ЛЕКАРСТВЕННЫЕ СРЕДСТВА ЕВРОПЕЙСКИХ ПРОИЗВОДИТЕЛЕЙ

Efficacy of topical therapy with vaginal ovules containing hyaluronic acid in the treatment of the side effects of radiotherapy and chemotherapy on the vagina.

N. Cassaro — G. Bianca — M. T. Meli

OBSTETRIC AND GYNAECOLOGY CLINIC «Italo Panella »
UNIVERSITY HOSPITAL VITTORIO EMANUELE, FERRAROTTO, S. BAMBINO

CATANIA
(Director : Prof. M. Panella)

Abstract

Women suffering from gynaecological tumours (carcinoma ofportio, endometrium and ovaries) or other tumours (breast or bowel carcinoma) are often subjected to a combined treatment which also includes, in addition to surgery, an adjuvant treatment with radiotherapy and / or chemotherapy, in presence of risk factors of recurrence.

On these patients, both radiotherapy and chemotherapy treatments result in rather significant side effects, not only on various organs, but also on the vagina which may be the seat of more or less serious toxicity.

The aim of our study is to evaluate the incidence, the type of vaginal toxicity following radiotherapy or chemotherapy and then to evaluate the efficacy of a local treatment through the use of vaginal ovules containing hyaluronic acid (Cicatridina® vaginal ovules, Farma-Derma) in order to reduce the side effects associated with this kind of treatment.

From January 2004 to December 2008 at the Obstetric and Gynaecology Clinic «Italo Panella» of the University of Catania we treated 79 patients suffering from different types of neoplasias and who were first treated with surgery, followed by, in presence of risk factors, an external radiotherapy or combined radiotherapy (external and /or internal) or cycles of chemotherapy.

In order to reduce the side effects associated with this kind of treatment, we performed a local treatment through the use of vaginal ovules containing 5 mg of hyaluronic acid sodium salt per vaginal ovule.

In conclusion, we noticed that radiotherapy and chemotherapy at vaginal level result in the typical symptoms of menopause, i.e. atrophy, decreased vaginal elasticity and reduced lubrication. Therefore, from the results of our case study, it becomes advisable in our opinion, the use of a local therapy with vaginal ovules containing 5 mg of hyaluronic acid sodium salt, as it promotes an excellent healing with epithelial regeneration and proliferation while maintaining a good trophism, a vaginal elasticity and a sufficient lubrication.

KEY WORDS: Gynaecological cancer — Pelvic radiotherapy — Vaginal toxicity — Prevention of vaginal stenosis — Hyaluronic acid.

The progress made in the last decades by adjuvant therapies have resulted in a substantial improvement of the prognosis of patients suffering from various kind of cancers.

In particular, women suffering from gynaecologic cancers (carcinoma of portio, endometrium and ovaries) are often subjected to a combined treatment which also includes, in addition to the surgical operation of total hysterectomy and/or adnexectomy (according to the various methods depending on

the histologic type and on the stage of disease), radiotherapy (external and / or brachytherapy) and / or chemotherapy, in the presence of risk factors of relapse.

Another group of patients treated for neoplasias of other organs, involving for example breast or intestine, who underwent surgery and chemotherapy as adjuvant treatment, can be added to the above-mentioned group.

Both radiotherapy and chemotherapy treatments produce quite important side effects in these patients, not only on the various organs, but also on the vagina which can be the seat of more or less severe toxicity. That happens not only in postmenopausal women but also in women of childbearing age, giving the increased incidence of malignancy in this age group. The aim of our study is to evaluate the incidence, the type of vaginal toxicity following radiotherapy or chemotherapy and then to evaluate the efficacy of a local treatment through the use of vaginal ovules containing hyaluronic acid (Cicatridina® vaginal ovules, Farma-Derma) in order to reduce the side effects associated with this kind of treatment.

Vaginal toxicity caused by radiotherapy

As noted above, various Authors agree in recognizing the importance of adjuvant treatment with radiotherapy of pelvic area with external beam and brachytherapy for the patients treated for gynaecologic cancers, in order to reduce the risk of relapse.

This therapy is responsible for vaginal complications from atrophies to vaginal stenosis.

These changes in the vagina after radiotherapy treatment can be of two types: the first is the consequence of direct local damage of radiotherapy on vaginal tissue (early or late) and the second is related to endocrine dysfunctions of the ovaries with consequent hypoestrogenism, particularly in women of childbearing age, which causes vaginal atrophy.

As already observed, radiotherapy treatment include external irradiation and endovaginal irradiation (brachytherapy). In the first case, the induced tissue alterations are evenly distributed throughout the vagina, while in the second case there is a less homogeneous distribution and thus many areas may be more damaged than the others.

A direct damage on epithelial layers with cell necrosis and block of proliferation is caused in the vagina by irradiations, so that the vaginal epithelium does not regenerate or regenerate in a reduced way.

That may be a transient effect because, as it happens after the treatment with diathermo-coagulation or laser, the healthy epithelium proliferates to re-cover the de-epithelialized or altered area.

In the connective tissue, instead, the radiotherapy causes a marked inflammatory infiltrate, as well as a damage in blood vessels with abundant collagen deposit and thus a perivaginal sclerosis and fibrosis (1).

The elastic vaginal tissue is thus replaced by strong fibrous tissue (2).

Irradiations are also responsible for an obliteration of blood vessels which interferes with the physiological vaginal lubrication.

As a result, the damaged epithelium easily exfoliates and it is more easily attacked by microorganisms, with an increase of vaginitis processes. This thin mucosa is not able to produce glycogen and the same vaginal flora is subjected to changes: there is indeed a marked reduction or disappearance of lactobacilli which cause a situation similar to advanced menopause .

These changes are thus responsible for various degrees of vaginal toxicity from vaginal atrophy to the onset of various degrees of stenosis, ulcerations, radionecrosis and a marked shortening of the vagina (3).

Vaginal toxicity is an effect commonly observed by our category of gynaecologist oncologists, but often poorly documented and not recognized as caused by radiotherapy treatment (4-6).

A variable percentage of incidence of vaginal toxicity has been reported by various Authors in their case studies.

A percentage of vaginal toxicity of between 78% and 96% was reported by Robinson J et al (1999) (2)

for those patients treated with adjuvant radiotherapy because of cancer of the portio and endometrium.

517 women with endometrial cancer which were submitted to TAHBSO surgical treatment were studied by Nunns D. et al (2001) (7), but only 252 of them had a following adjuvant radiotherapy due to the high risk of relapse (102 patients were treated with brachytherapy only, 51 with external radiotherapy, 99 with both types). An incidence of vaginal atrophy in 46 out of 75 women (61.3%) is reported in that case studies by Authors, while telangiectasias are found in 47/75 women (62.6%) followed by vaginal stenosis in 54.7% (41/75 women).

Brand AH et al. (2006) (3) report an incidence of vaginal toxicity (vaginal atrophy and stenosis) of between 1.2% and 88%. This marked variability depends on different ways to report the various case studies. In fact, if the study is specifically directed towards the vaginal toxicity its incidence varies between 24% and 88% (11-7), while, if it is reported as part of other complications caused by radiotherapy, the incidence falls to between 1.2% and 3.6% (16).

Chang I et al (2008) (10) report an incidence of vaginal toxicity of 12.7% in 173 women treated for endometrial cancer.

Brand AH et al (2006) (3) report various degrees of vaginal toxicity with a different incidence. It is in fact observed that the greatest incidence occurs on grade 0 (58%) and grade 1 (27%).

Moreover, it is important to establish the starting time of symptoms. In that case too, the case studies are different.

Brand AH et al. (2006) (3) claim that the vaginal complications occur 5-7 months after brachytherapy treatment.

According to Hartnam P Diddle AW (1972) (8) complications arise after 3 months from the end of therapy.

According to Katz A (2001) (1) the vaginal complication which causes the vaginal shortening already occurs during the interval between 2 treatments of brachytherapy; according to Schover LR et al (1989) (9) the biggest changes often occur within 3 months from radiation therapy and may continue for at least the first year after therapy.

Age too can influence the various degrees of vaginal complications.

Brand AH et al. (2006) (3) observed that women aged > 50 years have a greater risk of vaginal atrophy and stenosis than women aged <50 years.

Hartman et al P (1988) (8) reported an incidence of vaginal toxicity of 24% in the group of women aged <45 years, while it is present in 48% of women in the group aged> 45 years. That increased risk of development of vaginal complications in the group of older patients can be related to the reduction of oestrogens and / or to non-sexual activity in older women.

Vaginal toxicity caused by chemotherapy

Chemotherapy following the primary treatment of a tumour that affects not only the genitals but other organs too, causes the same effects in the vagina which can be found in menopausal women. These disorders can involve women of childbearing age who are treated for a malignant tumour, and as consequence they prematurely show local symptoms of an early menopause. Because of the effect of chemotherapy, vaginal epithelium takes the appearance of the atrophy caused by estrogen-deprivation and it becomes thin, pale, and rather transparent; the elasticity of the vaginal walls is also lost, therefore the coitus or the application of speculum into the vagina during the examination can cause small bleeding lacerations at the edges of which flaps of mucosa detached from the underlying connective can be seen and at the same time small haemorrhagic petechiae caused by the thinness of the epithelium and by the starting vascular fragility can be observed. Even if at the beginning of therapy those vaginal changes are more slight, they progressively get worse by continuing the same therapy.

Lubrication disorders occur as well and they are responsible for vaginal dryness, itching, burning leading to dyspareunia, a reactive vaginismus which causes difficulties in sexual intercourse.

The vaginal environment is also subjected to substantial changes consisting in a reduction of glycogen

leading to a decrease in B. Doederlein and subsequent predominance of coccus flora. The presence of this vaginal environment and the thinness of vaginal epithelium (atrophy) reduces local defences and as a consequence pathogenic microorganisms develop and are more aggressive. These disorders related to the use of chemotherapy can have an early onset, especially after a menopause caused by surgery or radiotherapy.

All these conditions, which are found in women treated with chemotherapy, lead to a significant decrease of the sexual intercourses which adversely affects the relationship with their partner.

Material and methods

From January 2004 to December 2008 at the Obstetric and Gynaecology Clinic «Italo Panella» of the University of Catania we treated 79 patients suffering from different types of neoplasias and who were first treated with surgery, followed by, in presence of risk factors, an external radiotherapy or combined radiotherapy (external and /or internal) or cycles of chemotherapy.

In order to reduce the side effects associated with this kind of treatment, we carried out a local treatment through the use of vaginal ovules containing 5 mg of hyaluronic acid sodium salt per vaginal ovule (Cicatridina® vaginal ovules, Farma-Derma).

Hyaluronic acid is a polysaccharide belonging to the class of glycosaminoglycans, and it has an important role in the process of cell re-epithelialization and tissue repair and regeneration, thus ensuring tropism, lubrication and elasticity to the vaginal tissue also thanks to its hygroscopic properties.

Our treatment protocol for the treatment and prevention of side effects caused by radiotherapy involved the administration of a hyaluronic acid-based vaginal ovule twice a day throughout the period of the treatment with radiotherapy and then it proceeded with 1 vaginal ovule a day for 2 months and then 1 vaginal ovule every other evening in the following months.

We carried out a therapeutic scheme for patients treated with surgery and chemotherapy which involved the administration of 1 vaginal ovules in the evening throughout the period of the chemotherapy treatment and then it proceeded with the administration of 3 vaginal ovules a week. All our patients were subjected to monthly follow-ups for the first 6 months and after they were followed up every 2 months for the first year and then every 3 months during the second year. In addition to the routine gynaecolocical examination, the clinical follow-up included a colposcopic examination of the vagina and vaginal bottom as well. On that occasion data were collected about the presence of subjective symptoms such as dyspareunia, vaginal dryness, vaginal itching and burning throughout the period of radiotherapy or treatment with antiblastic drugs.

Results

From January 2004 to December 2008 we treated 79 (Table 1) patients suffering from different types of neoplasias: 20 cases of carcinoma of portio 12 of which treated with radical hysterectomy followed by external radiotherapy, while 8 cases were also treated with brachitherapy.

The cases of endometrial cancer were 29 and to be more precise: 15 had a combined treatment of surgery and external radiotherapy, 10 were also treated with brachitherapy and just 4 cases were treated with surgery only.

Our sample also includes 13 cases of ovarian cancer, 12 of breast cancer and 5 cases of intestinal cancer who were treated with primary surgery followed by chemotherapy in the presence of risk factors for relapse.

The 12 cases of breast cancer and the 5 patients suffering from intestinal cancer were not treated within our institute but in another centre and came to our observation in the outpatient unit of gynaecologic oncology for problems related to side effects caused by chemotherapy.

TABLE 1 — TYPE OF TREATMENT FOR THE 79 PATIENTS SUFFERING FROM DIFFERENT TYPES OF CANCERS

Surgery Surgery+RT Surgery+RT+Brach Surgery.+Chemoth
Ca of portio (20) 12 8
Ca of endometrium (29) 4 15 10
Ca of ovaries (13) 13
Breast ca (12) 12
Ca of intestine (5) 5

Table 2 indicates the type and incidence of vaginal toxicity in 45 patients treated with radiotherapy. Vaginal atrophy with dryness and dyspareunia are the most frequently observed symptoms (respectively in the 73.3% and 71.1% of the cases). We also found 9 cases with telangiectasias which often cause blood loss and 11 cases with loose adhesions. Vaginal stenosis was found in 9 cases (20%) and, specifically, in 8 cases it involved the vaginal bottom only and in 1 case it also went to the middle third of the vagina. Concerning the 30 patients treated with adjuvant chemotherapy, the more easily identifiable symptoms were three (Table 3). Vaginal inflammation (itching and burning) was found in 23 cases (76.6%) followed by the atrophy of mucosa and vaginal dryness in 22 cases (73.3%) and then dyspareunia in 20 cases (66.6%).

TABLE 2 — INCIDENCE AND TYPE OF VAGINAL TOXICITY IN THE 45 PATIENTS TREATED WITH
ADJUVANT RADIOTHERAPY.

Type of vaginal toxicity Incidence
Atrophy of mucosa and vaginal dryness 33 (73.3%)
Dyspareunia 32 (71.1%)
Telangiectasias (blood leaks) 9 (20.0%)
Loose adhesions 11 (24.4%)
Vaginal stenosis 9 (20.0%)
Vaginal bottom 8
Middle third of the vagina 1

TABLE 3 — INCIDENCE AND TYPE OF VAGINAL TOXICITY IN THE 30 PATIENTS TREATED WITH
ADJUVANT CHEMOTHERAPY.

Type of vaginal toxicity Incidence
Atrophy of mucosa and vaginal dryness 22 (73.3%)
Dyspareunia 20 (66.6%)
Inflammation (itching and burning) 23 (76.6%)

Table 4 shows the results of the therapeutic response of our protocol after one, three and six monts of treatment with vaginal ovules containing hyaluronic acid (Cicatridina® vaginal ovules, Farma- Derma).

Since the first month of therapy vaginal atrophy and dryness was observed in only 48.8% of patients who had that symptom and then it reduced to only 2 women (6%) at the follow-up of the 6 th month.

After the first follow-up, dyspareunia too was showed only by 46.8% of the cases reducing afterwards to 1 case (3.1%) only. While the improvement of the loose adhesions was quite fast, at the first month the vaginal stenosis was still found in 77.7% of patients who had that symptom, then decreasing to the 44.4% and 33.3.1% respectively in the following follow-ups at the 3rd and 6th month. This persistence is undoubtedly linked to the serious effects of brachytherapy.

TABLE 4 — RESPONSE TO THE LOCAL THERAPY AT THE 1ST, 3RD, 6TH MONTH AFTER THE END OF RADIOTHERAPY (INTERNAL AND EXTERNAL).

1st month 3rd month 6th month
Vaginal atrophy and dryness (33) 16 (48.8%) 8 (24.4%) 2 (6.0%)
Dyspareunia (32) 15 (46.8%) 7 (21.8%) 1 (3.1%)
Loose adhesions (11) 5 (15.1%) 2 (18.1%)
Vaginal stenosis (9) 7 (77.7%) 4 (44.4%) 3 (33.1%)

Concerning the clinical response to the local treatment in patients treated with adjuvant chemotherapy, a marked improvement of the presented symptomatology has been already observed starting from the 3rd month. In fact, at the clinical follow-up of the sixth month we observed a reduction of the signs of vaginal atrophy, dyspareunia and inflammation in the 9%, 5% and 4.3%, respectively, of patients who were subjected to an adjuvant chemotherapy (Table 5).

1st month 3rd month 6th month
Vaginal atrophy and dryness (22) 10(45.5.%) 5(22.7%) 2(9.0%)
Dyspareunia (20) 10(50.0%) 6(30%) 1(5.0%)
Inflammation (23)(itching and burning) 11(47.8%) 6(26%) 1(4.3%)

Conclusions

Adjuvant radiotherapy and/or chemotherapy treatment causes changes in the vagina that can range from simple atrophy to vaginal stenosis with the possible onset of a more or less serious obliteration of the vagina.

All the signs of vaginal atrophy, namely vaginal dryness, dyspareunia, bleeding, itching and infections are experienced by the greater part of these women.

If these conditions are not treated they certainly cause a serious problem to woman which is not only physical but also psychological and which can negatively affect the relationships with partners as well.

In this context, dyspareunia becomes important from a symptomatic point of view because it represents a very common and psychologically heavy symptom in these women, which sets up a

vicious circle, because, since the sexual intercourse is uncomfortable, it is less frequent and therefore the vaginal atrophy and the decreased elasticity of the walls are accentuated even more. This loss of elasticity that causes the shrinkage of the vaginal walls and fornices is responsible for abrasions and superficial lesions of mucosa, which, as consequence, easily bleeds, not only after sexual intercourse, but also during a gynecological examination carried out during the follow-up. In most women that causes a state of anxiety.

The vagina frequently loses its spontaneous ability of lubrication because of the effect of radiotherapy and chemotherapy and thus these women often need a local therapy with wound healing products and lubricants whose aim is to improve the trophism of vaginal epithelium and to promote a physiological lubrication, an essential condition so that the gynaecological examination is sufficient in order to evaluate a possible relapse, but which is also an essential condition in order to make the same sexual intercourse well accepted by patients.

We consider an early start of the therapy of great importance since the side effects may occur precociously. In addition, the use of a vaginal ovules can have a mechanical action which markedly

reduces the coaptation of vaginal walls thus avoiding the formation of adhesions responsible for the onset of an obliteration and vaginal stenosis.

It also important to emphasize the role of the age of woman, because, although the effects are more serious in older women, in our opinion it is important to precociously treat women of childbearing age in order to reduce the effects of premature menopause.

In conclusion, we noticed that radiotherapy and chemotherapy in the vagina result in the typical symptoms of menopause, i.e. atrophy, decreased vaginal elasticity and reduced lubrication. Therefore, from the results of our case study, it becomes advisable, in our opinion, the use of a local therapy with vaginal ovules containing 5 mg of hyaluronic acid sodium salt, as it promotes an excellent healing with epithelial regeneration and proliferation while maintaining a good trophism, a vaginal elasticity and a sufficient lubrication.

In addition, its association with Centella (60 mg), Aloe vera (60 mg) and Calendula (60 mg) allowed for an improvement of various inflammatory symptoms, namely itching and burning which, as we observed, are often founded in our sample of examined patients. Also the presence of the essential oil of Tea Tree (2 mg) has allowed to act against bacteria and fungi thanks to its germicidal action, while respecting at the same time the normal saprophyte flora.

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BIBLIOGRAPHY

  1. Katz A.,et al (2001). Early development of vaginal shortening during radiation therapy for endometrial or cervical cancer .Int. J. of Gynecological Cancer 11(3),234-235.
  2. Robinson J. W. et al (1999).Psychoeducational group increases vaginal dilation for younger women and reduces sexual fears for women of all ages with gynecological cancinoma treated with radiotherapy. Int. J .Radiation Oncology Biol.Phys. 44(3),497-506.
  3. Brand A.H. et al. (2006). Vaginal stenosis in patients treated with radiotherapy for carcinoma of the cervix. Int. J. Gynecol Cancer 16,288-293.
  4. Lancaster L.(2004) Preventing vaginal stenosis after brachitherapy for gynaecological cancer: an overview of Australian practices. Europ J. of Oncology Nursing 8,30-39.
  5. Denton A.,Maher E.J. (2003). Inetrventions fort he physical aspects of sexual dysfunction in women following pelvic radiotherapy (Cochrane Review ).In :The Cochrane Library,Issue 1.Update Software,Oxford.
  6. Pearcey R.G.,Petereit D.G.(2002). Postoperative high dose rate brachitherapy in patients with low to intermediate risk endometrial cancer .Radiotherapy and oncology 56,17-22.
  7. Nunns D. et al (2001). The morbidity of surgery and adjuvant radiotherapy in the management of endometrial carcinoma. Int. J. of Gynecological Cancer 10(3),233-238.
  8. Hartman P.,Diddle A.W. (1972).Vaginal stenosis following irradiation therapy for carcinoma of the cervix.Cancer 30 (2),426-429.
  9. Schover L.R. et al(1989). Sexual dysfunction ande tretment for early stage cervical cancer.Cancer 63 (1).204-212.
  10. Chang I et al (2008). Vaginal vault brachytherapy as sole postoperative treatment fpr low- risk endometrial cancer.Brachytherapy 7, 195-199.
  11. Decruze S.B. et al (1999). Prevention of vaginal stenosis in patients following vaginal brachtherapy.Clinical Oncology 11 ,46-48.
  12. Tyree W.C. et al.(2002).High-dose-rate brachytherapy for vaginal cancer :learning from treatment complications. Int J Gynecol Cancer 12, 27-31
  13. MacLeod c. et al.(2001).Adjuvant high-dose rate brachytherapy with or without external beam radiotherapy post-hysterectomy for endometrial cancer. Int. J. of Gynecological Cancer 9 247-255.
  14. Lukka H. et al. (2006). Adjuvant radiotherapy in women with stage I endometrial cancer: A systematic revew.Gynecol Oncol 102 ,361-368.
  15. Saibishkumar E.P. et al (2006). Evaluation of late toxixities of patients with carcinoma of the cervic trated with radical radiotherapy :an audit from India. Clin Oncol 18,30-37.
  16. Eltabbakh G.H. et al (1997). Excellent long term survival and absence of vaginal recurrences in 332 patients with low risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling report of a prospective trial. In. J.of Radiation Oncology Biology and Physics 38(2),373-380.

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