Evaluation of late toxicities of patients with carcinoma of the cervix treated with radical radiotherapy: an audit from India.

AIMS: To evaluate the incidence of, and factors affecting, late toxicities of women with carcinoma of the cervix treated with radical radiotherapy. MATERIALS AND METHODS: Between 1996 and 2001, 1069 women with carcinoma of the cervix (stage I-IVA) were treated at our centre with external-beam radiotherapy (EBRT) and intra-cavitary radiotherapy (ICRT) (n = 871) or EBRT alone (n = 198). Median follow-up was 34 months. Median dose to point A was 81 Gy. RESULTS: Five-year actuarial incidence of overall (all grades) and severe (grade 3/4) late toxicities in the rectum, bladder, small intestine and subcutaneous tissue were 12.3% and 1.1%, 11.2% and 1.2%, 9.2% and 0.2%, and 23.1% and 1.2%, respectively. Vaginal adhesions were seen in 29.6% of cases and stenosis in 33.9% of cases. On multivariate analysis, factors adversely affecting overall incidence of proctitis were anterior-posterior (AP) separation of patient more than 18 cm and presence of comorbid diseases. Presence of comorbid diseases was the only factor affecting the incidence of severe proctitis (grade 3/4). AP separation more than 18 cm adversely affected the incidence of cystitis, both overall and severe. Late toxicities (all grades) in small bowel were increased in subsets, like women younger than 50 years and women with comorbid diseases, but no factor emerged as significant for incidence of severe toxicities. Subcutaneous fibrosis was significantly higher in patients with AP separation over 18 cm, those treated by cobalt machines and those who received EBRT only. Severe subcutaneous fibrosis was influenced by the use of EBRT alone. Overall incidence of vaginal toxicity was higher in women whose overall treatment time (OTT) was shorter and in women who received ICRT. Vaginal stenosis was higher in elderly women and in women who received ICRT by low dose rate. CONCLUSIONS: Even with telecobalt machines, impressive results with acceptable late toxicity can be achieved in the treatment of cancer of the cervix using an ideal combination of EBRT with ICRT.

Results of external-beam radiotherapy alone in invasive cancer of the uterine cervix: a retrospective analysis.

AIMS: In this retrospective audit, we describe the results of external-beam radiotherapy (EBRT) alone in patients with invasive cancer of the cervix treated at our centre. MATERIAL AND METHODS: We included 146 patients with invasive cancer of the cervix who were treated with EBRT to a total dose of 60-66 Gy between January 1996 and December 2001. None of these patients were suitable for intracavitary radiotherapy (ICRT) after a median dose of 46 Gy. A boost dose of 14-20 Gy was given after a gap of 2-4 weeks. Most patients belonged to stage IIIB (n = 124). RESULTS: Follow-up of patients at risk ranged from 19 to 89 months (median 48 months). One hundred and thirty-six patients (93.2%) received EBRT to a dose of 66 Gy, and 10 patients (6.8%) received 60 Gy. Overall treatment time (OTT) ranged from 56 to 160 days (median 78 days). At completion of 46 Gy of EBRT, 63 patients achieved partial response and 83 patients had stable disease. Five-year overall survival, disease-free survival (DFS) and pelvic control were 15.1% (median 9 months), 11.6% (median 5 months) and 21.9% (median 6 months), respectively. Factors found to affect 5-year pelvic control in univariate analysis by Kaplan-Meier method were response to EBRT at 46 Gy (partial response 36.5% and stable disease 10.8%), age (> or = 50 years 28.8% and < 50 years 13.6%) and OTT (< 90 days 26.5% and > or = 90 days 12.5%). For DFS and overall survival, response to EBRT was the only factor that was significant in univariate analysis. In multivariate analysis by Cox's proportional hazard model, response to EBRT was the only factor to influence pelvic control (P = 0.007), DFS (P = 0.01) and overall survival (P < 0.001). CONCLUSIONS: Overall outcome of patients in whom ICRT was not given remains less than satisfactory. Response to EBRT emerged as the most important factor to predict all clinical outcomes. To improve upon the dismal results of EBRT alone, we will have to decrease the OTT and consider concurrent chemo-radiation with cisplatin.

Clinical significance of geographic miss when using conventional four field radiotherapy technique in treatment of locally advanced carcinoma cervix.

BACKGROUND: Although conventional four- field radiotherapy based on bony landmarks has been traditionally used, areas of geographical miss due to individual variation in pelvic anatomy have been identified with advanced imaging techniques. AIMS: The primary aim of this study is to evaluate the geographical miss in patientswhen using the conventional four-field planningplanning and to find out the impact of 3-D conformal CT based in patients with locally advanced carcinoma cervix. MATERIALS AND METHODS: In 50 patients, target volume delineation was done on planning computed tomography (CT) scans, according to guidelines by Taylor et al. Patients were treated with modified four field plan, except for the superior, where field border was kept at L4-L5 interspace A dosimetric comparison was done between the conventional four-field based on bony landmarks and the target volume delineated on computed tomography. The disease free survival, pelvic and para aortic nodal free survival, distant failures free survival were calculated using Kaplan Meir Product Limit Method. RESULTS: Patients were followed-up for a median period of 11 months. The median V95 for conventional and modified extended four field plans were 89.4% and 91.3% respectively. Patients with V95 for modified extended pelvic fields less than 91.3% had a trend toward inferior disease free survival (mean DFS 9.8 vs. 13.9 months) though the difference was not statistically significant log rank test. CONCLUSIONS: Our preliminary data shows trend toward lower DFS in patients with inadequate target volume coverage. We recommend routine use of CT based planning for four field technique.

Dosimetric evaluation and clinical outcome in post-operative patients of carcinoma vulva treated with intensity-modulated radiotherapy.

BACKGROUND: To compare dosimetric parameters of intensity-modulated radiation therapy (IMRT) with 3D conformal radiotherapy (3DCRT) in post-operative patients of vulvar cancer and to assess clinical outcome and toxicity with IMRT. MATERIALS AND METHODS: A total of 8 post-operative patients of vulvar cancer were treated with IMRT. All patients were also planned by 3DCRT for comparison with IMRT. The two plans were compared in terms of conformity index, homogeneity index, tumor control probability (TCP) and normal tissue complication probability (NTCP) for the planning target volume and organs at risk (OAR). RESULTS: IMRT resulted in significantly lesser doses to rectum, bladder, bowel and femoral head as compared with 3DCRT plans. Mean conformity and homogeneity indices were better and within range with IMRT. The TCP was comparable between the two treatment plans and NTCP for rectum, bladder, bowel and femoral head was significantly less with IMRT as compared with 3DCRT. Treatment was well-tolerated and none of the patients developed Grade 3 or higher toxicity. CONCLUSION: IMRT yielded superior plans with respect to target coverage, homogeneity and conformality while lowering dose to adjacent OAR as compared with 3DCRT. Thus, IMRT offers a reduction in NTCP while maintaining TCP.

Epigenetic Alteration by DNA Methylation of ESR1, MYOD1 and hTERT Gene Promoters is Useful for Prediction of Response in Patients of Locally Advanced Invasive Cervical Carcinoma Treated by Chemoradiation.

AIMS: Locally advanced invasive cervical cancer [International Federation of Gynecology and Obstetrics (FIGO) IIB/III] is treated by chemoradiation. The response to treatment is variable within a given FIGO stage. Therefore, the aim of the present study was to evaluate the gene promoter methylation profile and corresponding transcript expression of a panel of six genes to identify genes which could predict the response of patients treated by chemoradiation. MATERIALS AND METHODS: In total, 100 patients with invasive cervical cancer in FIGO stage IIB/III who underwent chemoradiation treatment were evaluated. Ten patients developed systemic metastases during therapy and were excluded. On the basis of patient follow-up, 69 patients were chemoradiation-sensitive, whereas 21 were chemoradiation-resistant. Gene promoter methylation and gene expression was determined by TaqMan assay and quantitative real-time PCR, respectively, in tissue samples. RESULTS: The methylation frequency of ESR1, BRCA1, RASSF1A, MLH1, MYOD1 and hTERT genes ranged from 40 to 70%. Univariate and hierarchical cluster analysis revealed that gene promoter methylation of MYOD1, ESR1 and hTERT could predict for chemoradiation response. A pattern of unmethylated MYOD1, unmethylated ESR1 and methylated hTERT promoter as well as lower ESR1 transcript levels predicted for chemoradiation resistance. CONCLUSION: Methylation profiling of a panel of three genes that includes MYOD1, ESR1 and hTERT may be useful to predict the response of invasive cervical carcinoma patients treated with standard chemoradiation therapy.

Bladder-Rectum Spacer Balloon versus Vaginal Gauze Packing in High Dose Rate Brachytherapy in Cervical Cancer: A Randomised Study. Part II.

AIMS: To compare the inter-fraction dose variation for bladder and rectum using a bladder-rectum spacer balloon (BRSB) versus vaginal gauze packing (VGP) in patients treated with high dose rate intracavitary brachytherapy for carcinoma cervix. MATERIALS AND METHODS: After the completion of external radiotherapy, 80 patients were randomised to receive intracavitary brachytherapy using either the BRSB or VGP. The procedure was carried out under general anaesthesia using tandem ovoid applicators. Computed tomography-based planning was carried out and the dose was prescribed to point A. Doses to 0.1, 1 and 2 cm(3) volumes were reported for bladder and rectum for each fraction. The absolute inter-fraction dose variation for each subvolume was compared using the independent sample t-test. RESULT: The mean bladder and rectal volumes, as well as the inter-fraction volume variation, were comparable for the BRSB and VGP. The BRSB resulted in a significant reduction in absolute dose as well as the inter-fraction variation for dose to 2 cm(3) rectum volumes (BRSB 0.80 Gy, standard deviation 0.71 Gy versus VGP 1.16 Gy, standard deviation 0.83 Gy; P = 0.04). Cumulative bladder D2cm(3) doses of more than 90 Gy3 were observed in six patients in the BRSB arm versus four patients in the VGP arm (P = 0.73). In both the arms, the rectal D2cm(3) doses did not exceed 75 Gy3. CONCLUSIONS: Use of a BRSB resulted in a significant reduction in inter-fraction variation in D2cm(3) rectal dose. However, no significant difference in the inter-fraction dose variation for the other subvolumes of bladder and rectum could be shown between the BRSB and VGP. The use of a BRSB may enable rectal dose reduction and inter-fraction variation where anaesthesia is not routinely used or where there is limited physician expertise. The modification suggested in the BRSB may facilitate its additional usage.

Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial.

PURPOSE: This study is a prospective randomized clinical trial undertaken at our center to compare low dose rate versus high dose rate intracavitary brachytherapy for the treatment of carcinoma uterine cervix. METHODS AND MATERIALS: From June 1986 to June 1989, 482 patients with previously untreated invasive squamous cell carcinoma of the uterine cervix were entered into the study. After an initial clinical examination and investigative work-up the patients were staged according to FIGO staging system. Depending upon the stage of the disease, the size of the local growth and the local cervical anatomy, the patients were divided into two main groups. In group I patients, the predominant treatment was by intracavitary therapy and in group II patients, the predominant therapy was by external beam radiation. In both the groups at the time of intracavity brachytherapy the patients were alternately randomized to receive either low dose rate or high dose rate brachytherapy. There were thus two hundred forty-six patients in the low dose rate group and two hundred thirty-six patients in the high dose rate group. The patients were analyzed for local control, 5 years survival and late radiation morbidity. RESULTS: Stage for stage the local control rates in the low dose rate group and high dose rate group were similar. The overall local control achieved in the low dose rate group was 79.7% as compared to 75.8% in the high dose rate group. The 5 years survival figures in the low dose rate and high dose rate group were also comparable. In Stage I, it was 73% for low dose rate patients and 78% for high dose rate patients, for Stage II it was 62% and 64% respectively and for Stage III patients it was 50% and 43%. The only statistically significant difference was found in the incidence of overall rectal complications which was 19.9% for the low dose rate group as compared to only 6.4% for the high dose rate group. However, the more severe grade 3-4 complications were not significantly different between the two groups (2.4% vs. 0.4%, respectively). The bladder morbidity in both the groups was similar. CONCLUSION: Thus high dose rate intracavitary brachytherapy is an equally good alternative to conventional low dose rate brachytherapy in the treatment of carcinoma of the uterine cervix.

Dose rate correction in medium dose rate brachytherapy for carcinoma cervix.

PURPOSE: To establish the magnitude of brachytherapy dose reduction required for stage IIB and III carcinoma cervix patients treated by external radiation and medium dose rate (MDR) brachytherapy at a dose rate of 220+/-10 cGy/h at point A. MATERIALS AND METHODS: In study-I, at the time of MDR brachytherapy application at a dose rate of 220+/-10 cGy/h at point A, patients received either 3060 cGy, a 12.5% dose reduction (MDR-12.5), or 2450 cGy, a 30% dose reduction (MDR-30), to point A and they were compared to a group of previously treated LDR patients who received 3500 cGy to point A at a dose rate of 55-65 cGy/h. Study-II was a prospective randomized trial and patients received either 2450 cGy, a 30% dose reduction (MDR-II (30)) or 2800 cGy, a 20% dose reduction (MDR-II (20)), at point A. Patients were evaluated for local control of disease and morbidity. RESULTS: In study-I the 5-year actuarial local control rate in the MDR-30 and MDR-12.5 groups was 71.7+/-10% and 70.5+/-10%, respectively, compared to 63.4+/-10% in the LDR group. However, the actuarial morbidity (all grades) in the MDR-12.5 group was 58.5+/-14% as against 34.9+/-9% in the LDR group (P < 0.05). Similarly, the grade III and IV morbidity also in the MDR-12.5 group was 12.5+/-9% as against 5.3+/-5% in the LDR group (P < 0.05). No statistically significant difference in morbidity was seen between the MDR-30 and LDR groups. In study-II the 3-year actuarial local control rate in the MDR-II (30) and MDR-II (20) groups was 66.6+/-10% and 74.8+/-9%, respectively. There was a significant correlation between the rectal BED received and the percentage of patients developing rectal morbidity. Only 10% of patients receiving a rectal BED of (100 < 120) Gy3 developed complication as against 62.5% of those receiving a rectal BED of (140 < 160) Gy3 (chi2 = 46.43; P < 0.001). CONCLUSION: We suggest that at a dose rate of 220+/-10 cGy/h at point A the brachytherapy dose reduction factor should be around 30%, as suggested by radiobiological data, to keep the morbidity as low as possible without compromising the local control rates.

Primary gastrointestinal lymphoma--disease spectrum and management: a 15-year review from north India.

OBJECTIVE: To analyze retrospectively the disease spectrum and outcome of primary gastrointestinal lymphoma (PGIL) in a tertiary referral center in north India. MATERIAL: Seventy five patients presenting with PGIL between January 1971 and December 1985 were evaluated. RESULTS: The 49 males and 26 females were aged 3.5-69 years (mean 34) at presentation. Abdominal pain, weight loss and vomiting were cardinal symptoms at presentation; the stomach was the most common site of involvement. Histologically, a majority of patients were classified as having diffuse poorly-differentiated lymphocytic lymphoma (46.7%) and diffuse histiocytic type (30.7%). Twenty seven (36%) patients had stage I disease, 31 (40%) stage II, 11 (14.7%) stage III, and 6 (8%) stage IV. At laparotomy, primary resection and anastomosis was carried out in 66 patients, while only biopsies were taken in nine. Forty eight patients received adjuvant radiation with or without chemotherapy. The mean follow-up was 3.9 years (range 1-14). The 5-year actuarial survival was 34%, 25% and 16% for stages I, II, and higher-stage disease, respectively. The survival was significantly better (p < 0.01) for gastric location (44%) compared to other sites (24%). CONCLUSION: PGIL was more common in the 3rd and 4th decades of life, with the stomach being the predominant site of involvement. Survival was better among patients with stages I and II disease, and gastric location of lesion.

Local control of high-grade gliomas with limited volume irradiation versus whole brain irradiation.

INTRODUCTION: To evaluate the role of limited field radiation therapy in the management of high-grade gliomas and glioblastoma multiforme (GBM). MATERIAL AND METHODS: From July '96 to January '98, 50 newly diagnosed patients of high-grade gliomas (Grade III and IV) and glioblastoma multiforme who underwent surgery in the form of partial, sub-total or near-total excision as the primary treatment were enrolled in this study. The patients were randomized to receive two different postoperative external radiation protocols, Study Group A: Localized field external radiotherapy 50 Gy/25#/5 wks followed by Boost 10 Gy/5#/1 wk, Control Group B: Whole brain external radiotherapy 40 Gy/20#/4 wks followed by Boost 20 Gy/10#/2 wks by localized field. RESULTS: 20/25 (80%) patients in the study group and 14/25 (56%) patients in the control group showed improvement in their Karnofsky Performance Status (KPS). Thus a significant difference in the performance status was noted in favor of limited field irradiation. No significant difference in the local response was seen between the two groups after radiotherapy. Six months progression-free survival of the study group was 44% as compared to 26% in the control group. Six months overall survival was 66.67% in the study group and 50.72% in the control group (P<0.01). Maximum recurrences were noticed within 2 cm of the original tumor margin in both the groups. CONCLUSIONS: Although local control and survival of the patient in both the groups were same, performance status definitely improved in patients treated with localized field irradiation only.

Dose escalation by intensity-modulated radiotherapy boost after whole pelvic radiotherapy in postoperative patients of carcinoma cervix with residual disease.

AIMS: External beam radiotherapy followed by brachytherapy is the standard treatment for patients with carcinoma cervix. However, for patients who come from peripheral hospitals after incomplete surgery, whole pelvic radiotherapy (WPRT) followed by boost with either vaginal vault brachytherapy if suitable or further external beam radiotherapy is recommended. This study was conducted to evaluate if it was possible to give a higher tumour dose using intensity-modulated radiotherapy for that group of patients who were not suitable for high dose rate vaginal vault brachytherapy because of gross disease after WPRT. MATERIALS AND METHODS: A prospective study was carried out from 2005 to 2010 in which 25 postoperative patients of cervical carcinoma with gross residual disease after WPRT of 46 Gy/23 fractions/4.5 weeks were included. Nine patients were treated with 20 Gy to the planning target volume and 30 Gy to the clinical target volume in 10 fractions; 16 patients were treated with 30 Gy to the planning target volume and 35 Gy to the clinical target volume in 15 fractions. The end points of this study were local control, survival and treatment-related toxicity. RESULTS: The median follow-up was 38 months. The 3 year local control, progression-free survival and overall survival rates were 76, 74 and 67%, respectively. Late grade 2 rectal toxicity was seen in 11 patients. Grade 2 bladder toxicity occurred in two patients and grade 3 bowel toxicity in two patients. No other grade 3 or higher toxicity was seen. CONCLUSION: Inadequate and inappropriate surgery in invasive cervical cancer with resulting gross residual disease is common in India. It is possible to escalate the tumour dose by intensity-modulated radiotherapy boost after WPRT in postoperative cervical carcinoma patients with gross residual disease with low incidence of severe toxicity and excellent local control.

Can point doses predict volumetric dose to rectum and bladder: a CT-based planning study in high dose rate intracavitary brachytherapy of cervical carcinoma?

OBJECTIVE: Point doses, as defined by the International Commission on Radiation Units and Measurements (ICRU), are classically used to evaluate doses to the rectum and bladder in high dose rate intracavitary brachytherapy (HDR-ICBT) in cervical cancer. Several studies have shown good correlation between the ICRU point doses and the volumetric doses to these organs. In the present study we attempted to evaluate whether this correlation could be used to predict the volumetric doses to these organs. METHODS: A total of 150 HDR-ICBT insertions performed between December 2006 and June 2008 were randomly divided into two groups. Group A (n=50) was used to derive the correlation between the point and volumetric doses using regression analysis. This was tested in Group B (n=100) insertions using studentised residuals and Bland-Altman plots. RESULTS: Significant correlations were obtained for all volumetric doses and ICRU point doses for rectum and bladder in Group A insertions. The strongest correlation was found for the dose to 2 cc volumes (D(2cc)). The correlation coefficients for bladder and rectal D(2cc) versus the respective ICRU point doses were 0.82 and 0.77, respectively (p<0.001). Statistical validation of equations generated in Group B showed mean studentised residual values of 0.001 and 0.000 for the bladder and rectum. However, Bland-Altman analysis showed that the error range for these equations for bladder and rectum were ±64% and ±41% of the point A dose, respectively, which makes these equations unreliable for clinical use. CONCLUSION: Volumetric imaging is essential to obtain proper information about volumetric doses.

Quadruple malignancy in a single patient: a case report and comprehensive review of literature.

The occurrence of multiple primary malignant neoplasias (MPMN) is a rare but increasingly frequently reported event. Many theories have been proposed to explain MPMNs, but none have been proven. The key risk factors appear to be smoking and family history. While numerous studies have been published on the development of second malignancies following a first primary, the literature contains only few case reports and reviews of patients with three or more malignancies. We report a case of a young female who, over a period of 30 years, developed four different malignancies and was treated radically on each occasion.

Results of letrozole in postmenopausal women after tamoxifen treatment for advanced breast cancer.

AIM: To analyze overall and progression-free survival after letrozole in postmenopausal women with advanced breast cancer who failed after tamoxifen therapy. MATERIALS AND METHODS: This is a retrospective analysis of 95 patients with breast cancer who were postmenopausal and had failed after tamoxifen therapy. Dose of letrozole was 2.5 mg daily until disease progressed. Patients had estrogen receptor- and/or progesterone receptor-positive tumors or both receptors were unknown. One complete course of (6 cycles) chemotherapy for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, time to treatment failure (TTF), overall survival and tolerability. RESULTS: Median TTP was 10 months. ORR was 21% with complete response rate of 9%. Nine patients died of disease during treatment. Median overall survival was 36 months. Median time to response was three months and median duration of response was 13 months. Time to chemotherapy was 13.5 months and TTF was 9.3 months. Treatment failure was seen in 76% of patients. Disease progression was the main cause for treatment failure. Treatment was well-tolerated by all patients. CONCLUSION: This retrospective analysis shows that letrozole is quite effective as second line therapy in postmenopausal patients with advanced breast cancer who had failed after tamoxifen therapy.

Results of radiotherapy alone in the treatment of carcinoma of uterine cervix: a retrospective analysis of 1069 patients.

Carcinoma of the uterine cervix is the most common malignancy affecting women in developing countries like India. This retrospective study was made to analyze our results of radiotherapy alone in the treatment of carcinoma cervix. Between January 1996 and December 2001, 1069 patients of carcinoma cervix were treated at our center with external beam radiotherapy (EBRT) and intracavitary radiotherapy (871) or EBRT alone (198). The median dose to point A was 81 Gy. Overall survival (OS), disease-free survival (DFS), and pelvic control at 5 years were 51.8%, 49.4%, and 63.9%, respectively. For the patients who could receive intracavitary radiotherapy (871), the OS, DFS, and pelvic control rates were 60.7%, 58.6%, and 73.5%, respectively. On multivariate analysis, bulk, overall treatment time (OTT) and response to EBRT were found to affect OS and DFS independently. Similarly, OTT, response to EBRT, stage, and age were the factors that influenced pelvic control. Incidence of severe late toxicities (grade 3/4) in the rectum, bladder, small intestine, and skin were 1.1%, 1.2%, 0.2%, and 1.2%, respectively. In developing countries like India, where chemoradiation can be afforded by a minority only, judicious use of radiotherapy still produces satisfactory results with acceptable toxicity. The addition of chemotherapy may be beneficial in patients with adverse prognostic factors.

Management of mediastinal compression due to bronchogenic carcinoma.

Fifty-six cases of bronchogenic carcinoma with mediastinal compression were analyzed retrospectively. Microscopic confirmation was obtained in 23 patients and small cell carcinoma was most frequent. Radiation treatment gave complete remission in about 70 per cent when the total tumour dose exceeded 35 Gy fractionated during 3 weeks. Addition of cyclophosphamide marginally increased the remission rate to about 85 per cent. Total tumour doses of less than 35 Gy gave obviously poorer results. The response rate was highest in small cell carcinoma.

Side-effects of local hyperthermia: results of a prospectively randomized clinical study.

In 1986, 25 patients with stage II and III carcinoma of the cervix were treated by a combination of radiation and local hyperthermia using an endotract intravaginal applicator. Another 25 patients were treated with radiation alone. Both groups were followed up for a minimum period of 18 months. The acute and long-term toxicity of local hyperthermia was closely monitored. Our study shows that whereas local hyperthermia adds significantly to the local control achieved with radiation alone, it is not in any way associated with any significant short- or long-term toxicity, and does not enhance the radiation reactions.