Introduction To Cytotoxic Drugs

Since the publication of five randomized trials of platinum-containing chemo-radiation in women with cervical cancer in 1999, and the accompanying National Cancer Institute (NCI) Clinical Announcement, combined treatment has become the standard of care in this disease (Rose et al. 1999 Whitney et al. 1999 Morris et al. 1999 Keys et al. 1999 Peters et al. 2000). In women with vulvar cancer, trials of chemo-radiation for locally advanced tumors have shown good response rates, consistent with...

Conclusion For Cytotoxic Drugs

The last 20 years have yielded significant advances in the treatment of breast cancer. Adjuvant radiation therapy, chemotherapy, and hormonal therapy have all been shown to improve event-free and overall survival and are now part of the standard treatment in the management of breast cancer. Although there has been significant progress in determining the optimal combination and sequencing of these treatments, additional studies are still required to better integrate these therapies with each...

Conclusion

Antimetabolite agents have remarkable antineo-plastic activities, and their radiosensitizing effects have been reported for several decades both preclin-ically and clinically. Although the mechanisms of radiosensitization have not been fully understood, several preclinical studies have focused on the modulation of the metabolism, the changes in cell cycle distribution, the role of p53, and the induction of apoptosis. Chemoradiation with antimetabolites has become the standard therapy for the...

Carcinoma of the Vulva

Cunningham et al. (1997) reported on 14 patients with advanced vulvar carcinoma who were not candidates for standard radical vulvectomy that were submitted to combined radio-chemotherapy. Median age was 68 years. Patients were treated with a dose of 45-50 Gy to the pelvis and the total doses to the vulva with or without groins ranged from 50 to 65 Gy. Chemotherapy was administered in the first and last weeks of radiotherapy and consisted of 5-FU 1000 mg m2 24 h-1 continuous infusion over 96 h...

The Microenvironment in Cervical Cancer

The microenvironment in which cancer cells exist is abnormal, and is a potential target for novel drugs designed to enhance the cytotoxic effects of radiotherapy or more conventional chemotherapy. This has been explored in cervical cancer, and is a strong focus of ongoing new drug development. The microenvironment refers to the physiological and biochemical state of the extracellular space that surrounds the malignant cells, which is determined mainly by the tumor vasculature and interstitial...

Mechanisms of Radiosensitization with Antimetabolites

In addition to the cytotoxic effect of these antimetabolites themselves, they have been reported to enhance the effect of radiation as potent radiosensi-tizers in vitro. Recent in vivo studies have confirmed these activities and have reported significant tumor growth delay with the combination of antimetabo-lites and ionizing radiation in animal models however, the mechanism of radiosensitization has yet to be fully understood. Initial studies have focused, as the mechanism, on the modulation...

Introductiontocytotoxicdrugs

Anal cancer serves as a paradigm for the successful application of RCT and the concept of radiosensi-tization. For this solid tumor, combined-modality therapy is now the mainstay of a curative approach with surgery reserved as a salvage for non-respond-ers or recurrent disease. Before the 1980s, radical surgery with APR was the most frequently recommended treatment, as early results obtained with radiotherapy alone varied considerably with respect to oncological results, and radiation-related...

Topoisomerase Inhibition Enhances Radiation In Vivo and In Vitro

The principle mechanism of radiation's lethality is the creation of irreparable DNA damage. Chemotherapy that disrupts normal DNA repair may act definitively to cause cell death or serve to complete partial damage caused by ionizing radiation thereby causing cell death (Ng et al. 1994 Amorino et al. 2000 Kim et al. 2002). The DNA strand breaks are a critical pathway by which ionizing radiation exerts a lethal effect on a cell. Che-motherapeutic agents that induce or prevent repair of DNA strand...

Introduction

Malignant tumors, by definition, infiltrate the surrounding normal tissue structures therefore, it is inevitable that the target volume of curative radiotherapy of solid tumors includes a significant volume of normal tissues, which are exposed to tox-icity-inducing radiation doses. In addition, areas of suspected microscopic spread and safety margins accounting for organ- and patient motion are to be included. In principle, normal tissues refers to Professor, Medical Faculty Carl Gustav Carus,...

Combinations of Ionizing Radiation and Other Sensitizing Agents

10.2.1 Structure and Chemistry 140 10.3.1 Structure and Chemistry 143 10.3.4 Glioblastoma Multiforme 145 10.3.5 Conclusion 146 References 147 Several chapters in this book cover broad classes of radiosensitizing agents. Two specific agents, recently used as radiation enhancers, are addressed in the present chapter. They include the redox modulator motexafin-gadolinium (MGd), and the alkylating agent temozolomide. Each of these agents came to clinical testing through the recognition of unique...

Mercaptopurine as an Example for Purine Analogs

Purine Analogs Chemotherapy

6-Mercaptopurine (6-MP) is a 6-thiopurine analog of purine bases (see Fig. 2.1c), such as hypoxanthine and guanine, and has been in clinical use for over 30 years as an antileukemic agent. 6-MP is a prodrug that requires activation to exert its cytotoxic effect (see Fig. 2.5). It is first converted by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) into 6-thioinosine monophosphate (6-TIMP LeNNArD 1992). It is subsequently metabolized by a two-step process involving inosine monophosphate...

DNTP Depletion

Antimetabolite-induced perturbation of the intra-cellular dNTP pool and its radiosensitizing effect are summarized in Table 2.1. In the case of dFdCyd, it increases the radiosensitivity of cells even under conditions in which the drug alone shows no cytotoxicity (Shewach et al. 1994). The dFdCyd-mediated sensitization has been reported not to be dependent either on the intracellular concentration of dFdCTP or on the dFdCTP dCTP ratio, but correlates to the dFdCDP-mediated decrease in...

Lung Cancer

Approximately 67 of all new lung cancer cases in the United States are diagnosed in persons 65 years and older, and about 31 of the cases in persons > 75 years (Edwards et al. 2002). Schild et al. (2003) retrospectively analysed tox-icity and outcome data for 63 patients > 70 years who were treated within a North Central Treatment Group phase-III trial. The trial compared bid radio-chemotherapy (60 Gy, 1.5 Gy bid, 2-week break after 30 Gy) with once daily radio-chemotherapy (60 Gy, 2 Gy)...

Randomized Trials of RCT in Anal Cancer

Although these phase-II trials of combined modality anal cancer treatment demonstrated the feasibility and efficacy of this approach, the value of sensitizing chemotherapy remained unproven. Two European phase-III trials compared combined RCT with radiotherapy alone (Table 18.12). The EORTC trial required a locally advanced tumor (T3-4 or T1 2 N+), whereas the UKCCCR trial allowed patients with any stage of disease (Bartelink et al. 1997 UKCCCR Anal Cancer Trial Working Party 1996). Although no...

Current Randomized Trias to Optimize Concurrent RCT

Although the above-mentioned series have established that combined RCT is superior to radiotherapy alone in terms of local control, the most appropriate radiotherapy dose, fractionation, techniques, duration of gap (if any), and the most effective chemotherapy regimen (agents, number of neoad-juvant, concomitant, adjuvant cycles) await further investigation. Given the fact that MMC is associated with significant acute hematological toxicity and possibly also with long-term effects to the lungs...

Acute Toxicity of Concurrent Radiochemotherapy

Most of the patients treated with a curative radiation regimen experience some mild treatment toxicity, especially bladder and bowel toxicity. Mild to moderate acute radiation cystitis with dysuria and urinary frequency (grades 1 and 2) is present in about half of the patients, but few patients require specific medication (Zietman et al. 1993). The symptoms usually resolve within 2-4 weeks after completion of radiotherapy. In our own experience, patients with a history of multiple TURs or...

Concurrent Radiochemotherapy

The combination of chemotherapy and radiotherapy has yielded significantly higher local remission rates of far advanced tumors than radiation alone. The histologically proven complete remission (CR) rates of advanced, transurethrally unresectable tumors lie in the range of 40-50 with radiotherapy alone if standard radiation doses in the range of about 60 Gy are administered. The addition of two to three courses of cisplatin increased the pathological CR rate to 60-70 . The data suggest that the...

Mammalian Target of Rapamycin mTOR Inhibitors

9.3 mTOR-Dependent Signaling Pathways 129 9.4 Anti-Tumor Effects of mTOR Inhibition 131 9.5 Clinical Experience with mTOR-Inhibitor Monotherapy 132 9.6 Combination Therapies with mTOR Inhibitors 132 9.7 Conclusion 134 References 134 Rapamycin and its analogs are novel, molecularly targeted drugs that are being developed as anticancer agents. The parent compound, rapamycin (Sirolimus, Rapamune, Wyeth, Madison NJ, USA) is approved by the Food and Drug Administration (FDA) for the prevention of...

Potential Influences on Programmed Cell Death Pathways

In order to inactivate a tumor cell, several distinct yet overlapping pathways may be activated. Besides the induction of pure apoptosis, other cell inacti-vation modalities, including programmed necrosis, mitotic catastrophe (which recently turned out to be an abortive form of apoptosis), senescence, or terminal differentiation, may be triggered (BeLkA 2005). The influence of a combined modality treatment on any of these end points has never been analyzed in greater detail thus, only very few...

Randomized Trials to Optimize 5FUBased Postoperative RCT

Further trials by the GITSG (7180) and NCCTG (864751) investigated the need for methyl-CCNU in the chemotherapy regimen and found that it added no benefit to the 5-FU regimen (Table 18.2 Gastrointestinal Tumor Study Group 1992 O'Conneu et al. 1994) thus, this compound is no longer used for adjuvant RCT in rectal cancer. The NCCTG (864751) also tested the best method of administering 5-FU during radiotherapy Bolus 5-FU (500 mg m2 for 3 days during weeks 1 and 5 of radiation therapy) was compared...

Role of Salvage Cystectomy

Salvage cystectomy plays an important role in an organ-preserving treatment concept in bladder cancer. In contrast to local recurrences after radical cystectomy, which are considered as incurable and are therefore nearly exclusively treated with palliative intent, local recurrences in the preserved bladder can be treated with curative intent. Thirty to 40 of patients who undergo an organ-preserving treatment with radio- or radiochemotherapy present with residual microscopic disease or locally...

Early Stage Breast Cancer

Most of the patients diagnosed with breast cancer either present with stage-I or stage-II disease and are usually treated with a combination of surgery, radiation, and systemic therapy. Typically, patients who present with relatively small primary tumors (i.e., < 3 cm) undergo surgery as their initial treatment. For such patients, surgery can consist of either BCT or a modified radical mastectomy (MRM). Several large randomized trials have conclusively demonstrated that the outcome associated...

Rectal and Anal Cancer

Although the 1990 NIH consensus recommended adjuvant radio-chemotherapy for stage-II and stage-III rectal cancer without an upper age limit, this recommendation was far from being accepted for the wide majority of elderly patients treated in the 1990s (Neugut et al. 2002 Schrag et al. 2001). Neugut et al. (2002) carried out a population-based study on the use of adjuvant chemotherapy and radiation therapy for rectal cancer among patients 65 years or older who were diagnosed between 1992 and...

Small Cell Lung Cancer

Etoposide, a Topo-II inhibitor, has been in routine use with radiation for SCLC for many years (SieRocki et al. 1979 Turrisi et al. 1988). The current standard consists of cisplatin and etoposide concurrent and adjuvant to thoracic radiotherapy of 45 Gy delivered 1.5 Gy b.i.d. (Turrisi et al. 1999 TakADA et al. 2002). Recent trial paradigms for limited stage SCLC have begun integrating irinotecan. The RTOG initiated a phase-I trial, RTOG 0241, using a fixed dose of cisplatin 60 mg m2 combined...

Biological Basis of Combined Radio and Chemotherapy

CLaus BeLka, Carsten Nieder and MichaeL Molls 1.1.1 Clinical Relevance of Combined Modality Approaches 3 1.2.2 Additivity, Synergism, and Sub-Additivity 6 1.2.2.1 Synergism (Supraadditivity) 6 1.2.2.3 Infra (Sub)-Additivity (Protection) 7 1.3 Interaction of Radiation and Chemotherapy 8 1.4.2 Radiation Sensitization Via Cell Cycle Synchronization 11 1.5 Potential Influences on Programmed Cell Death Pathways 12 1.6 Effects of Protracted Drug Exposure 13 1.7 Combination of Radiation with Hormonal...

Late Toxicity After Radiochemotherapy

Late bladder toxicity may arise in a relevant subset of patients if radiation doses above 60-65 Gy are administered to large parts of the bladder or if high doses per fraction are used however, the total doses in current protocols lie in the range of about 60 Gy to the whole bladder and not more than 64 Gy to parts of the bladder. These doses, if administered in conventional fractionation with single doses < 2 Gy, can be considered as relatively safe with regard to late bladder toxicity...

Role of Hypoxia

As known for years, radiation-induced cell kill is strongly dependent on the presence of adequate oxygen tensions. In most larger tumors, e.g., head and neck cancers, areas of hypoxia and even anoxia are present leading to an increased radiation resistance of clonogenic tumor cell within such areas (Molls and VAupel 1998 StAdler et al. 1999 NordsmArk et al. 2005). It has been speculated that chemotherapeutic agents especially those which kill even hypoxic cells (mitomycin C) may overcome global...

Prodrugs of 5Fu Uft S1 and Capecitabine

A prodrug is defined as a pharmacologically inactive compound that is converted into an active agent by a metabolic biotransformation. The prodrugs of 5-FU are characterized by a pyrimidine ring with a fluorine atom in position 5. The first generations of prodrugs of 5-FU were represented by 5-fluoro-2'-deoxyuridine (5-FdUrd), which was more efficiently metabolized by the liver than 5-FU. As for the second generation, ftorafur (FTO, 1-(2-tetrahy-drofuryl)-5-fluorouracil, Tegaful or Futraful)...

Pathogenesis

Consequential Late Effects Radiation

Late effects of multimodal cancer therapy are essentially seen in all organs, with organ-specific manifestations and their respective clinical consequences. They occur after a latent time of months to years, are progressive, and are usually irreversible. Their pathomechanisms, however, follow some general principles, which are discussed briefly. Treatment effects on organ-specific paren-chymal cells usually result in cell death, which, however, in most tissues does occur before the cells...

Additivity Synergism and Sub Additivity

When combining two treatment modalities the resulting net effect on cell killing is mainly described by the terms additivity, synergism, and sub-addi-tivity, which are derived from experimental work. They are not applicable to the clinical situation and do not reflect the results of clinical trials, where changes from radiation as a monotherapy to multimodal treatment usually do not result in extraordinarily favorable cure rates (or supraaddi-tivity), although they have led to important gradual...

Sequencing of Radiation Therapy and Chemotherapy after Breast Conservation Therapy

With the increased use of adjuvant chemotherapy in early-stage disease, there has been significant interest in the sequencing of radiation therapy and chemotherapy after breast-conserving surgery. During the 1990s there was significant debate over this issue. One of the first retrospective studies to report on sequencing of radiation and chemotherapy showed that a delay in radiation treatments in order to give chemotherapy may increase the risk of breast recurrence. In this retrospective review...

Sequencing of Chemotherapy and Hormonal Therapy

Many patients with estrogen receptor-positive breast cancer are treated with both adjuvant chemotherapy and hormonal therapy. The optimal sequencing of chemotherapy and hormonal therapy was recently investigated in a phase-III trial run by the Southwest Oncology Group (SWOG 8814), which randomized patients with pathological stage-I to stage-IIIA breast cancer to concurrent chemotherapy with CAF (cyclophosphamide, doxorubicin, 5-fluroura-cil) chemotherapy with tamoxifen or chemotherapy followed...

References

Andreassen CN, Grau C, Lindegaard JC 2003 Chemical radio-protection a critical review of amifostine as a cytoprotec-tor in radiotherapy. Semin Radiat Oncol 13 62-72 Antonadou D, Pepelassi M, Synodinou M et al. 2002 Prophylactic use of amifostine to prevent radiochemother-apy-induced mucositis and xerostomia in head-and-neck cancer. Int J Radiat Oncol Biol Phys 52 739-747 Antonadou D, Throuvalas N, Petridis A et al 2003 Effect of amifostine on toxicities associated with radiochemother-apy in...

Combinations of Hypoxia Targeting Compounds and Radiation Activated Prodrugs with Ionizing Radiation

Diagram Egfr Under Hypoxic Conditions

5.3 Hypoxia-Selective Radiosensitizers 69 5.3.2 Mixed-Function Radiosensitizers 69 5.3.3 DNA-Affinic Radiosensitizers 71 5.4.2 Combination of Hypoxic Cytotoxins with Ionizing Radiation 72 5.4.4.3 RSU 1069 and RB 6145 74 5.4.6 Benzotriene di-N-Oxides 76 5.4.7 Tertiary Amine N-Oxides 78 5.5 Combination of Radiation-Activated Prodrugs with Ionizing Radiation 79 5.5.2 Nitro Hetero Cyclic Methylquarternary Ammonium Salts 79 5.5.3 5-Fluorouracil 5-FU -Releasing Prodrugs 81 5.5.4 Transition Metal...

Applications in Head and Neck Cancer

Radiotherapy Imrt Head And Neck

Traynor, Paul M. Harari, and Jean Bourhis 13.2 Randomized Trials with Definitive Chemoradiation 187 13.3 Induction Chemotherapy 191 13.4 Induction Chemotherapy Followed by Concurrent Chemoradiation 192 13.5 Adjuvant Chemoradiation after Primary Surgery 193 13.7 Conclusion 194 References 195 Head and neck H amp N cancer refers to a heterogeneous group of epithelial tumors involving the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, salivary glands, and...

Radiotherapy and Tumor Targeted Drug Delivery

Mcneil Scott Nanoparticles

Zhaozhong Han, GhazaL Hariri, and Dennis E. HaLLAhan 11.2 Radiation-Induced Neoantigens on Tumor Endothelium as Targets for Drug Delivery 152 11.3 Approaches for Discovery of Inducible Neoantigens 153 11.3.1 Gene-Based Approaches 153 11.3.2 Proteomics-Based Approaches 154 11.3.3 Bioinformatics and Other Approaches 155 11.4 Display Technologies for Isolation of Targeting Ligands 156 11.5 Delivery Vehicles from Liposome to Nanoparticle 157 11.6 Conclusions and Perspectives 159 References 160...

Combinations of Platinum Compounds and Ionizing Radiation

Combinations with Ionizing Radiation 94 Perspectives for Cisplatin Combinations with Addition of Other Drugs to Platinum Ionizing The contemporary clinical concepts of multimodal oncology include combined administration of ionizing radiation and three different platinum compounds cisplatin, carboplatin and oxaliplatin in a variety of common solid tumors. Examples are sites such as head and neck, esophagus, lung, cervix uteri, rectum, and bladder. All these platinum drugs have demonstrated...

Sub Additive Interaction

Sub-additive interactions between taxanes and radiation have also been reported but infrequently compared with supra-additive and additive effects Hennequin et al. 1996 Ingram and Redpath 1997 Liebmann et al. 1996 . Sub-additivity was observed when paclitaxel was added to, and maintained, in the culture medium for a prolonged period after radiation exposure Ingram and Redpath 1997 Liebmann et al. 1996 . Under these conditions, radiation alone induced both G1 and G2 cell cycle arrest which...

Chemo Radiation in Endometrial Cancer

Endometrial cancer is treated very successfully with surgery and radiation when diagnosed early unfortunately, advanced disease is still often seen and in this setting treatment outcome is poorer. Randan et al. 2006 have recently reported the results of a pivotal phase-III study in 422 patients with advanced stage III or IV endometrial cancer who underwent debulking surgery with less than 2 cm of residual disease, and were subsequently randomized to chemotherapy with doxorubicin and cisplatin...

Future Directions in Anal Cancer Treatment with New Agents

Given the positive results of combination chemotherapy and radiation therapy in the above-mentioned phase-III trials, a pilot study in the United Kingdom ACT II pilot is currently testing a triple chemotherapy and radiation approach with integration of 5-FU, MMC, and cisplatin into the combined modality treatment of anal cancer. A phase-II study at the M.D. Anderson Cancer Center Houston, Texas investigates the role of capecitabine and oxalipla-tin with radiation therapy in patients with...