Multidisciplinary treatment of cancer

1.- Surgery of peritoneal or pleural carcinomatosis with chemotherapy in hyperthermia (HIPEC), according to the Sugarbaker technique.

Peritoneal carcinomatosis is a frequent manifestation of therapeutic failure in patients with digestive and gynecological cancer, and often the form of presentation. Despite curative surgery, between 20-30% of patients will develop a local recurrence. It has been classically considered as a sign of generalized disease and a therapeutic challenge, treated in a palliative way and inevitably fatal outcome. Most patients with peritoneal carcinomatosis die in the first 6 months. These patients often suffer disabling symptoms as a result of local tumor progression, well above other cancer patients.

Despite the bad forecast of this entity, since the 1980s there is an interest in its treatment, highlighting the technique described by Prof. Paul H. Sugarbaker. This procedure consists in the combination of a radical excision surgery with the maximum possible dose of chemotherapy applied directly in the peritoneal cavity in the surgical act, the levels of drug in the area to be treated impossible to find systemically due to its toxicity. These drugs are enhanced by heat (43ºC), which also has a cytotoxic effect by itself. The international community at a consensus meeting agreed to refer to this technique as HIPEC.

Initially, this therapeutic modality was applied in peritoneal pseudomyxoma and malignant peritoneal mesothelioma, diseases in which it has been established as a standard treatment thanks to the clinical benefits achieved in patients affected by these infrequent pathologies. In the 2000s the application of CR + HIPEC has been extended to other types of peritoneal carcinomatosis, such as colorectal and ovarian origin, being used in a growing number of cancer centers in Europe and North America (around 250). The standardization of the surgical techniques initially described by Sugarbaker (Peritonectomy Procedures) to achieve radical debulking and the systematization achieved in the HIPEC, reported by Elias and other European groups, have made this multidisciplinary therapeutic approach safer and more reproducible.

The published clinical results describe important improvements in patient survival and acceptable morbidity and mortality rates that can convert the CRS + HIPEC into the new treatment standard.

Surgical procedure.
he procedure is performed under balanced general anesthesia (epidural catheter) and strict monitoring of all hemodynamic parameters as a first step. Subsequently, a midpiopubial laparotomy is performed and the entire abdominal cavity is explored. Firstly, the patient's tumor burden is evaluated and the carcinomatosis index (PCI) is obtained, dividing the abdomen into thirteen areas, from zero to twelve, as described by Sugarbaker, taking cytological samples and biopsies. The resection of the primary tumor when it is present, is done following the oncological criteria (lymphadenectomy and correct margins). Following the guidelines of Prof Sugarbaker, the removal of the peritoneum (peritonectomy) and of the tumoral masses is carried out with the final objective of not leaving a macroscopic tumor (visible to the human eye).

Peritoneal perfusion and hyperthermia.
After the first phase of surgery, peritoneal perfusion is continued following the open technique of Coliseum, as described by Sugarbaker. The catheters are connected to a sterile circuit and by means of rollers of an extracorporeal circulation machine and at a rate of 500-1000 ml / min., The perfusion of the drug diluted in 3 - 5 liters of peritoneal dialysis fluid is started. The circuit goes through a heat exchanger that raises the temperature to 48ºC. The duration of this perfusion varies according to the drug used (30-90 minutes), during which the surgeon distributes the fluid in the cavity intermittently, and there must be special attention to the hemodynamic parameters. The temperature of the liquid when entering the abdominal cavity ranges between 42º - 43º C.

Discussion.
Peritoneal carcinomatosis can occur concomitantly with the primary tumor or as a relapse after surgical resection. In the first, cell dissemination is spontaneous after a serous invasion by the tumor or perforation of the affected organ. In the second case, carcinomatosis can occur even in the absence of lymphatic or hematogenous metastases. The spread of tumor cells in the peritoneum can be spontaneous or occur during surgery, by mechanisms such as the formation of tumor emboli by pressure, the leakage of malignant cells by cutting the lymphatic vessels or planting them in the peritoneal cavity during the surgical dissection. It is usually followed by the invasion or perforation of the serosa.

Once the primary tumor is removed, the cell growth factors involved in healing stimulate the growth of viable malignant cells trapped or in intraabdominal blood clots, or by fibrin on traumatized peritoneal surfaces. In parallel, the entrapment of these cells makes it difficult for them to access systemic chemotherapy, diminishing or nullifying their efficacy.

Since 1980, new proposals have appeared in the literature for the treatment of patients affected by peritoneal tumor dissemination, a group of difficult therapeutic and emotional management, derived from the perspective of therapeutic failure with rapid and progressive loss of quality of life.

In 1982, Sugarbaker proposed the peritoneal dissemination of certain cancers as a locoregional stage of the disease and developed a therapeutic alternative based on the surgical treatment of macroscopic peritoneal disease by radical cytoreductive surgery followed by HIPEC to treat residual microscopic disease. The surgery allows the reduction of the peritoneal disease to a minimum size and liberates all the adhesions, creating the optimal conditions to obtain greater efficiency of the cytostatics. The antineoplastic effects of chemotherapy are enhanced by heat due to the increase in cell permeability, by alteration of the active transport of drugs and the alteration of cellular metabolism.
With this therapeutic approach, 5-year survivals of 30% and 50% were obtained in selected groups of patients who until then were considered terminal patients. Similar results were reported by other groups after the implementation of this complex technique.

A multicenter study with 506 patients affected by peritoneal carcinomatosis of colorectal origin, showed better prognosis for the complete cytoreduction arm and HIPEC compared with incomplete surgery only (mean survival 32.4 vs 8.4 months). He also reported a 5-year survival of 31%.
Verwaal et al. conducted the first phase III study, randomizing 105 patients with peritoneal carcinomatosis due to colorectal cancer. Half of the cases followed standard treatment and the other group surgery + HIPEC. After a mean follow-up of 21.6 months, the survival of the first group was 12.6 months and 22.4 months in the HIPEC group p = 0.032. In the latter, those patients in whom complete cytoreduction was performed (R1), only 1 patient of 18 died. 14 patients out of 21 who had residual tumor less than 2.5 mm (R1a) died, and 7 patients out of 10 who had extensive residual disease died at follow-up.
The same group analyzed the results of 117 patients treated with cytoreduction + HIPEC, obtaining a 5-year survival of 43% 18.

Data from the work of Elias et al. with oxaliplatin (460mg / m2) and 5-FU (400 mg / m2) with leucovorin (20 mg / m2) intravenously 1 hour before perfusion yielded the best results published to date (5-year survival of 48.5% with a median of 60.1 months).

We could compare the situation of limited peritoneal carcinomatosis to that of isolated hepatic metastases, in which good long-term survival results can be achieved, performing surgical exeresis of macroscopic disease and subsequent systemic treatment for residual microscopic disease. The combination of cytoreductive surgery and perioperative intraperitoneal chemotherapy in peritoneal carcinomatosis of colorectal origin achieves 5-year survivals similar to those published for the resection of liver metastases of the same origin.

2.- Liver surgery Ablation of tumors by radiofrequency.

3.- Perfusion of extremities with TNF and Melfalan in the treatment of Melanomas in transitoy Extremity sarcomas.

Isolated limb perfusion (ILP) provides excellent local control and prevents amputation in advanced tumors of the extremities, used palliatively significantly reduces local complications of uncontrolled disease (pain, bleeding, superinfection) with positive impact on quality of life.

Material and Methods: The procedure consists of the dissection of the main vessels of the limb, followed by the cannulation thereof and connection to an infusion set. All infusions were developed in hyperthermia, at a temperature of 39 ° C, with TNFα (90 ') and melphalan (60').

Conclusions: ILP with TNF, melphalan and hyperthermia is a very effective procedure to achieve local control and prevent the amputation of the affected limb, with the consequent curative or palliative impact.

Introduction.
Soft tissue sarcomas are a heterogeneous group of malignant tumors originating in mesenchymal tissues. Its incidence is relatively low (1.8 cases per 100,000 people / year).

The tumor grade, depth and size are the most important prognostic factors, tumors > 5cm and grade III have a high rate of therapeutic failure (> 60%). The initial treatment is based on surgical excision with wide margins and / or radiotherapy. The unfavorable prognostic factors are positive margins, local recurrence and localization in the lower extremities [1-3]. The rates of response to systemic chemotherapy are low, ranging between 20 and 40%. The most active agents in the first line are adriamycin and ifosfamide.

Melanoma is a malignant tumor originated from the melanocytes, cells derived from the neural crest, with a very aggressive behavior. After surgical treatment with appropriate margins, between 5% and 18% of high-risk melanomas (Breslow> 2 mm, presence of ulceration, positive or recurrent lymph nodes) will develop lesions in transit during their evolution [4]. The 5-year disease-free survival rate in patients with stage III melanoma treated with amputation ranges from 25 to 33% [5,6].

Currently there are different therapies for the treatment of lesions in transit of melanoma: electrochemotherapy, radiotherapy, carbon dioxide laser ablation, intralesional therapies (BCG, interleukin-2, interferon, TNFerade ....).

In an attempt to control locoregional disease, the technique of limb perfusion was developed in the United States. It was used for the first time by Creech et al. in 1958 [5,7].

ILP is indicated in locally advanced melanoma (metastasis in transit, bulky tumors, multicentric and unresectable) and in soft tissue sarcomas, as a single treatment or associated with other modalities [8-12]. It allows the use of concentrations of chemotherapy or biological agents 15-25 times greater than those that could be used systemically [10,13].

Hyperthermia itself produces cytotoxicity on tumor cells [5,13]. In neoformed tumor vessels it causes stasis and decreased flow, causing intrinsic damage to tumor tissues [5,10]. Its concomitant use in ILP increases the efficacy of antitumor agents, increasing the response rate.

Method.
After the histological diagnosis, all patients undergo complete staging with PET-CT, brain MRI and CT angiography or angiography, in order to obtain more information about the state of the affected limb. To the usual reasons for exclusion in high-risk surgery, the presence of brain disease not controlled by the need for systemic anticoagulation is added.

After the histological diagnosis, all patients undergo complete staging with PET-CT, brain MRI and CT angiography or angiography, in order to obtain more information about the state of the affected limb. To the usual reasons for exclusion in high-risk surgery, the presence of brain disease not controlled by the need for systemic anticoagulation is added.

The ILP is performed in the operating room. It begins with the dissection of the iliac, femoral or popliteal vessels in the event that the lesion is located in the lower limbs, depending on the height of the approach to the location of the lesions in the case of sarcomas; and in the axillary vessels when they are located in the upper limb. The collateral vessels are ligated and cannulas are inserted into the artery (Bardic 16-18 F) and into the vein (Portex 6-8 mm). Both cannulae are connected to the extracorporeal circuit with oxygenator (Performer, Medtronic®) .. A tourniquet is placed around the base of the extremity for the complete isolation of the systemic circulation [11,14] and 99Tc-albumin micro-colloid is injected (Vasculocis®) [15] in the perfusion circuit for leak monitoring.

Once the absence of leakage from the circuit of the limb to the systemic circulation is verified by means of a gamma detection probe placed in the precordium [15] and moderate hyperthermia (38.5ºC), controlled by subcutaneous and intramuscular thermometers, is administered. the drugs. The dose of TNF-α used is 3 mg for the upper extremity and 4 mg for the lower extremity for 30 minutes. After the same, melphalan was administered (13 mg / L volume of the upper limb and 10 mg / L volume of the lower limb). Perfusion is maintained for an additional 60 minutes, except for incidents that require the interruption of the procedure.

The described administration sequence enhances the joint effect of both drugs, increasing the efficacy of melphalan by changes in the microcirculation of the tumor lesions induced by TNF and hyperthermia [5].

After the perfusion, the extremity is infused with abundant physiological serum, the tourniquet and cannulae are removed, the hemostasis is checked and the blood vessels are repaired.

Discussion.
The current treatment of locally advanced melanoma presents different possibilities. Radiotherapy has been used as adjuvant treatment after resection of the primary lesion or regional metastatic nodules, for the control of the disease and prolongation of survival in patients who are not candidates for surgery or regional chemotherapy. Used in a palliative manner, a percentage of response between 60-79% in stage III has been demonstrated. High-dose hypofraction regimens have better results, with survival between 2 and 8 months [16-17].

In patients with melanoma and sarcoma, other local therapies have been used. Electrochemotherapy consists of the application of high intensity electrical impulses that generate pores in the cell membrane and allow them to selectively enter previously administered cytostatics. It produces local vasoconstriction (<24 h) that allows the drug to remain longer in the tissue. It can be used in areas previously irradiated or perfused (figure 3) It allows to improve the quality of life in patients with bleeding and painful lesions. The most common complaints are irritation at the site of the injection and sensation of electroshock [17].

For small and numerous injuries, carbon dioxide laser ablation has been used. It can be performed on an outpatient basis with local anesthesia and the procedure can be repeated. The wounds heal in about 6 weeks. It can be combined with other regional therapies [17].

Regarding the different intralesional therapies, the use of BCG (Bacillus Calmette-Guérin) has been abandoned due to high morbidity and without survival benefits; interleukin 2 and interferon have induced responses of varying intensity and duration [18]. TNFerade is a TNFα gene inserted into an adenovirus that is mitigated by radiation and chemotherapy. It is used intralesionally to reduce its toxicity. It has synergism with radiation, increasing its effects, without increasing tissue damage [19,20].

Systemic chemotherapy has low response rates (between 11% and 17% for distant metastases). It is an option to consider in patients who are not candidates for ILP [17].

ILP allows the selective treatment of the affected extremity with high doses of cytostatics and / or biological agents, favoring the response and avoiding the appearance of systemic effects. Hyperthermia is cytotoxic per se and produces a capillary dilation in tumor tissue that increases up to 6 times the flow. The use of TNF in combination with melphalan has been extensively studied in melanoma and locally advanced or unresectable sarcoma of the extremities [21-23]. Its use was approved in Europe in 1998 thanks to a multicenter study [11,24]. TNF acts synergistically with melphalan producing a greater peritumoral inflammatory response, increasing tumor vascular permeability and prolonging the effects of chemotherapy [5,25]. The control of loco-regional disease can turn an unresectable tumor into resectable and reduces the percentage of local recurrence; allows the conservation of the limb in curative or palliative programs (figure 5); significantly reduces local complications of uncontrolled disease, such as bleeding or superinfection, with a marked impact on quality of life [26,27].

In those patients in whom the first infusion has failed, it is feasible to repeat the procedure with a high percentage of responses and prolongation of the disease-free interval, with moderate toxicity [5,28,29].

The expression of EMAP II in melanoma biopsies is currently being analyzed to predict complete responses to ILP [30].

Being a local therapy, there is no impact on the overall survival of the patient that depends on the prognostic factors of his disease.
Morbidity is related to the local effects of chemotherapy and hyperthermia ranging from mild erythema to epidermolysis or amputation. A toxicity greater than grade II is not related to a greater response [31].

ILP with TNF and melphalan in the experience of the different centers that perform it achieve overall responses above 80% and avoids the amputation of about 87% of the perfused members [10,32,33]. The results reported here (93.4% of global responses, 86.7% of amputations avoided) are comparable to those of the literature.

Conclusions.
ILP with TNF, melphalan and hyperthermia in melanoma and sarcomas in extremities is a proven treatment option, not only in terms of response but also in better quality of life and limb preservation.

It requires an interdisciplinary team that has at its disposal the appropriate infrastructure and has passed the accreditation process.

The experience of the Oncology Platform reproduces the results of the literature, being a program of habitual application in candidate patients, own or referred.


4.- Electrochemotherapy for the treatment of non-operable skin tumors.

5.- Intraoperative radiotherapy in the treatment of breast cancer, retroperitoneal tumors, rectum, pancreas, gastric, etc.

6.- 'ONE STEP' therapy in early breast cancer

The primary objective of the initial surgical approach of early breast cancer is in general common, and it should be the extirpation of macroscopic disease with free margins (R0) and adequate axillary staging.

It is convenient to permanently review strategies in the initial approach to early breast cancer that comprise the so-called 'ONE STEP therapy'. Protocols that seek to optimize the processes of multidisciplinary coordination for a better result, anticipating difficulties and possible complications. The Mama Unit of the Hospital Quirónsalud Torrevieja strives to keep up with scientific and technological advances and to make available to patients all the elements necessary for an adequate control of the disease.

Our goal is to get the patient who intervenes for early breast cancer to leave the operating room with their controlled disease, properly staged and with the best possible aesthetic result.

All patients diagnosed with breast disease are referred to the Breast Unit Consultation.

The current experience of the Mama Unit of the Hospital Quirónsalud de Torrevieja and Hospital Quirónsalud San Carlos de Murcia is of more than 400 assessed patients. In women with early breast cancer (stages 0-IIA), the entire disease is limited to the breast or breast and regional lymph nodes and the process is potentially curable.

Thanks to this path we can say that the revolution of technological development in histopathology, immunohistochemistry and molecular biology differentiates as many breast cancers as patients and consequently the treatment of breast cancer has to be individualized and must be designed 'to measure'.

Initial ratings.
1. Initial senological consultation by Surgeon Mastologist. Preparation of the Senological Clinical History. Anamnesis and complete physical examination complemented according to the case by Nuclear Physician, Radiotherapist and Psycho-oncologist
2. Front mammary photographs - lateral obliques
3. Digital mammography in cranio-caudal and oblique projections
4. High resolution bilateral mammary and axillary ultrasound
5. Needle biopsy of the suspicious nodule and FNAP of any suspicious axillary ganglion in the presence of the pathologist.
6. Preoperative analysis (Chest x-ray, electrocardiogram, complete analysis, tumor markers)
7. Assessment by anesthesia
8. Study of paraffin blocks or histological plates by our pathologists when the patient comes from another hospital.
9. Stereotactic biopsy of microcalcifications. Marking with biopsied micro-calcification area clips
10. Biological characterization of tumor type with immunohistochemical analysis (RE, RPg, Ki67, HER2, FISH, LVI, grade.
11.Magnetic resonance with breast coil and analysis of biodynamic curves, measurement of tumor volume and breast volume. Assessment of commitment by mammary segments
12. Thoraco-abdominal CT for staging.
13. Multidisciplinary meeting and proposal for surgical intervention
14. Signature of informed consents for oncological and reconstructive surgical procedures
15. Indication of the BRCA1 and BRCA2 tests in patients with suspected genetic disease or high family component (previous assessment by consultation of genetic counseling).

In this way we make sure that the patient must arrive at perfectly staged surgery. Knowing exactly what kind of extirpation will be done and what kind of reconstruction will be used.

Pre-operative techniques.
1.Lymphatic mapping of the sentinel node with Nuclear Medicine techniques
2.ROLL and SNOLL ultrasound in non-palpable tumors visible by ultrasound
3.Harpoon placement by stereotaxy in grouped microcalcifications
4.Lymphatic mapping of the internal mammary chain in patients with tumors of internal quadrants

Surgical techniques.
1. Filming procedures
2. Use of intra-operative ultrasound and technical alternatives for the prevention of deformities originating in each breast segment:

  • Segment I (lateral): defect remodeling by mobilizing the upper pole tissue; medial mobilization of the CAP with circular pattern or lateral mammoplasty.
  • Segment II (upper): periareolar incision, remodeling of the defect with local tissue or Round Block, horizontal mammoplasty or vertical mammoplasty.
  • Segment III (infraclavicular): Periareolar incision, Incision not visible in segment II, axillary access in tumors near the axilla, or vertical mammoplasty with mobilization of tissue to segment III.
  • Segment IV (upper medial): Periareolar or inframammary incision, remodeling of the defect through mobilization of upper pole tissue or vertical mammoplasty with mobilization of tissue to segment IV.
  • Segment V (lower medial): infra-mammary incision, remodeling with adipofascial flap or lower rotation mammoplasty or vertical mammoplasty.
  • Segment VI (lower): vertical mammoplasty, remodeling with adipofascial flap.
  • Segment VII (infra-mammary): Infra-mammary incision or adipofascial flap or vertical mammoplasty.
  • Segment VIII (central): Central quadrantectomy and local remodeling or vertical mammoplasty with or without CAP reimplantation.

3. Mastectomy when appropriate in multi-centric tumors or with extensive intraductal component. We prefer conservative skin or skin approaches and CAP.
4. Sending of pieces duly marked and oriented to the pathologist for intraoperative assessment of margins.
5. X-ray of the surgical specimen in the presence of microcalcifications or ultrasound of the specimen in non-palpable tumors.
6. Axillary incision, identification with the help of the gamma probe and with the presence in the operating room of the Nuclear Physician and excision of the sentinel lymph nodes indicated in the preoperative gammagraphy
7. Intra-operative analysis of the sentinel lymph node by Pathological Anatomy.
8. Responses to written intraoperative studies (sentinel lymph node, tumor size and margin assessment). If the ganglion is positive, our behavior is the complete axillary emptying of the 3 levels of Berg with preservation of the pectoralis minor muscle, the thoracodorsal vasculo-nervous bundle and Bell's long thoracic nerve.
9. X-ray of the axillary dissection specimen (axillogram). Useful in the evaluation of suspicious lymph nodes and in the counting of the number of excised axillary lymph nodes
10. With the confirmation of negative margins and negative sentinel node in the indicated cases we proceed to intraoperative radiotherapy with the protocols of Milan and Salzburg using our linear electron accelerator Mobetron Intraop
11. In the cases that will do external radiotherapy: marking of surgical margins with titanium clips that will serve as guides for the administration of radiotherapy boost in the tumor bed
12. In cases of mastectomy we recommend immediate reconstruction with expander / prosthesis, or with large dorsal flaps + prostheses, TRAM or DIEP
13. Depending on the case, some mammary symmetrization technique may be proposed that may be performed during the same surgical procedure.

Duration of Hospitalization.
The duration of hospitalization is usually 24 to 48 hours depending on the type of intervention that has been performed (shorter in lumpectomy and quadrantectomy with sentinel lymph node, longer in mastectomy and in axillary dissections) and the need or not for the use of drains.

Postoperative recommendations.
At hospital discharge, a detailed report is delivered that includes the tests performed, the type of intervention and the treatment recommendations that generally refer to the daily cures of the surgical wound with antiseptic, the use of a fitted sports bra without hoops or the upper thoracic mastectomy band, the use of analgesics and the recommendation to request a control appointment for outpatient consultations.

Postoperative controls.

Normally the first cure is performed one week after the intervention, the wounds are checked, drains are removed and serum collections (seromas) are drained when they are present. The reports of pathological anatomy and the possible need for adjuvant oncological treatment will also be discussed in the controls. In patients who have undergone axillary emptying, it is necessary to start a lympho-drainage and shoulder rehabilitation therapy in this period.

Once the wound has healed the patient continues its adjuvant treatment by Oncology and / or Radiotherapy according to the biological characteristics of the tumor, the age of the patient and the pathological staging of the disease.

7.- Minimally Invasive Robotic Surgery and Assisted by the Da Vinci Robot