Progress in the Multidisciplinary Cancer Treatment

Old wisdom and breaking news in oncology 2015

Nicolae GhilezanCorresponding member of the Romanian Academy

The medical knowledge was always a fast developing field but since the advent of informatics the speed of change is tremendous and the amount of new data is overwhelming, so for a practitioner, the task to be up to date could be often, a very difficult one. Facing these problems, the physician today has to choose between a practice – not always fully satisfactory, but still quite reliable, and some breaking news, well touted, but not yet fully known. Fortunately, there is a good and rapid access to high level information from many very reliable sources but ultimately, it is our critical judgment based on a good clinical practice that should lead us toward our ultimate goal, a good quality of life for our patients.

In the last 10 years, two of the most impressive advances have been made in oncology: the advent of immunotherapy as the 4th pillar of cancer treatment, and the precision medicine, the way of how the medicine will be delivered in the near future.

For long time, even if signs of an immune defense have been recognized, the attempts to trigger efficient mechanisms failed until the inhibitory pathways were identified. The discovery by JP Allison of the role of CTLA-4, the molecule that acts as an “off” switch for T cells led to the development of ipilimumab, approved by FDA in 2011, for unprecedented survival rates in metastatic melanoma. Since then, immunotherapy is in a full and rapid development.

Precision medicine, a treatment targeted to the needs of individual patient, is based on his genetic, biomarker, phenotypic or psychological characteristics. This implies the convergence of an immense amount of information and new technologies, a tremendous challenge for the physician to manage it: memorization is no longer enough and increasingly the informatics must be used, not for replacing judgment but for providing facts. Besides the patient, many other actors are involved in this process as physicians,

Continous mediCal eduCation

payers, representatives of health system, diagnostic and pharmaceutical industries, whose goals are not always the same but for their mutual interest, all of them have to look for a rigorous and correct evaluation of pitfalls and benefits.

Both these new concepts, have in common as a starting point, the old medical wisdom – a sound clinical judgment, which identified and finally solved a difficult question – how really work the immune system, and the second, how to integrate and harness the tremendous progress in all fields of science, biological and informatics as well, for the benefit of the individual patient.

Continuity and innovation in the treatment of lung cancers

Tudor Eliade CiuleanuUniversity of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca.Cancer Institute “Prof. Dr.Ion Chiricuta” Cluj-Napoca

Lung cancer prognosis has slightly improved in the last decade as a result of a better multidisciplinary use of the traditional treatments (surgery, radiation oncology and chemotherapy) but also due to some novel innovative treatments such as EGFR-TKIs, ALK inhibitors, antiangiogenic MoAbs and checkpoint inhibitors.

Quantitative milestones of the last decade are represented by: establishing the value of the postoperative adjuvant chemotherapy (st. II, III, some IB); confirmation of the superiority of concomitant radiochemotherapy for the locoregionally advanced disease, as well as of the inappropriateness of the maintenance therapy in this setting (stage III); confirmation of the equivalence of the platinum plus 3rd generation cytotoxic agents as 1st line treatment for the metastatic disease (stage IV); demonstration of the role of docetaxel as 2nd line treatment.

Qualitative milestones are represented by: - the registration of a new cytotoxic agent (pemetrexed), - the registration of several novel targeted treatments

(EGFR-TKIs - erlotinib, gefitinib and afatinib; anti-VEGF

32 Progress in the multidisciplinary cancer treatment

MoAb – bevacizumab; anti-VEGFR MoAb –ramucirumab; ALK inhibitors –crizotinib, ceritinib; and anti PD-1 MoAbs – such as nivolumab).

- the confirmation of the value of some therapeutical strategies (maintenance treatment in stage IV; 1st line use of EGFR-TKIs or ALK inhibitors in patients with driver mutations, superiority of checkpoint immunomodulators over docetaxel as rescue treatment).

While the role of the classical chemotherapy seems to have reached a plateau, at the present time a better definition of the driver mutations permits an individualization of the treatment. Some strategies are tested to overcome resistance to targeted agents. An exciting near future seem to be represented by the introduction in the clinical practice of the immune-modulating drugs (such as the immune checkpoint modulators).

The role of Radiotherapy (RT) in improving treatment outcome in Small Cell Lung Cancer (SCLC)

Petronela RusuInstitute of Oncology “Prof.Dr.Ion Chiricuta”, Cluj – Napoca, Romania

Background: Major improvements of treatment outcome with RT in SCLC were the addition of RT to Chemotherapy (ChT) and prophylactic cranial irradiation (PCI) in limited disease (LD) as well as in extended disease (ED).

Purpose and Methods: For a further improvement in treatment outcome a review of literature and publications has been proceeded in order to answer questions concerning timing, fractionation, dose, volume and techniques of RT, and treatment decision for elderly patients.

Results: Although conflicting data and debatable evidence, further improvement in thoracic RT for LD can be summarized as use of RT as early as possible, preferably from the 2nd cycle of ChT in selected patients (pts), high but adapted intensity of RT concerning fractionation. For the appropriate volume the general approach is of inclusion in RT volume the initially involved lymph nodes but reduction of volume within pulmonary parenchyma according to ChT response and omission of elective nodal irradiation. Concerning technique a translation from NSCLC, with superior efficacy of 3D-CRT than 2D techniques, is expected in SCLC as well.

The use of PCI raised also questions for further improvements concerning brain imaging, timing in relation to ChT-RT, neurocognitive functions and QoL, use in early stages and elderly patients. The change of diagnostic policy from CT to MRI in brain imaging led to increase of detected brain metastases (BM) from 10% to 24%, meaning stage migration and fewer pts eligible for PCI. The short doubling time of 4-16 days, for BM from SCLC suggest an early start of PCI but concomitant use with ChT should be avoided because of increased toxicity. Neurotoxicity (NT) increased

also with higher total dose (p=0.03) and age. Neurocognitive functions as memory, communication and intellectual deficit worsened with time, therefore a hippocampal sparing technique has been proposed. Indication of PCI in early stages, especially in stage I should be weighted considering lower risk of BM versus higher risk of NT. Treatment in elderly needs a proper selection and evaluation of co-morbidity status, less intense ChT with earlier introduction of RT and carefully limited RT volume. Postoperative RT proved to be beneficial for N2 disease, but no benefit for early stages.

In Conclusion, an individualized, appropriate decision, should be used concerning volume, dose, fractionation and technique, in order to customize treatment according to patient needs.

State of the art in head and neck cancer

Elisabeta Ciuleanu Oncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca

Head and neck squamous carcinoma is a heterogeneous disease arising from the mucosal epithelia in the head and neck region, most commonly the oral cavity, oropharynx, hypopharynx, larynx and nasopharynx.

For nasopharyngeal carcinoma the radiotherapy is the cornerstone due to the radiosensitive behavior of this type of tumor and its deep-seated location. This is applied by single modality treatment for early stages (T1N0), and in addition with concurrent Cisplatin for loco-regional advanced stages (T2-3-4 N+). The addition of chemotherapy to radiotherapy significantly improved overall survival, with an absolute benefit at 5 years 6,3%.

It seems to be a strong relationship between post-IMRT 8-th week and 6 month undetectable plasma EBV DNA and 3-year survival. This suggested the use of early plasma EBV DNA as a predictor of survival.

In the early stages of laryngeal (T1-2N0-1) and hypopharyngeal (T1-2N0-1) carcinoma, gold standard is definitive radiotherapy or partial laryngectomy. For resectable, loco-regional advanced stages (T2N1-3Mo, T3-4N0-3Mo) concurrent chemoradiotherapy with Cisplatin, induction TPF followed in case of the response by chemoradiotherapy, or laryngectomy with neck dissection followed by radiotherapy are indicated. In unresectable stages concurrent chemoradiotherapy or induction TPF for obtaining a downstaging in view of laryngectomy is the treatment of choice.

In case of early node negative oral cancers (T1-2N0) elective neck dissection (END) improved significantly overall survival and disease free survival, compared with watch and wait policy with therapeutic neck dissection (TND). END should be the standard of care for early stage node-negative oral cancers (tumor depth >3 mm). For

Progress in the multidisciplinary cancer treatment 33

resectable loco-regional advanced oral cancers (T2-3-4 N+) the gold standard is the excision of primary and neck dissection, followed by radiotherapy. Unresectable tumors are treated by concurrent chemoradiotherapy.

For early oropharyngeal carcinoma (T1-2N0) the standard of care is definitive radiotherapy. In case of loco-regional advanced stages (T3-4N0-3) concurrent chemoradiotherapy is indicated; alternative surgery with postoperative radiotherapy. HPV + and HPV- , oropharyngeal carcinoma are separate entities with significant differences in outcomes. Current staging system does not reflect this differences. A new staging system will allow for rational development of treatment approaches.

Actualities in Melanoma and Sarcomas

Dana IancuOncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca

Melanoma is a malignancy that appears from melanocytes, a neural crest-derived cell migrated during the embryogenesis to the skin, mucosa, conjunctiva, meninges and uveal choroid. Incidence of malignant melanoma is increasing due to increased UV light exposure.

Wide excision of primary tumor with safety margins of 2 cm for tumor with Breslow thickness more than 2 mm is recommended. Complete lymphadenectomy is not associated with prolonged survival in patient with positive sentinel node.

Currently approved drug for adjuvant therapy in patients with high-risk primary melanoma(stage IIB/C, stage III) is Interferon alpha 2 B. Surveillance imaging with FDG-PET is effective to detecting asymptomatic relapses and thus favoring early treatment in the follow-up stage III melanoma.

Chemotherapy is not effective and is not associated with survival advantage in treatment of metastatic melanoma Due to identify of new targets in melanoma: BRAF-V600 mutation (approximately 50% of patients), CTLA4(cytotoxic T lymphocyte antigen 4) ,PD-1,PD-L1(programmed death-1 receptor and its ligand), the treatment of metastatic melanoma has been updated. In recent years, more new drugs (3 immunotherapy and 3 molecular targeted therapy) - Ipilimumab, Nivolumab, Pembrolizumab, Vemurafenib, Dabrafenib, Trametinb have received approval for treatment of metastatic malignant melanoma. Combination of 2 targeted agents or 2 immune checkpoint inhibitors (BRAFi/MEKi vs. BRAFi; antiCTLA4/antiPD1 vs. antiCTLA4) is better that one with higher response rate and improved progression free survival.

Sarcomas are rare and represent a heterogeneous group of solid tumors originating from mesenchimal tissue.

Doxorubicin, alone or in combination remains the standard first line treatment for inoperable/ metastatic sarcomas. It is superior to combination Docetaxel

+Gemcitabine and less toxic. There no consensus for second line treatment, most agents are available (Ifosfamide, Trabectedin, Pazopanib). Regorafenib, Eribulin have activity in leyomiosarcoma and liposarcoma.

For gastrointestinal stromal tumors, driver mutation of kit is present. Adjuvant therapy with 3 years of Imatinib remains standard for GIST with high-risk features, improving overall survival versus 1 year of Imatinib. For inoperable /metastatic GIST standard treatment is Imatinib in first line, Sunitinib in second line and Regorafenib in third line. Recently, Pazopanib is a new well tolerated active treatment in GIST resistant to Imatinib and Sunitinib.

State of Art for Ductal Carcinoma In Situ

Carmen Popa, Radu Tanasescu, Daniela MartinOncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca

Ductal Carcinoma In Situ (DCIS) is a neoplastic process that is confined to the ductal system of the breast and lacks histologic evidence of invasion. This entity lacks the ability to metastasize and is confined to the breast. Axillary-node involvement is rare (0% to 5%) and most likely is associated for invasive carcinoma.

Risk factors for the development of DCIS are the same as those identified for invasive carcinoma including family history, reproductive events such as delayed age of first live birth and nulliparity, history of benign breast biopsy, and dietary factors.

Before the use of screening mammography, DCIS is typically presented as a palpable mass or nipple discharge. The widespread use of mammography now routinely detects a small area of abnormal calcifications (DCIS <1 cm in diameter) in asymptomatic women and results in breast cancer-free survival rates that approach 100%. Clinicopathological features or molecular alterations can be identified in individuals with high-risk breast lesions that will progress to invasive breast carcinoma. Some evidence indicates that genetic heterogeneity and clonal evolution could result in the development of an invasive phenotype in DCIS lesions.

Current management options for DCIS include breast-conserving surgery plus radiation therapy or breast-conserving surgery alone or sometimes mastectomy. In situ malignancy (DCIS) is treated with breast conservation surgery providing clear resection margins can be achieved. There is no general consensus on what is regarded as an adequate margins; however, margins <2 mm are considered inadequate. With further definition of risk, patients in the lowest risk stratum might be able to forgot local excision and be treated by image-guided core biopsy and hormonal therapy. Adjuvant breast irradiation after BCS decreases the risk of local recurrence but has no effect on survival. Five randomized control trials have demonstrated that

34 Progress in the multidisciplinary cancer treatment

breast radiotherapy significantly reduces cancer recurrence following complete excision for DCIS. In the meta-analysis of trials of breast-conserving surgery plus radiotherapy versus breast-conserving surgery alone, the 10 year risk of an ipsilateral event in those allocated to lumpectomy alone was substantial at 30,1% and the addition of radiotherapy resulted in a 10 year absolute gain of 18%.

Adjuvant hormonal therapy, specifically Tamoxifen, is also becoming more standard in the management of estrogen receptor positive DCIS. Aromatase inhibitors (AI) are being investigated for the adjuvant therapy of DCIS but should not be used in routine care. Current guidelines recommend discussion of tamoxifen chemoprevention with premenopausal women at high risk of breast cancer, and discussion of tamoxifen, raloxifene and exemestan with postmenopausal women at high risk of the disease.

Local recurrence in patients with DCIS are usually detected on surveillance mammography, although one quarter may be detected on the basis of changes in physical examination of the breast or chest wall. Patients with recurrent DCIS have an excellent prognosis, with less than a 1% risk of further recurrence after salvage mastectomy. Patients with invasive recurrence after breast-conserving surgery for DCIS have a prognosis similar to those with early-stage breast cancer, with a 15% to 20% risk of recurrence at 10 years and 10% developing a contralateral breast cancer within 15 years of a DCIS diagnosis

The challenge remains to accurately predict an individual patient’s risk of recurrence post lumpectomy to make treatment recommendations. Identification of patients unlikely to benefit from radiation therapy postlumpectomy may also serve to reduce use of mastectomy.

This paper is a review of the currently available data regarding the management of DCIS when making individual patient decisions.

New Targets and Therapies for Her2-Positive Breast Cancer

Dana GreceaOncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca

Neoadjuvant systemic therapy improves surgical outcomes and is a platform for translational research and clinical trials. pCR is a surrogate marker in neoadjuvant setting, being associated with improvement in event rates [EFS] and overall survival [OS].

Five-year analysis of the phase II NeoSphere trial evaluated four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P). Three-year survival rates, hazard ratios (HRs), and 95% CIs for the main analysis of P_T_D compared with T_D. Longer-term outcomes as defined by three-year survival rates, are in line with the results of the primary endpoint (bpCR), suggesting a

benefit of P added to T_D that persists over time despite use of identical adjuvant therapy in the P_T_D and T_D arms. These results also support the association between pCR and improvements in long-term outcomes.

Efficacy of 12-weeks of neoadjuvant TDM1 with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer:

WSG-ADAPT HER2_/HR_ phase II trial. Evidence suggests differential efficacy of standard neoadjuvant chemo- targeted therapy in HER2_ early breast cancer (eBC) according to hormone-receptor (HR) status. ADAPT HER2_/HR_ aims to identify responders to dual targeted therapy, which has not been widely. Overall pCR rate was 30.8%: A: 40.5%, B: 45.8%, C: 6.7%. The difference between either arm A or B vs. C was significant (p _ 0.001), but not A vs. B. Exploratory analysis suggests benefit of adding ET to T-DM1 in pre- (pCR: 28.6% for T-DM1 single agent vs. 47.6% with ET). The interim analysis demonstrates for the first time clinically meaningful pCR rates (_ 40%) after only 12 weeks of T-DM1_ ET without systemic chemotherapy in HER2_/HR_ eBC.

Phase III, randomized study of trastuzumab emtansine (T-DM1) _ pertuzumab (P) vs. trastuzumab _ taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study. In phase II and III studies, treatment with T-DM1 or with P _ H _ docetaxel has shown statistically significant increases in progression-free survival

(PFS) and overall survival (OS) vs. control regimens in patients with HER2-positive MBC. The combination of T-DM1 _ P resulted in synergistic inhibition of tumor cell line proliferation in vitro. This and preliminary data from a phase II clinical trial provided the rationale for further study. In MARIANNE (NCT01120184), patients with centrally assessed HER2-positive (IHC3_ or ISH_) progressive/recurrent locally advanced BC or previously untreated MBC with a _ 6-month interval since treatment in the (neo)adjuvant setting with taxanes or vinca alkaloids were randomized 1:1:1 to HT (docetaxel or paclitaxel _ H), T-DM1 (T-DM1 _ placebo, hereafter T-DM1), or T-DM1 _ P, at standard doses. The primary end point was PFS assessed by independent review. Comparisons between HT and T-DM1 or T-DM1 _ P were considered separately. PFS was tested first for non-inferiority and for superiority only if non-inferiority was achieved. These data demonstrate non-inferiority in PFS between T-DM1–containing arms and control. T-DM1– containing regimens were associated with a different toxicity profile than the control regimen.

Predictive biomarkers of everolimus efficacy in HER2_ advanced breast cancer: Combined exploratory analysis from BOLERO-1 and BOLERO-3. Two phase 3 trials BOLERO-1 and BOLERO-3 evaluated the addition of everolimus (EVE) to trastuzumab (TRAS) _ chemotherapy in HER2_ advanced breast cancer (ABC). In BOL-3, heavily pretreated patients (pts) derived a statistically significant benefit from EVE, while BOL-1 (first-line EVE) did not

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meet the primary endpoints. This analysis aimed to identify biomarkers predictive of EVE efficacy using data from both trials. A trend of greater benefit from EVE was observed in pts with PI3K pathway activation (individual trials). In a combined analysis from both trials, pts with PIK3CA mutations (HR _ 0.69) or low PTEN (HR _ 0.5) derived more benefit from EVE. A robust positive correlation between PI3K hyperactivity and PFS benefit was observed using both narrow def (HR _ 0.67 vs.normal PI3K activity HR _ 1.2) and broad def (HR _ 0.61 vs. normal PI3K activity HR _ 1.38). In a multivariate analysis, interaction between PI3K status and treatment effect was statistically significant (p _ 0.016).This exploratory analysis suggests that pts with hyperactive PI3K signaling pathway derive greater benefit from adding EVE to TRAS _ chemotherapy in her-2 +.

Correlation of PIK3CA mutation with pathological complete response in primary HER2-positive breast cancer: the trial combined data from three studies evaluating PIK3CA mutations as predictor for pCR; the neoadjuvant GEPAR studies (n _ 504) (Loibl et al. JCO 2014), the Neo-ALTTO study (n _ 355) (Majewski et al. JCO 2015) and the CHERLOB study (n _ 108) (ESMO 2014). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to taxane-based chemotherapy. PIK3CA was genotyped in tumor biopsies prior to therapy. Overall, pCR rate was significantly lower in the PIK3CA mutant (mut) compared to the wild type (wt) group (16.2% vs. 29.6%; p _ 0.001). There was no difference in pCR rate whether the mutation was in exon 9 (15.7%) or exon 20 (16.4%). Within the HR_ subgroup the PIK3CA mut pts had a pCR rate of only 7.6% compared to 24.2% in the wt group (p _ 0.001). In contrast, the difference in pCR (27.2% vs. 36.4%) according to PIK3CAmutation status was not significant in the HER2_/HR- group (p _ 0.125; interaction p _ 0.036). The pCR rate for mut vs wt was 20.3% vs. 27.1% for T (p_0.343); 11.3% vs. 16.9% for L (0.369) and 16.7% vs. 39.1% for T/ L (p _ 0.001). In the HR_ T/L group the pCR rate was 5.5% vs. 33.9% (interaction p _ 0.008). This metaanalysis confirms a significantly lower pCR rate in HER_, PIK3CA mutant tumors after anti-HER2 treatment. Patients with a HER2_/HR_/PIK3CA mutant tumor had a pCR rate of 5.5% only when treated with double-blockade and might be considered for alternative treatment.

New challenges in Breast Cancer Radiotherapy

Daniela Martin, Radu Tănăsescu, Carmen Popa, Dana GreceaOncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca

The main goal of radiotherapy (RT) is to eradicate residual tumor deposits and to reduce their potential risk of dissemination. It has been recognized that post-operative radiotherapy decreases the risk of loco-regional relapse

of breast cancer by about two thirds 75%, irrespective of the type of surgery, the nodal status or the use of adjuvant systemic therapy. Improve in local control translates into a better cancer-specific and overall survival, validating the crucial role of radiotherapy in the primary treatment of non-metastatic breast cancer. In breast cancer, radiotherapy is given after conservative or radical surgery, adapted to patient and tumor characteristics.

This presentation is an overview of recent publications regarding two aspects: first, the evidence based data which validate the crucial role of radiotherapy in the primary treatment of non-metastatic breast cancer and, second, the new challenge of personalized local treatment.

The challenge of personalized loco regional treatment is to identify tools using new classification of LRR based on molecular subtypes/ gene assays to select patients for whom RT is indicated but who are not today’s candidates according to guidelines or very low risk patients for whom RT can be reduced or even omitted. The main questions are: Which patients will benefit from better local-regional control? How to improve prognosis to identity the patients in need for further treatment?

Before we try to answer these questions it’s important to review the progresses in technology, biology and clinical trials that have been made in the last years. The integration of RT with surgery and systemic therapy showed us several important facts:

1. breast conservative treatment is an alternative to radical mastectomy2. whole breast RT (WBRT) improves local control and survival3. local recurrence rate (LRR) is significantly reduced by boosting the tumor bed4. short fractionation is equivalent to standard for selected patients5. WBRT combined with SNB,1-2 + nodes is an alternative to ALND for selected patients6. postmastectomy RT (PMRT) in 1-3 + axillary nodes improves local control and survival.Irradiation of internal mammary nodes (IMN) was

controversial; incidence of clinically apparent IMN relapse is low in patients receiving adjuvant systemic therapy. In the era of multidisciplinary therapy is associated with low rates of IMN recurrence. Recently published trials showed significant benefit in DFS for WBRT+RNI in 1-3 N+ and N0 high risk patients – NCI Canada MA20; EORTC 22922/10925: postoperative RT to the IMN and supraclavicular nodes improves OS, DFS and DMFS in patients with stage I-III breast cancer.

In the contemporary management of breast cancer, several possibilities exist for local and regional treatment. A better understanding of the risk of local relapse (LR) and regional relapse (RR) would facilitate therapeutic decision making. Gene expression profiling can be used to separate breast cancers into distinct molecular subtypes with

36 Progress in the multidisciplinary cancer treatment

prognostic significance. Although most studies of molecular subtypes in breast cancer report differences in survival, few have examined the differences in local-regional recurrence. The influence of breast cancer molecular subtypes on local-regional relapse and their relevance compared with established clinicopathologic variables has not been defined.

Using new classification of LRR – based on molecular subtypes, gene assays may identify patients where RT is indicated but who are not candidates for it with today’s guidelines.

Until definitive treatment strategies are validated in large datasets and confirmed in randomized trials, TNBC subtype, in and of itself, should not direct local-regional management treatment decisions.

Ultimately, local-regional management decisions should be made for the individual patient while taking into consideration their age, stage of disease, clinical and pathologic variables, and patient preference.

Clinical Research in the Genomic Era

Gabriela Morar-BolbaOncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca

Cancer is the result of somatic evolution driven by diversity, selection and replication. Understanding the processes that shapes the evolution of individual tumors and the effect on the entire body might help us to treat cancer more efficiently. Heterogeneity among tumors and intra tumor heterogeneity has been demonstrated and recognized, but is still difficult to treat.

The increasing number of targeted agents warranting clinical assessment, coupled with the increasing molecular fragmentation of breast cancer and thus the respective decrease in prevalence of putative predictive biomarkers, render the current clinical trial paradigm inefficient. Clinical trial design strategies have evolved over the past few years as a means to accelerate the drug development process so that the right therapies can be given to the right patients. Basket, umbrella, window-of-opportunity trials, master-protocol trials, and adaptive enrichment strategies represent a class of novel designs for testing targeted therapeutics in oncology.

This presentation aims to discuss the fundamentals of these design strategies, advantages and disadvantages, challenges and the potential clinical benefit.

Hyperthermia – state of the art

Radu Tanasescu, Carmen Popa, Daniela MartinOncology Institute “Prof. Dr. Ion Chiricuta”, Cluj-Napoca

Although curative properties of heat are known from antiquity, the scientific basis of this method of treatment

were available only in 1960, when Crile noted potentiation effects of hyperthermia on radiotherapy mechanisms of action. There followed a series of fundamental and practical discoveries, and between the 80s and early XXI century it have been established the place and role of hyperthermia as a complementary therapy of standard methods, radio and chemotherapy, in patients with advanced or metastatic cancers.

In the early 2000s we assisted to a period of regression of thermotherapy, because the results have not been enhanced as technological advances did. However, no one noticed that the target group of patients was the same, advanced or metastatic stages, and standard methods were in largely exhausted.

Reviving hyperthermia occurs but now, through the introduction of a system called „oncothermia” or „electrohyperthermia”, which led to a paradigm shift „tissue necrosis” heat apoptosis induction model.

In this paper we try to point out what is actually hyperthermia treatment method in the present and possible role in perspective, considering that appear increasingly more patients with advanced disease, where „traditional” methods are no longer a viable solution, if applied singular.

Radiotherapy in the third millennium: A historical perspective

Valentin CerneaUniversity of Medicine and Pharmacy “Iuliu Hatieganu” Cluj NapocaOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca

Radiation a relatively young medical specialty registered spectacular advances from its beginning more than 150 year ago. Considerable evolution especially in two last decades is the result of great technological advances in production technology of X-rays and computerized planning systems but also in axial imaging techniques.

Long time seen as a local or loco-regional acting treatment radiation therapy has determined in many tumor sites survival benefits not only by improving local control but also by decreasing failures due to distant metastasis. These data underscore that the local/regional treatments essentially „stop metastases at source.”

Advances in knowledge of cancer biology but also in deciphering biology and tissue response to irradiation have been considerable over the past century but influenced less radiotherapy practice than technological advances.

Only in recent years knowledge of the molecular bases of DNA damage and repair is starting to influence clinical practice. Bystander effect recently discovered, highlights the need of investigation of the entire tumor microenvironment for understanding the response to irradiation. Many of these advances in the understanding of radiation effects are leading to new thinking in the design of targeted therapies.

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The radiotherapy major challenge will be represented by how research laboratory will be linked to the clinic. The goal of these efforts is to treat only patients that can benefit from treatment and only with the intensity that is required. Application of molecular biology in the clinic will make this possible.

Radiation oncology for elderly patients: review of evidence-based guidelines and future perspectives

Ovidiu CozaUniversity of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-NapocaOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca

Cancer in elderly patients represents an increasing complex problem. By 2020, more than 50% of all new diagnosed patients with cancer will be older than 65 years of age and more than 30% older than 75 years of age in most European countries. The complexity of this issue is represented, on one hand, by the host heterogeneity increased with ageing due to co-morbidities, less effective treatment regimens due to physiologic changes and the need for social support, and, on the other hand, by the lack of evidence-based guidelines, absence of randomized studies and inadequate observational research.

Radiotherapy remains a cornerstone of the multidisciplinary management of solid tumors and is an attractive curative option for older patients, significant advances in radiation planning and delivery having improved the efficacy of radiotherapy, while reducing toxicity.

We present a review of radiotherapy indications in the most frequent types of solid cancers in elderly patients, based on the evidence-based guidelines provided by the International Society of Geriatric Oncology (SIOG) task force. Also, priorities for future radiotherapy research in the elderly are briefly proposed.

The role of palliative radiotherapy for the metastatic disease

Claudia OrdeanuOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca

External beam radiotherapy (RT) is a safe, time-efficient, cost-effective treatment for patients with metastatic cancer. In the last years an increasing number of studies show the benefits of radiotherapy used in the final months of life. RT is effective in controlling pain, neurologic and obstructive symptoms.

Multiple randomized trials have demonstrated the efficacy of RT in palliating pain from uncomplicated bone metastases. A single fraction of 8 Gy is equivalent to 5/6 fractions of 4 Gy and 10 fractions of 3 Gy, according to the ASTRO guidelines.

For brain metastases, the ASTRO guidelines describe neurosurgical resection, stereotactic surgery (SRS) and whole-brain RT. The last one remains the standard of care for patients with no SRS or surgical resection indication. Multiple studies show no statistically significant differences in overall survival or symptoms control for the dose fractionation of 5 fractions of 4 Gy, 10 fractions of 3 Gy, 15 fraction of 2.5 Gy or 20 fractions of 2 Gy.

Palliative thoracic RT is indicated for patients with advanced lung cancer including cough, hemoptysis, dyspnea, symptoms of superior vena cava syndrome and chest pain. For patients with o good prognosis a higher dose of RT offers a survival advantage in contrast to the data for bone and brain metastases.

For liver metastases there are several RT techniques: whole liver RT (WLRT), selective internal RT, brachytherapy, conformal fractionated RT and stereotactic techniques (SBRT). SBRT is a highly effective treatment for ablation of liver metastases, due to mild or moderate toxicity. This treatment is indicated for patients with limited burden of intrahepatic and extrahepatic disease.

30 up to 40% of all radiation treatment are given with palliative intent, and due to availability of new technologies there has been an increasing complexity in treatment of oligometastatic disease.

Palliative RT is becoming more important; but to answer the questions regarding the best palliative RT technique and the optimal dose fractionation, research must continue.

State of the art in Gastrointestinal Cancer

Alina-Simona MunteanOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca

Bakground. Advanced oesophago-gastric cancer has a poor prognosis and has limited options follow failure of 1st or 2nd line chemotherapy. INTEGRATE, a randomized phase II trial, examined the efficacy and safety of regorafenib vs. placebo in refractory advanced oesophagogastric cancer (AOGC). Regorafenib was highly effective in prolonging PFS, with a nonsignificant trend in OS and was well tolerated. Phase III evaluation is warranted. In relationship between PD-L1 expression and clinical outcomes in patients with advanced gastric cancer, another monoclonal antibody, anti-PD-1, Pembrolizumab (MK-3475) was investigated in KEYNOTE-012 trial. Primary efficacy end point is ORR and secondary end points include duration of response, PFS and OS. The 6-month PFS rate was 24% and 6-month OS rate was 69%. Pembrolizumab demonstrated manageable toxicity and promising antitumor activity in advanced gastric cancer. These results support the ongoing development of pembrolizumab for gastric cancer. Also, Rilotumumab (R) is a fully human monoclonal antibody, targets selectively the only ligand of the MET receptor, HGF. In RILOMET-1 phase III randomized trial, R + ECX was evaluated as first-

38 Progress in the multidisciplinary cancer treatment

line therapy in 608 patients with advanced MET-positive G/GEJ cancer in terms of efficacy and safety compared with ECX. OS, PFS and ORR were statistically worse in the R arm. No subgroups seemed to benefit with R, including those with higher percentages of cells with ≥ 1+ MET expression. RILOMET-1 did not meet its primary endpoint; OS was statistically significantly worse with R. PK and MET biomarker analyses are pending. In nonmetastatic adenocarcinoma of G or GEJ, chemotherapy in addition to surgery improves outcomes. UK Medical Research Council OEO5 ( phase III trial) investigated whether intensification of neoadjuvant chemotherapy with 4 cycles ECX before surgery would improves OS, DFS, PFS, R0 vs. 2 cycles CF. A trend to improvement in pathologic resection rate was observed, but this not translate in an improvement of OS.

Patients with advanced pancreatic neuroendocrine tumors (pNET), have currently a number of different treatment options: somatostatin analogs, mTOR inhibitors, VEGF pathway inhibitors and cytotoxic chemotherapy. In CALGB 80701 (Alliance) patients with locally advanced or metastatic pancreatic neuroendocrine tumors were randomized in a phase II study to receive either everolimus (E) or everolimus plus bevacizumab (E+B). Patients in both arms received concurrent standard dose octreotide. The primary endpoint was PFS. Secondary endpoints included OS, response rate (RR) and safety; Treatment with E+B was associated with higher RR and superior PFS, compared with E alone, combination of mTOR and VEGF inhibitors warrant further investigation in advanced pNET.

Pancreatic cancer is a challenge in oncology, the primary endpoint in adjuvant treatment after R0 resection is to increase SV. CONKO-005, a randomized phase III study was designed to evaluate an additional effect of the EGFR-tyrosinkinase-inhibitor erlotinib in combination with Gemcitabine in pts after R0 resection. The primary endpoint was DFS, secondary objectives were median OS and treatment safety. The combination therapy of GemErlo for 24 weeks did not improve DFS or OS, erlotinib is not active in adjuvant setting, current aproaches focused on regimens active in the advanced disease setting. In conclusion, in adjuvant treatment of pancreatic cancer, gemcitabine or 5-FU remain standard of care. Borderlineresectable (BRPC) requires multidisciplinary approach and standard treatment

Metastatic colorectal cancer

Calin Cainap University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-NapocaOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca

Metastatic colorectal cancer (mCRC) represent a category of disease with impressive improvements of therapeutically means. These new methods and new drugs allow to personalize the treatment to individual and

disease particularity. The latest evolution of the therapy has prolonged the overall survival from several months until almost 3 years. New genetic markers rise up from laboratory research as new prognostic or predictive markers regarding targeting therapy. Between them BRAF seems to be the new important obstacle to increase even more the excellent results reached so far. The vemurafenib treatment is nowadays used in clinical trials for BRAF mutated patients with m CRC.

Biological agents have no role in adjuvant setting and the optimal sequence in metastatic patients is still a controversy subject to be discussed. Even in “neoadjuvant” intention where conversion to resectability is the main goal the role of targeted therapy seems to be less convincible.

Duration of chemotherapy administrated in metastatic setting represents a constant question not only for patient but also for oncologist in order to maintain the positive effect of chemotherapy without decreasing the survival or disease control.

First line chemotherapy used matters in terms of overall survival and rate of response as TRIBE trail showed in ASCO this year.

The new data for overall survival in metastatic colorectal cancer reflects a cruel reality from the economic point of view - the general costs increased more than 45 fold from 5FU era. It remains very difficult to quantify the value of a life regarding to the society expenditure.

The purpose of this presentation is to update with the latest information regarding new developments in chemotherapy trials.

Actualities in Gynaecological Cancers

Viorica Magdalena NagyUniversity of Medicine and Pharmacy “Iuliu Hatieganu” Cluj NapocaOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca

Cervical cancer: Despite the declining incidence as a result of the introduction of screening programs, globally it remains a leading cause of cancer-related death in women. The use of low-dose chemotherapy concurrent with pelvic radiation has been proven to improve survival, and became the standard of care for locally advanced cervical cancer. A number of ongoing clinical trials are examining the role of adjuvant chemotherapy in addition to the standard-of care treatment for locally advanced cervical cancer: the OUTBACK trial, theTACO trial, the INTERLACE trial.

Outcome for women diagnosed with metastatic or recurrent cervical cancer remains poor; there are a number of potential therapeutic targets actively under investigation. The first biologic agent, in combination with chemotherapy, to show a survival benefit was the anti-VEGF antibody bevacizumab. The benefıt from bevacizumab was maintained in women with prior platinum exposure,

Progress in the multidisciplinary cancer treatment 39

recurrent/persistent disease, and responses were seen in previously irradiated fıelds.

Single agent, orally administered,multitargeted receptor tyrosinekinases inhibitors pazopanib improved PFS and OS. Targeting angiogenesis in cervical cancer has benefıts in terms of effıcacy, but patient selection is key and consideration of maintenance of QOL essential when considering future investigation of this therapeutic approach.

Investigation of immunomodulating agents and strategies which either enhancethe innate immune response to cervical cancer or repress immune-protective pathways are a very active area of cervical cancer research.

Ovarian cancer: The retrospective analysis of candidate predictive tumor biomarkers (BMs) for efficacy in the GOG-0218 trial evaluating front-line carboplatin–paclitaxel (CP) ± bevacizumab (BEV) for epithelial ovarian cancer (EOC) suggest a positive correlation between expression levels of molecular (tVEGF-A) and cellular (endothelial cell) targets of anti-VEGF and magnitude of PFS and OS improvement from BEV in EOC. The predictive value of these candidate efficacy BMs requires validation in other relevant datasets.

An international, biomarker-directed, randomized, phase II trial of AZD1775 plus paclitaxel and carboplatin (P/C) for the treatment of women with platinum-sensitive, TP53-mutant ovarian cancer demonstrated that AZD1775/P/C was associated with a significant increase in PFS when compared with P/C alone and showed acceptable tolerability in women with TP53-mutant OC.

The ARIEL2 phase 2 trial prospectively tested a novel next generation sequencing-based HRD assay and algorithm to predict rucaparib sensitivity by assessing tumor BRCA status and genome-wide loss of heterozygosity (LOH).

Ovarian Cancer in Older Women is a real problem, almost half of women diagnosed with ovarian cancer are older than age 64, and 25% are older than age 74. Therefore it is crucial to discriminate those patients who will and will not tolerate standard cytoreductive surgery (CRS) and chemotherapy. The ability to assess who is fıt enough to undergo aggressive CRS followed by chemotherapy and who should be offered an alternative pathway, such as NACT and iCRS or primary chemotherapy alone, is an unmet need. Several reports suggest that NACT increases the chance of an optimal CRS (defıned as no gross residual disease post surgery) with less surgical morbidity and no signifıcant effect on survival. The standard of care chemotherapy remains taxane and platinum-based regimens that vary in schedule and route of administration. Modalities do exist for assessing an older woman’s ability to tolerate surgery and chemotherapy. Geriatric assessment (GA) provides information about a patient’s functional status, comorbid medical conditions, cognition, psychologic status, social functioning support, and nutritional status. Several studies have demonstrated the predictive value of GA for estimating the risk of severe toxicity from chemotherapy. The Preoperative Assessment of Cancer in the Elderly

(PACE) tool was developed to combine elements of the comprehensive GA with surgical risk assessment tools in an older cancer population.

Endometrial cancer: Paclitaxel (PC) is a standard initial therapy for advanced endometrial cancer (EC). MITO END-2 trial compares carboplatin-paclitaxel (CP) vs. carboplatin-paclitaxel-bevacizumab (CP-B) in advanced (stage III-IV) or recurrent endometrial cancer. The addition of B to CP significantly increased PFS in recurrent endometrial cancer.

The GOG-86P randomized phase II study evaluated efficacy and tolerability of incorporating three novel agents: paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus and ixabepilone/carboplatin/bevacizumab as initial therapy for measurable stage III or IVA, stage IVB or recurrent endometrial cancer. PFS is not significantly increased in any Arm. OS is significantly increased in the PC + Bev arm.

Controversies in urogenital tumors

Cristina Ligia CebotaruOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca

Controversies in the management of Germ Cell Tumors- This section will discuss the treatment options and controversies for stage I Germ Cell Tumors and for Refractory disease, and also ongoing trials and mutational biology studies

Beyond Tyrosine kinase Inhibitor Therapy: Incorporating Immunotherapy and Metastasectomy into Renal Cell Carcinoma Management

- This session`s purpose is to discuss the new pathways and targets for Advanced Renall Cell Carcinoma, the possibility to integrate immunotherapy and other new agents into the current treatment paradigm and also the role of Metastasectomyin patients with Renall Cell Tumors

Integrating new approaches in Complicated Bladder Cancer

- New data on detection and monitoring of Bladder Cancer will be reviewed, and we`ll also cover challenges and difficulties in clinical application of adjuvant and neoadjuvant chemotherapy

PROSTATE CANCER- Any News for2015?

Gabriel KacsoUniversity of Medicine and Pharmacy “Iuliu Hatieganu” Cluj Napoca

From a daily practice changing perspective, the 2015 news in prostate cancer management- in my vision- are:

1. Clinical setting: Biochemical recurrencea) After radical prostatectomy (RP):

40 Progress in the multidisciplinary cancer treatment

- Randomized phase III trial (SAKK 09/10- Ghadjar P et al)): 70 Gy vs. 64 Gy salvage RT (of which >50 % was IMRT) does not significantly increase GI or GU acute ≥ G2 toxicity. (A 5038);- Randomized phase III trial GETUG16 (Carrie C et al): 66Gy/33fr (of which 46Gy/23 fr included the pelvis lymphnodes if no lymphnode dissection and Partin risk of involvement > 10 %) vs. same EBRT + 6 months of Gosereline translates into a better 5-years progression-free-survival: 79.6% vs. 62.1%, HR=0.50 (0.39-0.66, p<0.0001, without significant differences in QoL , nor G2 or G3 GU & GI toxicity. The 5 years overall survival was 96.2% vs. 94.8% (NS).- Prognostic Use of Genomic Classifier (GC) to stratify risk of metastasis, and to individualized salvage therapy, e.g.RT for low GC vs. RT + HT for high GC (Freedland et al);

b) After RP and/or RT:- Randomized phase III trial TOAD (Duchesne G et al): Immediate ADT improved 5 years OS by 10 % (logrank test, p=0.047) in a pooled analysis including also asymptomatic patients not suitable for curative treatment (localized or metastatic disease).

2. Clinical setting: metastatic hormone naive- ADDING up front DOCETAXEL (6 cycles like in Chaarted trial- ASCO2014) is confirmed by a second randomized phase III trial (STAMPEDE) with median survival of 65 months vs. 43 months (HR 0.73, p=0.002).

3. Clinical setting: high-risk non-metastatic: -ADDING 6 cycles of Docetaxel improves 4 year OS from 89 to 93% (HR 0.70, p=0.04) in RTOG0521 randomized phase III trial (Sandler H et al)

4. New Prognostic models: For mCRPC: - integrating LDH, BPI (Brief Pain Inventory Index), alkaline phosphatise (ALP) and bone metastasis burden (<10 or ≥10) is prognostic for Abiraterone Acetate treated mCRPC prior or after chemotherapy (Ryan C et al)

5. Other drugs: associated to androgen deprivation therapy(ADT): beneficial effect of Statin use with or without Metformin, in regard to time to progression under ADT (TTP 27.5 months vs. 17.4 months, p=0.0005) or to overall and prostate cancer specific mortality (Lu-Yao G et al)

New options for diagnosis and treatment of gliomas

Dana Michaela CerneaOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca, Romania

The diagnostic of gliomas is traditional based on histological and immunohistochemical features but in last years molecular dates become more and more important and complex. Molecular studies have identified genetic and epigenetic molecular markers that could be used to

improve tumor classification and better prediction of response to therapy and prognosis in individual patient. Most important molecular tests include: the detection of genetic aberrations in IDH1, IDH2, ATRX, H3F3A genes; co-deletions of chromosomal arms 1p and 19q has become of clinical relevance as an independent predictive marker to favorable response to radio-chemotherapy and better survival of patients with anaplastic gliomas; the status of MGMT promoter methylation has been linked to response to chemotherapy with temozolomide. In addition, novel microarraying or next generation sequencing –based techniques are promising perspectives in glioma diagnosis.

The classification of diffuse glial tumors taking account of increasingly amount of molecular information obtained in last years is now under revision. According to the new proposal these specific tumors can be divided in three molecular categories: 1- those with IDH mutations and 1p19q co-deletions (oligodendroglioma molecular type), 2- those with IDH mutations and ATRX loss (astrocytoma molecular type) and 3- those without of any of the aberrations mentioned above.

Major challenges will be to integrate these molecular markers with conventional classification and grading to WHO criteria in a new classification and to standardize molecular testing procedures for their application in clinical practice.

Treatment of low grade-gliomas (LGG) is a clinical challenge because of young and active patients. The objective is not only a maximum survival length but also a best quality of life. All treatments may cause a decrease in functioning due to motor deficits related to surgery, fatigue and different type off toxicities after chemotherapy and cognitive impairments after radiotherapy. The best time of first treatment is still on debate but current tendency sustain early surgery. Previous trials focused on radiotherapy failed to provide any difference of improved outcome for patients treated with higher total dose opposed to lower total dose. In consequence most patients are now treated with TD= 50,4-54 Gy. Delaying radiotherapy after surgery until the radiological progression did not adversely affect the patient outcome.

In 2013 and 2014 two important trials have been focused on the role of chemotherapy. RTOG-9802 trial has compared radiotherapy alone to radiotherapy followed by PCV chemotherapy in high-risk LGG patients. Initially results show any impact of PCV chemotherapy in patients outcome but with passage of time is clear that PCV provides a major survival benefit: median PFS increased from 4 years for RT alone to 10,4 years for RT+PCV and median OS from 7,8 years to 13,3 years. Oligodendroglial histology and

The Applications of Immunotherapy in Oncology

Claudia BurzCancer Institute Prof. Dr. Ion Chiricuta” Cluj-NapocaUMF “Iuliu Hatieganu”, Cluj-Napoca.

Progress in the multidisciplinary cancer treatment 41

The immune system is able to distinguish self from non self. The immuno – editing theory suggests the ability of immune system to recognize and eradicate subclinical tumors or to find equilibrium between tumor cells and body. Many tumors escape from this equilibrium and cancer becomes clinically apparent. Cancer treatment represents a challenge for both scientist and clinician. The most common treatments for cancer are surgery, radiation, chemotherapy, hormone therapy and targeted therapies. Most recently, several mechanisms by which tumor cells are able to escape the immune system have been elucidated. Many interventions named “immunotherapies” such as cancer vaccines, cytokines, or agents that block immune checkpoints are used with different efficacy in the treatment of cancer.

A better understanding of the interaction between tumor and immune system is crucial to the development of immunotherapies in the future.

The aim of this presentation is to review the basic immunology underlying an anti-tumour immune response, the main methods used for modulating immune system with clinical implications in the treatment of cancer.

Early detection of cancer and diagnosis of genetic predisposition

Zsolt Fekete

UMF “Iuliu Hatieganu” Cluj NapocaOncology Institute “Prof. Dr. Ion Chiricuta” Cluj-Napoca

Classical screening tests for cancer or precancerous lesions are continuously refined to reach higher sensitivity and specificity, lower side effects and higher acceptability. Sophisticated and tailored breast imaging, multi-option colorectal screening, chest-CT for lung cancer in heavy smokers are now among standard screening tests offered in high/middle-resource countries.

Beside these standard screening tests there are now several emerging early detection tests, which are extremely promising in finding even earlier stages of cancer or tumors types for which no standard detection tests exist.

Circulating tumor DNA (ctDNA), automatized cytology of the sputum, miRNAs, cytokines and other peptides are the main representatives of these “advanced detection” methods. There are several proof-of-concept studies for each of these and confirmation of their reliability and cost-effectiveness will follow hopefully soon.

Detection of high risk individuals is another area of interest to radically change cancer-specific survival. This includes detailed family history, genetic-predisposition testing (BRCA mutation, Lynch syndrome etc.) and detection of potentially cancer-causing viral infections.

Beside standard, population-at-risk testing, opportunistic testing might be offered in the future on an individual basis