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Neoadjuvant treatment by ECT in cutaneous malignant neoplastic lesions
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NEO-ADJUVANT TREATMENT BY ECT IN CUTANEOUS MALIGNANT NEOPLASTIC LESIONS Tommaso Fabrizio MD , Luigi Cagiano MD , Francesca De Terlizzi MSc , Michele Pio Grieco MD PII: DOI: Reference:
S1748-6815(19)30577-7 https://doi.org/10.1016/j.bjps.2019.11.063 PRAS 6369
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Journal of Plastic, Reconstructive & Aesthetic Surgery
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2 September 2019 23 November 2019
Please cite this article as: Tommaso Fabrizio MD , Luigi Cagiano MD , Francesca De Terlizzi MSc , Michele Pio Grieco MD , NEO-ADJUVANT TREATMENT BY ECT IN CUTANEOUS MALIGNANT NEOPLASTIC LESIONS, Journal of Plastic, Reconstructive & Aesthetic Surgery (2019), doi: https://doi.org/10.1016/j.bjps.2019.11.063
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NEO-ADJUVANT TREATMENT BY ECT IN CUTANEOUS MALIGNANT NEOPLASTIC LESIONS Tommaso, Fabrizio MD*, Luigi Cagiano MD*, Francesca De Terlizzi, MSc**, Michele Pio Grieco MD* *Division of Plastic Surgery, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy **IGEA Biophysics Lab, Carpi, MO, Italy
Corresponding Author: Tommaso Fabrizio, MD Chief of Unit of Plastic Surgery IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy Via Padre Pio, 1 95098, Rionero in Vulture, Italy Tel: 0039 (0) 972 726735 e-mail: [email protected] Istitutional Ethical Approval Number: 2311.82/07
TITLE PAGE NEO-ADJUVANT TREATMENT BY ECT IN CUTANEOUS MALIGNANT NEOPLASTIC LESIONS
Tommaso, Fabrizio MD*, Luigi Cagiano MD*, Francesca De Terlizzi, MSc**, Michele Pio Grieco MD* *Division of Plastic Surgery, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy ** IGEA Biophysics Lab, Carpi, MO, Italy
DECLARATION OF NO SPONSORSHIP, FUNDING, OR CONFLICT OF INTEREST: None of the above-mentioned authors has a financial interest or sponsorship, or funding, or conflict of interest in any of the products, devices, or drugs mentioned in this manuscript. All the authors declare and confirm that no financial support or benefit have been received by the first or any coauthor, by any member of his and their immediate families or any individual or entity with whom or with which, He or They have a relationship from any commercial source, which is related directly or indirectly to the scientific work, which is reported on in the article. All the authors approve the codes obtained by their ethical committee about the present research.
ABSTRACT Electrochemotherapy (ECT) is a local treatment and its use has been standardized for cutaneous nodules of any histologic origin. In the present study we use ECT as a neoadjuvant therapy in order to reduce the size of neoplastic lesions to obtain an ideal cleavage plane where vital or very important vascular and/or nervous structures are separated from the tumor, thus allowing a radical surgical excision, otherwise unfeasible. In their retrospective study the authors identified 41 patients that were treated at our institution with neoadjuvant intent. ECT was performed under general (30 pts, 73%), regional (9 pts, 22%) or local anaesthesia with sedation (2 pts, 5%). At a median time of 2 months (range 0.3-9) after neoadjuvant ECT, all patients underwent surgical intervention, in order to resect the residual tumour. Median reduction of tumour volume after ECT was 55% (range 10%-65%). After ECT plus surgery, 25 patients (61%) had a complete response (CR), 16 patients (39%) a partial response (PR). The percentage of CR in patients with larger lesions (>100mm) was 27%, in patients with smaller lesions (≤100mm) was 73% (p=0.0119). Major side effects after ECT were: bleeding and/or ulceration (54%) and pain (59%) naturally resolved in 1-2 months. Side effects observed after surgery were: necrosis of the flap (N=3), a case of diastasis of the donor site. Median survival time in CR patients was 53 months (range 4-108), whereas in PR survival was 23 months (range 5-126), p=0.0400. ECT represents a safe and effective therapeutic approach that could be effectively used for neoadjuvant purposes.
Keywords: Electrochemotherapy (ECT), neo-adjuvant therapy, solid malignant cutaneous lesions, morphological and functional reconstructive surgery, survival rate, complete response (CR), partial response (PR). INTRODUCTION Electrochemotherapy (ECT) is a local treatment for neoplastic lesions that have standardized its field of application in the last 7-10 years (1-3), more than two decades after the initial preclinical and clinical studies published in the 80’s and 90’s (4-6). It is a treatment based on the combination of a chemotherapeutic drug, having a specific intracellular target, and the local application of electric pulses (electroporation) to tumour lesions (7-8). Several studies have shown and confirmed ECT efficacy and safety in the treatment of cutaneous and subcutaneous lesions from any histological origin (9-11). Recently, new indications have been explored for the treatment of internal organs such as bone, liver, pancreas, (12-15) and specific indications such as vulvar cancer, soft tissue sarcoma, Kaposi sarcoma (16-19) have been studied in depth. Considering the current evidence, the authors of the present study have hypothesized the potential role of ECT as a neo adjuvant treatment of cutaneous or subcutaneous neoplastic lesions. In fact ECT may reduce the size of neoplastic lesions and/or lead to obtain an ideal cleavage plane where vital or very important vascular and/or nervous structures are separated from the tumor, thus allowing a radical surgical excision, otherwise considered unfeasible. Although a surgical radicalization is closely linked to the histological diagnosis of the lesion, it is also directly related to the reduction of the size of the tumor before surgery. Meaning that a greater reduction of the initial size of the tumor will be directly related to the achievement of surgical radicality. Thus, the incidence of local recurrences and distant metastases, even though dependent on the histological type, will be reduced. All this obviously translates into a greater percentage of disease-free survival (20-25). The neoadjuvant role of ECT has been already considered, though, in single cases and reported in literature as case reports (2629). The present work is the first fairly large cohort of patients with cutaneous metastases of
different histology treated with ECT with neoadjuvant purposes 3 months before radical surgery and reconstruction.
MATERIAL AND METHODS Patients From February 2007 to February 2017, among the totality of patients treated with ECT at the IRCCS- Referral Cancer Center of Basilicata, in Rionero in Vulture, Italy, we identified 41 patients that were treated with neoadjuvant intent. We aimed at reducing the size of the target lesions of these patients, to facilitate the following excisional surgery. Our institution obtained approval from ethics committee and data protection authority. The clinical information that was retrieved from the database included: demographics, histologic diagnosis of tumour, number of target lesions, site and size of the lesions, absence of distant metastases, time and details of ECT treatments, time and details of surgery, duration of follow-up. Patients treated had measurable cutaneous or mucosal lesions, suitable for application of electric pulses. Patients were ≥18 years old, had Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (33), a life expectancy of at least three months, if fertile, were using adequate contraception, and had been offered standard treatment options. Patients were not treated if they previously had allergic reactions to bleomycin or to any of the components required for anaesthesia, if the cumulative dose of 250 mg bleomycin/m2 (400.000 IU bleomycin/m2) had previously been exceeded, had chronic renal dysfunction (serum creatinine >150 μmol/l) or acute lung infection. ECT Procedure ECT was performed according to the ESOPE Standard Operating Procedures (SOP) (1,2). Bleomycin was administrated intravenously (i.v) or with an intra-tumour injection using 15.000 IU/m2 of body surface, depending on the number and size of lesions treated. To deliver the
electric pulses one of the following electrodes was used: 1) Type I electrodes: two parallel rows of needles with 4 mm between rows; 2) Type II electrodes: a hexagonal array of needles with 7.9 mm distance between each couple. Electric pulses (eight pulses of 100 μs duration) were delivered using a square wave electroporator (Cliniporator, IGEA, Carpi, Italy). After ECT, the treated lesions were covered with compressive haemostatic dressing. For each patient wound care was carried out according to the protocol in use in our Institution, including a short-term antibiotic prophylaxis with wide spectrum antibiotics, pain-relieving therapy with non-opioid drugs and only in the most refractory cases with elastomer-based morphine derivatives. Moreover, the ECT treated area was managed with a thermo-healing system that resulted very beneficial, especially in the first week after the ECT treatment, when a closed-loop continuous flow system of cold physiological solution at a temperature between 18 and 24 ° C (Hilotherm ™) was used (34). Surgery procedure The purpose of the present retrospective study was to test the neo-adjuvant application of ECT, to make surgically feasible an intervention otherwise considered not possible, due to the size of the neoplasm, its location and / or its tight relation with vital vascular or nervous structures. In this scenario, ECT treatment aimed to reduce the lesions’ size or to create a cleavage plane where the tumor and the above-mentioned structures could be separated. Therefore, the final goal of the surgical procedures adopted in the present study was the achievement of the oncological radicality, followed by the reconstructive surgical procedures able to obtain aesthetic and functional restoration. In Table 1, a descriptive analysis of the study population and the various surgical reconstruction techniques according with the different anatomical districts, where the tumors were localized, are showed. Response evaluation Since the purpose of ECT in this study was tumour volume reduction to facilitate excisional surgery, local tumour response to ECT treatment was evaluated by calculating the percentage of
volume reduction with respect to the volume measured before treatment. Regardless of the clinical assessment, a MRI or a CT scan was performed on each patient that underwent neoadjuvant ECT before and not more than 3 months after ECT treatment, to objectively evaluate the reduction of the size of the neoplasm. The overall local response was evaluated 2 months after surgical procedure, according to the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) (35). Complete response (CR) was defined as disappearance of the target lesion; partial response (PR) with at least 30% decrease in the diameter of the target lesion. Progressive disease (PD) was defined as at least 20% increase in the diameter of the target lesion and stable disease (SD) with neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD. The longest diameter of the tumours was recorded. Photographs were taken at the time of treatment, and at follow-up visits. Statistics Continuous variables were described by median value and range, categorical variables by absolute number and percentage. Data in contingency tables have been analysed by Chi Square test for independence. Different groups have been compared based on clinical variables of interest: localisation (head/neck vs other), size of lesions 10cm, diagnosis (SCC vs BCC vs other), primary vs secondary presentation. Overall survival was calculated from the first ECT up to death or last follow-up. Survival curves were calculated by the Kaplan–Meier curve. One-year survival and 95% confidence interval (C.I. 95%) were calculated using Kaplan-Meier survival analysis. Comparison between curves has been performed by Cox regression analysis. A p value lower than 0.05 was considered statistically significant. Statistical analyses were performed with NCSS 9 software (NCSS, LLC. Kaysville, Utah, USA).
RESULTS Among the patients treated with ECT in Rionero in Vulture, we identified 41 patients that were treated with neoadjuvant intent. Descriptive data of the patients are also reported in Table 1. ECT treatment ECT Treatment was performed under general (30 pts, 73%), regional (9 pts, 22%) or local anaesthesia with sedation (2 pts, 5%). Intravenous administration of Bleomycin was adopted in 38 pts, (93%) and intra-tumoral injection was performed in the remaining 3 patients (7%). Median treatment duration was 27 min (range 12-45 min). Hexagonal electrode was used in 27 sessions (66%) whilst linear electrode in 14 sessions (34%). Median number of electric field applications in each session was 51 (range 8-111). Median reduction of tumour volume after ECT treatment was 55% (range 10%-65%). Surgical treatment At a median time of 2 months (range 0.3-9) after neoadjuvant ECT, all patients underwent surgical intervention, in order to completely resect the residual tumour. Table 1 analytically shows the study population as clearly as the treated cases in relation to the type of surgery and reconstruction performed after the reduction of the tumor volume obtained with ECT. The reconstructive procedures were subdivided according with the anatomical localization of the tumor. In total, a reconstruction with flaps was performed in 38 patients (92%): out of the 38 patients, mio-cutaneous pedicle flaps were used in 5 patients ( 13%), a microsurgical miocutaneous flap was used in 1 case (3%), arterialized fascio-cutaneous perforators flaps in 28 patients (74%) and 4 propeller flaps for the remaining cases (10%). An amputation below the knee joint was performed in 2 patients (5%), while a disarticulation was done in 1 patient (3%). Two patients received three surgical interventions for the treatment of their tumour, one patient received 2 surgical interventions. Histological examination confirmed the achievement of
oncological radicality in 85% of patients. The surgical procedures allowed to carry out reconstructive interventions, which lead in most cases, to an excellent morphological result and a satisfactory organ function restoration of the operated areas. Outcome of ECT plus surgery treatment After ECT plus surgical treatment, 25 patients (61%) had a complete response, 16 patients (39%) a partial response. Percentage of CR in primary tumours was 58% and in secondary tumours 67% (p=0.7421). In BCC the percentage of CR was 100%, in SCC 45% and in other histological types 71% (p=0.0684). Lesions located in the head/neck region had a 55% of CR, whilst in other regions the percentage was 68% (p=0.5224). Finally, the percentage of CR in patients with larger lesions (>100mm) was 27% in comparison with the one observed in patients with smaller lesions (≤100mm), 73% (p=0.0119). Side effects After ECT treatment 54% of patients (N=22) suffered for bleeding and/or ulceration, which naturally resolved in within 1-2 months. Twenty-four patients (59%) suffered for pain in the treated area during the first weeks after treatment managed with pain killers. Two patients (5%) had a hyperpigmentation of the treated area. The side effects observed after surgery were: a case of subtotal necrosis of the flap (greater than 50%), 2 cases of partial necrosis of the flap (less than 50%), a case of diastasis of the donor site. After the application of dressings, in case of sub-total necrosis, a reconstruction with a local rotation flap was performed. Plastic repair was performed with skin grafting in the cases of partial necrosis. Diastasis of the donor site was repaired with subsequent skin suture.
Long term follow-up Patients were followed up for a median time of 47 months (range 4-126 months). At the last followup time, 14 patients were alive without disease (34%), 14 patients were alive with disease (34%), and 13 (32%) died for disease progression and visceral metastases. In the group of patients with a complete response to the combined treatment ECT + surgery, 4 patients (16%) died, while in the group of patients with partial response the number of deaths was 9 (56%), with a significant difference between groups (p=0.0144). Median survival time in patients with a complete response was 53 months (range 4-108), whereas in partial responders’ group the time of survival was 23 months (range 5-126), p=0.0400. Five-years survival rate was 84% (C.I. 68%-100%) in complete response patients, and 35% (C.I. 5%-65%) in partial response patients (p=0.0013). Kaplan-Meier survival curves for the 2 groups are shown in Figure 1. When considering the survival time in relation to percentage of tumour volume decrease after neoadjuvant ECT, we observed a significantly lower median survival time in patients with a reduction of tumour volume smaller than 55% (p=0.0236), as shown in Figure 2.
DISCUSSION The authors' experience on the use of ECT dates back to 2007. In the first years we applied ECT in standardized conditions, as described in literature, for the treatment of cutaneous or subcutaneous metastases of any histological origin (1-3). As reported by several authors, we also could observe that ECT has numerous advantages: minimal side effects on the patient, repeatability, capability to preserve organ functions and surrounding healthy tissue, well-tolerated by the patient, allowing an immediate recovery. ECT is also indicated for some types of primitive cutaneous tumors such as basocellular and spinocellular carcinoma (29-32). Kis et al. (32) concluded in a review article, that
ECT can therefore be applied to improve the patient’s quality of life, independent of life expectancy, to heal painful or bleeding lesions and to preserve patients’ appearance and social interactions, does not cause significant organ dysfunction or permanent disfigurement. Based on our and other experiences (26-29) we decided to explore the possibility to apply ECT as a neoadjuvant treatment identifying a particular cohort of patients who could benefit from this approach. To demonstrate the efficacy of ECT as a neo-adjuvant treatment, the present study was designed, set up and conducted with the intent of using ECT to reduce the size of the tumor and / or to create a cleavage plane where the neoplasm was separated from vital structures, such as nerves and / or vascular pedicles. Moreover, emphasis was given to the most effective reconstructive methods. Our approach had two objectives: 1. to facilitate a surgical intervention and radicality otherwise considered impossible, 2. to perform an appropriate reconstructive intervention in terms of restoration of functional and morphological integrity to preserve or improve the quality of life of the patient. In the present study, we report the results of neoadjuvant ECT followed by radical surgery and reconstructive procedures in the management of cutaneous neoplasms of different histology. The reduction in tumor size with ECT treatment can be achieved, thus allowing a radical surgery and reconstructive interventions with arterialized and more favorable restorative oxygenated flaps (Table 1). Overall, this oncological multiple-treatment approach resulted in a cosmetic, morphological and organ function preservation that secured the return to daily good quality of life (Figure 3-5). Similar results have been observed in case reports studies by other authors, in the treatment of primary breast cancer (26), anal melanoma (28), vulvar cancer (29), metastatic melanoma (27) Interestingly, ECT has been employed as a tissue-sparing treatment to reduce tumor burden for further treatments and surgery: one report described the use of preoperative ECT of anal melanoma to enable surgical resection with organ and function-sparing [28], in another report ECT was
effectively targeted towards cancer cells, sparing adjacent healthy tissue of the cheek [27]. Finally, for what concern primary breast cancer, authors claimed that the first ECT session led to a mass of cytoreduction while the intraoperative local ECT treatment made possible to succeed in the complete reclamation of the coastal wall in a long-term survival, without any local recurrence after 30 months of follow-up. Another important observation we could evidence from our data: comparative analysis of the survival time and the response rate to the combined treatment, complete response (CR) or partial response (PR), seemed to indicate that the survival time is directly dependent upon the response to treatment (chi-square test p=0.0013, significant correlation) (Figure 1). Furthermore, when neoadjuvant ECT obtained a reduction of the tumor size greater than 55%, it seemed to result in an equally important increase of the median survival time (chi-square test p=0.0236, significant correlation). This interesting observation could be of help during the decision-making process when, after neoadjuvant ECT, the tumor reduction rate is lower than 55%, suggesting to carry out, when possible, a second ECT session in order to obtain a further reduction in the size of the tumor lesion.
CONCLUSIONS Overall ECT represents a safe and effective therapeutic approach that could be effectively used for neoadjuvant purposes, allowing reconstructive treatments, leading to the restoration of good functional and morphological integrity with the preservation of the patient quality of life. ECT is associated with clear benefits for patients in terms of quality of life (minimal discomfort, mild posttreatment pain and patient satisfaction) and may, in the neoadjuvant setting, offer the opportunity for a more conservative surgery and a better cosmetic effect with complete local tumor control. Furthermore, considering that the employment of ECT does not prevent the use of a systemic chemotherapeutic treatment, neo-adjuvant ECT can be considered a valid option for the locoregional control of malignant neoplasms even in advanced stage, who have developed large skin
localizations. Even if there is already a literature that speaks of ECT with a neo-adjuvant purpose, the present work is, in the opinion of the authors, one of the few that clearly shows that the neo-adjuvant ECT has value in the local control of the neoplastic disease, resulting in a significant improvement in disease-free survival, especially if it is able to reduce the volume of the neoplasm by a percentage higher to 55% (Figure 2). Therefore, if the first ECT treatment does not allow it, a second application should be performed until this objective is reached. This allows a reconstructive plastic surgeon, engaged in the oncology field, the really important and never explored possibility of performing reconstructive interventions such as to improve the quality of life of the patient.
ACKNOWLEDGEMENTS The principal author sincerely thanks so much Dr. Giovanni Bozza, Dr. Raffaele Ardito, and Dr. Michele Aieta, Division of Oncology, Dr. Nicoletta Telesca, Division of Pharmacology and Dr. Antonio Colasurdo, Medical Director of IRCCS-Referral Cancer Centre of Basilicata for the active support given to the realization of this study.
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Table 1. Descriptive analysis of the study population and surgical reconstruction technique, according with tumour lesions’ localization. Size a and Size b indicate the orthogonal dimensions of the tumour.
MEDIAN
MINMAX
AGE
77
49-90
# NODULES
2
1-17
SIZE a (mm)
60
17-350
SIZE b (mm)
58
12-270
DIAGNOSIS
N
%
SQUAMOUS CELL CARCINOMA
20
49%
KAPOSI SARCOMA
6
15%
BASAL CELL CARCINOMA
4
10%
MALIGNANT MELANOMA
3
7%
SARCOMA
2
5%
LEIOMIOSARCOMA
2
5%
ADENOCARCINOMA
1
2%
ISTOCITOMA
1
2%
FIBROXANTOMA
1
2%
BREAST CANCER (Cutaneous
1
2%
PRIMARY
26
63%
SECONDARY
15
27%
LOCALISATION
N
%
HEAD/NECK
22
54%
localisations)
RECONSTRUCTION (N) Arterialized fascio-cutaneous flaps (N=17) Mio cutaneous flaps (N=4) Micro surgical flap (N=1)
INFERIOR LIMB
12
29%
Amputation below the knee (N=2) Propeller flap (N=4) Anterior lateral thigh flap (N=2) Poster tibial artery flap (N=3) Mio cutaneous soleus flap (N=1)
SUPERIOR LIMB
4
10%
Brachio-radialis flap (N=2) Lateral arm flap (N=2)
TRUNK
1
2%
BACK
1
2%
Disarticulation (N=1) 2 Gluteal perforator flaps contraposed (N=1)
VULVA
1
2%
2 Inferior gluteal art. perforator flaps (N=1)
FIGURES LEGEND
P=0.0013
Figure 1. Kaplan-Meier survival curves for complete response (CR) and partial response (PR) patients.
Figure 2. Median time (years) of survival rate of patients with tumour size reduction above or below 55% after neoadjuvant ECT.
Figure 3. It shows the case of a right latero-cervical cutaneous recurrence from a laryngeal carcinoma strongly adherent to the neck vessels with a concrete risk of the ulceration of the vessels themselves (a). The implementation of neo-adjuvant ECT under intraoperative ultrasound control (b), in order to avoid the vessels walls or nerves damaging by ECT electrode needles (c), had allowed the reduction of the size of the neoplasia, verified by a CT scan performed after the treatment, and the formation of a good cleavage plane between the neoplasm and the neck vascular and nerve structures. This allowed the execution of a radical excision (d) and the contextual reconstruction with a homolateral myo-cutaneous pectoralis major flap (e).
Figure 4. It shows the case of a leiomiosarcoma of the right forearm (a). Due to the adhesion of the cancer to the vascular trunks an amputation of the right forearm was proposed (b). The neo-adjuvant ECT allowed the creation of a cleavage plan from the blood vessels and it was possible a radical demolition of the tumor (c) and the restoration of the anatomical and functional integrity of the arm with an anterolateral forearm flap and the functional recovery of the upper right limb with excellent grip control and return of the patient to his initial work as a lumberjack (d).
Figure 5. It shows the case of a recurrent squamous cell carcinoma of the sacral-coccygeal region adherent to the sacrum (a). The intervention proposed to the patient by other institutions was the complete removal of the sacral-coccygeal region including the bone, that should have conducted to a consequent permanent decubitus of the patient on a wheelchair. The neo-adjuvant ECT allowed the radical removal of the neoplasia, saving the sacral-coccygeal bone and the contextual reconstruction with two opposing fascialcutaneous gluteal flaps, based on the perforating vessels of the gluteal arteries (b). The patient is still living and walking (c).
NEO-ADJUVANT TREATMENT BY ECT IN CUTANEOUS MALIGNANT NEOPLASTIC LESIONS Tommaso Fabrizio MD , Luigi Cagiano MD , Francesca De Terlizzi MSc , Michele Pio Grieco MD PII: DOI: Reference:
S1748-6815(19)30577-7 https://doi.org/10.1016/j.bjps.2019.11.063 PRAS 6369
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Journal of Plastic, Reconstructive & Aesthetic Surgery
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2 September 2019 23 November 2019
Please cite this article as: Tommaso Fabrizio MD , Luigi Cagiano MD , Francesca De Terlizzi MSc , Michele Pio Grieco MD , NEO-ADJUVANT TREATMENT BY ECT IN CUTANEOUS MALIGNANT NEOPLASTIC LESIONS, Journal of Plastic, Reconstructive & Aesthetic Surgery (2019), doi: https://doi.org/10.1016/j.bjps.2019.11.063
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NEO-ADJUVANT TREATMENT BY ECT IN CUTANEOUS MALIGNANT NEOPLASTIC LESIONS Tommaso, Fabrizio MD*, Luigi Cagiano MD*, Francesca De Terlizzi, MSc**, Michele Pio Grieco MD* *Division of Plastic Surgery, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy **IGEA Biophysics Lab, Carpi, MO, Italy
Corresponding Author: Tommaso Fabrizio, MD Chief of Unit of Plastic Surgery IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy Via Padre Pio, 1 95098, Rionero in Vulture, Italy Tel: 0039 (0) 972 726735 e-mail: [email protected] Istitutional Ethical Approval Number: 2311.82/07
TITLE PAGE NEO-ADJUVANT TREATMENT BY ECT IN CUTANEOUS MALIGNANT NEOPLASTIC LESIONS
Tommaso, Fabrizio MD*, Luigi Cagiano MD*, Francesca De Terlizzi, MSc**, Michele Pio Grieco MD* *Division of Plastic Surgery, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy ** IGEA Biophysics Lab, Carpi, MO, Italy
DECLARATION OF NO SPONSORSHIP, FUNDING, OR CONFLICT OF INTEREST: None of the above-mentioned authors has a financial interest or sponsorship, or funding, or conflict of interest in any of the products, devices, or drugs mentioned in this manuscript. All the authors declare and confirm that no financial support or benefit have been received by the first or any coauthor, by any member of his and their immediate families or any individual or entity with whom or with which, He or They have a relationship from any commercial source, which is related directly or indirectly to the scientific work, which is reported on in the article. All the authors approve the codes obtained by their ethical committee about the present research.
ABSTRACT Electrochemotherapy (ECT) is a local treatment and its use has been standardized for cutaneous nodules of any histologic origin. In the present study we use ECT as a neoadjuvant therapy in order to reduce the size of neoplastic lesions to obtain an ideal cleavage plane where vital or very important vascular and/or nervous structures are separated from the tumor, thus allowing a radical surgical excision, otherwise unfeasible. In their retrospective study the authors identified 41 patients that were treated at our institution with neoadjuvant intent. ECT was performed under general (30 pts, 73%), regional (9 pts, 22%) or local anaesthesia with sedation (2 pts, 5%). At a median time of 2 months (range 0.3-9) after neoadjuvant ECT, all patients underwent surgical intervention, in order to resect the residual tumour. Median reduction of tumour volume after ECT was 55% (range 10%-65%). After ECT plus surgery, 25 patients (61%) had a complete response (CR), 16 patients (39%) a partial response (PR). The percentage of CR in patients with larger lesions (>100mm) was 27%, in patients with smaller lesions (≤100mm) was 73% (p=0.0119). Major side effects after ECT were: bleeding and/or ulceration (54%) and pain (59%) naturally resolved in 1-2 months. Side effects observed after surgery were: necrosis of the flap (N=3), a case of diastasis of the donor site. Median survival time in CR patients was 53 months (range 4-108), whereas in PR survival was 23 months (range 5-126), p=0.0400. ECT represents a safe and effective therapeutic approach that could be effectively used for neoadjuvant purposes.
Keywords: Electrochemotherapy (ECT), neo-adjuvant therapy, solid malignant cutaneous lesions, morphological and functional reconstructive surgery, survival rate, complete response (CR), partial response (PR). INTRODUCTION Electrochemotherapy (ECT) is a local treatment for neoplastic lesions that have standardized its field of application in the last 7-10 years (1-3), more than two decades after the initial preclinical and clinical studies published in the 80’s and 90’s (4-6). It is a treatment based on the combination of a chemotherapeutic drug, having a specific intracellular target, and the local application of electric pulses (electroporation) to tumour lesions (7-8). Several studies have shown and confirmed ECT efficacy and safety in the treatment of cutaneous and subcutaneous lesions from any histological origin (9-11). Recently, new indications have been explored for the treatment of internal organs such as bone, liver, pancreas, (12-15) and specific indications such as vulvar cancer, soft tissue sarcoma, Kaposi sarcoma (16-19) have been studied in depth. Considering the current evidence, the authors of the present study have hypothesized the potential role of ECT as a neo adjuvant treatment of cutaneous or subcutaneous neoplastic lesions. In fact ECT may reduce the size of neoplastic lesions and/or lead to obtain an ideal cleavage plane where vital or very important vascular and/or nervous structures are separated from the tumor, thus allowing a radical surgical excision, otherwise considered unfeasible. Although a surgical radicalization is closely linked to the histological diagnosis of the lesion, it is also directly related to the reduction of the size of the tumor before surgery. Meaning that a greater reduction of the initial size of the tumor will be directly related to the achievement of surgical radicality. Thus, the incidence of local recurrences and distant metastases, even though dependent on the histological type, will be reduced. All this obviously translates into a greater percentage of disease-free survival (20-25). The neoadjuvant role of ECT has been already considered, though, in single cases and reported in literature as case reports (2629). The present work is the first fairly large cohort of patients with cutaneous metastases of
different histology treated with ECT with neoadjuvant purposes 3 months before radical surgery and reconstruction.
MATERIAL AND METHODS Patients From February 2007 to February 2017, among the totality of patients treated with ECT at the IRCCS- Referral Cancer Center of Basilicata, in Rionero in Vulture, Italy, we identified 41 patients that were treated with neoadjuvant intent. We aimed at reducing the size of the target lesions of these patients, to facilitate the following excisional surgery. Our institution obtained approval from ethics committee and data protection authority. The clinical information that was retrieved from the database included: demographics, histologic diagnosis of tumour, number of target lesions, site and size of the lesions, absence of distant metastases, time and details of ECT treatments, time and details of surgery, duration of follow-up. Patients treated had measurable cutaneous or mucosal lesions, suitable for application of electric pulses. Patients were ≥18 years old, had Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (33), a life expectancy of at least three months, if fertile, were using adequate contraception, and had been offered standard treatment options. Patients were not treated if they previously had allergic reactions to bleomycin or to any of the components required for anaesthesia, if the cumulative dose of 250 mg bleomycin/m2 (400.000 IU bleomycin/m2) had previously been exceeded, had chronic renal dysfunction (serum creatinine >150 μmol/l) or acute lung infection. ECT Procedure ECT was performed according to the ESOPE Standard Operating Procedures (SOP) (1,2). Bleomycin was administrated intravenously (i.v) or with an intra-tumour injection using 15.000 IU/m2 of body surface, depending on the number and size of lesions treated. To deliver the
electric pulses one of the following electrodes was used: 1) Type I electrodes: two parallel rows of needles with 4 mm between rows; 2) Type II electrodes: a hexagonal array of needles with 7.9 mm distance between each couple. Electric pulses (eight pulses of 100 μs duration) were delivered using a square wave electroporator (Cliniporator, IGEA, Carpi, Italy). After ECT, the treated lesions were covered with compressive haemostatic dressing. For each patient wound care was carried out according to the protocol in use in our Institution, including a short-term antibiotic prophylaxis with wide spectrum antibiotics, pain-relieving therapy with non-opioid drugs and only in the most refractory cases with elastomer-based morphine derivatives. Moreover, the ECT treated area was managed with a thermo-healing system that resulted very beneficial, especially in the first week after the ECT treatment, when a closed-loop continuous flow system of cold physiological solution at a temperature between 18 and 24 ° C (Hilotherm ™) was used (34). Surgery procedure The purpose of the present retrospective study was to test the neo-adjuvant application of ECT, to make surgically feasible an intervention otherwise considered not possible, due to the size of the neoplasm, its location and / or its tight relation with vital vascular or nervous structures. In this scenario, ECT treatment aimed to reduce the lesions’ size or to create a cleavage plane where the tumor and the above-mentioned structures could be separated. Therefore, the final goal of the surgical procedures adopted in the present study was the achievement of the oncological radicality, followed by the reconstructive surgical procedures able to obtain aesthetic and functional restoration. In Table 1, a descriptive analysis of the study population and the various surgical reconstruction techniques according with the different anatomical districts, where the tumors were localized, are showed. Response evaluation Since the purpose of ECT in this study was tumour volume reduction to facilitate excisional surgery, local tumour response to ECT treatment was evaluated by calculating the percentage of
volume reduction with respect to the volume measured before treatment. Regardless of the clinical assessment, a MRI or a CT scan was performed on each patient that underwent neoadjuvant ECT before and not more than 3 months after ECT treatment, to objectively evaluate the reduction of the size of the neoplasm. The overall local response was evaluated 2 months after surgical procedure, according to the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) (35). Complete response (CR) was defined as disappearance of the target lesion; partial response (PR) with at least 30% decrease in the diameter of the target lesion. Progressive disease (PD) was defined as at least 20% increase in the diameter of the target lesion and stable disease (SD) with neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD. The longest diameter of the tumours was recorded. Photographs were taken at the time of treatment, and at follow-up visits. Statistics Continuous variables were described by median value and range, categorical variables by absolute number and percentage. Data in contingency tables have been analysed by Chi Square test for independence. Different groups have been compared based on clinical variables of interest: localisation (head/neck vs other), size of lesions 10cm, diagnosis (SCC vs BCC vs other), primary vs secondary presentation. Overall survival was calculated from the first ECT up to death or last follow-up. Survival curves were calculated by the Kaplan–Meier curve. One-year survival and 95% confidence interval (C.I. 95%) were calculated using Kaplan-Meier survival analysis. Comparison between curves has been performed by Cox regression analysis. A p value lower than 0.05 was considered statistically significant. Statistical analyses were performed with NCSS 9 software (NCSS, LLC. Kaysville, Utah, USA).
RESULTS Among the patients treated with ECT in Rionero in Vulture, we identified 41 patients that were treated with neoadjuvant intent. Descriptive data of the patients are also reported in Table 1. ECT treatment ECT Treatment was performed under general (30 pts, 73%), regional (9 pts, 22%) or local anaesthesia with sedation (2 pts, 5%). Intravenous administration of Bleomycin was adopted in 38 pts, (93%) and intra-tumoral injection was performed in the remaining 3 patients (7%). Median treatment duration was 27 min (range 12-45 min). Hexagonal electrode was used in 27 sessions (66%) whilst linear electrode in 14 sessions (34%). Median number of electric field applications in each session was 51 (range 8-111). Median reduction of tumour volume after ECT treatment was 55% (range 10%-65%). Surgical treatment At a median time of 2 months (range 0.3-9) after neoadjuvant ECT, all patients underwent surgical intervention, in order to completely resect the residual tumour. Table 1 analytically shows the study population as clearly as the treated cases in relation to the type of surgery and reconstruction performed after the reduction of the tumor volume obtained with ECT. The reconstructive procedures were subdivided according with the anatomical localization of the tumor. In total, a reconstruction with flaps was performed in 38 patients (92%): out of the 38 patients, mio-cutaneous pedicle flaps were used in 5 patients ( 13%), a microsurgical miocutaneous flap was used in 1 case (3%), arterialized fascio-cutaneous perforators flaps in 28 patients (74%) and 4 propeller flaps for the remaining cases (10%). An amputation below the knee joint was performed in 2 patients (5%), while a disarticulation was done in 1 patient (3%). Two patients received three surgical interventions for the treatment of their tumour, one patient received 2 surgical interventions. Histological examination confirmed the achievement of
oncological radicality in 85% of patients. The surgical procedures allowed to carry out reconstructive interventions, which lead in most cases, to an excellent morphological result and a satisfactory organ function restoration of the operated areas. Outcome of ECT plus surgery treatment After ECT plus surgical treatment, 25 patients (61%) had a complete response, 16 patients (39%) a partial response. Percentage of CR in primary tumours was 58% and in secondary tumours 67% (p=0.7421). In BCC the percentage of CR was 100%, in SCC 45% and in other histological types 71% (p=0.0684). Lesions located in the head/neck region had a 55% of CR, whilst in other regions the percentage was 68% (p=0.5224). Finally, the percentage of CR in patients with larger lesions (>100mm) was 27% in comparison with the one observed in patients with smaller lesions (≤100mm), 73% (p=0.0119). Side effects After ECT treatment 54% of patients (N=22) suffered for bleeding and/or ulceration, which naturally resolved in within 1-2 months. Twenty-four patients (59%) suffered for pain in the treated area during the first weeks after treatment managed with pain killers. Two patients (5%) had a hyperpigmentation of the treated area. The side effects observed after surgery were: a case of subtotal necrosis of the flap (greater than 50%), 2 cases of partial necrosis of the flap (less than 50%), a case of diastasis of the donor site. After the application of dressings, in case of sub-total necrosis, a reconstruction with a local rotation flap was performed. Plastic repair was performed with skin grafting in the cases of partial necrosis. Diastasis of the donor site was repaired with subsequent skin suture.
Long term follow-up Patients were followed up for a median time of 47 months (range 4-126 months). At the last followup time, 14 patients were alive without disease (34%), 14 patients were alive with disease (34%), and 13 (32%) died for disease progression and visceral metastases. In the group of patients with a complete response to the combined treatment ECT + surgery, 4 patients (16%) died, while in the group of patients with partial response the number of deaths was 9 (56%), with a significant difference between groups (p=0.0144). Median survival time in patients with a complete response was 53 months (range 4-108), whereas in partial responders’ group the time of survival was 23 months (range 5-126), p=0.0400. Five-years survival rate was 84% (C.I. 68%-100%) in complete response patients, and 35% (C.I. 5%-65%) in partial response patients (p=0.0013). Kaplan-Meier survival curves for the 2 groups are shown in Figure 1. When considering the survival time in relation to percentage of tumour volume decrease after neoadjuvant ECT, we observed a significantly lower median survival time in patients with a reduction of tumour volume smaller than 55% (p=0.0236), as shown in Figure 2.
DISCUSSION The authors' experience on the use of ECT dates back to 2007. In the first years we applied ECT in standardized conditions, as described in literature, for the treatment of cutaneous or subcutaneous metastases of any histological origin (1-3). As reported by several authors, we also could observe that ECT has numerous advantages: minimal side effects on the patient, repeatability, capability to preserve organ functions and surrounding healthy tissue, well-tolerated by the patient, allowing an immediate recovery. ECT is also indicated for some types of primitive cutaneous tumors such as basocellular and spinocellular carcinoma (29-32). Kis et al. (32) concluded in a review article, that
ECT can therefore be applied to improve the patient’s quality of life, independent of life expectancy, to heal painful or bleeding lesions and to preserve patients’ appearance and social interactions, does not cause significant organ dysfunction or permanent disfigurement. Based on our and other experiences (26-29) we decided to explore the possibility to apply ECT as a neoadjuvant treatment identifying a particular cohort of patients who could benefit from this approach. To demonstrate the efficacy of ECT as a neo-adjuvant treatment, the present study was designed, set up and conducted with the intent of using ECT to reduce the size of the tumor and / or to create a cleavage plane where the neoplasm was separated from vital structures, such as nerves and / or vascular pedicles. Moreover, emphasis was given to the most effective reconstructive methods. Our approach had two objectives: 1. to facilitate a surgical intervention and radicality otherwise considered impossible, 2. to perform an appropriate reconstructive intervention in terms of restoration of functional and morphological integrity to preserve or improve the quality of life of the patient. In the present study, we report the results of neoadjuvant ECT followed by radical surgery and reconstructive procedures in the management of cutaneous neoplasms of different histology. The reduction in tumor size with ECT treatment can be achieved, thus allowing a radical surgery and reconstructive interventions with arterialized and more favorable restorative oxygenated flaps (Table 1). Overall, this oncological multiple-treatment approach resulted in a cosmetic, morphological and organ function preservation that secured the return to daily good quality of life (Figure 3-5). Similar results have been observed in case reports studies by other authors, in the treatment of primary breast cancer (26), anal melanoma (28), vulvar cancer (29), metastatic melanoma (27) Interestingly, ECT has been employed as a tissue-sparing treatment to reduce tumor burden for further treatments and surgery: one report described the use of preoperative ECT of anal melanoma to enable surgical resection with organ and function-sparing [28], in another report ECT was
effectively targeted towards cancer cells, sparing adjacent healthy tissue of the cheek [27]. Finally, for what concern primary breast cancer, authors claimed that the first ECT session led to a mass of cytoreduction while the intraoperative local ECT treatment made possible to succeed in the complete reclamation of the coastal wall in a long-term survival, without any local recurrence after 30 months of follow-up. Another important observation we could evidence from our data: comparative analysis of the survival time and the response rate to the combined treatment, complete response (CR) or partial response (PR), seemed to indicate that the survival time is directly dependent upon the response to treatment (chi-square test p=0.0013, significant correlation) (Figure 1). Furthermore, when neoadjuvant ECT obtained a reduction of the tumor size greater than 55%, it seemed to result in an equally important increase of the median survival time (chi-square test p=0.0236, significant correlation). This interesting observation could be of help during the decision-making process when, after neoadjuvant ECT, the tumor reduction rate is lower than 55%, suggesting to carry out, when possible, a second ECT session in order to obtain a further reduction in the size of the tumor lesion.
CONCLUSIONS Overall ECT represents a safe and effective therapeutic approach that could be effectively used for neoadjuvant purposes, allowing reconstructive treatments, leading to the restoration of good functional and morphological integrity with the preservation of the patient quality of life. ECT is associated with clear benefits for patients in terms of quality of life (minimal discomfort, mild posttreatment pain and patient satisfaction) and may, in the neoadjuvant setting, offer the opportunity for a more conservative surgery and a better cosmetic effect with complete local tumor control. Furthermore, considering that the employment of ECT does not prevent the use of a systemic chemotherapeutic treatment, neo-adjuvant ECT can be considered a valid option for the locoregional control of malignant neoplasms even in advanced stage, who have developed large skin
localizations. Even if there is already a literature that speaks of ECT with a neo-adjuvant purpose, the present work is, in the opinion of the authors, one of the few that clearly shows that the neo-adjuvant ECT has value in the local control of the neoplastic disease, resulting in a significant improvement in disease-free survival, especially if it is able to reduce the volume of the neoplasm by a percentage higher to 55% (Figure 2). Therefore, if the first ECT treatment does not allow it, a second application should be performed until this objective is reached. This allows a reconstructive plastic surgeon, engaged in the oncology field, the really important and never explored possibility of performing reconstructive interventions such as to improve the quality of life of the patient.
ACKNOWLEDGEMENTS The principal author sincerely thanks so much Dr. Giovanni Bozza, Dr. Raffaele Ardito, and Dr. Michele Aieta, Division of Oncology, Dr. Nicoletta Telesca, Division of Pharmacology and Dr. Antonio Colasurdo, Medical Director of IRCCS-Referral Cancer Centre of Basilicata for the active support given to the realization of this study.
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Table 1. Descriptive analysis of the study population and surgical reconstruction technique, according with tumour lesions’ localization. Size a and Size b indicate the orthogonal dimensions of the tumour.
MEDIAN
MINMAX
AGE
77
49-90
# NODULES
2
1-17
SIZE a (mm)
60
17-350
SIZE b (mm)
58
12-270
DIAGNOSIS
N
%
SQUAMOUS CELL CARCINOMA
20
49%
KAPOSI SARCOMA
6
15%
BASAL CELL CARCINOMA
4
10%
MALIGNANT MELANOMA
3
7%
SARCOMA
2
5%
LEIOMIOSARCOMA
2
5%
ADENOCARCINOMA
1
2%
ISTOCITOMA
1
2%
FIBROXANTOMA
1
2%
BREAST CANCER (Cutaneous
1
2%
PRIMARY
26
63%
SECONDARY
15
27%
LOCALISATION
N
%
HEAD/NECK
22
54%
localisations)
RECONSTRUCTION (N) Arterialized fascio-cutaneous flaps (N=17) Mio cutaneous flaps (N=4) Micro surgical flap (N=1)
INFERIOR LIMB
12
29%
Amputation below the knee (N=2) Propeller flap (N=4) Anterior lateral thigh flap (N=2) Poster tibial artery flap (N=3) Mio cutaneous soleus flap (N=1)
SUPERIOR LIMB
4
10%
Brachio-radialis flap (N=2) Lateral arm flap (N=2)
TRUNK
1
2%
BACK
1
2%
Disarticulation (N=1) 2 Gluteal perforator flaps contraposed (N=1)
VULVA
1
2%
2 Inferior gluteal art. perforator flaps (N=1)
FIGURES LEGEND
P=0.0013
Figure 1. Kaplan-Meier survival curves for complete response (CR) and partial response (PR) patients.
Figure 2. Median time (years) of survival rate of patients with tumour size reduction above or below 55% after neoadjuvant ECT.
Figure 3. It shows the case of a right latero-cervical cutaneous recurrence from a laryngeal carcinoma strongly adherent to the neck vessels with a concrete risk of the ulceration of the vessels themselves (a). The implementation of neo-adjuvant ECT under intraoperative ultrasound control (b), in order to avoid the vessels walls or nerves damaging by ECT electrode needles (c), had allowed the reduction of the size of the neoplasia, verified by a CT scan performed after the treatment, and the formation of a good cleavage plane between the neoplasm and the neck vascular and nerve structures. This allowed the execution of a radical excision (d) and the contextual reconstruction with a homolateral myo-cutaneous pectoralis major flap (e).
Figure 4. It shows the case of a leiomiosarcoma of the right forearm (a). Due to the adhesion of the cancer to the vascular trunks an amputation of the right forearm was proposed (b). The neo-adjuvant ECT allowed the creation of a cleavage plan from the blood vessels and it was possible a radical demolition of the tumor (c) and the restoration of the anatomical and functional integrity of the arm with an anterolateral forearm flap and the functional recovery of the upper right limb with excellent grip control and return of the patient to his initial work as a lumberjack (d).
Figure 5. It shows the case of a recurrent squamous cell carcinoma of the sacral-coccygeal region adherent to the sacrum (a). The intervention proposed to the patient by other institutions was the complete removal of the sacral-coccygeal region including the bone, that should have conducted to a consequent permanent decubitus of the patient on a wheelchair. The neo-adjuvant ECT allowed the radical removal of the neoplasia, saving the sacral-coccygeal bone and the contextual reconstruction with two opposing fascialcutaneous gluteal flaps, based on the perforating vessels of the gluteal arteries (b). The patient is still living and walking (c).