Local Tumor Control Probability Research Articles

Survival of Patients and Metastatic and Local Recurrent Tumor Growth in Malignant Melanoma of the Uvea After Ruthenium Plaque Radiotherapy

ABSTRACT A series of 100 consecutive patients treated by ruthenium plaque radiotherapy for uveal malignant melanoma from 1981 to 1991 was studied to evaluate local recurrences, métastases, and melanomaspecific mortality. Follow up ranged from 1.0 to 10.1 years (mean, 3.3; median, 3.0 years). Local relapse was observed in 19 patients from 0.1 to 2.7 years (median, 0.7 years) after therapy. Six of these eyes were enucleated. The 5-year probability of local tumor control was 59%. Seven patients with local relapse developed metastasis O to 4.3 years (median. 1.4 years) later. Altogether, 18 patients developed métastases 0.9 to 4.6 years (median, 2.0 years) after the irradiation, and 15 of them died of melanoma 5 days to 3.3 years (median, 0.5 years) after detection of metastases. The 5-year probability of metastasis not developing was 61%. The overall 5-year survival was 78%, excluding causes other than malignant melanoma. Large tumor size and anterior tumor location, with or without ciliary body involvement, predicted poor prognosis both in terms of local growth, métastases, and melanoma-specific mortality. Local recurrent tumor growth was associated with a significant increase in metastasis but a nonsignificant increase in melanoma-specific mortality.

Intraocular Recurrence of Uveal Melanoma after Proton Beam Irradiation

The authors evaluated tumor recurrence as an end point in 1077 uveal melanoma patients treated by proton beam irradiation between 1975 and 1987, with a mean follow-up of 4.0 years. Twenty tumors (1.9%) exhibited definitive growth between 4 months and 66 months after irradiation (median, 19 months): 10 were marginal recurrences, 5 were ring melanomas, 3 were uncontrolled tumors, and 2 were extrascleral extensions. Ten of these eyes were enucleated without further intervention, 2 patients died of metastases soon after the growth was detected, and 8 patients had further conservative therapy. In 5 other patients, tumor growth was suspected but unconfirmed and the eye was enucleated elsewhere; the 5-year probability of local tumor control based on 25 recurrences was 97% +/- 1%. There was a nonsignificant increase in the rate of metastases among patients with documented tumor recurrence (adjusted relative risk, 1.5; 95% confidence interval, 0.66 to 3.4). Results suggest that recurrence of uveal melanomas treated by proton beam therapy is uncommon, but that treatment failure may increase risk of death from metastasis.

Dose fractionation and tumour repopulation in radiotherapy for bladder cancer

Local control of the 77 transitional cell carcinoma of the bladder was analysed with respect to total dose after normalization for variations in fraction size and to overall treatment time. For the TCD 50 of 63.3 Gy protraction of overall treatment time from 40 to 55 days average gave the decrease in local control rate from 50 % to about 5 %j The decrease in local tumour control with extension of overall treatment time likely reflects accelerated tumour repopulation during the treatment. To determine the time onset of the accelerated tumour clonogen repopulation, data taken from the literature were analysed. Results show that on average tumour clonogen repopulation in transitional cell cancer of the bladder accelerates after a lag period of about 5–6 weeks after the start of treatment and that a dose increment of 0.36 Gy per day is required to compensate for this repopulation. Such a dose increment is consistent with about 5–8 day clonogen doubling time. It suggests that overall treatment time is an important factor in the dose fractionation and protraction of time may have a significant impact on treatment outcome. Thus, radiotherapy for bladder cancer should be completed as soon as possible and total dose for high probability of local tumour control should consequently be delivered in more than 5 fractions per week.

An audit of head and neck cancer treatment in a regional centre for radiotherapy and oncology

All patients with head and neck cancer attending the Regional Centre for Radiotherapy and Oncology at Mount Vernon hospital during the 8-year period from 1 January 1980 to 31 December 1987 have been included in this review. The 545 patients presenting a new primary carcinoma without evidence for metastasis outside the locoregional area, who were treated primarily by radiotherapy are the subject of this present audit. The characteristics of the patients, of the tumours and of the treatment given have been related to outcome. Early tumours (T1 and T2 which were node-negative) showed a complete response (CR) rate of 94% whereas more advanced tumours (T1 and T2 with palpable lymph nodes) showed a CR of 59%. The probability of local tumour control at 5 years was 77% in those without nodes and 20% in those with nodes. For more advanced disease (T3 and T4 tumours), initial CR was 72% in node-negative disease and 32% when the nodes were positive. At 5 years, the probability of local tumour control fell to 37% and 0 respectively. CR, freedom from recurrence and survival were statistically significantly related to T stage, N stage and site of primary tumour. The results compare favourably with those reported by other institutions. The development of medical audit and its influence on treatment policy are considered.

Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx. Part 2. Normal tissue responses: acute and late effects

The early responses of normal tissues of the oral cavity and oropharynx in 498 patients, and the slowly-developing responses in 268 patients who survived a minimum of 18 months after radiotherapy for squamous cell carcinoma were analyzed. The severity of acute responses correlated with dose intensity. The incidence of severe late responses increased with increase in dose per fraction and was characterized by a low alpha/beta ratio. Severe late responses were significantly associated with severe acute responses independently of dose per fraction and total dose, and were also ameliorated slightly by protraction of treatment time suggesting that some late effects were, at least partly, a consequence of acute injury. Probability of local tumor control correlated with severity of acute response, suggesting that excessive protraction of overall treatment time to minimize acute toxicity may compromise local control of the tumor. There was no demonstrable correlation between the volume of tissue irradiated and the severity of acute or late response.

Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx: Tumor dose-response and repopulation

In a retrospective study, local control of the primary tumor in 498 squamous cell carcinomas of the oral cavity and oropharynx was analyzed with respect to initial tumor volume, total dose after normalization for variations in fraction size, and to overall treatment time. Primary tumors were grouped into 4 sites, tongue (175), oral cavity including floor of mouth, faucial pillar, soft and hard palate and gingiva (210), tonsil (72) and buccal mucosa (41). Total doses of 60Co irradiation ranged from 30 Gy to 72 Gy, overall treatment times from 15 to 80 days and dose per fraction from 1.8 to 6 Gy. The large number of patients and diversity of dose fractionation patterns permitted assessment of the independent contributions to treatment outcome of stage, fraction size and overall treatment duration. The following conclusions were drawn: (1) Overall treatment time influenced strongly the probability of local tumor control. Over the interval of about 30–55 days used in treating most of this series of patients, an increase of 60 cGy per day, on average, was required for a constant control rate. (2) The increase in dose was attributed to accelerated tumor clonogen growth rate. Such accelerated growth could be a major determinant of failure in protracted regimens. (3) The accelerated rate of regrowth was similar for all tumor sites and stages. (4) The dose for tumor control was relatively independent of variations in fraction size within a range of about 1.6 Gy to 3 Gy: the alpha /beta value in the linear quadratic isoeffect equation was at least 15 Gy. (5) Local control at the primary site required an average of about 3 Gy more for each increase in T stage. This increase most likely reflected an increased number of tumor clonogens, not a decreased tumor cell radiosensitivity. (6) The probability of control at the primary site was less likely if lymph nodes were positive, but this association was only shown to be statistically significant for primaries classified here as oral cavity and oropharynx, not tonsil, tongue or buccal mucosa. (7) After allowing for differences in treatment parameters, especially for heterogeneity in overall treatment times, tumor control probability increased steeply with increase in total dose. (8) A general principle of radiotherapy, at least for squamous carcinomas of head and neck, should be to deliver the desired fractionated dose regimen without unnecessary interruptions and in the shortest time compatible with no reduction in dose below that tolerated by the late-responding normal tissues.

Radiotherapy and hyperthermia. Analysis of clinical results and identification of prognostic variables.

Site- and tumor-specific data obtained from two groups of patients with head and neck and melanoma lesions, respectively, showed that both immediate response and response duration were enhanced by the addition of heat. Two important variables, however, such as tumor volume and "isoeffect thermal dose" appeared to influence local tumor control. The volume effect was less pronounced in the lesions treated with radiotherapy plus heat than in those treated with radiotherapy alone, suggesting that the addition of heat was more damaging to the large than to the small lesions. Furthermore, a striking isoeffect thermal dose-response relationship was shown in head and neck lesions. Those data were collected and used to design a mathematical model relating the probability of local control to clinical and treatment variables. The analysis shows that, by using the same radiation parameters, the probability of local tumor control is a function of both "isoeffect thermal dose" and tumor volume.

Effect of fractionated irradiation prior to conservative and radical surgery on therapeutic gain in a spontaneous fibrosarcoma of the C3H mouse.

The efficacy of fractionated irradiation given preoperatively was examined using early generation isotransplants of a spontaneous fibrosarcoma (FSaII) growing in the right leg of syngeneic C3Hf/Sed mice and employing as endpoints local tumor control probability, normal tissue damage (5 mm leg shortening), and distant metastasis. Complete dose response assays have been performed on small (4-5 mm) and large (8 mm) tumors. TCD50s (the dose that on average would be expected to control half the irradiated tumors) for radiation given in five equal doses (1 day between treatments) were 93.6 and 111.8 Gy for the 4-5 and 8-mm tumors, respectively. Surgery was performed under a dissecting (8X) microscope at 5-6 days after the completion of irradiation. For small tumors, radical (en bloc) and conservative (local) resection alone achieved 69.8 (30/43) and 21.9% (7/32) tumor control, respectively. The corresponding figures for large tumors were 25 (8/32) and 6.1% (2/33), respectively. Preoperative irradiation increased tumor control rate up to 100% at dose levels much lower than TCD50 for radiation alone. Enhancement ratios (ER) were computed for preoperative radiation as follows: TCD50 for radiation alone/TCD50 for radiation and surgery. ERs were computed for local and en bloc resection for tumor control and for leg shortening. From these ER values, therapeutic gain factors (TGF) were then computed for local and en bloc resection for tumor control and for leg shortening. From these ER values, therapeutic gain factors (TGF) were then computed as ER tumor response/ER leg shortening. In small tumors, the TGFs (TCD80 and leg shortening of 5 mm) were 2.1 and 2.0 for conservative and radical resection, respectively. Corresponding figures for large tumors were 1.5 and 1.5. In this experimental system for small and large tumors, radiation treatment prior to conservative surgery achieved a comparable therapeutic gain to that by combining radiation with radical surgery. No effect of preoperative fractionation on the frequency of distant metastasis was observed.

A tumor/normal tissue advantage for low dose rate neutron brachytherapy

Reports on clinical study of Cf-252 pelvic brachytherapy are reviewed and show that complication frequency is low. Low dose rate (LDR) neutron brachytherapy has been shown to be effective against cervical and advanced pelvic cancers; and produces 5 year cures without a high frequency of normal tissue complications. This is attributed to a high relative biological effectiveness (RBE) for the bulky, hypoxic tumor which along with an oxygen enhancement ratio (OER) advantage and dose-rate independent effects, produces rapid tumor regression and good local tumor control. Adjacent normal tissues which are oxygenated have lower RBE values than that of hypoxic tumors. Cf-252 brachytherapy increases the dose differential, therapeutic gain and the probability of local tumor control, since the high RBE of Cf-25:: for hypoxic tumor is much less in normal tissues. Cf-252 radiation concentrated in the tumor, and for this reason, has had much fewer attendant normal tissue complications compared to neutron beam therapy.

Conservative Surgery and Radiotherapy as Primary Treatment for Early Breast Cancer: Results of a 10 Year Experience

ABSTRACTA 10 year period of treatment at the Radiotherapy Department of the Royal Prince Alfred Hospital was analysed retrospectively in order to assess the efficacy of conservative management of early breast cancer. From May 1968 to May 1978 a total of 1,785 patients with breast cancer were treated. Of these, 30 underwent conservative surgery for Stage I or II disease, followed by a course of “radical” irradiation.Patient follow‐up ranged from 0.5 to 11.1 years (median 6.5). The 10 year actuarial probability of local tumour control for the entire group was 91% and the 5 and 10 year actuarial survivals were 82 and 53% respectively. Only three patients have died from their primary disease, and three have had local recurrences, all readily controlled with mastectomy. Sixteen patients remain alive and well, but six have died from inter‐current illness. No significant radiation complications have occurred although eight patients (28%) have developed a second primary malignancy over the ten year period.Local excision plus radiotherapy appears to be an effective alternative approach to the local treatment of primary breast cancer in selected patients. Recommendations are made concerning axillary node sampling, interstitial brachytherapy and adjuvant chemotherapy for patients treated by this technique.

Proton beam therapy.

Conventional radiotherapy with high energy photons and electrons has been remarkably successful in treating many localized tumors. However, if tumors are large or are located very close to critical normal structures, it becomes very difficult to deliver a tumoricidal dose to the entire tumor volume without compromising the function of these adjacent organs. In such situations the local tumor control probability may be enhanced by improving the therapeutic ratio, defined as the ratio of the probability of tumor control to the probability of normal tissue injury. An increase in the therapeutic ratio may be' obtained by choosing a radiation modality that is more effective at killing tumor cells than normal cells or by employing a type of radiation that provides improved dose distribution relative to that achievable by conventional radiation modalities. Historically, great improvements in local control rates of deep-seated tumors were obtained through an increase in the energy of photon treatment beams. This occurred both at the time of the introduction of the 60 Cobalt teletherapy unit into radiation therapy, replacing X-ray machines with maximum energies of about 300 kVp, and with the introduction of high energy electron accelerators capable of producing bremsstrahlung beams with energies in the supervoltage range, i.e. above 2 MeV, such as Betatrons and linear accelerators (4). Since the introduc­ tion of high energy photon beams, physicists have continued to try to improve dose distributions through the use of sophisticated treatment plans, including multiportal and rotational techniques, beam modifiers such as compensating wedges, etc, and by the development of computer­ directed dynamic therapy techniques (8).

Radiotherapy in the treatment of carcinoma of the vocal cords: results of a 10-year experience.

A 10-year period of treatment at the Department of Radiotherapy of the Royal Prince Alfred Hospital was analysed retrospectively to assess the efficacy of "radical" irradiation in patients with early glottic cancer (Stages I and II). From June, 1964, to June, 1974, 120 patients were treated primarily with radiotherapy, which was followed by salvage laryngectomy for those with locally recurrent disease. Patient follow-up ranged from 0.5 to 12 years (mean, 6.2 years). The incidence of disease recurrence after radiotherapy was 13.7% for patients with Stage-I disease and 13.6% for patients with Stage-II disease. The five-year actuarial probability of local tumour control was 85% for patients with Stage-I disease. Ninety-one patients (77.8%) remain alive and well without disease recurrence, with an actuarial five-year survival probability for patients with stage-I disease of 93.8%. "Radical" irradiation for early glottic cancer can result in excellent survival rates with a small probability of local recurrence and few complications.

Prognostic indicators in induction cis-platinum bleomycin chemotherapy for advanced head and neck cancer

A complete response to induction cis-platinum bleomycin chemotherapy significantly increases the probability of local tumor control and overall disease-free survival. Factors that favor a good response to chemotherapy are tumor histology (well differentiated), location of the primary site (oral cavity and oropharynx), nodal status (N 0) and size of the primary lesion (T 3 better than T 4). Increased cellular maturation after chemotherapy correlates with an improved clinical response. The importance of induction and maintenance chemotherapy in the treatment of advanced head and neck cancer still needs to be determined with larger randomized series. Reliable predictors of therapy outcome are needed for realistic treatment planning, especially when the potential morbidity is considered.

The utility of computed tomography in radiation therapy: An estimate of outcome

Several studies have shown that computed tomography (CT) scanning leads to changes in planned therapy for some 40 to 60 % of patients studied. An empirical model has been developed to estimate the improvement in local control and long term survival attributable to CT. The model is based upon an average dose-response relationship for the tumors and involves a technique for estimating the change in tumor control probability when part of the tumor is underdosed. Using this model, it was estimated that, in one series of patients, CT scanning improved the local tumor control probability by an average of 6 %, and improved the chance of 5-year survival by an average of 3.5 %.

Results of treating stage III carcinoma of the breast by primary radiation therapy

One hundred sixteen patients with stage III carcinoma of the breast were treated by primary radiation therapy. The 5-year actuarial survival and relapsefree survival were 25% and 22%, respectively. The 5-year actuarial probability of local tumor control for the entire group was 64%. In patients undergoing an excisional biopsy and an interstitial implant of the primary tumor area, local control was 100%. In patients who had either an excisional biopsy or an implant, the 5-year actuarial probability of local control was 77% and 76%, respectively. In contrast, in patients having neither an excisional biopsy nor an implant, local control was only 41%. In patients receiving a total dose of greater than 6000 rad, from external beam treatment or from external beam plus an interstitial implant, the local control was 78% compared to 39% in patients receiving a total dose of less than 6000 rad. Forty-one patients received some form of adjuvant therapy. Both local control and relapse-free survival were improved in patients receiving chemotherapy as the sole adjuvant and in patients receiving chemotherapy combined with an endocrine ablative procedure. However, patients treated with only an endocrine ablative procedure had no improvement in survival nor in local control. These results indicate that primary radiation therapy can provide local control in a high proportion of patients with stage III carcinoma of the breast and suggest that chemotherapy is effective in improving both local control and survival in these patients. Cancer 43:985–993, 1979.