Curaderm, the Long-Awaited Breakthrough for Basal Cell Carcinoma

Background: Basal cells form a continuous cell layer at the bottom of the epidermis, which is the outermost layer of the skin. Basal cell carcinoma occurs when a mutation occurs in the DNA of a basal cell. The mutation inhibits apoptosis—the programmed cell death mechanism. The cell continues to multiply but does not die, resulting in a change in the skin, such as a growth or sore that will not heal. Basal cell carcinoma is the most common form of skin cancer and the most frequently occurring form of all cancers. Key words searched for the database of this communication were: Curaderm, BEC 5, cancer, skin cancer, basal cell carcinoma, nonmelanoma skin cancer, solamargine, solasonine and solasodine glycosides. Treatments: Several types of treatments are available to remove or destroy basal cell carcinoma. All currently used treatments are indiscriminate and also remove or destroy normal skin cells resulting in compromised cosmetic outcomes. Development of Curaderm Pharmacotherapy: Curaderm pharmacotherapy discriminates and specifically activates apoptosis at the molecular level in cancer cells but not in normal cells. Accordingly, Curaderm pharmacotherapy for basal cell carcinoma effectively and safely treats virtually all types, sizes and lesion locations. This review describes studies from the inception of Curaderm pharmacotherapy and covers the discovery of the anti-cancer effects, mode of action, preclinical, clinical and field applications with emphasis on efficacy, safety, compliance, tolerance, cost effectiveness and especially cosmetic outcome. In 2018 Curaderm was approved by the European Health Authorities as a Medical Device Class 1 for the indication “Topical Treatment with Keratolytic Action, and Antineoplastic Activity in the Treatment and Healing of Localized Basal Cell Carcinoma of the Skin”.


Introduction
Basal cell carcinoma (BCC) is the most common form of skin cancer and the most frequently occurring form of all cancers. In the U.S. alone, more than 4 million cases are diagnosed each year. BCC is a disease of global health importance that causes substantial psychosocial impacts and requires considerable investment in terms of treatment and technologies. Conventional therapies have several drawbacks, thus, a long-awaited treatment breakthrough for BCC is very welcome. Apoptosis balances proliferation to maintain epidermal thickness and contributes to stratum corneum formation. When basal cells are mutated, apoptosis may not work correctly. Cells that should be eliminated may persist and become immortal, such as the case with BCC.

Aetiology
BCC starts when basal cells grow out of control and crowd out normal cells.
In BCC, the process of apoptosis is defunct but cell division is intact resulting in excessive numbers of cancer cells, resulting in a change in the skin, such as a growth or a sore that will not heal.
With BCC, these lesion changes in the skin may express one of the following characteristics: • A pearly white, skin-coloured or pink bump that is translucent. Tiny blood vessels are often visible. BCC often appears on the face and ears. The lesion may rupture, bleed and scab over.
• A flat, scaly, reddish patch with a raised edge often appears on the back or chest.
• A white, waxy, scar-like lesion without a clearly defined border, called morpheaform.
• A brown, blackish lesion with a slightly raised, translucent border. reported to be associated with intermittent and childhood sun exposure. UVB is a main causative factor in BCC and has been implicated to directly stimulate DNA mutation via covalent bonding between adjacent pyrimidines, whereas UVA stimulates production of reactive oxygen species that contribute to BCC formation. Factors other than exposure to UV (such as exposure to arsenic, pollutants, viral infections, skin type, age, defects in the immune system) may con-

Treatments
Several types of treatments are available to remove or destroy BCCs. Selected treatments are dependent on factors such as tumour size, location, a person's age, general health, and preference.
Excision surgery, Mohs surgery, Curettage and electrodesiccation, Radiation therapy, Photodynamic therapy, Chemotherapy, Cryotherapy, Immune response modifiers and Targeted therapy are currently used to treat BCCs.
All of these treatments for BCC have advantages and disadvantages. Other than targeted therapy, all other treatments are indiscriminate, and do not distinguish cancer cells from normal cells. The lack of specificity and selectivity of these treatments usually limit their applications and translate to poor cosmetic outcomes.
The biggest challenges for treatment of BCC are: • Education Understanding BCC causes, risk factors and warning signs may lead to early detection that can be easiest to treat and cure.

• Treatments
The common feature of conventional treatments for BCC is non-specificity without targeting the tumour itself. This leads to unwanted adverse effects in the surrounding tissue, such as scar formation or other cosmetically disfiguring outcomes. Less than favourable recurrence rates are obtained with conventional therapies.
• Depending on the type, location and size as well as preference and ability to do follow-up visits can be daunting for the patient, especially for elderly patients who are also prone to suffer more from this condition. • An alternative non-invasive, self-treatment modality that is very specific towards the BCC tumour that eliminates small and large BCCs, and is applicable to difficult-to-treat areas with remarkable cosmetic outcomes, resulting in very low recurrence rates, is overdue and welcome. International Journal of Clinical Medicine

Curaderm
In 2018, the product Curaderm was registered by the European Health Authorities as a Medical Device Class 1 for the indication Topical treatment with keratolytic action, and antineoplastic activity in the treatment and healing of localized basal cell carcinoma of the skin. The prime difference between Curaderm and other treatment modalities for BCC is; Curaderm pharmacotherapy discriminates cancer cells from normal cells, which translates to superior efficacy, safety and cosmetic outcomes.
The incidence of BCC is rising, representing approximately 70% -80% of all skin cancers. Accordingly, there is a definite need for more acceptable treatments of BCC as verified by the research into the causes, prevention, and treatment of BCC currently ongoing in many medical research centres throughout the world.
Fundamental studies of BCC have been hindered by a lack of a suitable and reproducible tissue-culture model system. Most available treatments for BCC did not require such models because most BCCs are currently, simply cut out or burnt out and no understanding of mechanism of action at the molecular and cellular levels are required for these indiscriminate procedures.

T. Chase et al. International Journal of Clinical Medicine
Since then, a plethora of further investigations have resulted in the placement of BEC and its individual components as very promising antineoplastic agents with vast potential to serve as targeted anticancer agents [10].
With BEC, solamargine accounts for 86% antineoplastic activity and solasonine accounts for 9% antineoplastic activity, whereas, the mono-and di-glycosides of solasodine contribute 5% anticancer activity. The anticancer activity of these glycoalkaloids is considered to be concerted and additive [11].
Furthermore, the absolute concentrations of these drugs to obtain comparable efficacy as BEC, are in the order of 6 -40 times higher [27].
Moreover, the therapeutic index (TI: also referred to as the therapeutic ratio) is much higher for BEC compared with other antineoplastic agents as shown with cell culture studies [28] and animal studies [29]. The high TI of BEC translates to high safety margins.

BEC and Basal Cell Carcinoma
The first human clinical studies with BEC were undertaken in the 1980s in Australia, at the University of Queensland, the Royal Brisbane Hospital, and St.
Johns Park Hospital, Tasmania. In 1987, it was reported that topical application of a cream formulation containing BEC was effective in the treatment of the malignant tumour BCC. Histological analyses of biopsies taken before, during and after treatment gave compelling evidence of the efficacy of the formulation. The International Journal of Clinical Medicine treated lesions did not recur for at least 3 years after cessation of therapy, and indeed, patients were subsequently followed up for over a decade with no recurrences. Thirteen patients with 24 BCC lesions were treated for 4 to 7 weeks.
With the BEC therapy, the BCCs responded rapidly in a characteristic pattern.
The pattern comprised initial swelling of the lesion, and erythema of surrounding tissue (approx. 10 mm around the lesion), followed in about 2 days by ulceration until neoplastic cells were destroyed. This was then followed by normal new non-malignant cell growth during the treatment. In the 13 patients treated, 20 of a total number of 24 lesions regressed totally. Partial regression was obtained with the other 4 lesions.
Two normal subjects were treated with the formulation for 8 weeks. Biopsies taken from the treated areas showed no macroscopic or microscopic changes. No clinical reaction was observed with the normal skin. The specificity towards abnormal cells in the skin was the most striking observation.
Biochemical, haematological and urinalytical studies demonstrated that there were no adverse effects on the liver, kidneys or haematopoietic system during or after treatment.
There were no major adverse side effects during BEC therapy except that transient mild itching and burning surrounding the treated lesions occurred in a few cases [5].
Following reports on the anti-cancer effects of BEC in cell culture and in whole animal models, together with the effective treatments for skin cancer, a monograph of BEC was published [44].
In the first human clinical studies, 10% (100,000 mg/L) BEC was used in a cetomacrogol base to treat the BCCs. In the monograph of BEC, it was reported that patients tolerated up to 50% BEC in the cetomacrogol cream without any side effects. It was interesting that in cell culture studies, 8 mg BEC/L cell culture medium was required to kill cancer cells but not harm normal cells. Similarly, 8 mg BEC/kg when injected into mice with terminal tumours resulted in survival. Identical doses of BEC injected into normal animals did not produce adverse effects [4].
The doses of BEC to obtain efficacy for the treatment of skin cancer was compared with the doses of BEC required for the treatment of cancers in cell culture and in animals, there was a difference of a factor of over 10,000. It was subsequently shown that this difference was due to the bioavailability of BEC with the cancer cells. Much further work led to a topical formulation that contained keratolytic components that markedly improved the bioavailability of BEC to interact with skin cancer cells. A concentration of BEC, as low as 50mg/L of cream, was shown to be effective to treat BCC. Curaderm had totally regressed. A placebo formulation had no effect on treated lesions. Curaderm had no adverse effect on the liver, kidneys or haematopoietic system. The treatment period to obtain complete regression of the BCC lesions ranged from 3 to 13 weeks. In the placebo group, treatment period was for 14 weeks, which was 1 week more than the longest treatment period with Curaderm [6].

Open Studies
It was remarkable that even at the early developmental stages, Curaderm was able to eliminate BCCs that were almost impossible, due to their locations and sizes, to successfully be treated by other modality treatment procedures.   Figure 2 is a BCC of the nose, which was present for at least 12 months before treatment started. Independent prognoses for this patient were plastic surgery of limited effect and/or complete loss of the nose, which was to be replaced with a prosthesis.   Another case was presented that could not be successfully treated by other procedures without losing the eye. The rest is history, many other clinical studies with Curaderm followed, confirming the original observations.

Double-Blind, Vehicle-Controlled, Randomized, Paralleled Group Studies
In the 1990s a double-blind, vehicle-controlled, randomized, paralleled group study to assess the efficacy and safety of BEC-5 (Curaderm) in the treatment of patients with basal cell carcinoma, was carried out by ten centres in the United It was reported that the cosmetic results offered by treatment with Curaderm were comparable to that resulting from surgical excision, but the risks of surgical intervention were well known.
The investigators at the Royal London Hospital further commented that excision of BCC from the facial area involved reconstructive surgery, of which could be both time consuming and costly.
They stated that an alternative, safe, efficacious and cost-effective method of treatment of BCC that did not require physician or hospital attendance should be encouraged, and that Curaderm was a much-needed alternative to surgery for both primary and secondary skin cancer care [46].
It is noteworthy that the trials in the United Kingdom were designed to treat the patients for 8 weeks, which resulted in a 78% success rate for both superficial and invasive BCCs. In analysing prior and subsequent studies that involved BCC treatments for 14 weeks, it becomes clear that a success rate at 8 weeks treatment was also approximately 80%. Longer treatment periods were required to obtain a higher success rate [27]. These observations complemented the clinical trials.
In order to determine the limitation of topical Curaderm pharmacotherapy, patients with a wider variety of BCCs were studied. In particular, factors indicating poor treatment prognosis in BCC such as size, type, depth, location and previous failure by other treatment modalities, were selected for the study.

Curaderm Pharmacotherapy and Size of Basal Cell Carcinoma
The recurrence rates of large BCCs

Curaderm Pharmacotherapy and Difficult to Treat Locations of Basal Cell Carcinoma
Location of BCCs largely determines, and, limits the choice of treatment.
Curaderm topical pharmacotherapy was shown to excel in these situations.  Figure 7. Periocular BCC, superior to the eye including part of the brow, of a patient before (a), during (b) and after (c) Curaderm therapy. During Curaderm treatment the lesion was much smaller and residual tumour can distinctly be seen which was surrounded by some inflammation. After treatment there was no sign of the BCC. Confirmation by histological analysis of the BCC before treatment (d), and after treatment (e) are shown. The total treatment period was 9 weeks. Clinical assessment 5 years post treatment showed that there was no recurrence [49].

Curaderm Pharmacotherapy on Previously Failed Treatment Procedures
A number of treatments are available for topical BCCs with varying success and recurrence rates. When a BCC recurs after treatment with virtually any procedure, scar tissue poses a problem for retreating the lesion. Curaderm pharmacotherapy was evaluated for its application under such circumstances. Twenty-three patients that had a recurrence by other modality treatments such as radiation therapy, photodynamic therapy, laser therapy, cryotherapy and then subsequently treated with Curaderm, resulted in 52% success rate with no recurrences with 5 years follow up [60].
Figures 10-12 illustrate various lesions that had recurred after treatment with radiation therapy, photodynamic therapy and laser therapy and then treated successfully with Curaderm [56]. Figure 13 shows a large lesion on the nose of a patient who had previous treatments with surgery, radiation and photodynamic therapy. On all occasions of the treatments, the lesion had recurred. Topical Curaderm pharmacotherapy of the same multiple recurred lesion successfully removed the lesion with no recurrence for over 3 years [61].

Curaderm and Elderly Patients
There is a correlation between the incidence of BCC and increasing age in humans. Clinicians are usually the frontline to encounter elderly patients with BCCs at their general check-up visits. Once the diagnosis of the BCC is made, both the clinician and the patient are faced with the challenge of treatment. All treatment modalities have special considerations when administered to older adults. The physical condition and ability of the patient and the characteristics of the BCC tumour type and locality may limit the choices of treatment. Dobrokhotova et al. [62] have considered the need of an appropriate treatment procedure for elderly patients. These investigators have appreciated that the elderly encounter restrictions when treatment is required for their BCC, and have evaluated Curaderm as a possible candidate and solution for this large group of patients. In particular, they selected patients with lesions at locations that are considered difficult to treat such as, on the head and neck.
In 2016, they published their findings in the journal "Tumors of the Head and Neck" [62]. They concluded that Curaderm is a successful treatment of BCC of the head and neck. Figure 14 and Figure 15 illustrate two elderly patients suffering with BCCs that have successfully been treated with Curaderm and their impressive cosmetic results after treatment. These observations contribute value to the patient and Health Care Providers. Figure 10. Recurrent BCC after radiation therapy but before Curaderm therapy (a), during treatment with Curaderm (b, c) and after 8 weeks treatment (d).
(a) (b) (c) (d) Figure 11. Recurrent BCC close to the eye after laser therapy but before Curaderm therapy (a), during treatment with Curaderm (b, c), and after 8 weeks treatment (d).

A study showing graphic and pictorial images what occurs clinically during
Curaderm pharmacotherapy has been reported in 2015 [55].
The clinical observations with Curaderm pharmacotherapy reveal that initially, the BCC lesion size increases over four-fold due to the interaction of International Journal of Clinical Medicine Curaderm with deeper and more lateral tumour cells, followed by a decrease in size, ultimately resulting in complete elimination of the BCC. Figure Figure 17. Appearances of BCC lesion during and after Curaderm therapy. Curaderm was applied 3 times daily at a dose of 0.1 g cream and covered with micropore paper tape occlusive dressing. The indicated days refer to the treatment periods. Cancer cells were being eliminated and replaced with normal epidermal skin cells during treatment. Treatment was stopped only after the original BCC lesion had healed (day 86).

Compliance and Tolerance
Many studies attest to good compliance and tolerance when on Curaderm pharmacotherapy. The only reported side effects were mild erythema with transient burning sensations at the treatment site. These sensations were dependent on the sizes of the lesions. Nevertheless, the treatment was well tolerated by all patients [63], confirming many other studies [5]

Rare and Long-Term Adverse Effects of Curaderm
Phase IV studies with Curaderm were designed to detect any rare or long-term adverse effects over a much larger patient population and timescale than was possible during the initial clinical trials. Curaderm has been available and used for over two decades and only a very small number of patients have experienced minor scar tissue caused by the salicylic acid in the Curaderm cream. The reasons for the scar tissue were applications of too much cream to the site, sensitivity to salicylic acid, and application to non-indicated conditions such as dry sensitive skin. These observations have secured Curaderm pharmacotherapy as having exceptional effective and safety profiles.

Coping with BCC Treatment, Does Curaderm Pharmacotherapy Assist?
There are different types of side effects, usually not reported, that patients endure when diagnosed and treated for BCC. Side effects such as emotional, physical and financial cost of BCC can be very high depending on mainly, size and location of the lesion.
Emotional and social effects, as well as physical effects, may include sadness, anxiety, anger or not being able to control stress levels. Not knowing the cosmetic outcome of the selected treatment procedure, places tremendous stress on the patient and if the cosmetic outcome of their treatment is not to their satisfaction, the patient has to live with this trauma from day to day, and the patient may lose confidence in the medical profession. can put the health of the patient at risk and may lead to higher cost in the future. The many advantages of having available self-treatments under the supervision of a health care professional are significant for both the patient and for the Health Care Professional. The safety and treatment outcomes are the prime considerations for the patient. Curaderm has proven to be very safe and the cosmetic outcome is impressive and is similar, if not better, than surgery, which may include reconstruction and grafting.

The Financial Stress Can Have a Significant Bearing on the Patient
The lower cost of the treatment with Curaderm, compared to established therapies, is beneficial for the patient and for the Health Care System. Any modality that can reduce the already financial burden to the Health Care System and to patients should be considered seriously.

Limitation of Curaderm Pharmacotherapy
The main limitation of topical pharmacotherapy with Curaderm is the duration of treatment, which depends on the type and size of the BCC and may take several weeks up to several months therapy for the complete removal of the BCC. Transient stinging and burning sensations are experienced in some patients for several minutes after application of Curaderm cream to the lesions. However, these limitations are considered minor when compared with the efficacy and impressive cosmetic outcomes, especially at difficult to treat locations.

Conclusions
The conventional treatments for BCC are surgical excision, Mohs micrographic surgery, curettage and electrodesiccation, chemotherapy, radiation, cryotherapy or laser therapy. The common feature of all of these treatments is that they are nonspecific without targeting the tumor itself. This leads to unwanted adverse effects in the surrounding tissue such as scar formation or other cosmetically disfiguring outcomes. In addition, treatment successes and morbidity of these treatments are questionable and mostly depended on the skill of the operator of the procedure. Hence, an alternative treatment modality that is very specific towards the BCC tumour that eliminates small BCCs rapidly, and also eliminates large BCCs, and difficult-to-treat areas that contain BCCs with amazing cosmetic outcomes, is overdue and welcome.
This astonishing BCC treatment has been achieved by extensive investigations of the natural compound BEC that has been shown invariably to suppress and reverse the cancer-causing biochemical changes. This has led to Curaderm, a pharmacological intervention for cutaneous BCC.
Self-administered, non-invasive topical Curaderm pharmacotherapy offers innumerable benefits unavailable with conventional therapies. Curaderm pharmacotherapy is preferable to invasive procedures, especially in cases of multifocal lesions, unclear lesion edges, risk of hypertrophic scarring and/or keloids re- Finally, the adage, "prevention is better than cure" is very applicable to BCC. There are many known risk factors that contribute to the cause of BCC. Many of the known risk factors, if taken into consideration when developing preventative measures, should result in fewer required treatments. Since solar radiation is a major environmental cause of BCC, a combination of sun protection measures should be encouraged. With the advanced understanding of the science of BCC and its aetiology, novel approaches should be motivated to prevent this disease from occurring. To that end, research has shown that BEC in combination with sunscreen agents in a formulation Curasol eliminates very early stages of skin cancer. This preventative manner of approach to influence the fight against BCC should be stimulated.
BCC is the most common form of skin cancer and the most frequently occurring form of all cancers. If allowed to grow, BCC can become disfiguring and dangerous. Neglected BCCs can become locally invasive, grow broad and deep into the skin and destroy skin, tissue and bone. It is therefore important to treat BCC as early as possible to avoid serious repercussions. There are various treatments available. The treatment choice depends on size, location, age of the BCC, age of the patient and the patient's overall health.
The most widely used treatments are all indiscriminate, these treatments do not distinguish cancer cells from normal cells and the ultimate effective and cosmetic success of the treatment relies on the skill of the treating doctor.
On the other hand, Curaderm pharmacotherapy distinguishes cancer cells from normal cells and only eliminates cancer cells at the molecular and cellular levels, resulting in impressive cosmetic outcomes as verified by Phases I to IV clinical studies and open field observations. The recurrence rate of BCC treated with Curaderm is minimal compared with other treatment modalities.
Curaderm pharmacotherapy has been approved in 2018 by the European Health Authorities as a Class 1 Medical Device for the indication "Topical Treatment with Keratolytic Action, and Antineoplastic Activity in the Treatment and Healing of Localized Basal Cell Carcinoma of the Skin".
Curaderm pharmacotherapy offers the long-awaited breakthrough for the treatment of skin cancer, in particular BCC.