Ranjan Sur

Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival

BACKGROUND Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival. METHODS Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227. FINDINGS Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002). INTERPRETATION For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash. FUNDING ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

The spectrum of HIV‐1 related cancers in South Africa

Despite the high prevalence of infection by the Human Immunodeficiency Virus (HIV) in South Africa, information on its association with cancer is sparse. Our study was carried out to examine the relationship between HIV and a number of cancer types or sites that are common in South Africa. A total of 4,883 subjects, presenting with a cancer or cardiovascular disease at the 3 tertiary referral hospitals in Johannesburg, were interviewed and had blood tested for HIV. Odds ratios associated with HIV infection were calculated by using unconditional logistic regression models for 16 major cancer types where data was available for 50 or more patients. In the comparison group, the prevalence of HIV infection was 8.3% in males and 9.1% in females. Significant excess risks associated with HIV infection were found for Kaposis sarcoma (OR=21.9, 95% CI=12.5–38.6), non‐Hodgkin lymphoma (OR=5.0, 95%CI=2.7–9.5), vulval cancer (OR=4.8, 95%CI=1.9–12.2) and cervical cancer (OR=1.6, 95%CI=1.1–2.3) but not for any of the other major cancer types examined, including Hodgkin disease, multiple myeloma and lung cancer. In Johannesburg, South Africa, HIV infection was associated with significantly increased risks of Kaposis sarcoma, non‐Hodgkin lymphoma and cancers of the cervix and the vulva. The relative risks for Kaposis sarcoma and non‐Hodgkin lymphoma associated with HIV infection were substantially lower than those found in the West. Int. J. Cancer 88:489–492, 2000.

Prospective randomized trial of HDR brachytherapy as a sole modality in palliation of advanced esophageal carcinoma—an International Atomic Energy Agency study

BACKGROUND Previous studies from South Africa have established that fractionated high-dose-rate (HDR) brachytherapy gives the best results in terms of palliation and survival in advanced esophageal cancer. A multicenter, prospective randomized study was therefore conducted under the auspices of the International Atomic Energy Agency to evaluate two HDR regimens. METHODS AND MATERIALS Surgically inoperable patients with histologically proven squamous cell cancer of the esophagus, tumor >5 cm in length on barium swallow and/or endoscopy, Karnofsky performance score >50, age 17-70 years, primary disease in the thoracic esophagus, no prior malignancy within the past 5 years, and any N or M status were included in the study. Exclusion criteria included cervical esophagus location, tumor extending <1 cm from the gastroesophageal junction, tracheoesophageal fistula, Karnofsky performance score <50, altered mental status, and extension to great vessels on CT. Patients were randomized to receive 18 Gy in 3 fractions on alternate days (6 Gy per fraction, Group A) or 16 Gy in 2 fractions on alternate days (8 Gy per fraction, Group B). The HDR dose was prescribed at 1 cm from the center of the source axis after dose optimization. A margin of 2 cm was included proximally and distally. The respective hospital and university committees gave approval for the study, and all patients provided informed consent. RESULTS A total of 232 patients were entered into the study (112 in Group A and 120 in Group B). There was no difference between the groups for any of the prognostic variables. All patients were followed until death. The dysphagia-free survival for the whole group was 7.1 months (Group A, 7.8 months; Group B, 6.3 months; p >0.05). The overall survival was 7.9 months for the whole group (Group A, 9.1 months; Group B, 6.9 months; p >0.05). On univariate analysis, the presenting weight (p = 0.0083), gender (p = 0.0038), race (p = 0.0105), the presenting dysphagia score (p = 0.0083), the treatment center (p = 0.0029), and tumor grade (p = 0.0029) had an impact on the dysphagia-free survival, and gender (p = 0.0011) and performance score (p = 0.0060) had an impact on dysphagia-free survival on multivariate analysis. Only age had an impact on overall survival on both univariate (p = 0.0430) and multivariate (p = 0.0331) analysis. The incidence of strictures (Group A, n = 12; Group B, n = 13; p >0.05) and fistulas (Group A, n = 11; Group B, n = 12; p >0.05) was similar in both groups. CONCLUSION Fractionated HDR brachytherapy alone is an effective method of palliating advanced esophageal cancers, surpassing the results of any other modality of treatment presently available. Dose fractions of 6 Gy x 3 and 8 Gy x 2 give similar results for dysphagia-free survival, overall survival, strictures, and fistulas and are equally effective in palliation of advanced esophageal cancer.

Fractionated high dose rate intraluminal brachytherapy in palliation of advanced esophageal cancer

PURPOSE To optimize the dose of fractionated brachytherapy for palliation of advanced esophageal cancer. METHODS AND MATERIALS One hundred and seventy-two patients with advanced esophageal cancer were randomized to receive 12 Gy/2 fractions (group A); 16 Gy/2 fractions (group B), and 18 Gy/3 fractions (group C) by high dose rate intraluminal brachytherapy (HDRILBT). Treatment was given weekly and dose prescribed at 1 cm from the source axis. Patients were followed up monthly and assessed for dysphagia relief and development of complications. RESULTS Twenty-two patients died before completing treatment due to advanced disease and poor general condition. The overall survival was 19.4% at the end of 12 months for the whole group (A--9.8%, B--22.46%, C--35.32%; p > 0.05). The dysphagia-free survival was 28.9% at 12 months for the whole group (A--10.8%, B--25.43%, C--38.95%; p > 0.05). Forty-three patients developed fibrotic strictures needing dilatation (A--5 of 35, B--15 of 60, C--23 of 55; p = 0.032). Twenty-seven patients had persistent luminal disease (A--11, B--6, C--10), 15 of which progressed to fistulae (A--7, B--2, C--6; p = 0.032). There was no effect of age, sex, race, histology, performance status, previous dilation, presenting dysphagia score, presenting weight, grade, tumor length, and stage on overall survival, dysphagia-free, and complication-free survival (p > 0.05). On a multivariate analysis, brachytherapy dose (p = 0.002) and tumor length (p = 0.0209) were found to have a significant effect on overall survival; brachytherapy dose was the only factor that had an impact on local tumor control (p = 0.0005), while tumor length was the only factor that had an effect on dysphagia-free survival (p = 0.0475). When compared to other forms of palliation currently available (bypass surgery, laser, chemotherapy, intubation, external radiotherapy), fractionated brachytherapy gave the best results with a median survival of 6.2 months. CONCLUSIONS Fractionated brachytherapy is the best modality for palliation of advanced esophageal cancer. It offers the best palliation to patient when compared to all other modalities currently available. The optimal brachytherapy dose ranges between 16 Gy in two fractions and 18 Gy in three fractions given a week apart.

Adenoid cystic carcinoma of the salivary glands: a review of 10 years.

A retrospective analysis was performed of 50 patients with adenoid cystic carcinoma who were seen in the Department of Radiation Oncology, University of Witwatersrand, Johannesburg, South Africa, in the past 10 years. There were 25 men and 25 women with a mean age of 52 years (age range, 21 to 88 years). Five patients had metastatic disease, and 17 had neural invasion. Thirty‐four patients had surgery (11, complete; 23, microscopic residual). Sixteen patients had radiotherapy as initial management. The disease‐free survival was 26%, overall survival was 29%, and local control was 30% at 10 years. Most recurrences occurred in the first 3 years. Nine patients had metastasis following treatment. The mean survival after metastasis was 15 months. Seven prognostic variables were analyzed using the log‐rank test. There was no impact of age, site, type of salivary gland (major vs. minor), tumor stage, node positivity, or neural invasion on disease‐free survival, overall survival, or local control. Extent of surgical resection (complete vs. microscopic residual) had a significant impact on disease‐free survival and local control (P < 0.05) but no impact on overall survival (P > 0.05) because of the slow‐growing nature of these tumors. Similarly, patients who had microscopic residual after surgery and were treated with radiotherapy did better than those who had biopsy and radiotherapy, although this was not significant statistically (P > 0.05). Thus, whenever possible, every attempt must be made to remove all microscopic tumor by surgery. Addition of postoperative radiotherapy with high‐energy photons did not improve the locoregional control or survival in our series. There is a place for neutrons in the treatment of adenoid cystic carcinomas in advanced cases of inoperable or recurrent tumors, as a review of literature shows.

Radiation therapy of esophageal cancer: Role of high dose rate brachytherapy

Fifty untreated cases of squamous cell carcinoma arising from the middle one-third of the esophagus, with no apparent extraesophageal spread on a computed tomography (CT) scan and with a Karnofsky performance status of over 70, were treated by external beam irradiation to a dose of 3500 cGy/15 fractions/3 weeks. Twenty-five patients (Group A) received treatment with further external beam irradiation to a dose of 2000 cGy/10 fractions/2 weeks. Another group of 25 patients (Group B) received treatment with high dose rate intracavitary irradiation to a dose of 1200 cGy delivered in two sessions of 600 cGy each a week apart. All patients were assessed symptomatically, endoscopically, and radiologically every 3 months. There was marked difference at the end of 1 year in relief of dysphagia (37.5% in Group A vs. 70.6% in Group B), local control (25% in group A vs. 70.6% in group B) although the results were statistically insignificant (p greater than 0.05) and actuarial survival (44% in group A vs. 78% in group B) which was, however, significant statistically (z = 2.83). The cumulative radiation effect (CRE) by external beam irradiation was 1729 reu and by external beam and intracavitary irradiation 1741 reu, but the biological dose effect was better with external beam and intracavitary irradiation. Eight percent of patients treated by external beam and intracavitary irradiation had strictures in contrast to 4% treated by external beam irradiation alone. Moderate doses of external beam and intracavitary irradiation can give a better local response than external beam irradiation alone for the same biological dose in the treatment of esophageal carcinoma.

Risk factors for oesophageal, lung, oral and laryngeal cancers in black South Africans.

The authors used data collected from 1995 to 1999, from an on-going cancer case–control study in greater Johannesburg, to estimate the importance of tobacco and alcohol consumption and other suspected risk factors with respect to cancer of the oesophagus (267 men and 138 women), lung (105 men and 41 women), oral cavity (87 men and 37 women), and larynx (51 men). Cancers not associated with tobacco or alcohol consumption were used as controls (804 men and 1370 women). Tobacco smoking was found to be the major risk factor for all of these cancers with odds ratios ranging from 2.6 (95% CI 1.5–4.5) for oesophageal cancer in female ex-smokers to 50.9 (95% CI 12.6–204.6) for lung cancer in women, and 23.9 (95% CI 9.5–60.3) for lung cancer and 23.6 (95% CI 4.6–121.2) for laryngeal cancer in men who smoked 15 or more grams of tobacco a day. This is the first time an association between smoking and oral and laryngeal cancers has been shown in sub-Saharan Africa. Long-term residence in the Transkei region in the southeast of the country continues to be a risk factor for oesophageal cancer, especially in women (odds ratio=14.7, 95% CI 4.7–46.0), possibly due to nutritional factors. There was a slight increase in lung cancer (odds ratio=2.9, 95% CI 1.1–7.5) in men working in ‘potentially noxious’ industries. ‘Frequent’ alcohol consumption, on its own, caused a marginally elevated risk for oesophageal cancer (odds ratio=1.7, 95% CI 1.0–2.9, for women and odds ratio=1.8, 95% CI 1.2–2.8, for men). The risks for oesophageal cancer in relation to alcohol consumption increased significantly in male and female smokers (odds ratio=4.7, 95% CI=2.8–7.9 in males and odds ratio=4.8, 95% CI 3.2–6.1 in females). The above results are broadly in line with international findings.

THREE DIMENSIONAL CONFORMAL RADIATION THERAPY IN PEDIATRIC PARAMENINGEAL RHABDOMYOSARCOMAS

PURPOSE We evaluated the utility of three dimensional (3D) treatment planning in the management of children with parameningeal head and neck rhabdomyosarcomas. METHODS AND MATERIALS Five children with parameningeal rhabdomyosarcoma were referred for treatment at our radiation oncology center from May 1990 through January 1993. Each patient was evaluated, staged, and treated according to the Intergroup Rhabdomyosarcoma Study. Patients were immobilized and underwent a computed tomography scan with contrast in the treatment position. Tumor and normal tissues were identified with assistance from a diagnostic radiologist and defined in each slice. The patients were then planned and treated with the assistance of a 3D treatment planning system. A second plan was then devised by another physician without the benefit of the 3D volumetric display. The target volumes designed with the 3D system and the two-dimensional (2D) method were then compared. The dosimetric coverage to tumor, tumor plus margin, and normal tissues was also compared with the two methods of treatment planning. RESULTS The apparent size of the gross tumor volume was underestimated with the conventional 2D planning method relative to the 3D method. When margin was added around the gross tumor to account for microscopic extension of disease in the 2D method, the expected area of coverage improved relative to the 3D method. In each circumstance, the minimum dose that covered the gross tumor was substantially less with the 2D method than with the 3D method. The inadequate dosimetric coverage was especially pronounced when the necessary margin to account for subclinical disease was added. In each case, the 2D plans would have delivered substantial dose to adjacent normal tissues and organs, resulting in a higher incidence of significant complications. CONCLUSIONS 3D conformal radiation therapy has a demonstrated advantage in the treatment of sarcomas of the head and neck. The improved dosimetric coverage of the tumor and its margin for subclinical extensions may result in improvement in local control of these tumors. In addition, lowering of radiation dose to adjacent critical structures may help lower the incidence of adverse late effects in children.

Adding external beam to intra-luminal brachytherapy improves palliation in obstructive squamous cell oesophageal cancer: A prospective multi-centre randomized trial of the International Atomic Energy Agency

BACKGROUND Whether the combination of high dose-rate brachytherapy (HDRBT) and External Beam Radiation Therapy (EBRT) is superior to HDRBT alone for the palliation of oesophageal cancer has only been explored in a previous IAEA pilot randomized trial. METHODS Two hundred and nineteen patients were randomized to adding EBRT or not, after receiving two fractions of HDRBT within 1 week. Each HDRBT consisted of 8 Gy prescribed at 1cm from source centre. Patients randomized to EBRT received 30 Gy in 10 fractions. The primary outcome was dysphagia-relief experience (DRE). Additional outcomes included various scores, performance status, weight and adverse events. A majority of charts, imaging and radiotherapy plans were externally audited. RESULTS Median follow-up was 197 days, with a median OS of 188 days and an 18% survival rate at 1 year. DRE was significantly improved with combined therapy, for an absolute benefit of +18% at 200 days from randomization (p=0.019). In longitudinal regression analyses, scores for dysphagia (p=0.00005), odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038) and performance status (p=0.0015) were all significantly improved. In contrast, weight, toxicities and overall survival were not different between study arms. CONCLUSION Symptom improvement occurs with the addition of EBRT to standard HDRBT. The combination is well tolerated and relatively safe.

ORAL SUCRALFATE IN ACUTE RADIATION OESOPHAGITIS

Eighty patients with carcinoma in the middle third of oesophagus and with acute radiation oesophagitis following external beam and intracavitary radiotherapy were managed by two different schedules. Group 1 (n = 40) received an antacid containing sodium alginate whereas Group 2 (n = 40) were given a 10% sucralfate suspension during 4 weeks. In Group 2, 32 patients had significant relief of symptoms within 7 days of treatment and most ulcers had healed by 12 days of treatment as seen on endoscopy. Patients in Group 1, on the other hand, showed little improvement of symptoms and had persistent ulcers even after 4 weeks of therapy. We conclude that sucralfate is useful in the management of acute radiation oesophagitis.