Jai Prakash Agarwal

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.

Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer

BACKGROUND Whether patients with early-stage oral cancers should be treated with elective neck dissection at the time of the primary surgery or with therapeutic neck dissection after nodal relapse has been a matter of debate. METHODS In this prospective, randomized, controlled trial, we evaluated the effect on survival of elective node dissection (ipsilateral neck dissection at the time of the primary surgery) versus therapeutic node dissection (watchful waiting followed by neck dissection for nodal relapse) in patients with lateralized stage T1 or T2 oral squamous-cell carcinomas. Primary and secondary end points were overall survival and disease-free survival, respectively. RESULTS Between 2004 and 2014, a total of 596 patients were enrolled. As prespecified by the data and safety monitoring committee, this report summarizes results for the first 500 patients (245 in the elective-surgery group and 255 in the therapeutic-surgery group), with a median follow-up of 39 months. There were 81 recurrences and 50 deaths in the elective-surgery group and 146 recurrences and 79 deaths in the therapeutic-surgery group. At 3 years, elective node dissection resulted in an improved rate of overall survival (80.0%; 95% confidence interval [CI], 74.1 to 85.8), as compared with therapeutic dissection (67.5%; 95% CI, 61.0 to 73.9), for a hazard ratio for death of 0.64 in the elective-surgery group (95% CI, 0.45 to 0.92; P=0.01 by the log-rank test). At that time, patients in the elective-surgery group also had a higher rate of disease-free survival than those in the therapeutic-surgery group (69.5% vs. 45.9%, P<0.001). Elective node dissection was superior in most subgroups without significant interactions. Rates of adverse events were 6.6% and 3.6% in the elective-surgery group and the therapeutic-surgery group, respectively. CONCLUSIONS Among patients with early-stage oral squamous-cell cancer, elective neck dissection resulted in higher rates of overall and disease-free survival than did therapeutic neck dissection. (Funded by the Tata Memorial Centre; ClinicalTrials.gov number, NCT00193765.).

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.

Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research

Background:Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed to validate the concept of LND in OSCC.Methods:The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan–Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis.Results:The OS was 49% for patients with LND⩽0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND⩽0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures.Conclusion:This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.

Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial

BACKGROUND Several large randomised studies from western Europe and the USA have shown that accelerated fractionation of radiotherapy might be beneficial in the treatment of squamous-cell carcinoma of the head and neck (HNSCC). The aim of this study--the International Atomic Energy Agency (IAEA) ACC trial--was to determine whether accelerated fractionation could be applied in developing countries, where there are fewer therapeutic resources and where tumour burdens can be heavier. METHODS Between Jan 6, 1999, to March 31, 2004, nine centres from Asia, Europe, the Middle East, Africa, and South America recruited patients with HNSCC of the larynx, pharynx, and oral cavity who were eligible for curative radiotherapy. Patients were randomly assigned in this open-label trial to receive an accelerated regimen of six fractions of radiotherapy per week (n=458) or to receive a conventional radiotherapy regimen of five fractions per week (n=450), receiving a total dose of 66-70 Gy in 33-35 fractions. Patients were stratified by tumour localisation, T classification, histopathological grade, and institution. Randomisation was done by a central computer-generated balanced randomisation algorithm. The primary endpoint was locoregional control, analysed for all eligible patients, irrespective of whether or not they had completed the course of radiotherapy. This trial is registered with ClinicalTrials.gov, number NCT00120211. FINDINGS Six patients in the accelerated group and two in the conventional group were excluded from analyses because of withdrawal of consent or missing data. The planned total radiotherapy dose was received by 418 (92%) of the 452 eligible patients in the accelerated radiotherapy group and 413 (92%) of the 448 patients in the conventional radiotherapy group. Median treatment time was 40 days in the accelerated group and 47 days in the conventional group. The 5-year actuarial rate of locoregional control was 42% in the accelerated group versus 30% in the conventional group (hazard ratio [HR] 0.63, 95% CI 0.49-0.83; p=0.004). Acute morbidity in the form of confluent mucositis was noted in 45 patients in the accelerated group and 22 patients in the conventional group (2.15, 1.27-3.35); severe skin reactions were noted in 87 patients in the accelerated group and 50 patients in the conventional group (1.91, 1.31-2.79). There were no significant differences in late radiation side-effects. INTERPRETATION An accelerated schedule of radiotherapy for HNSCC was more effective than conventional fractionation, and since it does not require additional resources, might be a suitable new worldwide standard baseline treatment for radiotherapy of HNSCC. FUNDING International Atomic Energy Agency, Coordinated Research Project (IAEA-CRP E.3.30.18), the Danish Cancer Society, the Danish Strategic Research Council, and the Lundbeck Centre for Interventional Research in Radiation Oncology (CIRRO).

Volumetric Modulation Arc Radiotherapy With Flattening Filter-Free Beams Compared With Static Gantry IMRT and 3D Conformal Radiotherapy for Advanced Esophageal Cancer: A Feasibility Study

PURPOSE A feasibility study was performed to evaluate RapidArc (RA), and the potential benefit of flattening filter-free beams, on advanced esophageal cancer against intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS The plans for 3D-CRT and IMRT with three to seven and five to seven fixed beams were compared against double-modulated arcs with avoidance sectors to spare the lungs for 10 patients. All plans were optimized for 6-MV photon beams. The RA plans were studied for conventional and flattening filter-free (FFF) beams. The objectives for the planning target volume were the volume receiving ≥ 95% or at most 107% of the prescribed dose of <1% with a dose prescription of 59.4 Gy. For the organs at risk, the lung volume (minus the planning target volume) receiving ≥ 5 Gy was <60%, that receiving 20 Gy was <20%-30%, and the mean lung dose was <15.0 Gy. The heart volume receiving 45 Gy was <20%, volume receiving 30 Gy was <50%. The spinal dose received by 1% was <45 Gy. The technical delivery parameters for RA were assessed to compare the normal and FFF beam characteristics. RESULTS RA and IMRT provided equivalent coverage and homogeneity, slightly superior to 3D-CRT. The conformity index was 1.2 ± 0.1 for RA and IMRT and 1.5 ± 0.2 for 3D-CRT. The mean lung dose was 12.2 ± 4.5 for IMRT, 11.3 ± 4.6 for RA, and 10.8 ± 4.4 for RA with FFF beams, 18.2 ± 8.5 for 3D-CRT. The percentage of volume receiving ≥ 20 Gy ranged from 23.6% ± 9.1% to 21.1% ± 9.7% for IMRT and RA (FFF beams) and 39.2% ± 17.0% for 3D-CRT. The heart and spine objectives were met by all techniques. The monitor units for IMRT and RA were 457 ± 139, 322 ± 20, and 387 ± 40, respectively. RA with FFF beams showed, compared with RA with normal beams, a ∼20% increase in monitor units per Gray, a 90% increase in the average dose rate, and 20% reduction in beam on time (owing to different gantry speeds). CONCLUSION RA demonstrated, compared with conventional IMRT, a similar target coverage and some better dose sparing to the organs at risk; the advantage against conventional 3D-CRT was more evident. RA with FFF beams resulted in minor improvements in plan quality but with the potential for additional useful reduction in the treatment time.

Primary Tumor Staging for Oral Cancer and a Proposed Modification Incorporating Depth of Invasion: An International Multicenter Retrospective Study

IMPORTANCE The current American Joint Committee on Cancer (AJCC) staging system for oral cancer demonstrates wide prognostic variability within each primary tumor stage and provides suboptimal staging and prognostic information for some patients. OBJECTIVE To determine if a modified staging system for oral cancer that integrates depth of invasion (DOI) into the T categories improves prognostic performance compared with the current AJCC T staging. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of 3149 patients with oral squamous cell carcinoma treated with curative intent at 11 comprehensive cancer centers worldwide between 1990 and 2011 with surgery ± adjuvant therapy, with a median follow-up of 40 months. MAIN OUTCOMES AND MEASURES We assessed the impact of DOI on disease-specific and overall survival in multivariable Cox proportional hazard models and investigated for institutional heterogeneity using 2-stage random effects meta-analyses. Candidate staging systems were developed after identification of optimal DOI cutpoints within each AJCC T category using the Akaike information criterion (AIC) and likelihood ratio tests. Staging systems were evaluated using the Harrel concordance index (C-index), AIC, and visual inspection for stratification into distinct prognostic categories, with internal validation using bootstrapping techniques. RESULTS The mean and median DOI were 12.9 mm and 10.0 mm, respectively. On multivariable analysis, DOI was a significantly associated with disease-specific survival (P < .001), demonstrated no institutional prognostic heterogeneity (I² = 6.3%; P = .38), and resulted in improved model fit compared with T category alone (lower AIC, P < .001). Optimal cutpoints of 5 mm in T1 and 10 mm in T2-4 category disease were used to develop a modified T staging system that was preferred to the AJCC system on the basis of lower AIC, visual inspection of Kaplan-Meier curves, and significant improvement in bootstrapped C-index. CONCLUSIONS AND RELEVANCE We propose an improved oral cancer T staging system based on incorporation of DOI that should be considered in future versions of the AJCC staging system after external validation.

Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck cancer: results of the IAEA multicentre randomised trial

BACKGROUND AND PURPOSE Single agent mitomycin c (MMC) has been shown to improve the outcome of radiotherapy in single institution trials. In order to confirm these findings in a broader worldwide setting, the International Atomic Energy Agency (IAEA) initiated a multicentre trial randomising between radiotherapy alone versus radiotherapy plus MMC. MATERIAL AND METHODS Patients with advanced head and neck cancer were treated with primary curative radiotherapy (66 Gy in 33 fractions with five fractions per week) +/-a single injection (15 mg/m(2)) of MMC at the end of the first week of radiotherapy. Stratification parameters were tumour localization, T-stage, N-stage, and institution. A total of 558 patients were recruited in the trial from February 1996 to December 1999. Insufficient accrual and reporting led to the exclusion of three centres. The final study population consisted of 478 patients from seven centres. Patients had stage III (n=223) or stage IV (n=255) squamous cell carcinoma of the oral cavity (n=230), oropharynx (n=140), hypopharynx (n=65) or larynx (n=43). Prognostic factors like age, gender, site, size, differentiation and stage were well balanced between the two arms. RESULTS The haematological side effects of MMC were very modest (<5% grade 3-4) and did not require any specific interventions. Furthermore, MMC did not enhance the incidence or severity of acute and late radiation side effects. Confluent mucositis and dry skin desquamation was common, occurring in 56% and 62% of patients, respectively. The overall 3-year primary locoregional tumour control, disease-specific and overall survival rates were 19, 36 and 30%, respectively. Gender, haemoglobin drop, tumour site, tumour and nodal stage were significant parameters for loco-regional tumour control. There was no significant effect of MMC on locoregional control or survival, except for the 161 N0 patients, where MMC resulted in a better loco-regional control (3-year estimate 16% vs. 29%, P=0.01). CONCLUSIONS The study did not show any major influence of MMC on loco-regional tumour control, survival or morbidity after primary radiotherapy in stage III-IV head and neck cancer except in N0 patients where loco-regional control was significantly improved.

Radiation therapy in T1–T2 glottic carcinoma: influence of various treatment parameters on local control/complications

PURPOSE To evaluate the influence of various treatment parameters on local control as well as complications in T1 and T2 glottic carcinomas. METHODS AND MATERIALS Between 1975 and 1989, 676 patients with early glottic carcinoma (460 T1 and 216 T2) received curative radiation with three different treatment regimens, as follows: Regimen 1-50 Gy/15 Fr/3 weeks (3.33 Gy/daily) for 192 patients; Regimen 2-60-62.5 Gy/24-25 Fr/5 weeks (2.5 Gy/daily) for 352 patients; and Regimen 3-55-60 Gy/25-30 Fr/5-6 weeks (2-2.25 Gy/daily) for 132 patients. RESULTS The local control at 10 years was 82% and 57% for T1 and T2 lesions respectively (p = 0.0). For the T1N0M0 group, field size had significant impact on local control with both univariate (p = 0.05) and multivariate (p = 0.03) analysis. For T2N0M0, group field size (p = 0.03) as well as registration year (p = 0.016) were significant in univariate analysis whereas only field size remained significant on multivariate analysis. Persistent radiation edema was noted in 146 (22%) patients and was significantly worse with larger field size (p = 0.000) but not related to different treatment regimens. CONCLUSION The shorter fractionation schedule had comparable local control, without increased complications in comparison to the protracted schedule and is best suited for a busy department.

Primary carcinoma of the vagina: Tata Memorial Hospital experience

PURPOSE Carcinoma of the vagina is a rare gynecological malignancy comprising approximately 2% of all the gynecological malignancies. We have analyzed the treatment outcome of the patients treated at the Tata Memorial Hospital from January 1984 to December 1993. METHODS AND MATERIALS In this 10-year period, 134 patients of primary vaginal cancers were registered at our hospital. Of these, 75 patients received complete treatment and are analyzed. RESULTS Disease-free survival (DFS) for the whole group is 50%, and overall survival (OAS) is 60%. Most locoregional recurrences and distant failures are noted in the 2 years following treatment. DFS at 5 years is as follows: Stage I (5 patients), Stage IIA (37 patients), Stage IIB (15 patients), Stage III (14 patients), and Stage IV (4 patients); are 40%, 55%, 60%, 50%, and 25%, respectively. The DFS for patients with complete response (42 patients) to external radiation at 5 years is 68%, with partial response (25 patients) is 35%, and with poor or no response (6 patients) is 18% (p = 0.0000). We observed that brachytherapy was an important part of the treatment, and patients who received brachytherapy (59 patients), either with a vaginal intracavitary applicator (30 patients) or interstitial implant (29 patients) had a DFS of 53% and 56%, respectively, while 15 patients who received external radiation alone had a DFS of 30%. Patients receiving brachytherapy within 4 weeks of external radiation had a DFS of 60% as compared to 30% when the interval was more than 4 weeks. CONCLUSION The factors indicating prognosis are: site and extent of involvement, presence of lymph nodes at presentation, technique of brachytherapy, and interval between external radiation and brachytherapy.