Ketayun A. Dinshaw

HPV Screening for Cervical Cancer in Rural India

BACKGROUND In October 1999, we began to measure the effect of a single round of screening by testing for human papillomavirus (HPV), cytologic testing, or visual inspection of the cervix with acetic acid (VIA) on the incidence of cervical cancer and the associated rates of death in the Osmanabad district in India. METHODS In this cluster-randomized trial, 52 clusters of villages, with a total of 131,746 healthy women between the ages of 30 and 59 years, were randomly assigned to four groups of 13 clusters each. The groups were randomly assigned to undergo screening by HPV testing (34,126 women), cytologic testing (32,058), or VIA (34,074) or to receive standard care (31,488, control group). Women who had positive results on screening underwent colposcopy and directed biopsies, and those with cervical precancerous lesions or cancer received appropriate treatment. RESULTS In the HPV-testing group, cervical cancer was diagnosed in 127 subjects (of whom 39 had stage II or higher), as compared with 118 subjects (of whom 82 had advanced disease) in the control group (hazard ratio for the detection of advanced cancer in the HPV-testing group, 0.47; 95% confidence interval [CI], 0.32 to 0.69). There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95% CI, 0.33 to 0.83). No significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group. Mild adverse events were reported in 0.1% of screened women. CONCLUSIONS In a low-resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer.

Reducing Uncertainties About the Effects of Chemoradiotherapy for Cervical Cancer : A Systematic Review and Meta-Analysis of Individual Patient Data From 18 Randomized Trials

BACKGROUND After a 1999 National Cancer Institute (NCI) clinical alert was issued, chemoradiotherapy has become widely used in treating women with cervical cancer. Two subsequent systematic reviews found that interpretation of the benefits was complicated, and some important clinical questions were unanswered. PATIENTS AND METHODS We initiated a meta-analysis seeking updated individual patient data from all randomized trials to assess the effect of chemoradiotherapy on all outcomes. We prespecified analyses to investigate whether the effect of chemoradiotherapy differed by trial or patient characteristics. RESULTS On the basis of 13 trials that compared chemoradiotherapy versus the same radiotherapy, there was a 6% improvement in 5-year survival with chemoradiotherapy (hazard ratio [HR] = 0.81, P < .001). A larger survival benefit was seen for the two trials in which chemotherapy was administered after chemoradiotherapy. There was a significant survival benefit for both the group of trials that used platinum-based (HR = 0.83, P = .017) and non-platinum-based (HR = 0.77, P = .009) chemoradiotherapy, but no evidence of a difference in the size of the benefit by radiotherapy or chemotherapy dose or scheduling was seen. Chemoradiotherapy also reduced local and distant recurrence and progression and improved disease-free survival. There was a suggestion of a difference in the size of the survival benefit with tumor stage, but not across other patient subgroups. Acute hematologic and GI toxicity was increased with chemoradiotherapy, but data were too sparse for an analysis of late toxicity. CONCLUSION These results endorse the recommendations of the NCI alert, but also demonstrate their applicability to all women and a benefit of non-platinum-based chemoradiotherapy. Furthermore, although these results suggest an additional benefit from adjuvant chemotherapy, this requires testing in randomized trials.

A treatment planning study comparing volumetric arc modulation with RapidArc and fixed field IMRT for cervix uteri radiotherapy

PURPOSE A treatment planning study was performed to evaluate the performance of the novel volumetric modulated single arc radiotherapy on cervix uteri cancer patients. Conventional fixed field IMRT was used as benchmark. METHODS AND MATERIALS CT datasets of eight patients were included in the study. Plans were optimised with the aim to assess organs at risk and healthy tissue sparing while enforcing highly conformal target coverage. Planning objectives for PTV were: maximum significant dose lower than 52.5 Gy and minimum significant dose higher than 47.5 Gy. For organs at risk, the median and maximum doses were constrained to be lower than 30 (rectum), 35 (bladder) and 25 Gy (small bowel) and 47.5 Gy; additional objectives were set on various volume thresholds. Plans were evaluated on parameters derived from dose volume histograms and on NTCP estimates. Peripheral doses at 5, 10 and 15 cm from the PTV surface were recorded to assess the low-level dose bath. The MU and delivery time were scored to measure expected treatment efficiency. RESULTS Both RapidArc and IMRT resulted in equivalent target coverage but RapidArc had an improved homogeneity (D(5%)-D(95%) = 3.5 +/- 0.6 Gy for RapidArc and 4.3 +/- 0.8 Gy for IMRT) and conformity index (CI(90%) = 1.30 +/- 0.06 for RapidArc and 1.41 +/- 0.15 for IMRT). On rectum the mean dose was reduced by about 6 Gy (10 Gy for the rectum fraction not included in the PTV). Similar trends were observed for the various dose levels with reductions ranging from approximately 3 to 14.4 Gy. For the bladder, RapidArc allowed a reduction of mean dose ranging from approximately 4 to 6Gy and a reduction from approximately 3 to 9 Gy w.r.t. IMRT. Similar trends but with smaller absolute differences were observed for the small bowel and left and right femur. NTCP calculations on bladder and rectum confirmed the DVH data with a potential relative reduction ranging from 30 to 70% from IMRT to RapidArc. The healthy tissue was significantly less irradiated in the medium to high dose regions (from 20 to 30 Gy) and the integral dose reduction with RapidArc was about 12% compared to IMRT. Concerning peripheral dose, the relative difference between IMRT and RapidArc was of 9 +/- 2%, 43 +/- 11% and 36 +/- 5% at 5, 10 and 15 cm from the PTV surface, respectively. The MU/Gy from RapidArc was 245 +/- 17 corresponding to an expected average beam on time of 73 +/- 10 s per fractions of 2 Gy. IMRT plans presented higher values with an average of MU/Gy = 479 +/- 63. CONCLUSION RapidArc was investigated for cervix uteri cancer showing significant improvements in organs at risk and healthy tissue sparing with uncompromised target coverage leading to better conformal avoidance of treatments w.r.t. conventional IMRT. This, in combination with the confirmed short delivery time, can lead to clinically significant advances in the management of this highly aggressive cancer type. Clinical protocols are now advised to evaluate prospectively the potential benefit observed at the planning level.

Volumetric modulated arc radiotherapy for carcinomas of the oro-pharynx, hypo-pharynx and larynx: A treatment planning comparison with fixed field IMRT

PURPOSE A planning study was performed to evaluate the performance of volumetric modulated arc radiotherapy on head and neck cancer patients. Conventional fixed field IMRT was used as a benchmark. METHODS AND MATERIALS CT datasets of 29 patients with squamous cell carcinoma of the oro-pharynx, hypo-pharynx and larynx were included. Plans for fixed beam IMRT, single (RA1) and double (RA2) modulated arcs with the RapidArc technique were optimised. Dose prescription was set to 66 Gy to the primary tumour (at 2.2 Gy/fraction), 60 Gy to intermediate-risk nodes and 54 Gy to low-risk nodal levels. The planning objectives for PTV were minimum dose >95%, and maximum dose <107%. Maximum dose to spinal cord was limited to 46 Gy, maximum to brain stem to 50 Gy. For parotids, mean dose <26 Gy (or median <30 Gy) was assumed as the objective. The MU and delivery time were scored to measure expected treatment efficiency. RESULTS Target coverage and homogeneity results improved with RA2 plans compared to both RA1 and IMRT. All the techniques fulfilled the objectives on maximum dose, while small deviations were observed on minimum dose for PTV. The conformity index (CI(95%)) was 1.7+/-0.2 for all the three techniques. RA2 allowed a reduction of D(2%) to spinal cord of approximately 3 Gy compared to IMRT (RA1 D(2%) increased it of approximately 1 Gy). On brain stem, D(2%) was reduced from 12 Gy (RA1 vs. IMRT) to 13.5 Gy (RA2 vs. IMRT). The mean dose to ipsi-lateral parotids was reduced from 40 Gy (IMRT) to 36.2 Gy (RA1) and 34.4 Gy (RA2). The mean dose to the contra-lateral gland ranged from 32.6 Gy (IMRT) to 30.9 Gy (RA1) and 28.2 Gy (RA2). CONCLUSION RapidArc was investigated for head and neck cancer. RA1 and RA2 showed some improvements in organs at risk and healthy tissue sparing, while only RA2 offered improved target coverage with respect to conventional IMRT.

Consolidation Radiation After Complete Remission in Hodgkin's Disease Following Six Cycles of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine Chemotherapy: Is There a Need?

PURPOSE Combined modality treatment using multidrug chemotherapy (CTh) and radiotherapy (RT) is currently considered the standard of care in early stage Hodgkins disease. Its role in advanced stages, however, continues to be debated. This study was aimed at evaluating the role of consolidation radiation in patients achieving a complete remission after six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy using event-free survival (EFS) and overall survival (OS) as primary end points. PATIENTS AND METHODS Two hundred and fifty-one patients with Hodgkins disease attending the lymphoma clinic at the Tata Memorial Hospital (Mumbai, India) from 1993 to 1996 received induction chemotherapy with six cycles of ABVD after initial staging evaluation. A total of 179 of 251 patients (71%) achieved a complete remission after six cycles of ABVD chemotherapy and constituted the randomized population. Patients were randomly assigned to receive either consolidation radiation or no further therapy. RESULTS With a median follow-up of 63 months, the 8-year EFS and OS in the CTh-alone arm were 76% and 89%, respectively, as compared with 88% and 100% in the CTh+RT arm (P =.01; P =.002). Addition of RT improved EFS and OS in patients with age < 15 years (P =.02; P =.04), B symptoms (P =.03; P =.006), advanced stage (P =.03; P =.006), and bulky disease (P =.04; P =.19). CONCLUSION Our study suggests that the addition of consolidation radiation helps improve the EFS and OS in patients achieving a complete remission after six cycles of ABVD chemotherapy, particularly in the younger age group and in patients with B symptoms and bulky and advanced disease.

A cluster randomized controlled trial of visual, cytology and human papillomavirus screening for cancer of the cervix in rural India†

The impact of screening by visual inspection with acetic acid (VIA), cytology or HPV testing on cervical cancer incidence and mortality is investigated in a cluster randomized controlled trial in India. We report findings after the screening phase, when 52 clusters, with a total of 142,701 women aged 30–59 years in Osmanabad District, India, were randomized into 4 arms for a single round of screening by trained midwives with either VIA, cytology or HPV testing as well as a control group. All laboratory tests were done locally. Test‐positive women underwent investigations (colposcopy/biopsy) and treatment in the base hospital. Data on participation, test positivity, positive predictive value and detection rates of cervical neoplasia were analyzed using cluster design methodology. Of the eligible women, 72–74% were screened. Test positivity rates were 14.0% for VIA, 7.0% for cytology and 10.3% for HPV. The detection rate of high‐grade lesions was similar in all intervention arms (0.7% for VIA, 1.0% for cytology and 0.9% for HPV testing) (p = 0.06, Mann‐Whitney test). While the detection rate for VIA dropped to 0.5% with declining test positivity during the course of the study, it remained constant for cytology and HPV testing. Over 85% of women with high‐grade lesions received treatment. Our results show that a high level of participation and good‐quality cytology can be achieved in low‐resource settings. VIA is a useful alternative but requires careful monitoring. Detection rates obtained by HPV testing were similar to cytology, despite higher investments.

Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: A randomized controlled trial

PURPOSE To compare three-dimensional conformal radiotherapy (3D-CRT) with intensity modulated radiation therapy (IMRT) in curative-intent irradiation of head-neck squamous cell carcinoma (HNSCC). METHODS Previously untreated patients with biopsy-proven squamous carcinoma of oropharynx, larynx, or hypopharynx (T1-3, N0-2b) were randomly assigned using computer-generated permuted-block design to either 3D-CRT or IMRT, with incidence of physician-rated Radiation Therapy Oncology Group (RTOG) grade 2 or worse acute salivary gland toxicity as primary end-point. RESULTS Between 2005 and 2008, 60 patients randomly allocated to either 3D-CRT (n=28 patients) or IMRT (n=32) were included and analyzed on an intention-to-treat basis. The proportion [95% confidence intervals (CI)] of patients with RTOG grade 2 or worse acute salivary gland toxicity was significantly lesser in the IMRT arm [19 of 32 patients (59%, 95%CI: 42-75%)] as compared to 3D-CRT [25 of 28 patients (89%, 95%CI: 72-97%; p=0.009)]. Late xerostomia and subcutaneous fibrosis were also significantly lesser with IMRT. There was significant recovery of salivary function over time in patients treated with IMRT (p-value for trend=0.0036). At 3-years, there were no significant differences in loco-regional control or survival between the two arms. CONCLUSION IMRT significantly reduces the incidence and severity of xerostomia compared to 3D-CRT in curative-intent irradiation of HNSCC.

Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: Results from a multicenter study in India

The knowledge that cervical neoplasia are caused by human papillomavirus (HPV) infection has led to the evaluation of its role in screening. We evaluated the accuracy of HPV testing by Hybrid capture II (HC II) method in detecting cervical intraepithelial neoplasia grade 2 and 3 (CIN 2 and 3) lesions in 4 cross‐sectional studies with common protocol and questionnaire in 3 different locations (Kolkata, Mumbai and Trivandrum) in India. These studies involved 18,085 women aged 25–65 years. The reference standard for final diagnosis was a combination of colposcopy/biopsy. All women were investigated with colposcopy and 3,116 received directed biopsy. The sensitivity of HPV testing for detecting CIN 2–3 lesions varied from 45.7% to 80.9% across the study sites; the specificity varied from 91.7% to 94.6% and the positive predictive value from 6.7% to 13.7%. Retesting of 298 randomly chosen denatured samples in France revealed an agreement rate of 85.9% and a κ‐value of 0.72. Although HPV testing seems to be a promising approach for cervical cancer prevention, a large range in sensitivity was observed in our study, possibly due to variations in the quality of specimen collection and reference standards. A higher sensitivity was associated with the center performing the test well. Further developments in terms of more reproducible, less expensive and less sophisticated testing are essential to make the test feasible and effective in low‐resource settings.

Concurrent evaluation of visual, cytological and HPV testing as screening methods for the early detection of cervical neoplasia in Mumbai, India

OBJECTIVE Naked eye visual inspection with acetic acid (VIA), magnified VIA (VIAM), visual inspection with Lugols iodine (VILI), cytology and human papillomavirus (HPV) testing were evaluated as screening methods for the detection of high-grade squamous intraepithelial lesions (HSIL) of the uterine cervix in a cross-sectional study in Mumbai, India. METHODS Cytology, HPV testing, VIA, VIAM and VILI were carried out concurrently for 4039 women aged 30-65 years. All women were investigated with colposcopy and biopsies were taken from 939 women who had colposcopic abnormalities. The reference standard for final disease status was histology or negative colposcopy. The presence of HSIL was confirmed in 57 women (1.4%). The test characteristics for each method were calculated using standard formulae. RESULTS The sensitivities of cytology, HPV testing, VIA, VIAM and VILI were 57.4%, 62.0%, 59.7%, 64.9%, and 75.4%, respectively (differences were not statistically significant). The specificities were 98.6%, 93.5%, 88.4%, 86.3%, and 84.3%, respectively. Adding a visual test to cytology or HPV testing in parallel combination resulted in a substantial increase in sensitivity, with a moderate decrease in specificity. The parallel combination of VILI and HPV testing resulted in a sensitivity of 92.0% and a specificity of 79.9%. CONCLUSION As a single test, cytology had the best balance of sensitivity and specificity. Visual tests are promising in low-resource settings, such as India. The use of both VIA and VILI may be considered where good quality cytology or HPV testing are not feasible. The sensitivity of cytology and HPV testing increased significantly when combined with VIA or VILI.

Determinants of women’s participation in cervical cancer screening trial, Maharashtra, India

OBJECTIVE To determine the factors associated with participation in cervical cancer screening and follow-up treatment in the context of a randomized controlled trial. The trial was initiated to evaluate the efficacy and cost effectiveness of visual inspection with acetic acid, cytological screening and testing for human papillomavirus in reducing the incidence of and mortality from cervical cancer in Maharashtra, India. METHODS Between October 1999 and November 2003 women aged 30-59 years were randomized to receive one of the three tests or to a control group. Participation was analysed for all three intervention arms. The differences between those who were screened versus those who were not was analysed according to the sociodemographic characteristics of the 100,800 eligible women invited for screening. Those who were treated versus those who were not were analysed according to the sociodemographic characteristics of the 932 women diagnosed with high-grade lesions. Participation in screening and compliance with treatment were also analysed according to the type of test used. FINDINGS Compared with women who were not tested, screened women were younger (aged 30-39), better educated and had ever used contraception. A higher proportion of screened women were married and a lower proportion had never been pregnant. Of the 932 women diagnosed with high-grade lesions or invasive cancer, 85.3% (795) received treatment. Women with higher levels of education, who had had fewer pregnancies and those who were married were more likely to comply with treatment. There were no differences in rates of screening or compliance with treatment when results were analysed by the test received. CONCLUSIONS Irrespective of the test being used, good participation levels for cervical cancer screening can be achieved in rural areas of developing countries by using appropriate strategies to deliver services. Communication methods and delivery strategies aimed at encouraging older, less-educated women, who have less contact with reproductive services, are needed to further increase screening uptake.