About Authors:
Nishant Gupta
Department of pharmaceutics,
B.N. College of pharmacy,
Udaipur-313002,
Rajasthan
ABSTRACT:
Cancer is the leading cause of death in the United States among people younger than 85 years, and for the first time has surpassed heart disease as the number one killer. This worrisome statistic has resulted not from an increase in the incidence of cancer, but because deaths from heart disease have dropped nearly in half while the number of cancer-related deaths has remained about the same. This fact accentuates the need for a new generation of more effective therapies for cancer. Cancer patients are typically exposed to chemotherapy and radiation therapy in separate treatment rounds, doubling their emotional and physical stress. Biopharmaceutical researchers are now working on 887 medicines for cancer, according to a new report by the Pharmaceutical Research and Manufacturers of America (PhRMA). Many are high-tech weapons to fight the disease, while some involve innovative research into using existing medicines in new ways. Few things cause patients more fear and apprehension than a cancer diagnosis. But today—because of early detection and a steady stream of new and improved treatments—cancer increasingly can be managed and even beaten.
Reference Id: PHARMATUTOR-ART-1198
A deep commitment to patients and research is at the core of the remarkable progress made in fighting cancer that has led to declines in cancer deaths. According to the National Cancer Institute, cancer deaths in the United States decreased 1.6 percent per year from 2001-2006. Meanwhile, the number of cancer survivors living in the United States has increased from 3 million in 1971 to 11.7 million in 2007. The increase in survivors is attributed in large measure to earlier diagnosis and detection and better treatments and follow-up care.
VARIOUS TECHNIQUES AND INNOVATIONS:
Over the past decades, significant progress has been achieved in the cytotoxic treatment of colorectal cancer (CRC) by the use of fluoropyrimidines, irinotecan and oxaliplatin. However, as not all patients do respond to chemotherapy, there is a need for predictive and prognostic factors in order to optimise the treatment for individual patients. Although many potential molecular markers have been studied, none of these have been implemented in the standard of care for colorectal cancer patients. The following markers were included for cytotoxic drugs in CRC. The following markers were included: dihydropyrimidinedehydrogenase, orotate phosphoribosyl transferase, thymidine phosphorylase, thymidylate synthase, mismatch repair deficiency, topoisomerase , excision crosscomplementing gene and carboxylesterases. With the exception of mismatch repair deficiency, these molecular markers showed divergent and inconsistent results on their prognostic and/or predictive value. Thisunderscores the complexity of the role of these markers. further retrospective testing of these markers is unlikely to add clinically useful results. More definite results may only be expected when these markers are included in the design of prospective randomised studies (Miriam Koopmana et al., 2009).
The integral radiation dose in 27 patients is studied who had adaptive radiotherapy for bladder cancer using kilo voltage cone beam CT imaging. Compared to conventional radiotherapy the reduction in margin and choice of best plan of three for the day resulted in a lower total dose in most patients despite daily volumetric imaging. A possible approach is to prepare several treatment plans and select the plan every day which covers the target volume best . Adaptive radiotherapy requires frequent imaging with modalities that can reveal soft tissue contrast such as cone beam CT (CBCT). While this results in additional dose to the patient from imaging it can result in more conformal radiation delivery, which has the potential to decrease the overall radiation burden to the patient (Tomas Kron et al., 2010).
Aromatherapy is a popular complementary therapy within oncology settings and is known to help relieve patients’ anxiety. A new method of delivering aromatherapy to patients was adopted by a complementary therapy service at a UK hospital; aromasticks are similar in design to the Vicks_ Vapour Inhaler_, with the intention of helping patients manage anxiety, nausea and sleep disturbance. Patients referred to the complementary therapy service were, if appropriate, offered an aromastick. If the offer was accepted patients’ details were captured on an evaluation form. One week later the patients were followed up by a different therapist. Frequency of using the aromastick and perceived benefits were documented. A total of 160 patients were included in this evaluation. Aromasticks represent a tool patients can use to self-manage their own symptoms and help them retain an internal locus of control (Jacqui Stringer., 2011)
Tumor responses to therapy in the clinic are still evaluated primarily from non-invasive imaging measurements of reductions in tumor size. This approach, however, lacks sensitivity and can only give a delayed indication of a positive response to treatment. Major advances in our understanding of the molecular mechanisms responsible for cancer, combined with new targeted clinical imaging technologies designed to detect the molecular correlates of disease progression and response to treatment, are set to revolutionize our approach to the detection and treatment of the disease. We describe here the imaging technologies available to image tumor cell proliferation and migration, metabolism, receptor and gene expression, apoptosis and tumor angiogenesis and vascular function, and show how measurements of these parameters can be used to give early indications of positive responses to treatment or to detect drug resistance and/or disease recurrence. Special emphasis has been placed on those applications that are already used in the clinic and those that are likely to translate into clinical application in the near future or whose use in preclinical studies is likely to facilitate translation of new treatments into the clinic (Andre A. Neves et al., 2006).
Cathepsin L, a cysteine protease, is considered to be a potential therapeutic target in cancer treatment. Proteases are involved in the development and progression of cancer. Inhibition of activity of specific proteases may slow downcancer progression. In this review,we evaluate recent studies on the inhibition of cathepsin L in cancer. The effects of cathepsin L inhibition as a monotherapy on apoptosis and angiogenesis in cancer are ambiguous. Cathepsin L inhibition seems to reduce invasion and metastasis, but there is concern that selective cathepsin L inhibition induces compensatory activity by other cathepsins. The combination of cathepsin L inhibition with conventional chemotherapy seems to be more promising and has yielded more consistent results (Jacqueline M. Lankelma., 2010).
Currently, combinations of chemotherapy and radiotherapy are the standard treatment approach for locally advanced NSCLC patients. Concomitant chemo-radiotherapy, although associated with increased acute toxicity, has demonstrated to be the better strategy over sequential chemoradiotherapy, and it is to be considered a standard approach in patients with good performance status (0–1). However, the approach to locally advanced NSCLC and to chemo-radiotherapy regimens remains heterogeneous among oncologists, and clinical outcomes are yet disappointing. Thus, the search of newstrategies is mandatory. The main fields of research aiming at improving the survival of locally advanced NSCLC patients are: the addition of further combination chemotherapy as induction or consolidation to concurrent chemo-radiotherapy, and the integration of molecularly targeted therapies into conventional chemo-radiotherapy regimens (Cesare Guida et al., 2008).
Recent advances in radiotherapy (RT) are founded on the enhanced tumour visualisation capabilities of new imaging modalities and the precise deposition of individualised radiation dose distributions made possible with the new systems for RT planning and delivery. These techniques have a large potential to also improve the results of RT of urinary bladder cancer. Major challenges to take full advantage of these advances in the management of bladder cancer are to control, and, as far as possible, reduce bladder motion, and to reliably account for the related intestine and rectum motion. If these obstacles are overcome, it should be possible in the near future to offer selected patients with muscle invading bladder cancer an organ-sparing, yet effective combined-modality treatment as an alternative to radical surgery (Ludvig Paul Murena et al., 2004).
In the last decade, FDG-PET scans have had a major impact on the treatment of patients with NSCLC. The benefits of staging PET scans are well established, with improved selection of patients for curative radiotherapy or aggressive chemo-radiotherapy. The large body of literature correlating FDG-PET with nodal pathology in NSCLC makes it rational to use PET for designing mediastinal radiation fields. However, suboptimal image-fusion and a low spatial resolution for PET scans, makes use of PET for defining target volumes for primary tumours questionable. Data on the role of PET scans for radiotherapy planning for limited stage small-cell lung cancer is limited, although the incorporation of FDG-PET positive regions would appear to be reasonable (Suresh Senan et al., 2005).
Systemic treatment represents the cornerstone of endometrial cancer management in advanced, relapsed and metastatic disease, which is still characterized by poor prognosis. Progestins remain an effective option for patients with low grade, estrogen and/or progesterone receptor positive disease, with some of them achieving prolonged survival. Platinum compounds, anthracyclines and more recently taxanes have been implemented in combination regimens achieving response rates more than 50% and resulting in overall survival above 1 year in randomized trials. Adjuvant chemotherapy with the same agents may be useful for patients with early stage disease and high-risk features, such as high grade or non-endometrioid histology. Combination of chemotherapeutic agents with radiotherapy remains investigational. Hematologic, cardiac toxicity and neurotoxicity represent the main concern of chemotherapy and increase the risk for treatment-related morbidity and death, especially in pretreated patients bearing substantial co-morbidities. The gradual elucidation of the molecular aspects of endometrial carcinogenesis has led to the development of novel, selective antineoplastic agents, targeting specific molecular pathways and mediators of signal transduction implemented in cell proliferation, survival and angiogenesis. In the current review, we report on the recent advances regarding systemic therapy of endometrial carcinoma with special emphasis on results of large, randomized phase III clinical trials. Biomarkers with potent prognostic significance or predictive value for response to treatment are presented and novel molecular agents showing promising results in early clinical trials are discussed (Giannis Mountzios et al., 2010).
Intraoperative radiotherapy (IORT) has been proposed as an encouraging treatment for colorectal cancer. The aim of this study is to assess the efficacy and safety of IORT for this cancer through a systematic review. Studies located in electronic databases were selected according to established criteria, read and analysed and the results extracted by two independent reviewers. Fifteen studies met the selection criteria. Five-to-six-year local control (LC) was over 80% and 5-year overall survival (OS) was close to 65%. For recurrences, the 5- year overall survival was 30%. The main acute complications were gastrointestinal. Adding IORT to conventional treatment reduces the incidence of local recurrences within the radiation area over 10%. IORT is a safe technique as it does not increase toxicity associated with conventional treatment (P. Cantero-Munoz et al., 2011).
The EBCTCG has clearly demonstrated that the use of RT after either breast conserving surgery (BCS) or after mastectomy in node-positive patients not only reduces local recurrence (LR), but also improves long-term survival. The EBCTCG specifically found that the absolute reduction in the 5-year rate of LR was proportional to the absolute reduction in 15-year breast cancer mortality with a 4:1 ratio. Studies from the EBCTCG have also clearly shown that when RT for breast cancer inadvertently delivers ‘excessive’ dose to the heart, there is an increased rate of late cardiac deaths. Over time, LR rates with RT have decreased, particularly after BCS, and this is largely due to a favorable interaction of RT with adjuvant systemic therapy. There has also been development of fractionation and treatment techniques to complete RT faster for purposes of patient convenience and to assure its optimal level of use. There are now 10-year results from a Canadian trial showing equivalent LR and cosmetic outcome with RT using the convential 25 treatments to the whole breast compared to 16 treatments using a higher dose per day. Few randomized patients, however, were treated with adjuvant chemotherapy and a boost was not used. For patients treated after BCS, there has been great interest in the use of accelerated partial breast irradiation (APBI), which can be accomplished using interstitial, intracavitary, external-beam or intraoperative techniques (Larissa J. Leea et al., 2009).
Effective cancer therapy continues to be a daunting challenge due mainly to considerable tumor cell heterogeneity, drug resistance, and dose-limiting toxicity of therapeutics. Here we review a versatile nano-cellular (minicell) delivery vehicle that can be packaged with therapeutically effective concentrations of chemotherapeutic drugs, siRNAs or shRNAs and can be targeted to tumors via minicell-surface attached bispecific antibodies. A range of minicell-based therapeutics have shown highly effective tumor stabilization/regression in the murine xenograft model and in case studies in canines with late-stage endogenous tumors. Repeat intravenous dosing shows absence of toxicity or immunogenicity in both species. The minicell-based therapeutic has potential applications in personalized cancer medicine (Jennifer A Mac Diarmid et al., 2011).
In this review, the development of new therapies will be discussed in the context of advances in nanotechnologies related to cancer detection, analysis, diagnosis, and therapeutic intervention. First, several nanoanalytical methods, such as the use of quantum dots in detection and imaging of cancer, will be described. These techniques will be essential to the process of precisely describing cancer at the level of the cell and whole organism. Second, examples of how nanotechnologies can be used in the development of new therapies will be given, including methods that might allow for more efficient and accurate drug delivery and rationally designed, targeted drugs. Finally, a new initiative — the National Cancer Institute Alliance for Nanotechnology in Cancer — will be described and discussed with respect to the scientific issues, policies, and funding (Ernest S. Kawasaki et al., 2005).
Arc therapies have gained widespread clinical interest in radiation oncology over the past decade. Arc therapies have several potential advantages over standard techniques such as intensity-modulated radiation therapy, with implications for patients, administrators, and oncologists. This review focuses on the rationale for arc therapy, descriptions of the modern arc techniques that are currently clinically available, and highlights some distinguishing features of arc therapies, such as dose distributions, treatment times, and imaging capabilities. Arc therapies are exciting examples of progress in radiotherapy through technological innovation, aimed at ultimately improving the therapeutic ratio for patients receiving radiation. Arc-based radiotherapy is a complex approach to IMRT made possible by advances in technology. Compared to standard fixedfield IMRT, arc-based radiotherapy allows tumors to be treated from all angles, and can provide advantages in terms of dose distribution, ease of real-time imaging, reduced treatment time, and/or reduced monitor unit requirements. Tomotherapy has the longest history of clinical experience, and can produce highly conformal dose distributions using a helical delivery analogous to spiral CT scanning. VMAT algorithms treat the whole target volume at once, using a standard linear accelerator. Most of the published VMAT data has evaluated RapidArc, which can quickly deliver highly conformal plans, often in 1–3 min (David A. Palma et al., 2010).
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The use of PT in NSCLC is mainly based on the theoretical advantages in dose distribution. Little clinical data are available, in terms of number of institutions involved, number of treated patients and quality of studies conducted (i.e. lack of randomized controlled trials), making it impossible to draw definitive conclusions about its efficacy. Current data suggest that PT is a promising modality of irradiation in the treatment of early-stage disease, producing favorable results and low toxicity (both acute and late). Indications for PT in advanced stages are based mainly on planning studies, that should be followed up by further clinical investigations. Well-designed clinical trials and prospective studies will allow to better evaluate the benefits of PT with respect to other high-precision radiotherapy treatments (e.g. tomotherapy, stereotactic RT, cyberknife and IMRT), provided that the technical peculiarities of PT in lung treatment will be adequately taken into account (Lamberto Widesott et al., 2008).
Radiation oncology plays an important role in the curative treatment of patients with lung cancer. New technological developments have enabled delivery of higher radiation doses while better sparing surrounding normal tissues, thereby increasing the likelihood of local control without increased toxicity. Multi-modality imaging enables better target definition, improved planning software allows for correct calculation of delivered doses, and tools to verify accurate treatment delivery are now available. A good example of the results of applying these developments is the high local control rates achieved in stage I NSCLC with stereotactic radiotherapy (SRT). These advances are rapidly becoming available outside academic institutions, and pulmonologists, surgeons and medical oncologists need to understand and critically assess the potential impact of such developments in the routine care of their patients. Aspects of cost-effectiveness of technical innovations, as well as the level of evidence required before widespread clinical implementation, will be addressed (Cornelis J. et al., 2009).
Whereas first-line chemotherapy (CT) with single-agent gemcitabine or gemcitabine-based combinations provides a proven benefit in patients with locally advanced or metastatic pancreatic cancer (PC), the role of salvage CT after gemcitabine-failure is not well-established and to date no regimen has emerged as preferred in this setting. Several clinical trials have investigated the efficacy and toxicity-profile of second- line CT and indicated that selected patients may obtain significant benefit from it, also with regard to survival. However, definitive results from large randomized phase III studies are still lacking, and the evidence for clinical benefit of salvage CT is based on small phase II trials that evaluated different treatment schedules in heterogeneous populations. After failure to first-line therapy, all patients with advanced PC and adequate PS should be enrolled on clinical trials testing new strategies. When investigational therapy is not available, no evidencebased treatment recommendation can be given and each therapeutic decision is based on individual patient. The clinical factors that may help to select patients with advanced PC who will benefit most from second-line therapy are good PS, previous response to first-line CT and late recurrence after primary pancreatectomy. Furthermore, better understanding of validated predictions markers will provide new opportunities to optimize the management (Ana Custodio et al., 2009).
Stereotactic body radiotherapy (SBRT) is a novel form of noninvasive, highly conformal radiation treatment that delivers a high dose to tumor. The advantage of the technique resides in its ability to provide a high dose to tumor but spare normal tissues to an extent not previously possible. In this paper we will provide an introduction and review of this technology with regard to its use in gynecologic malignancies. Preliminary results from our experience are presented for the purpose of illustrating the range of SBRT applications in gynecologic oncology. Six case series are published that report results of SBRT for gynecologic malignancies. Sixteen gynecologic patients have been treated with SBRT at our institution. Treatment sites include pelvic and periaortic nodes (9 patients), oligometastatic disease (2), and cervical or endometrial primary tumors when other conventional external radiation or brachytherapy techniques were unsuitable (5). Preliminary followup at a median of 11 months (range, 0.3–33 months) demonstrates 79% locoregional control, 43% distant failure, and 50% overall survival. SBRT boosts to macroscopic periaortic node recurrences and other sites seem to provide local control and a possibility of long-term disease-free survival in carefully selected patients. Previously this had been difficult to achieve with conventional radiotherapy because of the proximity of periaortic nodes to small bowel. SBRT also offers a novel approach for minimally invasive treatment in the management of gynecological cancer where current surgical and radiotherapy techniques are unsuitable (Daniel S. Higginson et al., 2011).
High-intensity focussed ultrasound (HIFU) is an emerging minimally invasive treatment option for prostate cancer. High-quality evidence on the efficacy and safety of HIFU in prostate cancer is still lacking. To assess the true role of HIFU in prostate cancer, (randomised) controlled trials of good quality and sufficient sizecomparing HIFUwith conventional surgical (RP) and nonsurgical (radiotherapy) treatment options or to no treatment (active surveillance) are urgently required. Such studies must include previously overlooked data on patient-relevant outcomes like overall survival, prostate-cancer specific survival, adverse events, and quality of life if they are to be truly meaningful. Applying the GRADE approach, the available evidence on efficacy and safety of HIFU in prostate cancer is of very low quality, mainly due to study designs that lack control groups (Marisa Warmuth et al., 2010).
Endometrial cancer is one of the most common gynecologic malignancies. In patients with advanced or recurrent endometrial cancer survival is greatly diminished. Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Endocrine therapy provides a 10–20% response rate (RR) and survival of less than 1 year. Combination chemotherapy offers a RR of 40–60%, but the survival is still less than 1 year. The combination of cisplatin plus doxorubicin is the most commonly used regimen, but carboplatin plus paclitaxel represents an efficacious, low toxicity regimen in advanced or recurrent endometrial cancer. The addition of paclitaxel to cisplatin plus doxorubicin appears to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. At this time the focus of future research should be on the use of novel targeted agents, since it is unlikely that further significant advances could be made with chemotherapy and endocrine therapy. mTOR inhibitors represent a promising therapeutic strategy for endometrial cancer. Anti-HER-2/neu targeted therapy might be a novel and attractive therapeutic option in patients with biologically aggressive variants (uterine serous papillary carcinoma, clear cell carcinoma) of endometrial cancer. Research in better understanding the signal transduction pathways in endometrial carcinogenesis will allow the development of specific and selective molecularly targeted inhibitors (D. Pectasides et al., 2007).
Nanotechnology applications in medicine, termed as nanomedicine, have introduced a number of nanoparticles of variable chemistry and architecture for cancer imaging and treatment. Nanotechnology involves engineering multifunctional devices with dimensions at the nanoscale, similar dimensions as those of large biological vesicles or molecules in our body. Nanoparticles have the advantage of targeting cancer by simply being accumulated and entrapped in tumours (passive targeting). The phenomenon is called the enhanced permeation and retention effect, caused by leaky angiogenetic vessels and poor lymphatic drainage and has been used to explain why macromolecules and nanoparticles are found at higher ratios in tumours compared to normal tissues. Although accumulation in tumours is observed cell uptake and intracellular drug release have been questioned. Polyethyleneglycol (PEG) is used to protect the nanoparticles from the Reticulo-Endothelial System (RES), however, it prevents cell uptake and the required intracellular drug release. Grafting biorecognition molecules (ligands) onto the nanoparticles refers to active targeting and aims to increase specific cell uptake. Nanoparticles bearing these ligands are recognised by cell surface receptors and this leads to receptor-mediated endocytosis. Several materials are suggested for the design of nanoparticles for cancer. Polymers, linear and dendrimers, are associated with the drug in a covalent or non-covalent way and have been used with or without a targeting ligand. Stealth liposomes are suggested to carry the drug in the aqueous core, and they are usually decorated by recognition molecules, being widely studied and applied. Inorganic nanoparticles such as gold and iron oxide are usually coupled to the drug, PEG and the targeting ligand. It appears that the PEG coating and ligand decoration are common constituents in most types of nanoparticles for cancer. There are several examples of successful cancer diagnostic and therapeutic nanoparticles and many of them have rapidly moved to clinical trials. Nevertheless there is still a room for optimisation in the area of the nanoparticle kinetics such as improving their plasma circulation and tumour bioavailability and understanding the effect of targeting ligands on their efficiency to treat cancer (M. Wanga et al., 2010).
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