Thomas J. Keane

Oxygenation predicts radiation response and survival in patients with cervix cancer

BACKGROUND AND PURPOSE Hypoxia appears to be an important factor in predicting tumor relapse following radiation therapy. This study measured oxygenation prior to treatment in patients with cervix cancer using a polarographic oxygen electrode to determine if oxygenation was an important prognostic factor with regard to tumor control and survival. MATERIALS AND METHODS Between May 1994 and June 1997, 74 eligible patients with cervix cancer were entered into an ongoing prospective study of tumor oxygenation prior to primary radiation therapy. All patients were evaluated with an Eppendorf oxygen electrode during examination under anesthesia. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of pO2 readings of <5 mm Hg (abbreviated as HP5). RESULTS The HP5 ranged from 2 to 99% with a median of 52%. With a median follow-up of 1.2 years, the disease-free survival (DFS) rate was 69% for patients with HP5 of < or =50% compared with 34% for those with HP5 of >50% (log-rank P = 0.02). Tumor size above and below the median of 5 cm was also significantly related to DFS (P = 0.0003) and patients with bulky hypoxic tumors had a significantly lower DFS (12% at 2 years) than either bulky oxygenated or non-bulky oxygenated or hypoxic tumors (65%, P = 0.0001). CONCLUSIONS Hypoxia and tumor size are significant adverse prognostic factors in a univariate analysis of disease-free survival in patients with cervix cancer. A high risk group of patients with bulky hypoxic tumors have a significantly higher probability of relapse and death.

Epidermoid anal cancer: Treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C

One hundred ninety-two patients with primary epidermoid cancer of the anal canal were treated by a series of prospectively designed, sequential non-randomized protocols of radiation alone (RT), radiation with concurrent 5-Fluorouracil and Mitomycin C (FUMIR), or radiation with concurrent 5-Fluorouracil only (FUR). The 5-year cause-specific survival rates were 69% overall, 68% RT, 76% FUMIR, 64% FUR. The primary tumor was controlled by radiation with or without chemotherapy in 68% (130/191) overall, 56% (32/57) by RT, 86% (59/69) by FUMIR, 60% (39/65) by FUR. The results with FUMIR were significantly better than with either RT alone or FUR, and except in tumors up to 2 cm in size, this superiority was found in all T stages. Regional lymph node metastases were controlled in 33 of 38 (87%) overall. The finding of clinically detectable regional lymph node metastases at presentation did not affect survival significantly in any treatment group. Anorectal function was preserved in 88% of the patients in whom the primary tumor was controlled, and in 64% overall. The delivery of 5FU and MMC concurrently with uninterrupted radical irradiation, 50 Gy in 20 fractions in 4 weeks, produced severe acute and late normal tissue morbidity. Split course treatment, and reduction of the daily fractional dose to 2 Gy, diminished the severity of normal tissue damage. Omission of Mitomycin C reduced acute hematological toxicity, but was associated with a decreased primary tumor control rate. The most effective treatment protocols as measured by survival rates, primary anal tumor control rates, and the likelihood of conservation of anorectal function included the administration of both Mitomycin C and 5-Fluorouracil concurrently with radiation therapy.

The effect of treatment duration in the local control of cervix cancer.

A significant effect of treatment duration on pelvic control was found in 830 patients with cervix cancer treated by radical radiation therapy. Using three methods of analysis, the loss of control consistently approximated 1% per day of treatment prolongation beyond 30 days, although analysis of stage subgroups showed that this effect was predominantly manifested in Stages III/IV compared with Stages I/II. In multivariate analyses using both a logistic regression and a Cox regression model, stage (p = 0.0001 for Stage I/IIA and 0.0036 for Stage IIB relative to Stage III/IV) treatment time (p = 0.0001), and age (p = 0.0067) were independently correlated with pelvic control. Exclusion from analysis of patients with delays due to tumour or treatment related complications, intercurrent illness or manifestations of poor tumour response did not significantly change the magnitude of the time effect nor the ranking of the significant covariates. These results are consistent with the occurrence of accelerated repopulation and warrant further investigation, preferably in a randomized trial of accelerated versus conventionally fractionated radiation therapy.

Radiation pneumonitis following large single dose irradiation: A re-evaluation based on absolute dose to lung

Abstract The acute radiation paeumonitis syndrome is a major complication for patients receiving total thoracic irradiation in a large single dose. Previous studies have evaluated the onset of radiation pneumonitis on the basis of radiation doses calculated assuming unit density tissues. In this report, the incidence of radiation pneumonitis is determined as a function of absolute dose to lung. A simple algorithm relating dose correction factor to anterior-posterior patient diameter has been derived using a CT-aided treatment planning system. This algorithm was used to determine, retrospectively, the dose to lung for a group of 303 patients who had been treated with large field irradiation techniques. Of this group, 150 patients had no previous lung disease and had virtually no additional lung irradiation prior or subsequent to their large field treatment. The actuarial incidence of radiation pneaunoniitis versus dose to lung was evaluated using a simplified probit analysis. The resultant best fit sigmoidal complication curve demonstrates the onset of radiation pneumonitis to occur at about 750 red with the 5% actuarial incidence occuring at approximately 820 red. The errors associated with the dose determination procedure as well as the actuarial incidence calculations are considered. The time of onset of radiation paeumonitis occurs between 1 to 7 months after irradiation for 90% of the patients who developed pneumonitis with the peak incidence occurring at 2 to 3 months. No correlation was found between time of onset and the dose to lung over a dose range of 650 to 1250 red.

The effect of treatment time and treatment interruption on tumour control following radical radiotherapy of laryngeal cancer

A significant effect of overall treatment time on local control was found in a retrospective review of 1012 radically irradiated squamous cell carcinomas of the larynx. The actuarial local relapse free rate (LRFR) at 5 years for the whole group was 59%. The effect of treatment time on local control was modelled to the linear-quadratic equation. Using logistic regression analysis treatment time and dose were significant (p = 0.008 and p = 0.04, respectively). When the analysis was adjusted for the influence of stage and laryngeal subsite treatment time remained a significant prognostic factor (p = 0.02). The derived value of gamma/alpha was 0.7 Gy/day and when adjusted for stage and sub-site 0.8 Gy/day. This equates to a dose increment to maintain iso-effective local control of 0.64 Gy/day and 0.73 Gy/day respectively for daily fractions of 2.5 Gy and an assumed alpha/beta for tumour of 25 Gy. To provide an estimate of the clinical impact of treatment interruptions not compensated for by dose escalation a Cox regression was performed. Significant variables were T stage, N stage, sex, total dose and total length of treatment interruption. Using the proportional hazard model it was calculated that each day of treatment interruption resulted in an increase in the hazard of local relapse by 4.8% (p = 0.006). Based on our data it was calculated that this would result in a decrease in local control of 1.4% for each day of uncompensated treatment interruption.

Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy.

The results of treating anal canal carcinoma by radical external beam radiation alone (RT) or by combined 5‐fluorouracil, mitomycin C and radiation (FUMIR), were compared in nonrandomized groups of patients treated in a single center. In each treatment regimen, surgery was reserved for those patients with residual carcinoma. The uncorrected 5‐year survival rate in each group was approximately 70%, but primary tumor control was achieved in 93% (28/30) with FUMIR compared to 60% (15/25) treated with RT. Acute hematologic and enterocolic toxicity with uninterrupted external beam radiation courses of 5000 cGy in 4 weeks plus chemotherapy led to the adoption of split‐course treatment. Serious late toxicity requiring surgical intervention occurred in 3 of 25 following RT, and in 5 of 30 following FUMIR. Colostomies were needed as part of treatment for residual carcinoma or for the management of treatment‐related toxicity in 11 of 25 treated by RT and have been required to date in 4 of 30 treated by FUMIR. The improvement in the primary tumor control rate and the reduction in the number of patients requiring colostomy when compared with the results of RT favor combined chemotherapy and radiation as the initial treatment for anal canal carcinoma.

Idiopathic interstitial pneumonia following bone marrow transplantation: the relationship with total body irradiation

Abstract Interstitial pneumonia is a frequent and often fatal complication of allogenic bone marrow transplantation. Thirty to 40 percent of such cases are of unknown etiology and have been labelled as cases of idiopathic interstitial pneumonia. Idiopathic cases are more commonly associated with the use of total body irradiation; their occurrence appears to be independent of immunosupression or graft versus host disease. Evidence is presented from the literature suggesting that the development of idiopathic interstitial pneumonia is related to the absolute absorbed dose of radiation to lung. The similarity of idiopathic pneumonia to radiation paeumonitis seen in a different clinical setting is described.

T1/T2 GLOTTIC CANCER MANAGED BY EXTERNAL BEAM RADIOTHERAPY: THE INFLUENCE OF PRETREATMENT HEMOGLOBIN ON LOCAL CONTROL

Abstract Purpose: Pretreatment hemoglobin (Hb) level has been reported to be an important prognostic factor for local control and survival in various malignancies. However, in many settings, the adverse effect of a low Hb may be related to more advanced disease. The purpose of this analysis was to assess the influence of pretreatment Hb on local control in a large series of patients with a localized cancer (T1/T2 glottic cancer, AJCC 1992) treated in a standard fashion. Materials and Methods: Between January 1981 and December 1989, 735 patients (median age 63; 657 males, 78 females) with T1/T2 glottic cancer were treated with radiation therapy (RT). The standard RT prescription was 50 Gy in 20 fractions over 4 weeks (97% of patients). Factors studied for prognostic importance for local failure included pretreatment Hb, age, sex, T category, anterior commissure involvement, subglottic extension, and tumor bulk (presence of visible tumor vs. subclinical disease). Results: With a median follow-up of 6.8 years (range 0.2–14.3), 131 patients have locally relapsed for an actuarial 5-year relapse-free rate of 81.7%. The 5-year actuarial survival was 75.8%. The mean pretreatment hemoglobin level was 14.8 g/dl and was similar in all prognostic categories. On multivariate analysis, using the Cox proportional hazards model, pretreatment Hb predicted for local failure after RT. The hazard ratio (HR) for relapse was calculated for various Hb levels. For example, the HR for a Hb of 12 g/dl vs. a Hb of 15 g/dl was 1.8 (95% confidence interval 1.2–2.5). Previously established factors, including gender, T category, subglottic extension, as well as tumor bulk, were also prognostically important for local control. Conclusions: This analysis, in a large number of similarly treated patients, indicates that pretreatment Hb is an independent prognostic factor for local control in patients with T1/T2 carcinoma of the glottis treated with RT. The underlying biology of this observation needs to be explored, and using this information, it may be possible to develop strategies to improve treatment outcome.

Local control of carcinoma of the tonsil by radiation therapy: An analysis of patterns of fractionation in nine institutions

PURPOSE To investigate the importance to outcome of treatment for squamous cell carcinomas of the tonsillar fossa, of dose per fraction, overall treatment duration, and total dose. METHODS AND MATERIALS A collaborative retrospective study was undertaken in nine centers that used widely different dose-fractionation patterns for external beam radiation therapy. RESULTS There were 676 eligible cases treated only with photon beams during the years 1976-1985. The probability of local control (of the tonsillar fossa primary) was influenced by both T-stage and N-stage. Significant treatment parameters were total dose and overall treatment duration, but not dose per fraction. Over the range of about 40 to 90% and for a constant overall treatment duration, local tumor control probability increased by nearly 2% for each 1 Gy increase in total dose. For a constant total dose there was a decrease in the probability of local control associated with prolongation of overall treatment duration, presumed to result from accelerated regrowth of surviving tumor clonogens during the course of treatment. If it is assumed that accelerated regrowth occurred at a constant rate and began within 9 days of the start of treatment, an average of 0.53 Gy extra dose per days extension of treatment would be required to maintain a constant probability of local control. Correspondingly, the probability of local control from a constant dose would be lowered by an average of at least 1% for each days extension of treatment duration. However, the data are slightly more consistent with an average delay of as long as 30 days before onset of accelerated repopulation, with a consequent increase to an average of 0.73 Gy per day for the value of the compensatory dose. The alpha/beta ratio for this tumor is high enough that the effect of fraction size on the probability of local control can be ignored; a precise estimate is not possible because the best value for beta was close to zero. After accounting for the significant variables studied (treatment time, T-stage, N-stage), the dose-response curves for tumor control were still shallow, suggesting that there are additional causes for heterogeneity of responses among these tumors. CONCLUSIONS Total dose is important to treatment outcome: After accounting for other treatment variables, there is about a 2% per Gy increase in probability of tumor control over the ranges of control commonly achieved. Overall treatment duration is important. There is at least a 1% per day decrease in tumor control probability if delivery of a constant total dose is prolonged, requiring a compensatory increase in dose by 0.5-0.7 Gy per day to achieve a constant rate of tumor control. Fraction size is not, of itself, an important factor in the response of primary carcinoma of the tonsil. If a tumor has demonstrated a capacity for metastatic spread to lymph nodes, a higher total dose should be considered to achieve control rates at the primary site equivalent to those in node negative patients. Even after accounting for variables such as tumor stage, total dose, and overall treatment duration, there is sufficient heterogeneity in other undocumented determinants of tumor control to cause the tumor control probability curve to be a shallow function of dose.

Similar decreases in local tumor control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers

PURPOSE Data on patients with cancer of the larynx are analyzed using statistical models to estimate the effect of gaps in the treatment time on the local control of the tumor. METHODS AND MATERIALS Patients from four centers, Edinburgh, Glasgow, Manchester, and Toronto, with carcinoma of the larynx and treated by radiotherapy were followed up and the disease-free period recorded. In all centers the end point was control of the primary tumor after irradiation alone. The local control rates at > or = 2 years, Pc, were analyzed by log linear models, and Cox proportional hazard models were used to model the disease-free period. RESULTS T stage, nodal involvement, and site of the tumor were important determinants of the disease-free interval, as was the radiation schedule used. Elongation of the treatment time by 1 day, or a gap of 1 day, was associated with a decrease in Pc of 0.68% per day for Pc = 0.80, with a 95% confidence interval of (0.28, 1.08)%. An increase of 5 days was associated with a 3.5% reduction in Pc from 0.80 to 0.77. At Pc = 0.60 an increase of 5 days was associated with an 7.9% decrease in Pc. The time factor in the Linear Quadratic model, gamma/alpha, was estimated as 0.89 Gy/day, 95% confidence interval (0.35, 1.43) Gy/day. CONCLUSIONS Any gaps (public holidays are the majority) in the treatment schedule have the same deleterious effect on the disease free period as an increase in the prescribed treatment time. For a schedule, where dose and fraction number are specified, any gap in treatment is potentially damaging.