Gilbert H. Fletcher

Accelerated fractionation vs hyperfractionation: Rationales for several treatments per day

Treatment with several doses per day offers the prospect of a significant therapeutic gain using readily available low LET beams. These regimens can be classified as either accelerated fractionation or hyperfractionation according to their rationales. With accelerated fractionation a conventional number of dose fractions is delivered in a significantly shortened overall treatment time in order to reduce the opportunity for tumor cell regeneration during treatment. With hyperfractionation, on the other hand, a large number of significantly reduced dose fractions is used to give a greater total dose in a conventional overall treatment time. The rationale for this strategy is threefold: 1) increased opportunity for tumor cell redistribution and reoxygenation between dose fractions: 2) a possibly lower oxygen enhancement ratio with small incremental doses; and 3) different sparing of late reacting normal tissues with small dose fractions. A review of the published clinical experience with multiple fractions per day treatment reveals few studies of either pure accelerated fractionation or hyperfractionation since both are limited by acute normal tissue reactions. This has led to a variety of hybrid regimens, some of which have no clear rationale. The choice between accelerated fractionation and hyperfractionation is determined by the regenerative capability of tumor clonogens during treatment. A method of selection based on potential doubling times is presented.

An analysis of distant metastases from squamous cell carcinoma of the upper respiratory and digestive tracts

The charts of 5,019 previously untreated patients with squamous cell carcinoma of the upper respiratory and digestive tracts who completed treatment for cure from January 1948 through August 1973, were reviewed. These patients had no evidence of distant metastases when initially evaluated. Five hundred and forty‐six patients developed clinical evidence of distant metastases. The overall incidence of distant metastases was 10.9%, varying from 3.1% for vocal cord cancers to 28.1% for cancer of the nasopharynx. The lungs and bones were the most common first sites of metastases, accounting for 52% and 20.3% respectively, whereas metastases to the mediastinum (2.9%) were rare. Forty‐eight percent of the metastases were detected within nine months after treatment and 80% were detected within two years. The rate of distant metastases increased with the stage (2% for Stage I to 19.5% for Stage IV). The rate also increased with the T and N classification; however, the N stage had greater influence on the rate of metastases than the T stage. The incidence of distant metastases was significantly higher when there was a recurrence above the clavicles (16.7%) than when there was no recurrence (7.9%, < 0.001). In patients whose primary lesion was treated by radiotherapy or surgery alone, the incidence was essentially the same. Patients receiving postoperative irradiation had double the incidence of the preoperative group (20.1% vs 9.9%—p < .005); however, the sequence of modalities was not randomized. Cancer 40:145–151, 1977.

Megavoltage irradiation of epithelial tumors of the nasopharynx

Abstract The present analysis is limited to 251 patients treated with megavoltage irradiation at M. D. Anderson Hospital and Tumor Institute between 1954 and December 1977. The 5-year actuarial disease-free survival for all patients studied is 52%; it is 42%, 65%, and 14%, respectively, for those with squamous cell carcinoma, lympbepitbelioma, and unclassified carcinoma. There were 49 (19.5%) local failures, 32 (12.7%) regional failures, and 73 (29.19%) distant metastases. A previous review had shown an unsatiafactory control rate for T 1 and T 2 squamous cell carcinoma, the reason for which may have been that the actual delivered dose to the nasopbarynx was less thin the calculated dose. Since 1972, an additional 500 to 750 rad has been delivered through parallel opposed small fields centered over the angle of the nassopharynx. Thus, this analysis is divided into two periods, 1954 through December 1971, and January 1972 through December 1977, to evaluate the effectiveness of the treatment changes. The control rate for T 1 and T 2 squamous cell carcinomas has increased from 76.4% to 94.2%.

Keynote address—the problem: Tumor radioresistance in clinical radiotherapy

Abstract Tumor radioresistance in clinical radiotherapy implies failure to achieve loco-regional disease control with radiation doses producing an acceptable degree of morbidity. Such radioresistance may be a result of many different causes (biological and technical) which are reviewed in terms of possible remedial actions. Dose response relationships for human cancers suggest that in many sites, tumors are heterogenous with respect to their cure-limiting characteristics. The case is developed that unless the predominant cure-limiting factor can be predicted, little benefit may be seen in trials of new treatment strategies using heterogeneous tumor populations. The fundamental problem of clinical radioresistance is therefore perceived as the inability to predictively identify its cause in the individual patient.

Malignant mixed Müllerian tumors of the uterus.

One hundred and eight patients with a diagnosis of malignant mixed müllerian tumors of the uterus treated at the M.D. Anderson Hospital from 1948 through 1977 were analyzed. Pathology was reviewed and subdivided according to the sarcomatous element. No difference in pattern of recurrence or survival could be demonstrated between homologous, heterologous, or undifferentiated sarcomatous elements. Nine patients were treated with only palliative intent due to advanced local disease combined with poor medical condition. Of the remaining 99 patients, 87% had minimum surgical procedures of total abdominal hysterectomy. All but two of these patients had adjunctive radiation either preoperatively or postoperatively. The 5‐year survival rate was 38%. There was frequent upstaging at surgery in all stages except IA. Patients with tumor confined to the uterus at the time of surgery had a 5‐year disease‐free survival of 52%. When there was extension outside of the uterus, the 5‐year disease‐free survival dropped to 28%. The locoregional recurrence rate was 17%.

Causes, time of death, and sites of failure in squamous-cell carcinoma of the uterine cervix on intact uterus.

There is a considerable literature on five-year survival rates in patients with cancer of the uterine cervix who have been treated by radiations, surgery, or a combination of both. Reports on long-term follow-ups are few. Those from the Radiumhemmet (1) and Radium Centre in Copenhagen (8) are on patients treated prior to World War II. The purpose of this essay is to study the time distribution and causes of death (active disease, complications, intercurrent disease), as well as the sites of active disease at the time of death in 2,220 patients treated at The University of Texas M. D. Anderson Hospital and Tumor Institute from Sept. 1, 1948, through Dec. 31, 1963, for squamous-cell carcinoma of the uterine cervix on intact uterus. Of those 2,220 patients, 965 are known to be dead. In addition to this broad statistical review, specific aspects of the disease will be discussed, as will some sites of recurrent disease. Modalities of Treatment At the M. D. Anderson Hospital and Tumor Institute, irradiation has...

Late complications of radiation only for advanced breast cancer

Abstract Between 1960 and 1972, 158 patients with American Joint Committee (AJC) Stages III and IV breast carcinoma were treated with high dose protracted radiation only using megavoltage equipment and five dose/week fractionation. The local-regional control rate was 72%. All patients had some fibrosis. Severe fibrosis and necrosis were used as end points for analysis of complications. When the complications were separated by length of patient survival, the rate of severe fibrosis and necrosis was independent of the length of survival. Complications continued to appear at an undiminished rate in patients surviving more than 10 years. There was a trend toward increasing complications for doses above 8,100 rad which was not statistically significant. For doses below 8,000 rad only one complication appeared after six years, whereas for higher doses, complications continued to appear after 10 years. There was no correlation between boost technique and complication. Although high dose protracted radiation is no longer used for breast carcinoma, this data provides a warning that late complications may develop many years after treatment in patients who had large volumes irradiated.

Carcinoma of the cervix: the effect of age on survival.

Abstract A significant decrease in 5-year survival was found in 265 patients with invasive cervical cancer under the age of 35 compared to 820 over the age of 35 in all stages except Stage I-A and Stage IV. The exact reasons for the differences remain obscure. The greatest number of failures occurred in Stage II-B patients where, despite central control of disease, distant metastases developed. This suggests that the pretreatment evaluation of younger patients, especially those with Stage II-B cancer, should be more aggressive at attempts to detect cancer beyond the usual treatment fields. The poorer prognosis for patients under age 35 could not be explained on the basis of cell type. It was found that patients with large-cell, keratinizing cancers had a somewhat improved survival over patients with large-cell, non-keratinizing cancers.

Conservation surgery and irradiation for the treatment of favorable breast cancer.

The results in 162 patients with clinically favorable breast cancer treated with conservation surgery and radiation therapy are presented. The surgical procedures were simple excision with and without positive microscopic margins, segmental mastectomy, and segmental mastectomy with axillary dissection. Details of the radiation techniques are described with an explanation of the modifications in technique depending on the prior surgical procedure. Excellent control of local and regional tumor (96%) gives support to the combined treatment without removing the breast. Cancer 43:1058–1061, 1979.

Treatment of the neck in patients with squamous cell carcinoma of the head and neck.

A retospective study of 702 patients with clinically positive nodes associated with squamous cell carcinoma of the oral cavity, supraglottic larynx, and hypopharynx observed from 1954 to 1968 was done. The policies of treatment for the neck were not standardized during those years. Three hundred eleven patients who survived 24 months with the primary lesion controlled were divided into two groups: 1) those whose neck was treated by surgery alone; and 2) those who had combined radiation therapy and surgery to the neck, to test the efficacy of the two forms of treatment. For the three sites, the recurrence rate in the necks for the surgically treated group was 14% for stage N1, 26% for N2 and 34% N3. Rates for the group receiving combined treatment were 2%, 11% and 25% respectively. Results of the study also showed that elective irradiation, 5,000 rads in five weeks, will prevent metastasis from occurring in the N0 staged neck.