For many solid tumor types, simply the absence or presence of lymph node involvement is recorded, and the tumor is categorized either as N0 or N1. For other tumor types, the number of lymph nodes involved, the size of the lymph nodes or the lymph node metastasis, or the regional lymph node basin involved also has been shown to have prog-nostic value. In these cancers, the designations N1, N2, and N3 suggest an increasing abnormality of lymph nodes based on size, characteristics, and location. NX indicates that the lymph nodes cannot be fully assessed.Cases in which there is no distant metastasis are designated M0, cases in which one or more distant metastases are detected Brunicardi_Ch10_p0305-p0354.indd 33322/02/19 2:14 PM 334BASIC CONSIDERATIONSPART Iare designated M1, and cases in which the


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Surgery_Schwartz. M0, cases in which one or more distant metastases are detected Brunicardi_Ch10_p0305-p0354.indd 33322/02/19 2:14 PM 334BASIC CONSIDERATIONSPART Iare designated M1, and cases in which the presence of distant metastasis cannot be assessed are designated MX. In clinical practice, negative findings on clinical history and examination are sufficient to designate a case as M0. However, in clinical trials, routine follow-up often is performed to standardize the detection of distant metastases.The practice of dividing cancer cases into groups accord-ing to stage is based on the observation that the survival rates are higher for localized (lower-stage) tumors than for tumors that have extended beyond the organ of origin. Therefore, staging assists in selection of therapy, estimation of prognosis, evalu-ation of treatments, and exchange of information among treat-ment centers. Notably, the AJCC regularly updates its staging system to incorporate advances in prognostic technology to improve


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Surgery_Schwartz. evalu-ation of treatments, and exchange of information among treat-ment centers. Notably, the AJCC regularly updates its staging system to incorporate advances in prognostic technology to improve the predictive accuracy of the TNM system. There-fore, it is important to know which revision of a staging system is being used when evaluating studies.TUMOR MARKERSPrognostic and Predictive Tissue MarkersTumor markers are substances that can be detected in higher than normal amounts in the serum, urine, or tissues of patients with certain types of cancer. Tumor markers are produced either by the cancer cells themselves or by the body in a response to the cancer.Over the past decade, there has been an especially high interest in identifying tissue tumor markers that can be used as prognostic or predictive markers. Although the terms prognostic marker and predictive marker are sometimes used interchange-ably, the term prognostic marker generally is used to describe molecular markers that


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Surgery_Schwartz. or predictive markers. Although the terms prognostic marker and predictive marker are sometimes used interchange-ably, the term prognostic marker generally is used to describe molecular markers that predict disease-free survival, disease-specific survival, and overall survival, whereas the term predic-tive marker often is used in the context of predicting response to certain therapies.The goal is to identify prognostic markers that can give information on prognosis independent of other clinical charac-teristics and therefore can provide information to supplement the projections based on clinical presentation. This would allow practitioners to further classify patients as being at higher or lower risk within clinical subgroups and to identify patients who may benefit most from adjuvant therapy. For example, ideal prognostic tumor markers would be able to help determine which patients with node-negative breast cancer are at higher risk of relapse so that adjuvant systemic therapy could


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Surgery_Schwartz. For example, ideal prognostic tumor markers would be able to help determine which patients with node-negative breast cancer are at higher risk of relapse so that adjuvant systemic therapy could be given only to that group. However, although a large number of studies have identified potential novel prognostic markers, most have not been tested with enough vigor to be shown to be of clinical util-ity. In the 2017, American Society of Clinical Oncology (ASCO) guidelines, it was decided that level of uPA/PAI-1 measured by enzyme-linked immunosorbent assay could be used to determine prognosis in cases of newly diagnosed node-negative, hormone receptor positive breast cancer.111 In contrast, the data for many other markers, including Ki-67, p27, HER1/EGFR, and p53 were felt to be insufficient to support their use in the management of these breast cancer patients.111 Similarly, guidelines are avail-able for the management of patients with colorectal cancer and emphasize the processes that


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Surgery_Schwartz. to support their use in the management of these breast cancer patients.111 Similarly, guidelines are avail-able for the management of patients with colorectal cancer and emphasize the processes that need to be in place for accurate measurement of abnormalities in DNA mismatch repair genes as well as EGFR and BRAF mutational status.112Predictive markers are markers that can prospectively identify patients who will benefit from a certain therapy. For Low-riskgroupIntermediate-risk groupHigh-riskgroup005510101515202025253030353540404550Rate of distant recurrence at 10 y(% of patients)Recurrence scoreFigure 10-13. Distant recurrence as a continuous function of the recurrence score derived from tumor levels of expression of 21 genes. (Redrawn from Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer, N Engl J Med. 2004 Dec 30;351(27):2817-2826.)example in breast cancer, estrogen receptor (ER), and HER2 assessment can


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Surgery_Schwartz. assay to predict recurrence of tamoxifen-treated, node-negative breast cancer, N Engl J Med. 2004 Dec 30;351(27):2817-2826.)example in breast cancer, estrogen receptor (ER), and HER2 assessment can identify patients who can benefit from anti-estrogen therapies (e.g., tamoxifen) and anti-HER2 targeted therapies (e.g., trastuzumab), respectively, and the ASCO guide-lines recommend that these markers be routinely assessed.111 High-throughput techniques such as transcriptional profiling allow for assessment of the relative mRNA levels of thou-sands of genes simultaneously in a given tumor using micro-array technology. With the advent of such molecular profiling technologies, researchers have focused on identifying expres-sion profiles that are prognostic for different cancer types. For breast cancer, although many such multiparameter tests are under development, few have reached the large-scale valida-tion stage.113 In 2007, ASCO guidelines suggested that one of these, the Oncotype DX


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Surgery_Schwartz. cancer, although many such multiparameter tests are under development, few have reached the large-scale valida-tion stage.113 In 2007, ASCO guidelines suggested that one of these, the Oncotype DX assay, can be used to predict recurrence in women with node-negative, ER-positive breast cancer who are treated with tamoxifen.111 Oncotype DX is a quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) test that used paraffin-fixed tissue. A 21-gene recurrence score (RS) is generated based on the expression of 16 cancer genes and 5 reference genes. The levels of expression are used to derive an RS that ranges from 0 to 100, using a prospectively defined mathematical algorithm. This novel quantitative approach to the evaluation of the best-known molecular pathways in breast cancer has produced impressive results. Use of this multigene assay to predict recurrence was validated in the National Surgi-cal Adjuvant Breast and Bowel Project (NSABP) B-14 trial, in which ER-positive,


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Surgery_Schwartz. has produced impressive results. Use of this multigene assay to predict recurrence was validated in the National Surgi-cal Adjuvant Breast and Bowel Project (NSABP) B-14 trial, in which ER-positive, node-negative patients had received tamoxifen.114 By multivariate Cox proportional analysis, RS was found to be independently associated with recurrence risk, with a hazard ratio of 3.21 (95% confidence interval of 2.23 to 4.65, P <.001). The RS was indeed able to stratify patients by freedom from distant recurrence (Fig. 10-13).114 The Trial Assessing Individualized Options for Treatment for breast cancer (TAILORx) is evaluating the utility of Oncotype DX for predicting prognosis in patients with ER-positive, node-negative tumors and will focus on women with intermediate RS scores in whom the role of chemotherapy is unclear. Several other multigene predictors for breast cancer are available including MammaPrint, a gene expression profiling platform assessing a


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Surgery_Schwartz. RS scores in whom the role of chemotherapy is unclear. Several other multigene predictors for breast cancer are available including MammaPrint, a gene expression profiling platform assessing a Brunicardi_Ch10_p0305-p0354.indd 33422/02/19 2:14 PM 335ONCOLOGYCHAPTER 1070-gene transcriptional signature.115 This assay was approved by the Food and Drug Administration (FDA) in February 2007. The usefulness of this assay in making therapy-related decisions was tested prospectively in a large-scale study, the Microarray in Node-Negative Disease May Avoid Chemotherapy (MIND-ACT) trial. Among women with early-stage breast cancer who were determined to be at high clinical risk and low genomic risk for cancer recurrence, the receipt of no adjuvant chemotherapy on the basis of the 70-gene signature result led to a 5-year metas-tasis survival rate that was 1.5% lower than the rate in patients who had received chemotherapy. In light of these findings, 45% of women with breast cancer who are


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Surgery_Schwartz. result led to a 5-year metas-tasis survival rate that was 1.5% lower than the rate in patients who had received chemotherapy. In light of these findings, 45% of women with breast cancer who are considered to be at high clinical risk might not require adjuvant chemotherapy.116Multigene profiles to predict prognosis are in development or in validation phases for many other solid tumor types, includ-ing lung cancer, ovarian cancer, pancreatic cancer, colorectal cancer, and melanoma. Gene signatures and genomic alterations also are being studied for their ability to predict response to specific chemotherapy regimens or targeted therapies. Many of these multigene marker sets will likely be incorporated into clinical practice in the years to come.Serum MarkersSerum markers are under active investigation because they may allow early diagnosis of a new cancer or may be used to follow cancer response to therapy or monitor for recurrence. Unfor-tunately, identification of serum markers of


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Surgery_Schwartz. investigation because they may allow early diagnosis of a new cancer or may be used to follow cancer response to therapy or monitor for recurrence. Unfor-tunately, identification of serum markers of clinical value has been challenging. Many of the tumor markers proposed so far have had low sensitivities and specificities.113 Tumor marker levels may not be elevated in all patients with cancer, especially in the early stages, when a serum marker would be most use-ful for diagnosis. Therefore, when a tumor marker is used to monitor recurrence, it is important to be certain that the level of the tumor marker was elevated before primary therapy. More-over, tumor marker levels can be elevated in benign conditions. Many tumor markers are not specific for a certain type of cancer and can be elevated with more than one type of tumor. Since there may be significant laboratory variability, it is important to obtain serial results from the same laboratory. In spite of these many clinical


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Surgery_Schwartz. be elevated with more than one type of tumor. Since there may be significant laboratory variability, it is important to obtain serial results from the same laboratory. In spite of these many clinical limitations, several serum markers are in clinical use. A few of the commonly measured serum tumor markers are discussed in the following sections.Prostate-Specific Antigen. Prostate-specific antigen (PSA) is an androgen-regulated serine protease produced by the pros-tate epithelium. PSA is normally present in low concentrations in the blood of all adult males. PSA levels may be elevated in the blood of men with benign prostate conditions such as pros-tatitis and benign prostatic hyperplasia, as well as in men with prostate cancer. PSA levels have been shown to be useful in evaluating the effectiveness of prostate cancer treatment and monitoring for recurrence after therapy. In monitoring for recur-rence, a trend of increasing levels is considered more significant than a single absolute


Surgery_Schwartz

Surgery_Schwartz. of prostate cancer treatment and monitoring for recurrence after therapy. In monitoring for recur-rence, a trend of increasing levels is considered more significant than a single absolute elevated value.Although PSA has been widely used for prostate cancer screening, the utility of PSA screening remains controversial. There is concern that the number of men who avoid dying from prostate cancer due to screening is small, while the harms related to the treatment of screen-detected cancers, including inconti-nence and erectile dysfunction are at least moderate. In 2012, the U.S. Preventive Services Task Force concluded with moder-ate certainty that the harms of PSA testing outweigh the benefits and on that basis recommended against PSA-based screening for all men.117 In 2010, the American Cancer Society updated its guidelines for the early detection of prostate cancer to state that men who have at least a 10-year life expectancy should have an opportunity to make an informed decision


Surgery_Schwartz

Surgery_Schwartz. Cancer Society updated its guidelines for the early detection of prostate cancer to state that men who have at least a 10-year life expectancy should have an opportunity to make an informed decision with their health care provider about whether to be screened for prostate cancer with digital rectal exam and serum PSA, after receiving information about the benefits, risks, and uncertainties associated with pros-tate cancer screening118; this recommendation was reinforced in their most recent guidelines.96Carcinoembryonic Antigen. Carcinoembryonic antigen (CEA) is a glycoprotein found in the embryonic endodermal epithelium. Elevated CEA levels have been detected in patients with primary colorectal cancer as well as in patients with breast, lung, ovarian, prostate, liver, and pancreatic cancer. Levels of CEA also may be elevated in benign conditions, including diverticulitis, peptic ulcer disease, bronchitis, liver abscess, and alcoholic cirrhosis, especially in smokers and in elderly


Surgery_Schwartz

Surgery_Schwartz. Levels of CEA also may be elevated in benign conditions, including diverticulitis, peptic ulcer disease, bronchitis, liver abscess, and alcoholic cirrhosis, especially in smokers and in elderly persons.CEA measurement is most commonly used in the man-agement of colorectal cancer. However, the appropriate use of CEA testing in patients with colorectal cancer has been debated. Use of CEA level as a screening test for colorectal cancer is not recommended. CEA levels may be useful if obtained pre-operatively and postoperatively in patients with a diagnosis of colorectal cancer. Preoperative elevation of CEA level is an indicator of poor prognosis. However, the ASCO clinical prac-tice guidelines state that the data are insufficient to support the use of CEA to determine whether to give a patient adjuvant therapy; the data are stronger for the use of CEA for monitoring for postoperative recurrence.111 CEA measurement is the most cost-effective approach for detecting metastasis, with over


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Surgery_Schwartz. adjuvant therapy; the data are stronger for the use of CEA for monitoring for postoperative recurrence.111 CEA measurement is the most cost-effective approach for detecting metastasis, with over 60% of recurrences being detected first by an elevation in CEA level. Therefore, in cases in which the patient would be a candidate for resection of recurrent colorectal cancer or systemic therapy, the ASCO guidelines recommend that postoperative CEA testing be performed every 3 months in patients with stage II or III disease for at least 3 years.112 CEA is the marker of choice for monitor-ing metastatic colorectal cancer during systemic therapy.112Alpha-Fetoprotein. Alpha-fetoprotein (AFP) is a glycoprotein normally produced by a developing fetus. AFP levels decrease soon after birth in healthy adults. An elevated level of AFP sug-gests the presence of either primary liver cancer or a germ cell tumor of the ovary or testicle. Rarely, other types of cancer such as gastric are associated with


Surgery_Schwartz

Surgery_Schwartz. adults. An elevated level of AFP sug-gests the presence of either primary liver cancer or a germ cell tumor of the ovary or testicle. Rarely, other types of cancer such as gastric are associated with an elevated AFP level. Benign conditions that can cause elevations of AFP include cirrhosis, hepatic necrosis, acute hepatitis, chronic active hepatitis, ataxia-telangiectasia, Wiskott-Aldrich syndrome, and pregnancy.119The sensitivity of an elevated AFP level for detecting HCC is approximately 60%. AFP is considered to be sensitive and specific enough to be used for screening for HCC in high-risk populations. Current consensus recommendations are to screen healthy hepatitis B virus carriers with annual or semi-annual measurement of AFP level and to screen carriers with cirrhosis or chronic hepatitis and patients with cirrhosis of any etiology with twice-yearly measurement of AFP level and liver ultrasonography.120 Although AFP testing has been used widely for a long time, its efficacy in


Surgery_Schwartz

Surgery_Schwartz. and patients with cirrhosis of any etiology with twice-yearly measurement of AFP level and liver ultrasonography.120 Although AFP testing has been used widely for a long time, its efficacy in early diagnosis of HCC is limited. With improvements in imaging technology, a larger proportion of patients diagnosed with HCC are now AFP seronegative.Cancer Antigen 19-9. Cancer antigen 19-9 (CA 19-9) is a tumor-related antigen that was originally defined by a monoclo-nal antibody produced by a hybridoma prepared from murine Brunicardi_Ch10_p0305-p0354.indd 33522/02/19 2:14 PM 336BASIC CONSIDERATIONSPART Ispleen cells immunized with a human colorectal cancer cell line.112 The data are insufficient to recommend use of CA 19-9 for screening, diagnosis, surveillance, or monitoring of therapy for colon cancer.112 Based on the 2006 ASCO guidelines, there are also insufficient data to recommend use of CA 19-9 for screening, diagnosis, or determination of the operability of pan-creatic cancer.112


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Surgery_Schwartz. cancer.112 Based on the 2006 ASCO guidelines, there are also insufficient data to recommend use of CA 19-9 for screening, diagnosis, or determination of the operability of pan-creatic cancer.112 However, for patients with locally advanced or metastatic cancer receiving active therapy, CA 19-9 can be measured at the start of therapy and every 1 to 3 months while therapy is given; elevations in serial CA 19-9 levels may indi-cate progressive disease and should be confirmed by additional studies.112Cancer Antigen 15-3. Cancer antigen 15-3 (CA 15-3) is an epitope of a large membrane glycoprotein encoded by the MUC1 gene that tumor cells shed into the bloodstream. The CA 15-3 epitope is recognized by two monoclonal antibodies in a sandwich radioimmunoassay. CA 15-3 levels are most useful in following the course of treatment in women diagnosed with advanced breast cancer. CA 15-3 levels are infrequently elevated in early-stage breast cancer. CA 15-3 levels can be increased in benign


Surgery_Schwartz

Surgery_Schwartz. in following the course of treatment in women diagnosed with advanced breast cancer. CA 15-3 levels are infrequently elevated in early-stage breast cancer. CA 15-3 levels can be increased in benign conditions such as chronic hepatitis, tuberculosis, sar-coidosis, pelvic inflammatory disease, endometriosis, systemic lupus erythematosus, pregnancy, and lactation, and in other types of cancer such as lung, ovarian, endometrial, and GI cancers.The sensitivity of CA 15-3 is higher for metastatic disease, and in these cases studies have shown sensitivity to be between 54% and 87%, with specificity as high as 96%. This has led to interest in using CA 15-3 for monitoring patients with advanced breast cancer for recurrence. Elevated CA 15-3 levels have been reported before relapse in 54% of patients, with a lead time of 4.2 months. Therefore, detection of elevated CA 15-3 levels dur-ing follow-up should prompt evaluation for recurrent disease. However, 6% to 8% of patients without recurrence


Surgery_Schwartz

Surgery_Schwartz. with a lead time of 4.2 months. Therefore, detection of elevated CA 15-3 levels dur-ing follow-up should prompt evaluation for recurrent disease. However, 6% to 8% of patients without recurrence will have ele-vated CA 15-3 levels that require evaluation. Furthermore, moni-toring with the use of CA 15-3 levels has shown no demonstrated impact on survival. Therefore, the 2007 ASCO guidelines state that the routine use of CA 15-3 for screening, diagnosis, stag-ing, or surveillance of breast cancer is not recommended because available data are insufficient.111 For monitoring patients during active therapy, CA 15-3 can be used in conjunction with diag-nostic imaging and history and physical examination.111 In the absence of measurable disease, an increase may be interpreted to indicate treatment failure. However, caution is advised when interpreting rising levels in the first 4 to 6 weeks of therapy.111Cancer Antigen 27-29. The MUC-1 gene product in the serum may be quantitated by using


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Surgery_Schwartz. failure. However, caution is advised when interpreting rising levels in the first 4 to 6 weeks of therapy.111Cancer Antigen 27-29. The MUC-1 gene product in the serum may be quantitated by using radioimmunoassay with a monoclonal antibody against the cancer antigen 27-29 (CA 27-29). CA 27-29 levels can be elevated in breast cancer as well as in cancers of the colon, stomach, kidney, lung, ovary, pan-creas, uterus, and liver. First-trimester pregnancy, endometrio-sis, benign breast disease, kidney disease, and liver disease also may be associated with elevated CA 27-29 levels.CA 27-29 has been reported to have a sensitivity of 57%, a specificity of 98%, a positive predictive value of 83%, and a negative predictive value of 93% in detecting breast cancer recurrences.121 Although CA 27-29 has been found to predict recurrence an average of 5.3 months before other symptoms or tests, testing of CA 27-29 levels has not been demonstrated to affect disease-free and overall survival


Surgery_Schwartz

Surgery_Schwartz. CA 27-29 has been found to predict recurrence an average of 5.3 months before other symptoms or tests, testing of CA 27-29 levels has not been demonstrated to affect disease-free and overall survival rates.121,122 Therefore, the ASCO guidelines state that, as with CA 15-3, the routine use of CA 27-29 for screening, diagnosis, staging, or surveillance of breast cancer is not recommended because available data are insufficient.111 CA 27-29 levels can be used together with diag-nostic imaging and history and physical examination to monitor patients during active therapy.111 When no measurable disease is present, an increase in level may be considered to indicate treat-ment failure. However, rising levels in the first 4 to 6 weeks of therapy should be interpreted with caution.111Circulating Tumor CellsCirculating tumor cells (CTCs) are cells present in the blood that possess antigenic or genetic characteristics of a specific tumor type.111 One CTC detection methodology is capture and


Surgery_Schwartz

Surgery_Schwartz. Tumor CellsCirculating tumor cells (CTCs) are cells present in the blood that possess antigenic or genetic characteristics of a specific tumor type.111 One CTC detection methodology is capture and quantita-tion of CTCs with immunomagnetic beads coated with antibody specific for cell-surface, epithelial, or cancer antigens. Another methodology used to detect cancer cells in the peripheral blood is RT-PCR. It has been suggested that measurement of CTCs can be an effective tool for selecting patients who have a high risk of relapse and for monitoring efficacy of cancer therapy.CTCs have probably been most extensively studied in breast cancer.111 The most promising data come from the use of CTC measures in metastatic breast cancer. In a prospective multicenter trial, the number of CTCs (≥5 CTCs vs. <5 CTCs per 7.5 mL of whole blood) before treatment of metastatic breast cancer was an independent predictor of progression-free and overall survival rates.123 The presence of >5 CTCs after the


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Surgery_Schwartz. vs. <5 CTCs per 7.5 mL of whole blood) before treatment of metastatic breast cancer was an independent predictor of progression-free and overall survival rates.123 The presence of >5 CTCs after the first course of therapy predicted lack of response to treatment. This technology, known as CellSearch, has been approved by the FDA for clinical use. In a well-designed single institutional study, detection of one or more CTCs in stage I to III breast cancer patients was associated with both decreased progres-sion-free survival and overall survival.124 A large clinical trial was launched by the German SUCCESS study group to evalu-ate the prognostic significance of CTCs in early breast cancer. Blood samples were obtained from over 2000 average-to-high-risk nonmetastatic breast cancer patients before chemotherapy and nearly 1500 patients post chemotherapy and examined for CTCs. Women with detectable CTCs before chemotherapy had significantly worse disease-free and overall survival, and those


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Surgery_Schwartz. chemotherapy and nearly 1500 patients post chemotherapy and examined for CTCs. Women with detectable CTCs before chemotherapy had significantly worse disease-free and overall survival, and those with five or more CTCs had the highest relapse risk.125 How-ever, there is limited data to prove that the use of CTC testing leads to improved survival or improved quality of life; thus, the ASCO 2017 guidelines update did not recommend the use of CTC measurement in any clinical setting.111 The clinical util-ity of measuring CTC response to initial therapy is now being tested prospectively in multiple clinical trials. The ability to conduct comprehensive analyses of cancer genomes within indi-vidual cells is becoming a real possibility, although the clinical utility of such information is still evolving. In addition to CTC, it has become possible in recent years to conduct a so-called “liquid tumor biopsy” by measuring levels of circulating tumor DNA and also circulating microRNAs. These new


Surgery_Schwartz

Surgery_Schwartz. In addition to CTC, it has become possible in recent years to conduct a so-called “liquid tumor biopsy” by measuring levels of circulating tumor DNA and also circulating microRNAs. These new techniques are investigational but have the potential to provide prognos-tic and diagnostic information via their presumed correlation with tumor progression and the development of genomic altera-tions.126 The prognostic implications of detection of CTCs by RT-PCR have been intensively studied for melanoma. In the recent multicenter Sunbelt Melanoma Trial, serial RT-PCR was performed on peripheral blood samples using four markers—tyrosinase, melanoma antigen reacting to T cell (MART-1), melanoma antigen 3 (MAGE3), and gp 100—to detect occult Brunicardi_Ch10_p0305-p0354.indd 33622/02/19 2:14 PM 337ONCOLOGYCHAPTER 10melanoma cells in the bloodstream.127 Although there were no differences in survival rates among patients in whom at least one marker was detected and those in whom no markers were


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Surgery_Schwartz. 10melanoma cells in the bloodstream.127 Although there were no differences in survival rates among patients in whom at least one marker was detected and those in whom no markers were detected, the disease-free survival and distant disease-free sur-vival rates were worse for patients in whom more than one marker was detected at any time during follow-up.127Bone Marrow MicrometastasesMicrometastatic disease in the bone marrow, also referred to as minimal residual disease, continues to be investigated as a potential prognostic marker. Bone marrow micrometastatic disease usually is detected by staining bone marrow aspirates with monoclonal antibodies to cytokeratin, but other method-ologies such as flow cytometry and RT-PCR are in use. Breast cancer patients with bone marrow micrometastasis have larger tumors, tumors with a higher histologic grade, more lymph node metastases, and more hormone receptor-negative tumors than patients without bone marrow micrometastasis. In 4700 patients with


Surgery_Schwartz

Surgery_Schwartz. larger tumors, tumors with a higher histologic grade, more lymph node metastases, and more hormone receptor-negative tumors than patients without bone marrow micrometastasis. In 4700 patients with stage I, II, or III breast cancer, micrometastasis was a sig-nificant prognostic factor associated with poor overall survival, breast cancer-specific survival, disease-free survival, and distant disease-free survival during a 10-year observation period.128 The American College of Surgeons Oncology Group Z0010 trial enrolled women with clinical T1 to T2N0M0 invasive breast carcinoma in a prospective observational study to determine the association between survival and metastases detected by immunochemical staining of bone marrow specimens from patients with early-stage breast cancer.129 Of 3413 bone mar-row specimens examined by immunocytochemistry, only 104 (3.0%) were positive for tumor. Bone marrow involvement was associated with a decreased overall survival, but this association was not


Surgery_Schwartz

Surgery_Schwartz. bone mar-row specimens examined by immunocytochemistry, only 104 (3.0%) were positive for tumor. Bone marrow involvement was associated with a decreased overall survival, but this association was not significant on multivariable analysis. The prognostic implication of bone marrow involvement continues to be stud-ied by the National Surgical Adjuvant Breast and Bowel Project.At this time, the routine use of bone marrow testing is not recommended.111 Ongoing clinical trials are evaluating the role of routine assessment of bone marrow status in the care of patients with early and advanced breast cancer. The utility of assessment of bone marrow micrometastasis has also been evaluated in other tumor types, including gastric, esophageal, colorectal, lung, cervical, and ovarian cancer.130SURGICAL APPROACHES TO CANCER THERAPYMultidisciplinary Approach to CancerAlthough surgery is an effective therapy for most solid tumors, patients who die from cancer usually die of metastatic disease.


Surgery_Schwartz

Surgery_Schwartz. APPROACHES TO CANCER THERAPYMultidisciplinary Approach to CancerAlthough surgery is an effective therapy for most solid tumors, patients who die from cancer usually die of metastatic disease. Therefore, to improve patient survival rates, a multimodality approach, including systemic therapy and radiation therapy, is key for most tumors. It is important that surgeons involved in cancer care not only know the techniques for performing a cancer operation but also know the alternatives to surgery and be well versed in reconstructive options. It is also crucial that the surgeon be familiar with the indications for and complications of preoperative and postoperative chemotherapy and radiation therapy. Although the surgeon may not be delivering these other therapies, as the first physician to see a patient with a cancer diagnosis, he or she is ultimately responsible for initiating the appropriate consultations. For this reason, the surgeon often is responsible for determining the most


Surgery_Schwartz

Surgery_Schwartz. to see a patient with a cancer diagnosis, he or she is ultimately responsible for initiating the appropriate consultations. For this reason, the surgeon often is responsible for determining the most appropriate adjuvant ther-apy for a given patient as well as the best sequence for therapy. In most instances, a multidisciplinary approach beginning at the patient’s initial presentation is likely to yield the best result.Surgical Management of Primary TumorsThe goal of surgical therapy for cancer is to achieve oncologic cure. A curative operation presupposes that the tumor is confined to the organ of origin or to the organ and the regional lymph node basin. Patients in whom the primary tumor is not resectable with negative surgical margins are considered to have inoperable disease. The operability of primary tumors is best determined before surgery with appropriate imaging studies that can define the extent of local-regional disease. For example, a preoperative thin-section CT scan is


Surgery_Schwartz

Surgery_Schwartz. of primary tumors is best determined before surgery with appropriate imaging studies that can define the extent of local-regional disease. For example, a preoperative thin-section CT scan is obtained to determine resectability of pancreatic cancer, which is based on the absence of extrapancre-atic disease, the absence of tumor extension to the superior mes-enteric artery and celiac axis, and a patent superior mesenteric vein-portal vein confluence.131 Disease involving multiple distant metastases is deemed inoperable because it is usually not curable with surgery of the primary tumor. Therefore, patients who are at high risk of having distant metastasis should undergo a staging work-up before surgery for the primary tumor. On occasion, pri-mary tumors are resected in these patients for palliative reasons, such as improving the quality of life by alleviating pain, infec-tion, or bleeding. An example of this is toilet mastectomies for large ulcerated breast tumors. Patients with limited


Surgery_Schwartz

Surgery_Schwartz. reasons, such as improving the quality of life by alleviating pain, infec-tion, or bleeding. An example of this is toilet mastectomies for large ulcerated breast tumors. Patients with limited metastases from a primary tumor on occasion are considered surgical candi-dates if the natural history of isolated distant metastases for that cancer type is favorable or the potential complications associated with leaving the primary tumor intact are significant.In the past, it was presumed that the more radical the sur-gery, the better the oncologic outcome would be. Over the past three decades, this has been recognized as not necessarily being true, which has led to more conservative operations, with wide local excisions replacing compartmental resections of sarcomas, and partial mastectomies, skin-sparing mastectomies, and breast-conserving therapies replacing radical mastectomies for breast cancer. The uniform goal for all successful oncologic operations seems to be achieving widely negative


Surgery_Schwartz

Surgery_Schwartz. mastectomies, and breast-conserving therapies replacing radical mastectomies for breast cancer. The uniform goal for all successful oncologic operations seems to be achieving widely negative margins with no evidence of macroscopic or microscopic tumor at the surgical margins. The importance of negative surgical margins for local tumor control and/or survival has been documented for many tumor types, including sarcoma, breast cancer, pancreatic cancer, and rectal cancer. Thus, it is clear that every effort should be made to achieve microscopically negative surgical margins. Inking of the margins, orientation of the specimen by the surgeon, and immediate gross evaluation of the margins by a pathologist using frozen-section analysis when necessary may assist in achiev-ing negative margins at the first operation. In the end, although radiation therapy and systemic therapy can assist in decreasing local recurrence rates in the setting of positive margins, adjuvant therapy cannot substitute


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Surgery_Schwartz. the first operation. In the end, although radiation therapy and systemic therapy can assist in decreasing local recurrence rates in the setting of positive margins, adjuvant therapy cannot substitute for adequate surgery.Although it is clear that the surgical gold standard is nega-tive surgical margins, the appropriate surgical margins for optimal local control are controversial for many cancer types. In contrast, in melanoma the optimal margin width for any tumor depth has been better defined, owing to the systematic study of this ques-tion in randomized clinical trials.132,133 Although such randomized studies may not be possible for all tumor types, it is important to determine optimal surgical margins for each cancer type so that adjuvant radiation and systemic therapy can be offered to patients deemed to be at increased risk for local treatment failure.Brunicardi_Ch10_p0305-p0354.indd 33722/02/19 2:14 PM 338BASIC CONSIDERATIONSPART IFigure 10-14. Lymphatic mapping and


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Surgery_Schwartz. to patients deemed to be at increased risk for local treatment failure.Brunicardi_Ch10_p0305-p0354.indd 33722/02/19 2:14 PM 338BASIC CONSIDERATIONSPART IFigure 10-14. Lymphatic mapping and sen-tinel lymph node biopsy specimen for breast cancer. A. Peritumoral injection of blue dye. B. Blue dye draining into the sentinel lymph node.Surgical Management of the Regional Lymph Node BasinMost neoplasms have the ability to metastasize via the lymphat-ics. Therefore, most oncologic operations have been designed to remove the primary tumor and draining lymphatics en bloc. This type of operative approach usually is undertaken when the lymph nodes draining the primary tumor site lie adjacent to the tumor bed, as is the case for colorectal cancers and gastric can-cers. For tumors in which the regional lymph node basin is not immediately adjacent to the tumor (e.g., melanomas), lymph node surgery can be performed through a separate incision. Unlike most carcinomas, soft tissue sarcomas rarely


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Surgery_Schwartz. lymph node basin is not immediately adjacent to the tumor (e.g., melanomas), lymph node surgery can be performed through a separate incision. Unlike most carcinomas, soft tissue sarcomas rarely metasta-size to the lymph nodes (<5%); therefore, lymph node surgery usually is not necessary.It is generally accepted that a formal lymphadenectomy is likely to minimize the risk of regional recurrence of most cancers. For example, the introduction of total mesorectal excision of rectal cancer has been associated with a large decline in local-regional recurrence, and this procedure has become the new standard of operative management.134 On the other hand, there have been two opposing views regarding the role of lymphadenectomy in survival of cancer patients. The traditional Halsted view states that lymphadenectomy is important for staging and survival. The opposing view coun-ters that cancer is systemic at inception and that lymphade-nectomy, although useful for staging, does not affect


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Surgery_Schwartz. that lymphadenectomy is important for staging and survival. The opposing view coun-ters that cancer is systemic at inception and that lymphade-nectomy, although useful for staging, does not affect survival. For most cancers, involvement of the lymph nodes is one of the most significant prognostic factors. Interestingly, in some studies removal of a larger number of lymph nodes has been found to be associated with an improved overall survival rate for many tumors, including breast cancer, colon cancer, and lung cancer. Although this seems to support the Halsted the-ory that more extensive lymphadenectomy yielding of nodes reduces the risk of regional recurrence, there may be alterna-tive explanations for the same finding. For example, the sur-geon who performs a more extensive lymphadenectomy may obtain wider margins around the tumor or even provide better overall care, such as ensuring that patients receive the appropri-ate adjuvant therapy or undergo a more thorough staging work-up.


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Surgery_Schwartz. may obtain wider margins around the tumor or even provide better overall care, such as ensuring that patients receive the appropri-ate adjuvant therapy or undergo a more thorough staging work-up. Alternatively, the pathologist may perform a more thorough examination, identifying more nodes and more accurately stag-ing the nodes. The effect of appropriate staging on survival is twofold. Patients with nodal metastases may be offered adjuvant therapy, which improves their survival chances. Further, the enhanced staging can improve perceived survival rates through a “Will Rogers effect.” Such a phenomenon is observed when moving an element from one set to another set raises the average value of both sets. When commenting on the 1930s migration of poor farmers from a dustbowl state to a more prosperous west-ern state, humorist Will Rogers quipped that this event raised the average intelligence of both states. Thus, identification of small metastases that had formerly been silent and


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Surgery_Schwartz. more prosperous west-ern state, humorist Will Rogers quipped that this event raised the average intelligence of both states. Thus, identification of small metastases that had formerly been silent and unidenti-fied leads to stage migration for these patients and thus to a perceived improvement in chances of survival for the higher stage. In addition, there is improved survival for the lower stage, which is now minus the patients with low volume nodal disease. Clearly the impact of lymphadenectomy on survival will con-tinue to be a topic of clinical research.Surgical management of the clinically negative regional lymph node basin has evolved with the introduction of lym-phatic mapping technology (Fig. 10-14).135 Lymphatic mapping and sentinel lymph node biopsy specimen were first reported in 1977 by Cabanas for penile cancer.136 Now, sentinel node biopsy specimen is the standard of care for the management of melanoma and breast cancer. The utility of sentinel node biopsy is being


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Surgery_Schwartz. in 1977 by Cabanas for penile cancer.136 Now, sentinel node biopsy specimen is the standard of care for the management of melanoma and breast cancer. The utility of sentinel node biopsy is being explored in other cancer types such as head and neck squamous cell cancer and vulvar cancer.The first node to receive drainage from the tumor site is termed the sentinel node. This node is the node most likely to contain metastases, if metastases to that regional lymph node basin are present. The goal of lymphatic mapping and senti-nel lymph node biopsy specimen is to identify and remove the lymph node most likely to contain metastases in the least inva-sive fashion. The practice of sentinel lymph node biopsy speci-men followed by regional lymph node dissection for selected patients with a positive sentinel lymph node avoids the morbid-ity of lymph node dissections in patients with negative nodes. An additional advantage of the sentinel lymph node technique is that it directs attention to a


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Surgery_Schwartz. sentinel lymph node avoids the morbid-ity of lymph node dissections in patients with negative nodes. An additional advantage of the sentinel lymph node technique is that it directs attention to a single node, which allows more careful analysis of the lymph node most likely to have a positive yield and increases the accuracy of nodal staging. Two criteria are used to assess the efficacy of a sentinel lymph node biopsy specimen: the sentinel lymph node identification rate and the false-negative rate. The sentinel lymph node identification rate Brunicardi_Ch10_p0305-p0354.indd 33822/02/19 2:14 PM 339ONCOLOGYCHAPTER 10is the proportion of patients in whom a sentinel lymph node was identified and removed among all patients undergoing an attempted sentinel lymph node biopsy specimen. The false-negative rate is the proportion of patients with regional lymph node metastases in whom the sentinel lymph node was found to be negative. False-negative biopsy specimen results may be due to


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Surgery_Schwartz. false-negative rate is the proportion of patients with regional lymph node metastases in whom the sentinel lymph node was found to be negative. False-negative biopsy specimen results may be due to identifying the wrong node or to missing the sentinel node (i.e., surgical error) or they may be due to the cancer cells’ establishing metastases not in the first node encountered but in a second-echelon node (i.e., biologic variation). Alternatively, false-negative biopsy specimen results may be due to inadequate histologic evaluation of the lymph node. The false-negative rates for sentinel lymph node biopsy specimen in study series range between 0% and 11%. Both increases in the identification rate and decreases in the false-negative rate have been observed as surgeons gain experience with the technique.Lymphatic mapping is performed by using isosulfan blue dye, technetium-labeled sulfur colloid or albumin, or a combi-nation of both techniques to detect sentinel nodes. The combina-tion of


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Surgery_Schwartz. technique.Lymphatic mapping is performed by using isosulfan blue dye, technetium-labeled sulfur colloid or albumin, or a combi-nation of both techniques to detect sentinel nodes. The combina-tion of blue dye and technetium has been reported to improve the capability of detecting sentinel lymph nodes. The nodal drainage pattern usually is determined with a preoperative lym-phoscintigram, and the “hot” and/or blue nodes are identified with the assistance of a gamma probe and careful nodal basin exploration. Careful manual palpation is a crucial part of the procedure to minimize the false-negative rate.The nodes are evaluated with serial sectioning, hematoxy-lin and eosin staining, and immunohistochemical analysis with S-100 protein and homatropine methylbromide staining for mel-anoma and cytokeratin staining for breast cancer. The utility of molecular techniques such as RT-PCR to assess the sentinel nodes is still being explored.Another area of active investigation is the prognostic


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Surgery_Schwartz. cytokeratin staining for breast cancer. The utility of molecular techniques such as RT-PCR to assess the sentinel nodes is still being explored.Another area of active investigation is the prognostic value of minimal nodal involvement. For example, in breast cancer, nodes with isolated tumor cell deposits of <0.2 mm are considered to be N0 by the sixth edition of the AJCC staging manual. However, some retrospective studies have suggested that even this amount of nodal disease burden has negative prognostic implications.137 Molecular ultrastaging with RT-PCR for patients with node-negative disease was assessed in a pro-spective multicenter trial and was found not to be prognostic in malignant melanoma.127 However, a recent meta-analysis of 22 studies enrolling 4019 patients found that PCR positivity was associated with worse overall and disease-free survival.138 Fur-ther study of the utility of ultrastaging of nodes in breast cancer, melanoma, and several other tumor types is


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Surgery_Schwartz. that PCR positivity was associated with worse overall and disease-free survival.138 Fur-ther study of the utility of ultrastaging of nodes in breast cancer, melanoma, and several other tumor types is ongoing.Until recently, in breast cancer management, when senti-nel node mapping revealed a positive sentinel node, this was fol-lowed by a completion axillary lymph node dissection. Results of the American College of Surgeons Oncology Group Z0011 trial, challenged this practice. ACOSOG Z11 was a phase 3 mul-ticenter noninferiority trial conducted to determine the effects of complete axillary lymph node dissection on survival of patients with sentinel lymph node metastasis of breast cancer.129 Patients were women with clinical T1-T2 invasive breast cancer, no pal-pable adenopathy, and 1 to 2 SLNs containing metastases identi-fied by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. All patients underwent breast-conserving surgery and tangential


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Surgery_Schwartz. 1 to 2 SLNs containing metastases identi-fied by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. All patients underwent breast-conserving surgery and tangential whole-breast irradiation. Those with sentinel node metastases identified by sentinel node biopsy specimen were randomized to undergo axillary lymph node dissection or no further axillary treatment. At a median follow-up of 6.3 years, 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%–94.5%) with axillary lymph node dissection and 92.5% (95% CI, 90.0%–95.1%) with sen-tinel node alone. The 5-year disease-free survival was 82.2% (95% CI, 78.3%–86.3%) with axillary lymph node dissection, and 83.9% (95% CI, 80.2%–87.9%) with sentinel node alone. Thus, ACOSOGZ11 demonstrated that among breast cancer patients with limited sentinel node metastasis treated with breast conservation and systemic therapy, the use of sentinel node alone compared with axillary lymph node dissection


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Surgery_Schwartz. among breast cancer patients with limited sentinel node metastasis treated with breast conservation and systemic therapy, the use of sentinel node alone compared with axillary lymph node dissection did not result in inferior survival. This study challenges the traditional surgical dictum of regional management, and has led to a selec-tive utilization of completion axillary lymph node dissection in breast cancer patients undergoing breast conservation. The role of completion lymph node dissections in melanoma is under investigation. In the MSLT-II clinical trial, melanoma patients with sentinel-node metastases were randomized to immediate completion lymph-node dissection or nodal observation with ultrasonography. The primary end point of this study was mela-noma-specific survival. Immediate completion lymph-node dis-section led to increased regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with


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Surgery_Schwartz. survival. Immediate completion lymph-node dis-section led to increased regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with intermediate-thickness melanoma and sentinel-node metastases.139Surgical Management of Distant MetastasesThe treatment of a patient with distant metastases depends on the number and sites of metastases, the cancer type, the rate of tumor growth, the previous treatments delivered and the responses to these treatments, and the patient’s age, physical condition, and desires. Although once a tumor has metastasized it usually is not curable with surgical therapy, such therapy has resulted in cure in selected cases with isolated metastases to the liver, lung, or brain.Patient selection is the key to the success of surgical therapy for distant metastases. The cancer type is a major determinant in surgical decision making. A liver metastasis from a colon cancer is more likely to be an isolated


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Surgery_Schwartz. to the success of surgical therapy for distant metastases. The cancer type is a major determinant in surgical decision making. A liver metastasis from a colon cancer is more likely to be an isolated and thus resectable lesion than a liver metastasis from a pancreatic carcinoma. The growth rate of the tumor also plays an important role and can be determined in part by the disease-free interval and the time between treatment of the primary tumor and detection of the distant recurrence. Patients with longer disease-free intervals have a higher survival rate after surgical metastasectomy than those with a short disease-free interval. Similarly, patients who have synchronous metastases (metastases diagnosed at the initial cancer diagnosis) do worse after metastasectomy than patients who develop metachronous metastases (metastasis diagnosed after a disease-free interval). The natural history of metastatic disease is so poor for some tumors (e.g., pancreatic cancer) that there is no role at


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Surgery_Schwartz. metachronous metastases (metastasis diagnosed after a disease-free interval). The natural history of metastatic disease is so poor for some tumors (e.g., pancreatic cancer) that there is no role at this time for surgical metastasectomy. In cancers with a more favorable outlook, observation for several weeks or months, potentially with initial treatment with systemic therapy, can allow the sur-geon to monitor for metastases at other sites.In curative surgery for distant metastases, as with surgery for primary tumors, the goal is to resect the metastases with negative margins. In patients with hepatic metastases that are unresectable because their location near intrahepatic blood ves-sels precludes a margin-negative resection, or because they are multifocal or hepatic function is inadequate, tumor ablation with cryotherapy or radiofrequency ablation is an alternative.140,141 Curative resections or ablative procedures should be attempted Brunicardi_Ch10_p0305-p0354.indd 33922/02/19


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Surgery_Schwartz. tumor ablation with cryotherapy or radiofrequency ablation is an alternative.140,141 Curative resections or ablative procedures should be attempted Brunicardi_Ch10_p0305-p0354.indd 33922/02/19 2:14 PM 340BASIC CONSIDERATIONSPART Ionly if the lesions are accessible and the procedure can be per-formed safely.CHEMOTHERAPYClinical Use of ChemotherapyIn patients with documented distant metastatic disease, chemo-therapy is usually the primary modality of therapy. The goal of therapy in this setting is to decrease the tumor burden, thus prolonging survival. It is rare to achieve cure with chemother-apy for metastatic disease for most solid tumors. Chemotherapy administered to a patient who is at high risk for distant recur-rence but has no evidence of distant disease is referred to as adjuvant chemotherapy. The goal of adjuvant chemotherapy is eradication of micrometastatic disease, with the intent of decreasing relapse rates and improving survival rates.Adjuvant therapy can be


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Surgery_Schwartz. as adjuvant chemotherapy. The goal of adjuvant chemotherapy is eradication of micrometastatic disease, with the intent of decreasing relapse rates and improving survival rates.Adjuvant therapy can be administered after surgery (post-operative chemotherapy) or before surgery (preoperative che-motherapy, neoadjuvant chemotherapy, or induction therapy). A portion or all of the planned adjuvant chemotherapy can be administered before the surgical removal of the primary tumor. Preoperative chemotherapy has three potential advantages. The first is that preoperative regression of tumor can facilitate resection of tumors that were initially inoperable or allow more conservative surgery for patients whose cancer was operable to begin with. In the NSABP B-18 project, for example, women were randomly assigned to receive adjuvant doxorubicin and cyclophosphamide preoperatively or postoperatively. More patients treated before surgery than after surgery underwent breast-conserving surgery (68% vs.


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Surgery_Schwartz. assigned to receive adjuvant doxorubicin and cyclophosphamide preoperatively or postoperatively. More patients treated before surgery than after surgery underwent breast-conserving surgery (68% vs. 60%).142 The second advan-tage of preoperative chemotherapy is the treatment of microme-tastases without the delay of postoperative recovery. The third advantage is the ability to assess a cancer’s response to treat-ment clinically, after a number of courses of chemotherapy, and pathologically, after surgical resection. This is especially impor-tant if alternative treatment regimens are available to be offered to patients whose disease responded inadequately. Molecular characterization of the residual disease may also give insight into mechanisms of chemoresistance and possible therapeutic targets.There are some potential disadvantages to preoperative chemotherapy, however. Although disease progression while the patient is receiving preoperative chemotherapy is rare in


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Surgery_Schwartz. therapeutic targets.There are some potential disadvantages to preoperative chemotherapy, however. Although disease progression while the patient is receiving preoperative chemotherapy is rare in chemotherapy-sensitive tumors such as breast cancer, it is more frequent in relatively chemotherapy-resistant tumors such as sarcomas.143 Thus, patient selection is critical to ensure that the opportunity to treat disease surgically is not lost by giving pre-operative chemotherapy. Often, rates of postoperative wound infection, flap necrosis, and delays in postoperative adjuvant therapy do not differ between patients who are treated with preoperative chemotherapy and patients who are treated with surgery first. However, preoperative chemotherapy can intro-duce special challenges to tumor localization, margin analysis, lymphatic mapping, and pathologic staging.Response to chemotherapy is monitored clinically with imaging studies as well as physical examinations. Response usually is defined as


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Surgery_Schwartz. margin analysis, lymphatic mapping, and pathologic staging.Response to chemotherapy is monitored clinically with imaging studies as well as physical examinations. Response usually is defined as complete response, partial response, stable disease, or progression. Response generally is assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.144 Objective tumor response assessment is critical because tumor response is used as a prospective endpoint in clinical trials and tumor response is a guide to clinicians regard-ing continuation of current therapy.Principles of ChemotherapyChemotherapy destroys cells by first-order kinetics, which means that with the administration of a drug a constant percent-age of cells is killed, not a constant number of cells. If a patient with 1012 tumor cells is treated with a dose that results in 99.9% cell kill (3-log cell kill), the tumor burden will be reduced from 1012 to 109 cells (or 1 kg to 1 g). If the patient is retreated


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Surgery_Schwartz. with 1012 tumor cells is treated with a dose that results in 99.9% cell kill (3-log cell kill), the tumor burden will be reduced from 1012 to 109 cells (or 1 kg to 1 g). If the patient is retreated with the same drug, which theoretically could result in another 3-log cell kill, the cells would decrease in number from 109 to 106 (1 g to 1 mg) rather than being eliminated totally.Chemotherapeutic agents can be classified according to the phase of the cell cycle during which they are effective. Cell-cycle phase-nonspecific agents (e.g., alkylating agents) have a linear dose-response curve, such that the fraction of cells killed increases with the dose of the drug.145 In contrast, the cell-cycle phase-specific drugs have a plateau with respect to cell killing ability, and cell kill will not increase with further increases in drug dose.Anticancer AgentsAlkylating Agents. Alkylating agents are cell-cycle– nonspecific agents, that is, they are able to kill cells in any phase of the cell


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Surgery_Schwartz. increase with further increases in drug dose.Anticancer AgentsAlkylating Agents. Alkylating agents are cell-cycle– nonspecific agents, that is, they are able to kill cells in any phase of the cell cycle. They act by cross-linking the two strands of the DNA helix or by causing other direct damage to the DNA. The damage to the DNA prevents cell division and, if severe enough, leads to apoptosis. The alkylating agents are composed of three main subgroups: classic alkylators, nitrosoureas, and miscellaneous DNA-binding agents (Table 10-10).Antitumor Antibiotics. Antitumor antibiotics are the prod-ucts of fermentation of microbial organisms. Like the alkylat-ing agents, these agents are cell-cycle nonspecific. Antitumor antibiotics damage the cell by interfering with DNA or RNA synthesis, although the exact mechanism of action may differ by agent.Antimetabolites. Antimetabolites are generally cell-cycle–specific agents that have their major activity during the S phase of the cell cycle and


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Surgery_Schwartz. the exact mechanism of action may differ by agent.Antimetabolites. Antimetabolites are generally cell-cycle–specific agents that have their major activity during the S phase of the cell cycle and have little effect on cells in G0. These drugs are most effective, therefore, in tumors that have a high growth fraction. Antimetabolites are structural analogues of naturally occurring metabolites involved in DNA and RNA synthesis. Therefore, they interfere with normal synthesis of nucleic acids by substituting for purines or pyrimidines in the metabolic path-way to inhibit critical enzymes in nucleic acid synthesis. The antimetabolites include folate antagonists, purine antagonists, and pyrimidine antagonists.Plant Alkaloids. Plant alkaloids are derived from plants such as the periwinkle plant, Vinca rosea (e.g., vincristine, a vinca alkaloid), or the root of American mandrake, Podophyllum peltatum (e.g., etoposide, a podophyllotoxin).145 Vinca alkaloids affect the cell by binding to


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Surgery_Schwartz. Vinca rosea (e.g., vincristine, a vinca alkaloid), or the root of American mandrake, Podophyllum peltatum (e.g., etoposide, a podophyllotoxin).145 Vinca alkaloids affect the cell by binding to tubulin in the S phase. This blocks microtubule polymerization, which results in impaired mitotic spindle formation in the M phase. Taxanes such as paclitaxel, on the other hand, cause excess polymerization and stability of microtubules, which blocks the cell cycle in mitosis. The epi-podophyllotoxins (e.g., etoposide) act to inhibit a DNA enzyme called topoisomerase II by stabilizing the DNA-topoisomerase II complex. This results in an inability to synthesize DNA, and thus the cell cycle is stopped in the G1 phase.145Brunicardi_Ch10_p0305-p0354.indd 34022/02/19 2:14 PM 341ONCOLOGYCHAPTER 10Combination ChemotherapyCombination chemotherapy may provide greater efficacy than single-agent therapy by three mechanisms: (a) it provides maxi-mum cell kill within the range of toxicity for each drug


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Surgery_Schwartz. ChemotherapyCombination chemotherapy may provide greater efficacy than single-agent therapy by three mechanisms: (a) it provides maxi-mum cell kill within the range of toxicity for each drug that can be tolerated by the host, (b) it offers a broader range of coverage of resistant cell lines in a heterogeneous population, and (c) it prevents or delays the emergence of drug-resistant cell lines.145 When combination regimens are devised, drugs known to be active as single agents usually are selected. Drugs with different mechanisms of action are combined to allow for additive or syn-ergistic effects. Combining cell-cycle–specific and cell-cycle–nonspecific agents may be especially advantageous. Drugs with differing dose-limiting toxic effects are combined to allow for each drug to be given at therapeutic doses. Drugs with differ-ent patterns of resistance are combined whenever possible to minimize cross-resistance. The treatment-free interval between cycles is kept to the shortest


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Surgery_Schwartz. at therapeutic doses. Drugs with differ-ent patterns of resistance are combined whenever possible to minimize cross-resistance. The treatment-free interval between cycles is kept to the shortest possible time that will allow for recovery of the most sensitive normal tissue.Drug ToxicityTumors are more susceptible than normal tissue to chemothera-peutic agents, in part because they have a higher proportion of dividing cells. Normal tissues with a high growth fraction, such as the bone marrow, oral and intestinal mucosa and hair follicles are sensitive to chemotherapeutic effects. Therefore, treatment with chemotherapeutic agents can produce toxic effects such as bone marrow suppression, stomatitis, ulceration of the GI tract, and alopecia. Toxic effects usually are graded from 0 to 4 on the basis of World Health Organization standard criteria.146 Significant drug toxicity may necessitate a dosage reduction. A toxic effect requiring a dose modification or change in dose intensity is


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Surgery_Schwartz. the basis of World Health Organization standard criteria.146 Significant drug toxicity may necessitate a dosage reduction. A toxic effect requiring a dose modification or change in dose intensity is referred to as a dose-limiting toxic effect. Because maintaining dose intensity is important to preserve as high a tumor cell kill as possible, several supportive strategies have been developed, such as administration of colony-stimulating factors and erythropoietin to treat poor bone marrow reserve and administration of cytoprotectants such as mesna and amifostine to prevent renal dysfunction. Some toxicities, such as neuropa-thy, are not as easily reversible, and their potential effects on lifestyle must be considered when evaluating a patient prior to the initiation of chemotherapy.Administration of ChemotherapyChemotherapy usually is administered systemically (IV, IM, SC, or PO). Systemic administration treats micrometastases at widespread sites and prevents systemic recurrence.


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Surgery_Schwartz. of ChemotherapyChemotherapy usually is administered systemically (IV, IM, SC, or PO). Systemic administration treats micrometastases at widespread sites and prevents systemic recurrence. However, it increases the drug’s toxicity to a wide range of organs through-out the body. One method to minimize systemic toxicity while enhancing target organ delivery of chemotherapy is regional administration of chemotherapy. Many of these approaches require surgical access, such as intrahepatic delivery of chemo-therapy for hepatic carcinomas or metastatic colorectal cancer using a hepatic artery infusion pump, limb perfusion for extrem-ity melanoma and sarcoma, and intraperitoneal hyperthermic Table 10-10Classification of chemotherapeutic agentsAlkylating agents Classic alkylating agents Busulfan Chlorambucil Cyclophosphamide Ifosfamide Mechlorethamine (nitrogen mustard) Melphalan Mitomycin C Triethylene thiophosphoramide (thiotepa) Nitrosoureas Carmustine (BCNU) Lomustine


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Surgery_Schwartz. (nitrogen mustard) Melphalan Mitomycin C Triethylene thiophosphoramide (thiotepa) Nitrosoureas Carmustine (BCNU) Lomustine (CCNU) Semustine (MeCCNU) Streptozocin Miscellaneous DNA-binding agents Carboplatin Cisplatin Dacarbazine (DTIC) Hexamethylmelamine ProcarbazineAntitumor antibiotics Bleomycin Dactinomycin (actinomycin D) Daunorubicin Doxorubicin Idarubicin Plicamycin (mithramycin)Antimetabolites Folate analogues Methotrexate Purine analogues Azathioprine Mercaptopurine Thioguanine Cladribine (2-chlorodeoxyadenosine) Fludarabine Pentostatin Pyrimidine analogues Capecitabine Cytarabine Floxuridine Gemcitabine Ribonucleotide reductase inhibitors Hydroxyurea Plant alkaloids Vinca alkaloids Vinblastine Vincristine Vindesine Vinorelbine Epipodophyllotoxins Etoposide Teniposide Taxanes Paclitaxel Docetaxel Miscellaneous agents Asparaginase Estramustine MitotaneBrunicardi_Ch10_p0305-p0354.indd


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Surgery_Schwartz. agents Asparaginase Estramustine MitotaneBrunicardi_Ch10_p0305-p0354.indd 34122/02/19 2:14 PM 342BASIC CONSIDERATIONSPART Iperfusion for pseudomyxoma peritonei. Alternately, percutane-ous access may be utilized, such as limb infusion with percuta-neously placed catheters.HORMONAL THERAPYSome tumors, most notably breast and prostate cancers, origi-nate from tissues whose growth is under hormonal control. The first attempts at hormonal therapy were through surgical ablation of the organ producing the hormones involved, such as oophorectomy for breast cancer. Currently, hormonal anti-cancer agents include androgens, antiandrogens, antiestrogens, estrogens, glucocorticoids, gonadotropin inhibitors, progestins, aromatase inhibitors, and somatostatin analogues. Hormones or hormone-like agents can be administered to inhibit tumor growth by blocking or antagonizing the naturally occurring sub-stance, such as with the estrogen antagonist tamoxifen. Other substances that block the


Surgery_Schwartz

Surgery_Schwartz. agents can be administered to inhibit tumor growth by blocking or antagonizing the naturally occurring sub-stance, such as with the estrogen antagonist tamoxifen. Other substances that block the synthesis of the natural hormone can be administered as alternatives. Aromatase inhibitors, for exam-ple, block the peripheral conversion of endogenous androgens to estrogens in postmenopausal women. Hormonal therapy pro-vides a highly tumor-specific form of therapy in sensitive tis-sues. In breast cancer, estrogen and progesterone receptor status is used to predict the success of hormonal therapy. Androgen receptor is also being pursued as a therapeutic target for breast cancer treatment.TARGETED THERAPYOver the past decade, increased understanding of cancer biol-ogy has fostered the emerging field of molecular therapeutics. The basic principle of molecular therapeutics is to exploit the molecular differences between normal cells and cancer cells to develop targeted therapies. Thus, targeted


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Surgery_Schwartz. of molecular therapeutics. The basic principle of molecular therapeutics is to exploit the molecular differences between normal cells and cancer cells to develop targeted therapies. Thus, targeted therapies usually are directed at the processes involved in tumor growth rather than directly targeting the tumor cells. The ideal molecular target would be exclusively expressed in the cancer cells, be the driv-ing force of the proliferation of the cancer cells, and be critical to their survival. A large number of molecular targets are cur-rently being explored, both preclinically and in clinical trials. The major groups of targeted therapy agents are inhibitors of growth factor receptors, inhibitors of intracellular signal trans-duction, cell-cycle inhibitors, apoptosis-based therapies, and anti-angiogenic compounds.Protein kinases have come to the forefront as attrac-tive therapeutic targets with the success of imatinib mesylate (Gleevec) in treating chronic myelogenous leukemia and GI


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Surgery_Schwartz. anti-angiogenic compounds.Protein kinases have come to the forefront as attrac-tive therapeutic targets with the success of imatinib mesylate (Gleevec) in treating chronic myelogenous leukemia and GI stromal tumors, and trastuzumab (Herceptin) in treating breast cancer, and vemurafanib in treating melanoma. These drugs work by targeting bcr-abland c-kit (imatinib) and HER2 and BRAF, respectively. For example, a phase 3 randomized trial demonstrated that, compared with dacarbazine, standard of care chemotherapy option for patients with metastatic melanoma with a V600E BRAF mutation, the BRAF inhibitor vemurafenib led to significantly higher response rates (48% vs. 5%).147 At 6 months, overall survival was 84% (95% CI, 78–89) in the vemurafenib group and 64% (95% CI, 56–73) in the dacarba-zine group. The hazard ratio for tumor progression in the vemu-rafenib group was 0.26 (95% CI, 0.20–0.33; P<0.001). The estimated median progression-free survival was 5.3 months in the vemurafenib


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Surgery_Schwartz. group. The hazard ratio for tumor progression in the vemu-rafenib group was 0.26 (95% CI, 0.20–0.33; P<0.001). The estimated median progression-free survival was 5.3 months in the vemurafenib group and 1.6 months in the dacarbazine group. This trial highlights the fact that in at least some tumor types targeted therapies that inhibit a genomic alteration that is a driver is likely to be more effective than an unselected thera-peutic option.Sequencing of the human genome has revealed approxi-mately 500 protein kinases. Several tyrosine kinases have been shown to have oncogenic properties and many other protein kinases have been shown to be aberrantly activated in cancer cells.93 Therefore, protein kinases involved in these aberrantly activated pathways are being aggressively pursued in molecular therapeutics. Potential targets like HER2 can be targeted via dif-ferent strategies, such as transcriptional downregulation, targeting of mRNA, RNA inhibition, antisense strategies, direct


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Surgery_Schwartz. molecular therapeutics. Potential targets like HER2 can be targeted via dif-ferent strategies, such as transcriptional downregulation, targeting of mRNA, RNA inhibition, antisense strategies, direct inhibition of protein activity, and induction of immunity against the protein. Most of the compounds in development are monoclonal antibod-ies like trastuzumab or small-molecule kinase inhibitors like ima-tinib or vemurafanib. Some other agents, such as sunitinib, are multitargeted kinase inhibitors. Selected FDA-approved targeted therapies are listed in Table 10-11. Many of the promising path-ways, such as the PI3K/Akt/mTOR pathway, are being pursued as therapeutic targets with several drugs in development, targeting different aspects of the pathway (Fig. 10-15).148Development of molecularly targeted agents for clinical use presents several unique challenges. Once an appropriate compound is identified and confirmed to have activity in pre-clinical testing, predictive markers for activity


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Surgery_Schwartz. targeted agents for clinical use presents several unique challenges. Once an appropriate compound is identified and confirmed to have activity in pre-clinical testing, predictive markers for activity in the preclinical setting must be defined. Expression of a target may not be suf-ficient to predict response because the pathway of interest may not be activated or critical to the cancer’s survival. Although in traditional phase 1 trials the goal is to identify the maximum tol-erated dosage, the maximum dosage of biologic agents may not be necessary to achieve the desired biologic effect. Thus, assays to verify modulation of the target need to be developed to deter-mine at what dosage the desired effect is achieved. When phases 2 and 3 clinical trials are initiated, biomarker modulation studies should be integrated into the trial to determine whether clinical response correlates with target modulation and thus to identify additional parameters that impact response. Rational dose


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Surgery_Schwartz. studies should be integrated into the trial to determine whether clinical response correlates with target modulation and thus to identify additional parameters that impact response. Rational dose selec-tion and limitation of study populations to patients most likely to respond to the molecular therapy as determined by predictive markers are most likely to lead to successful clinical transla-tion of a product. Finally, most biologic agents are cytostatic, not cytotoxic. Thus, rational combination therapy mixing new biologic agents with either established chemotherapeutic agents that have synergy or with other biologic agents is more likely to lead to cancer cures.IMMUNOTHERAPYThe aim of immunotherapy is to induce or potentiate inherent antitumor immunity that can destroy cancer cells. Central to the process of antitumor immunity is the ability of the immune sys-tem to recognize tumor-associated antigens present on human cancers and to direct cytotoxic responses through humoral or


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Surgery_Schwartz. Central to the process of antitumor immunity is the ability of the immune sys-tem to recognize tumor-associated antigens present on human cancers and to direct cytotoxic responses through humoral or T-cell–mediated immunity. Overall, T-cell–mediated immunity appears to have the greater potential of the two for eradicating tumor cells. T cells recognize antigens on the surfaces of target cells as small peptides presented by class I and class II MHC molecules.Several antitumor strategies are under investigation. One approach to antitumor immunity is nonspecific immunotherapy, which stimulates the immune system as a whole through admin-istration of bacterial agents or their products, such as bacille Brunicardi_Ch10_p0305-p0354.indd 34222/02/19 2:14 PM 343ONCOLOGYCHAPTER 10Table 10-11Selected FDA-approved targeted therapiesGENERIC NAMETRADE NAMETARGETFDA-APPROVED INDICATIONSAdo-trastuzumab emtansineKadcylaHER2Breast cancerAxitinibInlytaKIT, FDGFRβ,


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Surgery_Schwartz. 343ONCOLOGYCHAPTER 10Table 10-11Selected FDA-approved targeted therapiesGENERIC NAMETRADE NAMETARGETFDA-APPROVED INDICATIONSAdo-trastuzumab emtansineKadcylaHER2Breast cancerAxitinibInlytaKIT, FDGFRβ, VEGFR1/2/3RCCBevacizumabAvastinVEGFColorectal cancer, lung cancer, glioblastoma, NSCLCRCCBortezomibVelcadeProteasomeMyelomaBosutinibBosulifABLCML (Philadelphia chromosome+)CabozantinibCometriqFLT3, KIT, MET, RET, VEGR2Medullary thyroid cancerCetuximabErbituxEGFRColorectal cancer (KRAS wild-type)Squamous cell cancer of the head and neckCrizotinibXalkoriALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitorNon-small cell lung carcinomaDabrafenibTafinolarBRAF V600E mutationMelanomaDasatinibSprycelABL, src family, KIT, EPHA2, PDGFR-βCMLErlotinibTarcevaEGFRNSCLC,Pancreatic cancerEverolimusAfinitormTORPNET,RCC,Breast cancer.Nonresectable subependymal giant cell astrocytoma associated with tuberous sclerosisGefitinibIressaEGFRNSCLC with known/previous benefit from gefitinib


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Surgery_Schwartz. cancer.Nonresectable subependymal giant cell astrocytoma associated with tuberous sclerosisGefitinibIressaEGFRNSCLC with known/previous benefit from gefitinib (limited approval)IbrutinibImbruvicaBruton’s Tyrosine KinaseChronic lymphocytic leukemiaImatinibGleevecKIT, ABL, PDGFRCML,GIST (KIT+),Dermatofibrosarcoma protuberansLapatinibTykerbEGFR and HER2Breast cancer (HER2+)NilotinibTasignaABLCML (Philadelphia chromosome+)PanitumumabVectibixEGFRColorectal cancer (KRAS wild type)PazopanibVotrientVEGFR, PDGFR, KITRCCPertuzumabPerjetaHER2Breast cancer (HER+)PonatinibIclusigABL, FGFR1-3, FLT3, VEGFR2CML, ALL (Philadelphia chromosome+)RegorafenibStivargaKIT, PDGFRβ, RAF, RET, VEGFR1/2/3Colorectal cancer, GISTSorafenibNexavarVEGFR, PDGFR, KIT, RAFHCCRCCSunitinibSutentVEGFR PDGFR KIT, Flt-3, RETGIST,RCC,PNETTemsirolimusToriselmTORRCCTrastuzumabHerceptinHER2Breast cancer (HER2+)Gastric cancer (HER2+)VandetanibCaprelsaEGFR, RET, VEGFR2Medullary thyroid cancerVemurafenibZelborafBRAFMelanoma (BRAF


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Surgery_Schwartz. cancer (HER2+)Gastric cancer (HER2+)VandetanibCaprelsaEGFR, RET, VEGFR2Medullary thyroid cancerVemurafenibZelborafBRAFMelanoma (BRAF V600E mutant)VorinostatZolinzaHistone deacetylasesCutaneous T-cell lymphomaCML = chronic myelogenous leukemia; EGFR = epidermal growth factor receptor; EPHA2 = ephrin A2; FDA = Food and Drug Administration; Flt-3 = fms-related tyrosine kinase 3; GIST = GI stromal tumor; HCC = hepatocellular cancer, HER2 = human epidermal growth factor receptor 2; mTOR = mammalian target of rapamycin; NSCLC = non-small cell lung cancer, PDGF = platelet-derived growth factor; PDGFR = platelet-derived growth factor receptor; PNET = pancreatic neuroendocrine tumor; RCC = renal cell carcinoma; RET = rearranged during transfection; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.Brunicardi_Ch10_p0305-p0354.indd 34322/02/19 2:14 PM 344BASIC


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Surgery_Schwartz. RET = rearranged during transfection; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.Brunicardi_Ch10_p0305-p0354.indd 34322/02/19 2:14 PM 344BASIC CONSIDERATIONSPART IGlucoseAminoAcidsIRS1PI3KPDK1PIP2PIP3ATPAMPKActivatorsMAP4K3AMPKRapalogsFKBP12AktTSC2TSC1PI3KInhibitorsAktInhibitorsPTENmTORC2ProctorRICTORmTORmLST8SIN1GSK3FOXOBADASK1GDPGTPRhebRhebmTORC1PRAS40mTORRAPTORmLST84EBP1S6KeIF4EPDCD4eEF3KS6eIF4BmTORKinase InhibitorsDual Pl3K/mTORKinase InhibitorsPPFigure 10-15. Targeting PI3K/Akt/mTOR signaling. This central pathway is altered in many tumor types and is being pursued as a therapeu-tic target through development of numerous pathway inhibitors targeting PI3K, Akt, mTOR, and dual inhibitors as well as several upstream and downstream regulators. (Reproduced with permission from McAuliffe PF, Meric-Bernstam F, Mills GB, et al: Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis, Clin Breast


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Surgery_Schwartz. regulators. (Reproduced with permission from McAuliffe PF, Meric-Bernstam F, Mills GB, et al: Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis, Clin Breast Cancer. 2010 Nov;10 Suppl 3:S59-S65.)Calmette-Guérin. This approach is thought to activate the effec-tors of antitumor response such as natural killer cells and macro-phages, as well as polyclonal lymphocytes.149 Another approach to nonspecific immunotherapy is systemic administration of cytokines such as interleukin-2, interferon-α, and interferon-γ. Interleukin-2 stimulates proliferation of cytotoxic T lympho-cytes and maturation of effectors such as natural killer cells into lymphokine-activated killer cells. Interferons, on the other hand, exert antitumor effects directly by inhibiting tumor cell prolif-eration and indirectly by activating host immune cells, includ-ing macrophages, dendritic cells, and natural killer cells, and by enhancing human leukocyte antigen (HLA) class I expression


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Surgery_Schwartz. prolif-eration and indirectly by activating host immune cells, includ-ing macrophages, dendritic cells, and natural killer cells, and by enhancing human leukocyte antigen (HLA) class I expression on tumor cells.149Antigen-specific immunotherapy can be active, as is achieved through antitumor vaccines, or passive. In pas-sive immunotherapy, antibodies to specific tumor-associated antigens can be produced by hybridoma technique and then administered to patients whose cancers express these antigens, inducing antibody-dependent cellular cytotoxicity.The early attempts at vaccination against cancers used allo-geneic cultured cancer cells, including irradiated cells, cell lysates, and shed antigens isolated from tissue culture supernatants. An alternate strategy is the use of autologous tumor vaccines. These have the potential advantage of being more likely to contain anti-gens relevant for the individual patient but have the disadvantage of requiring a large amount of tumor tissue for


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Surgery_Schwartz. vaccines. These have the potential advantage of being more likely to contain anti-gens relevant for the individual patient but have the disadvantage of requiring a large amount of tumor tissue for preparation, which restricts eligibility of patients for this modality. Strategies to enhance immunogenicity of tumor cells include the introduction of genes encoding cytokines or chemokines, and fusion of the tumor cells to allogeneic MHC class II-bearing cells.150 Alternatively, heat shock proteins derived from a patient’s tumor can be used because heat shock protein peptide complexes are readily taken up by dendritic cells for presentation to T cells.150Identification of tumor antigens has made it possible to perform antigen-specific vaccination. For example, in the case of melanoma, several antigens have been identified that can be recognized by both CD8+ cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100, MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.151 Antigens tested


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Surgery_Schwartz. have been identified that can be recognized by both CD8+ cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100, MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.151 Antigens tested usually are over-expressed or mutated in cancer cells. Tissue specificity and immunogenicity are important determinants in choosing an appropriate target. Vaccines directed at defined tumor antigens aim to combine selected tumor antigens and appropriate routes for delivering these antigens to the immune system to optimize antitumor immunity.152 Several different vaccination approaches have been studied, including tumor cell-based vaccines, pep-tide-based vaccines, recombinant virus-based vaccines, DNA-based vaccines, and dendritic cell vaccines.In adoptive transfer, antigen-specific effector cells (i.e., cytotoxic T lymphocytes) or antigen-nonspecific effector cells Brunicardi_Ch10_p0305-p0354.indd 34422/02/19 2:14 PM 345ONCOLOGYCHAPTER 10(i.e., natural killer cells) can be transferred to a


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Surgery_Schwartz. cytotoxic T lymphocytes) or antigen-nonspecific effector cells Brunicardi_Ch10_p0305-p0354.indd 34422/02/19 2:14 PM 345ONCOLOGYCHAPTER 10(i.e., natural killer cells) can be transferred to a patient. These effector cells can be obtained from the tumor (tumor-infiltrating lymphocytes) or the peripheral blood.Clinical experience in patients with metastatic disease has shown objective tumor responses to a variety of immunothera-peutic modalities. It is thought, however, that the immune sys-tem is overwhelmed with the tumor burden in this setting, and thus adjuvant therapy may be preferable, with immunotherapy reserved for decreasing tumor recurrences. Trials to date sug-gest that immunotherapy is a potentially useful approach in the adjuvant setting. How to best select patients for this approach and how to integrate immunotherapy with other therapies are not well understood for most cancer types.Tolerance to self-antigens expressed in tumors is a limi-tation in generating antitumor


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Surgery_Schwartz. approach and how to integrate immunotherapy with other therapies are not well understood for most cancer types.Tolerance to self-antigens expressed in tumors is a limi-tation in generating antitumor responses.153 Recently, several pathways that modulate tolerance and approaches to manipulat-ing these pathways have been identified: pathways that activate professional antigen-presenting cells such as Toll-like receptors, growth factors, and the CD40 pathway; cytokines to enhance immunoactivation; and pathways that inhibit T-cell inhibitory signals or block the activity of immune-suppressive regulatory T cells (Tregs).153A new and highly effective strategy to activate the T-cell arm of anticancer immunity is the use of monoclonal antibodies to block inhibitory signaling pathways employed by the immune system to prevent T cell over activation and the development of auto-immunity. CTLA-4 and PD-1 are two important inhibitory T-cell checkpoints that can be blocked with neutralizing


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Surgery_Schwartz. by the immune system to prevent T cell over activation and the development of auto-immunity. CTLA-4 and PD-1 are two important inhibitory T-cell checkpoints that can be blocked with neutralizing antibod-ies and result in an effective antigen-specific anti-tumor response.CTLA-4 is an inhibitory receptor expressed by activated T cells that belongs to the immunoglobulin superfamily. CTLA4 is related to the T-cell costimulatory receptor, CD28, and both are bound by CD80 and CD86 (also known as B7-1 and B7-2) which are expressed on antigen-presenting cells. CTLA-4 con-veys an inhibitory signal to the T cell, whereas engagement of CD28 with ligand sends a stimulatory signal. CTLA-4 is able to outcompete CD28 for CD80 and CD86 ligands and therefore is able to dominate immune signaling in the setting of antigen recognition. CTLA-4 is also expressed by regulatory T cells, which contributes to their ability to inhibit T-cell function.154 Programmed death ligand 1 (PD-L1) is a 40 kDa type 1


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Surgery_Schwartz. setting of antigen recognition. CTLA-4 is also expressed by regulatory T cells, which contributes to their ability to inhibit T-cell function.154 Programmed death ligand 1 (PD-L1) is a 40 kDa type 1 trans-membrane protein that is thought to play an important role in suppressing the immune system. PD-L1 binds to its receptor, PD-1, which is found on activated T cells. The PD1/PDL1 path-way is increasingly recognized as a key contributor to tumor-mediated immune suppression. The interaction between PD-1 leads to reduced proliferation, altered production of stimulatory cytokines, and reduced T-cell lytic activity. Thus, both anti-PD1 and anti-PD-L1 strategies are actively being pursued for cancer therapy.155The FDA-approved CTLA-4 blocking antibody ipi-limumab has shown efficacy in patients with metastatic mela-noma.156,157 Nivolumab and pembrolizumab are antibodies that target PD-1, whereas blockade of PD-L1 is accomplished with agents such as atezolizumab.158 Cancers for which


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Surgery_Schwartz. with metastatic mela-noma.156,157 Nivolumab and pembrolizumab are antibodies that target PD-1, whereas blockade of PD-L1 is accomplished with agents such as atezolizumab.158 Cancers for which checkpoint inhibitors have found utility include melanoma, renal cell car-cinoma, bladder carcinoma, squamous cell carcinoma of the head and neck, and carcinoma of the lung. These agents pro-duce durable shrinkage of advanced disease in 20% to 40% of patients, and combination strategies that employ checkpoint inhibitors with cytokines, vaccines, cellular therapies, and other targeted agents are under active investigation.GENE THERAPYGene therapy is being pursued as a possible approach to modify-ing the genetic program of cancer cells as well as treating meta-bolic diseases. The field of cancer gene therapy uses a variety of strategies, ranging from replacement of mutated or deleted tumor-suppressor genes to enhancement of immune responses to cancer cells.159 Indeed, in preclinical models,


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Surgery_Schwartz. gene therapy uses a variety of strategies, ranging from replacement of mutated or deleted tumor-suppressor genes to enhancement of immune responses to cancer cells.159 Indeed, in preclinical models, approaches such as replacement of tumor-suppressor genes leads to growth arrest or apoptosis. However, the translation of these findings into clinically useful tools presents special challenges.One of the main difficulties in getting gene therapy tech-nology from the laboratory to the clinic is the lack of a perfect delivery system. An ideal vector would be administered through a noninvasive route and would transduce all of the cancer cells and none of the normal cells. Furthermore, the ideal vector would have a high degree of activity, that is, it would produce an adequate amount of the desired gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect, cancer


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Surgery_Schwartz. gene product to achieve target cell kill. Unlike genetic diseases in which delivery of the gene of interest into only a portion of the cells may be sufficient to achieve clinical effect, cancer requires either that the therapeutic gene be delivered to all of the cancer cells or that a therapeutic effect be achieved on nontransfected cells as well as transfected cells through a bystander effect. However, treatment of a meta-bolic disease requires prolonged gene expression, whereas tran-sient expression may be sufficient for cancer therapy.Several vector systems are under study for gene ther-apy; however, none is considered ideal. One of the promising approaches to increase the number of tumor cells transduced is the use of a replication-competent virus like a parvovirus, human reovirus, or vesicular stomatitis virus that selectively replicates within malignant cells and lyses them more efficiently than it does normal cells. Another strategy for killing tumor cells with suicide genes


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Surgery_Schwartz. or vesicular stomatitis virus that selectively replicates within malignant cells and lyses them more efficiently than it does normal cells. Another strategy for killing tumor cells with suicide genes exploits tumor-specific expression elements, such as the MUC-1, PSA, CEA, or VEGF promoters, that can be used to achieve tissue-specific or tumor-specific expression of the desired gene.Because the goal in cancer therapy is to eradicate systemic disease, optimization of delivery systems is the key to success for gene therapy strategies. Gene therapy is likely to be most successful when combined with standard therapies, but it will provide the advantage of customization of therapy based on the molecular status of an individual’s tumor.MECHANISMS OF INTRINSIC AND ACQUIRED DRUG RESISTANCESeveral tumor factors influence tumor cell kill. Tumors are het-erogeneous, and, according to the Goldie-Coldman hypothesis, tumor cells are genetically unstable and tend to mutate to form different cell


Surgery_Schwartz

Surgery_Schwartz. tumor factors influence tumor cell kill. Tumors are het-erogeneous, and, according to the Goldie-Coldman hypothesis, tumor cells are genetically unstable and tend to mutate to form different cell clones. This has been used as an argument for giv-ing chemotherapy as soon as possible in treatment to reduce the likelihood that resistant clones will emerge. Tumor size is another important variable. Larger tumors may have greater het-erogeneity, although heterogeneity may also differ based on bio-logic subtype. Tumor growth may be described by a Gompertz curve, named after Benjamin Gompertz, which has the form of a sigmoid function. Gompertzian models have thus been used to describe changes in tumor cell numbers over time where growth is slowest at the start and end of a time period, but are quite rapid in the middle. Theoretically, for any tumor, there is a period of time where cancer cells grow rapidly (exponential growth Brunicardi_Ch10_p0305-p0354.indd 34522/02/19 2:14 PM 346BASIC


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Surgery_Schwartz. rapid in the middle. Theoretically, for any tumor, there is a period of time where cancer cells grow rapidly (exponential growth Brunicardi_Ch10_p0305-p0354.indd 34522/02/19 2:14 PM 346BASIC CONSIDERATIONSPART Iphase), and then the growth slows down owing to hypoxia and decreased nutrient supply. Because of the larger proportion of cells dividing, smaller tumors may be more chemosensitive.Multiple mechanisms of systemic therapy resistance have been identified (Table 10-12).160 Cells may exhibit reduced sen-sitivity to drugs by virtue of their cell-cycle distribution. For example, cells in the G0 phase are resistant to drugs active in the S phase. This phenomenon of “kinetic resistance” usually is temporary, and if the drug level can be maintained, all cells will eventually pass through the vulnerable phase of the cell cycle.145 Alternatively, tumor cells may exhibit “pharmacologic resistance,” in which the failure to kill cells is due to insuffi-cient drug concentration. This may


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Surgery_Schwartz. the vulnerable phase of the cell cycle.145 Alternatively, tumor cells may exhibit “pharmacologic resistance,” in which the failure to kill cells is due to insuffi-cient drug concentration. This may occur when tumor cells are located in sites where effective drug concentrations are difficult to achieve (such as the central nervous system) or can be due to enhanced metabolism of the drug after its administration, decreased conversion of the drug to its active form, or decrease in the intracellular drug level caused by increased removal of the drug from the cell associated with enhanced expression of P-glycoprotein (Pgp). Pgp is the protein product of multidrug resis-tance gene 1 and extrudes cytotoxic drugs at the expense of ATP hydrolysis. Other mechanisms of resistance include decreased affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect. For drug-sensitive cancers, another factor limiting optimal killing is


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Surgery_Schwartz. affinity of the target enzyme for the drug, altered amount of the target enzyme, or enhanced repair of the drug-induced defect. For drug-sensitive cancers, another factor limiting optimal killing is inadequate dosing. Relative dose intensity (RDI) is defined as the actual amount of a particular chemotherapy given over a specific time in relation to what was ordered and is usually expressed as a percentage. An RDI below 80% is considered suboptimal and may impact survival in the adjuvant setting.145Cancer cells demonstrate adaptive responses to targeted therapy, like activating alternate pathways of survival; thus, these alterations may blunt therapeutic efficacy. Cancer cells also acquire resistance upon prolonged treatment with targeted therapy through a variety of mechanisms. One mechanism is through the loss of the target. For example, this was observed in a study of patients with HER2-positive breast cancer patients who were treated with neoadjuvant trastuzumab-based