European Journal of Cardiovascular Medicine

Carcinoma cervix is the commonest malignancy affecting female population in our country. Globally cervical cancer is the second most common cancer among women. Approximately 80% of total cases occur in developing countries. Carcinoma of the uterine cervix is the most common cancer in Indian women and occupies the top rank among cancers in women in most developing countries, constituting 34% of all women’s cancers. To an estimated annual global incidence of 5,00,000 cervical cancers, India contributes 1,00,000 i.e. 1/5 of the worlds burden. The magnitude of the problem is thus more than evident. The world pattern of cervical cancer, together with the age adjusted rate and ranking, clearly indicate that cervical cancer is predominantly a problem of poorer socio-economic societies. It is more common in women with early initial sexual activity and/or multiple sexual partners, and in smokers. Venereal transmission of human papilloma virus (HPV) has important etiologic role.

A number of factors may influence the choice of local treatment for cervical cancer, including tumor size, stage, histological features, evidence of lymph node metastasis, risk factor for complications of surgery or radiotherapy, and patient preference.

Smegma of the man also is said to contribute in the development of carcinoma cervix. Incidence of carcinoma cervix is 23% higher in fertile women than infertile women. Similarly single, widowed, divorced women were found to have smaller percentage of carcinoma cervix. Second wife of a man whose first wife died from carcinoma cervix has higher risk of developing carcinoma cervix. CCRT is the standard treatment for stage III-IV a cervical cancer in various guidelines including: the National Comprehensive Cancer Network (NCCN)[1]; the National Cancer Institute[2]; the European Society of Medical Oncology[3]; the Arbeitsgemeinschaft fur Gynakologische Onkologie[4]; and the Japan Society of Gynecologic Oncology[5]. Among them,the description in the NCCN clinical guidelines is noteworthy; surgical staging,namely extra peritoneal or laparoscopic lymph node dissection is listed as an alternative for stage IB2-IVA patients. Unless surgical staging is performed,the guideline instructs physicians to consider resection of radiologically enlarged lymph nodes. In a nutshell,the NCCN clinical guidelines imply that some LACC with lymph node metastasis cannot be cured by CCRT alone. The prognosis of this disease is directly related to the stage at presentation. Surgery or radical radiotherapy (RT) in the early stages of disease (stage IA-IIA) results in cure in more than 80% of women, five year survival rate is 60% for stage IIB, 30-35% for stage III and <15% for stage IVA disease following radiotherapy. Loco-regional recurrence (seen in 40% to 70% of patients) is the main cause of failure in post radiation and about 20% patients fail due to distant metastasis.

In GOVERNMENT CANCER HOSPITAL INDORE annually approximately 250 to 300 new patients of carcinoma cervix are registered. About 20 % patient reported after HYSTERECTOMY mainly after simple or pan hysterectomy and very few after radical hysterectomy. The duration between hysterectomy and reporting to cancer hospital is variable, ranging from immediately post operative period to one to two years after surgery with or without recurrence/distant metastasis. The prevalence and burden of cervical cancer is much higher among women of low socioeconomic status  as well as among rural women in India.  The primary reason given for this is lack of access to screening and health services, and lack of awareness of the risk factors among rural women in India The primary reason given for this is lack of access to screening and health services, and lack of awareness of the risk factors of cervical cancer. HPV infection and precancerous lesions go unnoticed and develop into full blown cancer before women realise they need to go for medical help. Moreover, due to difficulties of access and affordability, compliance to, and follow up of, treatment is much worse for women of low Socioeconomic status , leading to further morbidity and mortality from the disease. In this study we evaluate the response of external radiotherapy with concomitant weekly carboplatin in  carcinoma cervix. Carboplatin has been reported to enhance the cytotoxicity of radiation in a number of studies in both, the cell culture and the tumor bearing animals. The precise biochemical mechanism of this interaction has not been defined although inhibition of repair of sub lethal damage by carboplatin has been postulated to occur .Also carboplatin is the most active cytotoxic agent in advance, metastatic and recurrent squamous cell carcinoma of the cervix. Carboplatin is less nephrotoxic and less neurotoxic than cisplatin. 

Objectives:

1. To determine the clinical response of simultaneous CARBOPLATIN and external radiation therapy in advance cases of carcinoma cervix.
2. To know the normal tissue toxicity to simultaneous carboplatin and external radiation therapy in carcinoma cervix.

Out of the total patients reported to govt cancer hospital Indore with cancer of the cervix during the period of April 2012 to October 2012 fourty identical cases are studied in this work. Patients are randomly studied in two groups. One is a trial group of 20 patients who received EBRT with concomitant weekly Carboplatin and the other one is control group of 20 patients who received EBRT alone.

The patients were identical on basis of following criterion. Informed consent were taken before enrolling the patient into the study.

#.  Selection of cases:

  Inclusion criterion:

1. Biopsy proved carcinoma of cervix.
2. Clinical stage IIA to IVB.
3. Patients with performance status (Karnofsky status) of 60 or more.
4. . patients with normal renal profile.

 Exclusion criterion:

1. Patients who have already received chemotherapy or radiotherapy.
2. Patients of more than 70 years of age.

Clinical work-up:

1. Biopsy
2. Haemogram
3. Blood sugar
4. Blood urea
5. Serum creatinine
6. X- Ray chest
7. USG Abdomen & Pelvis

Intervention:

In this prospective study two groups of patients were taken.

One group were receive 46 Gy in 20# in four weeks 230 cGy daily from Monday to Friday with two days interval of last two days of week. Other group were receive same schedule with concomitant weekly carboplatin which is given to the patient 4 to 5 hours before the radiation.

All the necessary precautions were taken in administering radiation and chemotherapy.

      Reassessment of the patient will be done by –

* Symptom relief

*Examination:      General examination

                            Local examination (changes in tumour size & nodal

                            status).

  Gynaecological examination

*Investigations:  Routine Investigation

                           USG abdomen & pelvis

                           X- ray Chest

CT Abdomen

Those patients with positive biopsy were taken, according to the parameters of the treatment schedule, the responses during treatment and follow up were observed.

WARREN graded the cancer cervix as follows:-

GRADE I: Presence of numerous epitheloid pearls, considerable keratinization, visible intercellular bridges and less than 2 mitosis per high power field.

GRADE II: Pearls are rare or absent, moderate amount of keratinization with some intercellular bridges, 2-4 mitotic figures per high power field.

GRADE III: No pearls, slight evidence of keratinization, no intercellular bridges, more than 4 mitotic figures per high power field and marked variation in shape and size of tumor cells.

SKIN REACTION:

EARLY REACTION

The observations are taken after evaluating the patients with proper examination and history taking, fulfilling the inclusion criteria, registered in Govt. Cancer Hospital Indore from April 2012 to October 2012. Total patients studied were 40. Among those 20 patients had received EBRT+ Concomitant chemotherapy with weekly carboplatin 150mg and 20 patients out of 40 patients received EBRT alone.

TABLE 1: AGE WISE DISTRIBUTION

The above table shows the maximum patients in our study are from the age group of 15-44 years.

TABLE 2: HPE DISTRIBUTION

The above table shows that Squamous cell carcinoma is the most common histopathology found in Carcinoma Cervix.

TABLE: 3 CLINICAL STAGING WISE DISTRIBUTION

TABLE: 4 HISTOPATHOLOGIC GRADE

TABLE: 5 SKIN REACTION GRADING

TABLE: 6 RESPONSE OF TWO DIFFERENT TREATMENT SCHEDULE

TABLE:7 URINARY TOXICITY (BURNING MICTURITION)

TABLE:8 GASTROINTESTINAL TOXICITY (DIARRHOEA) and HAEMATOLOGICAL TOXICITY (MYELOSUPPRESSION)

Above table shows maximum number of patients experienced myelosuppression were from trial arm. After evaluating all the patients in my study I have found that in trial arm fourteen patients (70%) experienced complete response in association with resolution of symptoms and 6 patients (30%) experienced partial response.

Four with partial response are improving further and one is being maintained in partial response and one responder has relapsed during therapy.

From control arm Nine patients (45%) experienced complete response in association with resolution of symptoms and Eight patients (40%) experienced partial response and Three patients (15%) had no response

Number of patients attending the Govt Cancer Hospital Indore is approximately 3000 every year out of which 250 to 300 are of carcinoma cervix. As the scenario in other part of India, Rural population, Hindu religion and Squamous cell carcinoma occupies most common data in their categories. The acute toxicity seen after Radiotherapy is mostly of Grade 2 skin reaction and mucositis which can be easily manageable. Pelvic failures with or without a systemic component is a frequent problem for patients with locally advanced cervical carcinoma, despite the recent encouraging results of concomitant chemoradiation based on cisplatin [2–6] or other radiosensitizing drugs[6,7]. These results emphasize the need to test new treatment alternatives in order to improve survival. Our study revealed that external radiotherapy with concomitant weekly carboplatin gave excellent response rate in carcinoma cervix, in comparison with external radiation alone. To our knowledge, this is the first study that has compared the new standard of treatment, chemoradiation, against neoadjuvant chemotherapy followed by surgery or chemoradiation in unresectable cases. Within the limitations of a nonrandomized study, our results suggest that this neoadjuvant approach is at least as effective as cisplatin-based chemoradiation and deserves further evaluation in phase III randomized studies. After many years of studying neoadjuvant chemotherapy its role in the treatment of locally advanced cervical carcinoma remains unclear. Several phase III randomized studies of this form of chemotherapy delivery failed when radiotherapy was used to consolidate the response to induction chemotherapy. In fact, two of them not only failed but showed negative effects on the survival of patients assigned to this treatment as compared with radiation alone [8,9].

Even though the length of follow-up in our study was short, the comparable responses and survival shown between the neoadjuvant chemotherapy/surgery group and the group treated with chemoradiation can be explained as follows. First, the use of a new drug combination highly active for advanced, pretreated cervical carcinoma[10,11] and for untreated patients, which is able to achieve better clinical and pathological responses[12] as compared with older regimens such as cisplatin–vincristine–bleomycin, cisplatin–bleomycin, cisplatin–ifosfamide and many others[13]; as well as compared with newer combinations, such as cisplatin–navelbine[14], cisplatin–irinotecan[15] and cisplatin–ifosfamide–paclitaxel[16]. Secondly, the use of surgical resection, even in tumors that only showed partial responses to chemotherapy, and finally, the use of concomitant chemoradiation for those cases considered unresectable. In this prospective study they evaluate carboplatin is a radio sensitizer in advanced cervical cancer. Standard radiotherapy techniques were used to treat patients with Stage IIA-IIIB cervical cancer. Intravenous carboplatin was administered twice weekly concurrent with external beam radiation. Of 22 evaluable patients, there were 19 complete responders of whom 15 remain alive: 11 patients were alive and disease free at last visit for a median duration of 15 months follow-up (range, 4-43 months) and 4 patients remain alive with disease for a median duration of 17 months (range, 3-55 months). Seven have died, one of whom was without evidence of disease. There were no treatment-related deaths and no grade 4 toxicity. The most significant adverse effect was hematologic resulting in four patients with grade 3 neutropenia or anemia. There were no fistula or late gastrointestinal or genitourinary complications.

On the basis of my study, I concluded that Patients with cervix cancer can be treated on schedule with concurrent carboplatin and pelvic radiation therapy. This regimen is well tolerated and produces excellent response rates and acceptable toxicities. All these above-mentioned studies along with my study suggests that carboplatin administered with standard radiation is safe, well-tolerated, and thus may be useful as a radiation sensitizer in the treatment of locally advanced cervical cancer. 

Conflict of interest: None declared

Funding: Nil

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