Antitumor Therapies


Cancer Staging

  1. Clinical Importance
    • staging assists in selection of therapy, estimation of prognosis, evaluation of treatment and comparison of results, and exchange of information among treatment centers
    • staging incorporates tumor size (T), nodal status (N), and distant metastasis (M)
    • some tumors (sarcomas) include grade (G)

    1. Clinical Staging (cTNM)
      • based on information obtained before treatment
      • tumor size is estimated from physical exam or imaging studies
      • nodal status estimated from physical exam or imaging studies (ultrasound, CT scan)
      • metastases are evaluated by imaging studies (CT, PET scan, bone scan)

    2. Pathologic Staging (pTNM)
      • includes clinical information and information obtained from the resected specimen and regional nodes
      • T1 – T4 indicates increasing tumor size, wall invasion, and involvement of adjacent structures
      • N0 = no nodal metastases; N1 - N3 indicates progressive involvement of nodes
      • M0 = no distant metastases; M1 = distant metastases

Surgery

  1. Management of Primary Tumors
    1. Curative Surgery
      • presupposes that the tumor is confined to the organ of origin, or the organ and regional lymph nodes
      • patients at high risk for metastatic disease should have a staging workup with appropriate imaging studies, with the goal being avoidance of an incurable operation

      1. Margins
        • goal of oncologic surgery is to obtain microscopically negative margins at the first operation
        • inking of the margins, orientation of the specimen by the surgeon, and immediate frozen section evaluation of margins can assist in achieving negative margins
        • adjuvant radiation and chemotherapy cannot substitute for adequate surgery
        • optimal macroscopic and microscopic margin amounts are unknown for most tumor types

    2. Palliative Surgery
      • goal is to alleviate pain, infection, bleeding, obstruction without curative intent
      • large operations may be justified if there is no effective non-surgical palliation

  2. Management of Regional Lymph nodes
    • since most solid tumors can metastasize through the lymphatics, many oncologic operations remove the primary tumor and draining lymphatics en bloc
    • node dissections minimize the risk of local recurrence (total mesorectal excision in rectal cancer)
    • lymphadenectomy is important for staging and prognosis, and helps guide the use of adjuvant therapy
    • for colon cancer and stomach cancer, retrieval of a large number of nodes is associated with improved survival

    1. Sentinel Node Biopsy (SLN)
      • standard of care in breast cancer and melanoma for clinically negative nodes
      • defined as the first node to receive drainage from the tumor site
      • the SLN is the node most likely to contain metastases, if metastases are present in that nodal basin
      • goal is to identify the presence or absence of metastases in the least invasive way

      1. Lymphatic Mapping
        • nodal drainage pattern is determined preoperatively by lymphoscintigraphy
        • intraoperatively, use of blue dye and a hand-held gamma probe are used to find the SLNs
        • any ‘blue’ node is a SLN
        • any node with a gamma count > 10x background is a SLN
        • intraoperative detection of the SLN should approach 100% using both the blue dye and gamma probe techniques

        1. False Negative SLN Biopsy
          • defined as the development of regional node metastases in a patient in whom the SLN was negative
          • may be due to surgical error (removing a non SLN), pathological error, or biologic variation (metastases bypassing the SLN in favor of a second echelon node)
          • reported rates vary between 0% and 11%

      2. Pathologic Evaluation
        • SLN biopsy allows for careful pathologic review of 1 - 2 nodes, which increases the accuracy of nodal staging
        • SLN is serially sectioned (bread loafed) and first examined by H + E staining
        • if H + E stains are negative, then immunohistochemistry stains are done (S-100, HMB for melanoma; cytokeratin staining for breast cancer)
        • ultrastaging by molecular techniques (RT-PCR) are investigational

      3. Management of a Positive SLN
        1. Breast Cancer
          • until recently, a positive SLN biopsy mandated a completion axillary node dissection
          • a recent ACS multicenter trial demonstrated that in patients with 1 or 2 positive SLNs treated with breast conservation and systemic therapy, omission of axillary dissection did not result in a worse outcome

        2. Melanoma
          • trials are underway to determine the role of completion node dissection
          • currently, standard management is completion node dissection

  3. Management of Distant Metastases
    • on occasion, patients with metastases to the liver, lung, or brain can be resected for cure
    • some tumor types are more amenable to surgical resection than others (colon vs pancreas)
    • growth rate of the tumor is also important: patients with a longer disease-free interval have a higher cure rate after metastasectomy than patients with shorter disease-free intervals
    • some surgeons will monitor a potentially resectable patient for several months to see if additional metastases develop
    • surgical goal is resection of the metastases with negative margins
    • tumor ablation with cryotherapy or radiofrequency ablation is an alternative if tumor location or inadequate hepatic reserve precludes a safe, negative margin resection

Radiation

  1. Mechanism of Action
    • XRT damages cells by transferring energy and causing ionization of the atoms
    • ionization results in double strand DNA breaks
    • ionizing radiation is produced by a linear accelerator
    • cell viability is determined by the ability of DNA to repair itself
    • malignant cells often lack the ability to repair DNA breaks and mutations
    • biologic effect of XRT is lessened by hypoxia
    • cells in the G2 or M phase are most sensitive to radiation

    1. Fractionation
      • total radiation dose is given in divided doses over 3 – 7 weeks
      • allows some time for damaged nonmalignant tissues to repair themselves
      • also allows time for cells in G1 and S phases to progress to the more radiosensitive G2 and M phases

  2. XRT Delivery
    1. Simulation
      • defines the target and any dose-limiting adjacent organs
      • simulation is the process of evaluating which beam path will deliver a homogenous dose to the target and the smallest possible dose to surrounding tissues
      • once the best distribution path has been determined, immobilization devices or skin markings are used to ensure that daily treatments are given in the same way

    2. Post Op XRT (Adjuvant)
      • usually given 3 – 6 weeks after surgery to allow for wound healing
      • allows dose modification based on margin status and histology
      • surgical contamination of tissue planes may result in a larger volume of normal tissue requiring irradiation
      • post op tumor bed may be relatively hypoxic and more radioresistant
      • post op adhesions may increase the risk of small bowel radiation injury in abdominal or pelvic XRT
      • usually administered as external beam therapy, but brachytherapy has value in breast cancer

      1. Brachytherapy
        • radiation source is in direct contact with the tissue requiring treatment
        • allows delivery of high radiation doses to the tumor bed while reducing to dose to the surrounding normal tissues
        • brachytherapy catheters (MammoSite) are placed during breast cancer surgery or percutaneously soon after surgery
        • a major advantage of the MammoSite catheter is the short treatment duration (3 days)

    3. Pre-Op XRT (Neoadjuvant)
      • has several advantages: may minimize seeding during surgery, allows for smaller treatment fields since the operative field has not been contaminated
      • may also make inoperable tumors operable, or allow for more conservative surgical treatment
      • disadvantages include poorer post op wound healing, and inability to give additional doses in cases of close or positive margins
      • often combined with chemotherapy

    4. Palliative XRT
      • valuable in patients with symptomatic bone or brain metastases
      • may also be used prophylactically in lytic metastases in weight-bearing bones such as the femur, tibia, humerus

  3. Side Effects
    • increasing XRT dose causes increased tumor control as well as increased damage to normal tissues (therapeutic ratio)
    • fractionation allows normal cell healing before the next dose, but requires an increased total dose of radiation to achieve the same biologic effect
    • side effects may be acute (swelling, tissue irritation) or chronic (tissue fibrosis)
    • a small increase in secondary malignancies is attributable to XRT

Chemotherapy

  1. Biologic Basis
    • destroys cells by first-order kinetics: each dose kills a constant percentage of cells, not a constant number of cells
    • drugs target rapidly dividing cells
    • drugs are either cell-cycle specific or cell-cycle nonspecific

    1. Alkylating Agents
      • cell-cycle nonspecific
      • act by cross-linking DNA or damaging DNA, preventing cell division
      • cyclophosphamide, cisplatin

    2. Antitumor Antibiotics
      • cell-cycle nonspecific
      • interfere with DNA, RNA synthesis
      • doxorubicin, bleomycin

    3. Antimetabolites
      • active against cells in S phase
      • interfere with normal synthesis of DNA, RNA by substituting for purines or pyrimidines
      • methotrexate, azathioprine

    4. Plant Alkaloids
      • block the cell cycle in mitosis by impairing mitotic spindle formation
      • vincristine, paclitaxel

  2. Combination Chemotherapy
    • drugs with different mechanisms of action are combined to allow for additive or synergistic effects
    • prevents or delays the emergence of drug-resistant cell lines
    • offers a broader range of coverage of resistant cell lines in a heterogenous population
    • as tumor size increases, so does the likelihood of drug resistance (Goldie-Coldman hypothesis)
    • treatment-free interval is kept as short as possible to allow for recovery of the most sensitive normal tissue

  3. Drug Toxicity
    • common side effects include bone marrow suppression, stomatitis or enteritis, and hair loss
    • significant toxicities will require dose reduction, but this will greatly limit the antitumor effects (dose reduction of 20% can be associated with a 50% decrease in cure rate)
    • colony-stimulating factors and erythropoietin will help to keep blood counts normal

  4. Clinical Uses
    1. Adjuvant Chemotherapy (Post op)
      • used in patients at high risk for metastases, but with no evidence of distant disease
      • goal is to eliminate micrometastatic disease

    2. Neoadjuvant Chemotherapy (Pre-op)
      • tumor regression may make inoperable tumors operable
      • may allow for more conservative surgery (breast conservation, e.g.)
      • allows for treatment of micrometastases without the delay of postop recovery
      • allows for assessment of clinical and pathological response to treatment – patients who have an inadequate response may be offered alternative therapies, if available
      • postop wound complications are not higher in patients treated with neoadjuvant chemo
      • can complicate tumor localization, margin analysis, SLN mapping, pathologic staging

    3. Routes of Administration
      • systemic administration treats micrometastases all over the body, but also causes systemic toxicity
      • regional chemotherapy allows targeted organ delivery and minimizes systemic complications
      • uses of regional chemotherapy include hepatic artery infusion catheters for colorectal metastases, limb perfusion for extremity melanoma or sarcoma, intraperitoneal hyperthermic perfusion for pseudomyxoma peritonei

Hormonal Therapy

  1. Biologic Basis
    • growth of many tumors is under hormonal control
    • initial therapy for hormonal control was surgery (oophorectomy, orchiectomy)

  2. Drugs
    • tumor growth can be inhibited by blocking or antagonizing the hormone causing growth (tamoxifen)
    • some drugs block the synthesis of the hormone (aromatase inhibitors block the conversion of androgens to estrogen in postmenopausal women)
    • in breast cancer, presence or absence of estrogen and progesterone receptors is used to guide the use of hormonal therapy

Immunotherapy

  1. Tumor Antigens
    • cancer cells can overexpress or abnormally express a variety of normal cellular proteins that are potentially recognizable by T cells
    • an abnormal gene product (oncogene) could also serve as a good antigen candidate

    Tumor antigens
  2. Tumor Defense Mechanisms
    • clinically evident cancers have acquired many defense mechanisms against the immune system
    • some tumors lack MHC molecules
    • tumors may produce immunosuppressive substances (TGF-β)
    • antigen overload: antigens shed from tumor surfaces may bind to circulating antibody and effectors cells, preventing them from interacting with tumor cells
    • antigenic modulation: nonreactive clones of tumor cells replace those destroyed by the immune system
    • immune system naturally downregulates itself as a normal protective measure
    • induction of tolerance: nonreactivity to antigens may result from high doses of antigen and persistence of antigen

    Immune Evasion by Tumors
  3. Evidence for an Immune Response Against Tumors
    • frequency of malignant disease is much higher in immunosuppressed patients (AIDS, transplant patients)
    • spontaneous regression of metastatic melanoma and renal cell carcinoma is well-described
    • 3% - 5% of melanoma patients present with nodal metastases with an unknown primary
    • tumor infiltration with lymphocytes in melanoma may be associated with an improved prognosis
    • in a small subset of patients, immune therapies can cure patients of widely metastatic melanoma and renal cell carcinoma

  4. Clinical Immunotherapy
    1. Nonspecific Immunotherapy
      • activates NK cells, macrophages, and lymphocytes
      • IL-2 and IFN-α have some efficacy in metastatic melanoma and renal cell carcinoma

      1. IL-2
        • promotes T cell division, B cell growth, and activation of NK cells and monocytes
        • has significant toxicities resembling septic shock
        • overall response rate is only 15%
        • however, a complete and durable tumor response is seen in 4% to 7% of patients
        • may be combined with chemotherapeutic agents or other biologic agents

      2. IFN-α
        • antitumor effects include increased expression of MHC class I and class II molecules, activation of NK cells and macrophages, stimulation of B cells
        • approved for use as adjuvant treatment in node positive melanoma – there is a delayed time to recurrence, but no overall survival benefit

    2. Vaccines
      • earliest strategy was to use allogeneic cultured cancer cells
      • autologous tumor vaccines have the advantage of containing antigens relevant to the individual patient, but they require a large amount of tumor tissue for preparation
      • vaccines are usually administered along with nonspecific immune-activating agents
      • identification of tumor rejection antigens has made it possible to make antigen-specific vaccinations
      • there are multiple studies and clinical trials underway to evaluate different vaccine approaches
      • overall, tumor vaccination in patients with metastatic disease has had disappointing results (response rate of 3.6%)
      • most human cancer antigens are normal, nonmutated self-proteins that are well tolerated by the immune system

      1. Why Doesn’t Tumor Vaccination work
        • most human cancer antigens are normal, nonmutated self-proteins that the immune system does not react strongly to
        • also, the large tumor burden overwhelms the immune response

    3. Immunomodulatory Pathways (Checkpoint Inhibitors
      • CTLA-4 and PD-1 are inhibitory receptors on T-cells that serve to downregulate the immune response (prevents autoimmunity)
      • these mechanisms are active in the tumor microenvironment, because of its chronic antigenic stimulation
      • some patients treated with a CTLA-4 blocking antibody (ipilimumab) have had durable complete regression of their metastases
      • side effects include autoimmune problems: colitis, dermatitis

      Checkpoint Inhibitors
    4. T-Cell Adoptive Therapy
      • T cells are the main effectors of tumor rejection
      • fundamental concept is to isolate, expand, and readminister tumor-reactive T cells
      • resected metastatic melanoma lesions often contain tumor-infiltrating lymphocytes, which can be activated and expanded in vitro by adding IL-2 to the culture medium
      • systemic high-dose IL-2 is also administered to support TIL survival
      • lymphodepletion techniques improve TIL survival in vivo and improve durable response rates

      T Cell Adoptive Therapy
    5. Monoclonal Antibody Therapy
      • fastest growing class of new therapeutic agents in cancer
      • initially created from mouse hybridoma technology – mABs were specific but were limited in use by human anti-mouse antibodies
      • molecular engineering techniques now allow fully human antibodies to be produced

      1. Mechanism of Action
        1. Physical Binding
          • mAB binds to a specific tumor antigen
          • Herceptin (trastuzumab) blocks signaling through an overexpressed growth factor receptor (Her2/neu)

        2. Immune system Activation
          • mAB directed against a tumor antigen can activate the patient’s immune system to attack the tumor tissue
          • Fc region of the antibody can bind to NK cells, phagocytes, and neutrophils, leading to tumor cell destruction mediated through the ADCC mechanism

        Monoclonal Antibodies
      2. Unconjugated mABs
        • Erbitux (cetuximab) targets the EGFR by binding in a non-activating way, leading to receptor blockade
        • Avastin (Bevacizumab) targets VEGF, the ligand of the VEGFR on endothelial cells, inhibiting angiogenesis and is approved for use in metastatic colorectal cancer
        • mABs usually used in combination with chemotherapy

      3. Conjugated mABs
        • mABs conjugated to radionuclides can be used as targeted systemic radiation therapy
        • radiation source is delivered to the site of the tumor
        • limitation of this approach is poor tumor penetration and bone marrow suppression







References

  1. Schwartz, 10th ed., pgs 300 – 316
  2. Sabiston, 20th ed., pgs 705 - 721
  3. Simmons and Steed, pgs 151 - 158/