Cancer is characterized by uncontrolled and invasive growth of cells. These cells may spread to other parts of the body and this is called metastasis [1]. It is very difficult to study and indentify efficacious anticancer agents. One of the major issues associated with anticancer research is that traditional target directed strategies are confronted with the essentiality Inevitably, targeting proteins that have essential functions are likely to lead to chemical entities with narrow therapeutic windows and significant toxic effects. An additional challenge is the unstable epigenetic and genetic status of cancer cells, undergoing multiple mutations, gene copy alterations and chromosomal abnormalities that have a direct impact on the efficacy of anticancer agents at different stages of the disease [2]. All these aspects make cancer drug discovery extremely difficult and have led to poor clinical approval success rates compared to other therapeutic areas.

Cancer is one of the main causes of death worldwide and in the past decade, many research studies have focused on finding new therapies to reduce the side effects caused by conventional therapies. During cancer progression, tumours become highly heterogeneous, creating a mixed population of cells characterised by different molecular features and diverse responsively to therapies. This heterogeneity can be appreciated both at spatial and temporal levels and is the key factor responsible for the development of resistant phenotypes promoted by a selective pressure upon treatment administration [3]. Usually, cancer is treated as a global and homogeneous disease and tumours are considered as a whole population of cells. Thus, a deep understanding of these complex phenomena is of fundamental importance in order to design precise and efficient therapies.              

Nanomedicine offers a versatile platform of biocompatible and biodegradable systems that are able to deliver conventional chemotherapeutic drugs in vivo, increasing their bioavailability and concentration around tumour tissues and improving their release profile [4]. Nanoparticles can be exploited for different applications, ranging from diagnosis to therapy [4]. Recently, extracellular vehicles (EVs), responsible for cancer development, microenvironment modification and required for metastatic progression, have been widely investigated as efficient drug delivery vehicles [5]. Natural antioxidants and many photochemical have been recently introduced as anti-cancer adjuvant therapies due to their anti-proliferative and pro-apoptotic properties. Targeted  therapy is another branch of cancer therapy aiming at targeting a specific site, such as tumour vasculature or intracellular organelles, leaving the surroundings unaffected. This enormously increases the specificity of the treatment, reducing its drawbacks. Another promising opportunity relies on gene therapy and expression of genes triggering apoptosis and wild type tumour suppressors, or the targeted silencing mediated by siRNAs, currently under evaluation in many clinical trials worldwide. Thermal ablation of tumours and magnetic hyperthermia are opening new opportunities for precision medicine, making the treatment localised in very narrow and precise areas. These methods could be a potential substitute for more invasive practices, such as surgery Furthermore, new fields such as radiomics and pathomics are contributing to the development of innovative approaches for collecting big amounts of data and elaborate new therapeutic strategies and predict accurate responses, clinical outcome and cancer recurrence [6,7]. Taken all together, these strategies will be able to provide the best personalised therapies for cancer patients, highlighting the importance of combining multiple disciplines to get the best outcome. In this review, we will provide a general overview of the most advanced basic and applied cancer therapies, as well as newly proposed methods that are currently under investigation at the research stage that should overcome the limitation of conventional therapies; different approaches to cancer diagnosis and therapy and their current status in the clinical context will be discussed, underlining their impact as innovative anti-cancer strategies.

Recent Innovation in Cancer Therapy

By Surgery

Robotic Surgery: Minimally invasive surgery over the past two decades has revolutionised surgical management of colorectal cancers. Despite its initial scepticism, various randomised controlled trials have now demonstrated its short-term and long-term benefits over conventional open surgery in the treatment of colonic cancer such as faster recovery, decreased morbidity and reduced hospital length of stay with comparable oncological result and survival outcome. However, laparoscopic colorectal surgery has limitations. These concerns were high-lighted not only by the high conversion rate but also the initially high proportion of circumferential resection margin (CRM) positive rates in the medical research council colorectal cancer (MRC-CLASICC) trial for laparoscopic rectal surgery. The ability to perform total mesorectal excision (TME) laparoscopically requires intensive training. Limitations of conventional laparoscopic surgery include: 2-dimension view, unstable assistant controlled camera, poor ergonomics, straight tip instruments, fulcrum effect and enhanced tremor effect.

Various attempts have been made to seek alternative techniques to overcome some of these limitations. For example, single incision laparoscopic surgery has reduced the number of incisions and ports required for minimal invasive colonic surgery producing a better cosmetic result and reduction in wound pain. Natural orifice translumenal endoscopic surgery (NOTES) aims to eliminate external incision by gaining access using the transvaginal, transgastric, transvesical and transrectal approach, which has been shown to be feasible on animal models However, there are still many hurdles in NOTES (e.g., determining a safe access into the peritoneal cavity, developing a reliable method on the closure of viscotomy, minimising the infection and tumour seedling r.isk, developing a stable and versatile platform for suturing, managing complications from NOTES and training issues), which need to be addressed before its routine application on Human subjects [8].

Robotic rectal surgery has potential advantages over conventional laparoscopic rectal surgery: Surgeon motion filter for tremor-free surgery, high definition three-dimensional images, surgeon control camera on a stable platform and increased degree of freedom of the operating instruments. The master and slave system allows improved ergonomics for the surgeon. As the surgical field mainly confines to the pelvic cavity, it allows a stable platform for precision surgery to be performed in a confined space. For the above reasons, robotic technology may be more suitable and may translate more benefits when used for rectal cancers than colonic cancers.

Several review articles have attempted to summarize up-to-date practice and results of robotic colorectal surgery. However, some studies included data from both robotic colonic and rectal resections, which may not give a focused overview of the benefits and risks of robotic rectal surgery. Other studies included more than one study from the same institute with overlapping period of assessment, which may cause duplication of results. Although meta-analysis of robotic rectal resection has been published, studies included were from non-randomized studies [9].

Transanal TMS

Transanal TME (TaTME) was first introduced by Sylla et al in 2010 Since then, the feasibility and safety of this surgery has been reported by many case studies with acceptable short‐term outcomes Most recently, de Lacy's group reported the pathological results of 186 constitutive cases with mid and low rectal cancer [44] Complete TME was achieved in 95.7% and overall positive CRM (≤1 mm) and distal resection margin (DRM) (≤1 mm) were 8.1% and 3.2%, respectively. The international TaTME registry also reported the results of 720 patients. In 634 patients with rectal cancer, complete TME was obtained in 503 (79.3%) and positive CRM and DRM rates were 2.4% and 0.3%, respectively. Perdawood et al carried out a retrospective, case‐matched analysis including 300 patients (100 each who underwent TaTME, laparoscopic TME and open TME, respectively). The CRM positive rate was comparable among the three groups. More favorable outcomes in terms of shorter operation time, less blood loss and shorter hospital stay were observed in TaTME than in the other two groups. Marks et al. first reported the long‐term outcomes of rectal cancer patients who were treated by TaTME. Rates of successful TME, negative CRM and negative DRM were 96%, 94% and 98.6%, respectively. Overall local recurrence, distant recurrence and 5‐year OS rates were 7.4%, 19.5% and 90%, respectively. According to a systematic review in 2016, total morbidity of TaTME was 40.3%, which was comparable with that of conventional laparoscopic TME in a previous large RCT. It showed favorable outcomes of low rates of anastomosis leakage (5.7%) and conversion (3.0%). The rate of positive CRM was 4.7% and complete TME was achieved in 87.6%. DRM involvement developed in 0.2% only. Importantly, operative and oncological outcomes were better in high‐volume centers (>30 cases in total) than in low‐volume centers (<30 cases in total) including operative time, conversion rate, major complication rate, TME quality and local recurrence rate. Currently, a multicenter RCT comparing TaTME versus laparoscopic TME for mid and low rectal cancer (COLOR III) is ongoing [10].

Lateral Pelvic Lymph Node Dissection

The beneficial effect of lateral pelvic lymph node dissection (LLND) had been under debate for a long time until the results of the JCOG0212 trial were published in 2017. Five‐year OS and 5‐year local‐recurrence‐free survival in the mesorectal excision (ME) with LLND and ME‐alone groups were 92.6% and 90.2% and 87.7% and 82.4%, respectively. Local recurrence rates were 7.4% and 12.6% in the ME with LLND and ME‐alone groups, respectively (p = 0.024). Kanemitsu et al. also reported the outcomes from a total of 1191 consecutive patients with lower rectal cancer who underwent TME with LLND. They described that dissection of the internal iliac nodes and obturator nodes yielded similar therapeutic benefits to those expected from dissection of the superior rectal artery nodes. They also showed that the relative risk for local recurrence was 2.0 for patients with unilateral LLND compared with those with bilateral LLND. Based on these results, ME with LLND is still a standard treatment in Japan. It should be noted that patients with lateral lymph nodes (LLN) larger than 10 mm were excluded and that no patient received any preoperative treatments in JCOG0212.

The effect of additional LLND after preoperative treatment is unclear. Ishihara et al. reported that the incidence of LLN metastasis was estimated to be 8.1% (18/222) even after preoperative CRT. Yamaoka et al also reported that LLN metastasis was detected in seven out of 19 patients who underwent preoperative CRT, suggesting preoperative CRT followed by ME alone is not sufficient, especially when LLN involvement is clinically suspicious. Ishihara's group carried out TME + LLND for patients with swollen LLN following preoperative CRT. Akiyoshi's group also carried out LLND with a similar theory and reported 3‐year relapse‐free survival of 75.1% for patients with LLN metastasis. [5,8] Currently, RCT to assess the efficacy and safety of LLND after preoperative CRT for rectal cancer patients with suspicious LLN metastases is ongoing in China.

Kusters et al reported that the lateral local recurrence rate was significantly higher in patients with LLN larger than 10 mm than in patients with smaller nodes despite the use of preoperative radiation. The optimal cut‐off value of LLN size for prediction of metastasis varies among the investigators. Ishibe et al [61] reported that a cut‐off value of 10 mm was useful for avoiding unnecessary LLND. Akiyoshi's group reported that the optimal cut‐off value before CRT was 8 mm. Yamaoka reported an optimal cut‐off value of 6.0 mm, with a sensitivity of 78.5% and a specificity of 82.9%. Before the start of preoperative treatment, accurate estimation of LLN size by MRI is useful.

Although JCOG0212 reported that LLND did not increase male sexual dysfunction, LLND is considered technically challenging. Recently, the safety and feasibility of laparoscopic versus open LLND was shown by a subgroup analysis of a large multicenter cohort study from Japan. They also showed similar oncological outcomes between the groups. [11]

Establishment of criteria to accurately predict LLN status as well as standardization of the technique of LLND is necessary in the future.

Preoperative/Neoadjuvant Therapy

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality and is associated with an extremely poor prognosis, reflected by a median survival of 5– 8 mo and a 5-y survival probability of less than 5% when all stages are combined. At present, the only chance for cure and prolonged survival is surgical resection with macroscopic tumor clearance. However, only approximately 10%–20% of patients are considered candidates for curative resection. The majority of patients (50%–60%) present with metastatic disease and thus palliative chemotherapy remains the only option for almost all of these patients [12].

In a substantial number of patients (approximately 30%–40%) the disease is considered ‘‘locally advanced’’ at the time of diagnosis. This group of patients has been intensively discussed during the last years and neoadjuvant therapies have been proposed to achieve better local tumor control or tumor down-staging with a subsequent potentially resectable tumor [13]. Neoadjuvant therapy in this context is defined as any preoperative therapy aiming to convert unresectable to resectable tumors and/or to increase microscopic complete tumor resection rates. Unfortunately, however, no data regarding the role of neoadjuvant therapy for pancreatic cancer from randomized phase III trials are available. In addition, a thorough analysis of this group of patients has been hampered by the lack of an accepted and widely used definition of respectability and unrepeatability. For example, while current guidelines generally consider encasement/involvement of the superior mesenteric artery/celiac trunk as signs of unresectability [14,15], portal vein/superior mesenteric vein involvement has been more critically discussed and categories such as ‘‘borderline resectable’’ have been introduced [16]. Furthermore, all criteria depend heavily on the experience and technical expertise of the involved radiologists, Gastroenterologists and surgeons. Although neoadjuvant therapy for pancreatic cancer has been proposed for more than two decades and although there is strong evidence of its benefit for other tumor entities, up to now there is no compelling evidence for a clinical benefit of neoadjuvant therapy in pancreatic cancer. Here, we systematically reviewed and performed a meta-analysis of the available data regarding neoadjuvant chemo- and/or radiotherapy with special emphasis on tumor response/progression rates, toxicities and clinical benefit, i.e. resection probabilities and survival estimates [17,18].

Radiomics and Pathomics

Efficient cancer therapy currently relies on surgery and, in approximately 50% of patients, on radiotherapy, that can be delivered by using an external beam source or by inserting locally a radioactive source (in this case, the approach is named brachytherapy), thus obtaining focused irradiation. Currently, localisation of the beam is facilitated by image-guided radiotherapy (IGRT), where images of the patient are acquired during the treatment allowing the best amount of radiation to be set. Thanks to the introduction of intensity-modulated radiotherapy (IMRT), radiation fields of different intensities can be created, helping to reduce doses received by healthy tissues and thus limiting adverse side effects. Finally, by means of stereotactic ablative radiotherapy (SABR), it has become feasible to convey an ablative dose of radiation only to a small target volume, significantly reducing undesired toxicity [19]. Unfortunately, radioresistance can arise during treatment, lowering its efficacy. This has been linked to mitochondrial defects; thus, targeting specific functions have proven to be helpful in restoring anti-cancer effects [20]. A recent study has shown, for example, that radioresistance in an oesophageal adenocarcinoma model is linked to an abnormal structure and size of mitochondria and the measurement of the energy metabolism in patients has allowed discrimination between treatment resistant and sensitive patients [21]. Targeting mitochondria with small molecules acting as radiosensitizers is being investigated for gastrointestinal cancer therapy [22]. Cancer is a complex disease and its successful treatment requires huge efforts in order to merge the plethora of information acquired during diagnostic and therapeutic procedures. The ability to link the data collected from medical images and molecular investigations has allowed an overview to be obtained of the whole tridimensional volume of the tumour by non-invasive imaging techniques. This matches with the main aim of precision medicine, which is to minimise therapy-related side effects, while optimising its efficacy to achieve the best individualised therapy [23]. Radiomics and pathomics are two promising and innovative fields based on accumulating quantitative image features from radiology and pathology screenings as therapeutic and prognostic indicators of disease outcome [24-26]. Many artificial intelligence technologies, such as machine learning application, have been introduced to manage and elaborate the massive amount of collected datasets and to accurately predict the treatment efficacy, the clinical outcome and the disease recurrence. Prediction of the treatment response can help in finding an ad hoc adaptation for the best prognosis and outcome. Radiomics is intended as the high throughput quantification of tumour properties obtained from the analysis of medical images [27-29]. Pathomics, on the other side, relies on generation and characterisation of high-resolution tissue images. Many studies are focusing on the development of new techniques for image analysis in order to extrapolate information by quantification and disease characterization. Flexible databases are required to manage big volumes of data coming from gene expression, histology, 3D tissue reconstruction (MRI) and metabolic features (positron emission tomography, PET) in order to identify disease phenotypes [30].

Currently, there is an urgent need to define univocal data acquisition guidelines. Some initiatives to establish standardized procedures and facilitate clinical translation have been already undertaken, such as quantitative imaging network or the German National Cohort Consortium. Precise description of the parameters required for image acquisition and for the creation and use of computational and statistical methods is necessary to set robust protocols for the generation of models in radiation therapy. According to the US National Library of Medicine, approximately 50 clinical trials involving radiomics are currently recruiting patients and a few have already been completed [31].

Bacterial Therapy

After Coley's initial observations, scientists discovered that certain species of anaerobic bacteria, such as those belonging to the genus Clostridium, thrive and consume oxygen-poor cancerous tissue whereas die when they come in contact with the tumor's oxygenated sides, meaning they would be harmless to the rest of the body [32]. These findings provided the rationale for using the bacteria as oncolytic agents. However, bacteria don't consume all parts of the malignant tissue thus underlying the need of combining the therapy with chemotherapeutic treatments. Thus bacteria can be implied as sensitizing agents for chemotherapy. Bacterial products like endotoxins (Lipopolysaccharides) have to some extent already been tested for cancer treatment. Bacterial toxins can be used for tumor destruction and cancer vaccines can be based on immunotoxins of bacterial origin [33]. Bacteria can be exploited as delivery agents for anticancer drugs and as vectors for gene therapy. Spores of anaerobic bacteria can be used for the aforementioned strategies because only spores that reach an oxygen starved area of a tumour will germinate, multiply and become active. The use of genetically modified bacteria for selective destruction of tumors and bacterial gene-directed enzyme prodrug therapy have shown promising potential.

Stereotactic Radiotherapy (SRT)

SRT is highly targeted specific treatment used to treat a variety of brain lesions, using traditional fractionations such as 60 Gy in 30 fractions.

Proton Beam Therapy

Proton beam therapy is an established technology that uses protons to deliver the radiation dose.This treatment is widely being used in the treatment of spinal and base of the skull tumors, prostate cancer especially in children and young adults.

Recent Discover Drug

Antibiotic: According to Encyclopaedia Britannica, antibiotics are the chemical compounds produced mostly by the microorganisms and injurious to other organisms from this group. It has been observed that some of the antibiotics also have anticancer activity and recently they have been used mainly as antitumor drugs.

Actinomycin D

Actinomycin D (dactinomycin) is a well-known antibiotic produced by Actinomyces antibioticus that exhibits antibacterial and antitumor activity. This drug has a chemical formula of C62H86N12O16 and a molecular weight of 1.26 kDa.  Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis. Mitoxanthrone, a quinone antibiotic has lower toxicities as compared to anthracycline antibiotic drugs. Actinomycin D is effective in the treatment of Wilms cancer, Ewing sarcoma, neuroblastomas and trophoblastic tumours, primarily in children. It is also used as a tool in the study of many cellular processes, such as the biosynthesis of cell macromolecules, RNA transport or viral replication. Following drugs containing actinomycin D: Actinomycin D, Cosmegen and Lyovac are available, among others, on the market [34].

Bleomycin

Bleomycin (BLM) is a mixture of glycopeptide antibiotics with cytotoxic properties, obtained from Streptomyces verticillus. Bleomycin A2 has a chemical formula of C55H84N17O21S3 and a molecular mass of 1.42 kDa, while in the case of bleomycin B2 it is C55H84N20O21S2 and 1.43 kDa. Bleomycin, another class of antibiotics which include bleomycinic acid, BLMA2 and B2 are also structurally related phleomycinins and tallysomycins, are a family of glycopeptide derived antibiotics isolated from the Streptococcus verticullis species and are essentially used with other agents for treating tumors like squamous cell carcinomas and malignant lymphomas. The basic core structure consists of the basic glycopeptide with a pyrimidine chromophore linked to a propanamide, a β aminoalanine amide and L-glucose and 3-O carbmoyl-d-mannose. A tripeptide chain and a bithiazole moiety are attached to this core. The major issue of this drug is early drug resistance and pulmonary toxicity. Their mode of action is exerted using sequence selective metal dependent oxidative cleavage of DNA and RNA in the presence of oxygen, mitochondrial damage and also DNA fragmentation. They have been seen to produce abnormal G2 phase cells during cell cycle. Other adverse effects include significant skin reactions, erythema and gastric ulcers [35].

Doxorubicin

Doxorubicin (DOX) is an anthracycline antibiotic with antitumor activity, originally isolated from Streptomyces peucetius var. caesius. It is an amphiphilic molecule containing two parts: water-insoluble aglycone (adriamycinone: C21H18O9) and water-soluble, amino-sugar functional group (daunosamine: C6H13NO3) [36]. DOX acts on the nucleic acids of dividing cells by two main mechanisms: (i) intercalation between the base pairs of the DNA strands and inhibition of the synthesis of DNA and RNA in rapidly growing cells by blocking the replication and transcription processes; and (ii) generation of iron-mediated free radicals, causing oxidative damage to cellular membranes, proteins and DNA. DOX belongs to the most commonly used drugs in chemotherapy. Nowadays, this substance is recommended by the Food and Drug Administration (FDA) in the case of acute lymphoblastic leukaemia, acute myeloblastic leukaemia, Wilms’ tumour, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin’s disease, malignant lymphoma and bronchogenic carcinoma in which the small-cell histologic type is the most responsive compared with other cell types Preet et al. demonstrated that combining doxorubicin with nisin may improve the treatment efficiency of the skin cancers. Adriblastine PFS, Caelyx, Doxorubicin medac, Doxorubicin-Ebewe, Doxorubicinum Accord and Myocet belong to the drugs containing doxorubicin [37].

Mitomycin C

Mitomycin C was isolated from a strain of actinomyces, Streptomyces caespitosus. Its molecular formula is C15H18N4O5 and a molecular weight of 334 Da. Mitomycin, class of antibiotics is a broad spectrum antibiotic and in contrast to others form covalent linkages to DNA and function as bioreductive alkylating agents in the absence of oxygen [38]. They were isolated from the broth culture of Streptomyces caespitosus. The core structure is a configuration of a quinone, an aziridine and a carbamate moiety around a pyrrole 1,2-indole nucleus. The mechanism of action involves crosslinking of two complementary strands of DNA and attachment of the drug to a single strand for alkylation. Reduction of the quinone moiety makes the drug a potent alkylator and the acid activation considering the acidic environment around tumor cells, of mitomycin is a second mechanism that activates it as an alkylater. It is also postulated to form reactive oxidative species apart from alkylation. The side effects are often unpredictable and dose dependent. Anorexia, necrosis and ulcers have been reported for most patients. Pulmonary reactions anemia, renal failure has also been indicated with this treatment.

Another class of antibiotics is the enediyne antibiotics that are very amenable for design and have remarkable biological activity. Their anticancer activity is apparently due to their ability to damage DNA through radical-mediated hydrogen abstraction. The enediyne antibiotics show markedly cytotoxicity’s against cancers in vitro and in vivo [39]. One example of this class is Lidamycin.

Enzymes

Some of the bacterial enzymes, like arginine deiminase and l-asparaginase, are utilized in the treatment of selected cancer diseases.

Arginine Deiminase

Arginine deiminase (ADI) is an enzyme secreted by Mycoplasma hominis or M. arginini that degrades arginine to citrulline in vivo, releasing ammonia [40]. Recent studies are based on pegylated arginine deiminase (ADI-PEG20). The efficacy of ADI-PEG20 is directly correlated with the deficiency of argininosuccinate synthetase (ASS) [41]. Arginine deiminase in its native form is strongly antigenic with a half-life of 5 h [42]. ADI-PEG20 (arginine deiminase conjugated to 20,000 mw polyethylene glycol) decreases antigenicity and increases serum half-life [43]. Arginine deiminase may control the growth of argininosuccinate synthase deficient or arginine auxotrophic hepatocellular carcinoma (HCC). The pegylated ADI shows moderate disease-stabilizing activity in HCC and constitutes a promising drug utilizing a high enzymatic deficiency in HCC. This is a safe and well-tolerated therapy, which may benefit patients with unresectable hepatocellular carcinoma. Recently, usage of arginine deiminase as a drug is in the phase II clinical study [44]. Also, prostate cancer cells (CWR22Rv1) are susceptible to ADI-PEG20 in vitro. Apoptosis, observed after 96 h of treatment by 0.3 mg/mL ADI-PEG20 is caspase-independent. The effect of ADIPEG20 in vivo reveals reduced tumour activity and growth. Additionally, authors describe autophagy induced by single amino acid depletion by ADI-PEG20. Autophagy was reported within 1 to 4 h of 0.3 mg/mL ADI-PEG20 treatment and it was an initial protective response to ADI-PEG20 in CWR22Rv1 cells [45]. A significant reaction, with cytotoxicity up to 50%, was also detected in the case of 4 glioblastoma cell lines (HROG02, HROG05, HROG10 and HROG17). The anticancer effect of ADI was independent of apoptosis, while reduction of cell proliferation was observed [46].

L-Asparaginase

l-asparaginase (ASNase) enzyme was obtained from Escherichia coli or Erwinia species. The anti-tumour action of bacterial ASNases is caused by their ability to reduce asparagine blood concentration causing a selective inhibition of growth of sensitive malignant cells [47]. Panosyan et al. [48] presented that ASNase treatment in vitro resulted in dose-dependent growth inhibition of the following brain tumour cell lines: a paediatric medulloblastoma (DAOY), p53 and PTEN null human glioblastomas (GBM-ES and U87). Recently, ASNase has been utilized in the treatment of acute lymphoblastic leukaemia (ALL), myeloblastic leukaemia, Hodgkin and non-Hodgkin lymphomas, myelosarcoma, multiple myeloma, extranodal NK/T cell lymphoma and ovarian carcinomas [49]. Erwinia asparaginase should be used for the second- or third-line treatment of acute lymphoblastic leukaemia (ALL), depending upon regulatory requirements, in patients developing hypersensitivity to E. coli asparaginase preparations [50].

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