The time factor in oncology: consequences on tumour volume and therapeutic planning.

The rules that govern tumour treatment depend largely on clinical stage (tumour volume, localization and/or metastasis presence). These rules are applied assuming that tumor growth is relatively static without considering the time factor, the number of clonogenic cells in the tumour or the volume reduction following initial cytotoxic therapy. Time and neoplastic growth (with a subsequent change in volume) are generally not considered in 90% of clinical trials, where chemotherapy is administered on the first and eighth day and radiotherapy is carried out five days a week with different schedules. In the clinical situation, however, a tumour has more complex growth times that should be appropriately assessed to improve the treatment results (1). The aim of this paper is to stress the influence of the time factor to optimize the schedule of the cytotoxic therapies, based on different mathematical models developed to describe the tumour growth. To better understand the role of the neoplastic growth at its different clinical stages and the subsequent response to cytotoxic therapies, several elements concerning such growth should be thoroughly analyzed.

Influence of time interval between surgery and radiotherapy on tumor regrowth.

UNLABELLED: In order to evaluate the influence of time intervals between tumor cell injection and radiotherapy on tumor control and regrowth after surgery, we performed two kinds of experiments on C3D2F1 mice bearing a mammary carcinoma inoculated in the foot or leg. 1st experiment: tumor in foot. END POINT: Tumor Control Probability (TCP). Single dose radiation treatments (RT) were administered at different period times from injection time of tumor cells (day 1). 1st group: unirradiated control, 2nd group: RT on day 2 (TCP50 29 +/- 2.1 Gy), 3rd group: RT on day 7 (TCP 52.5 +/- 2.9 Gy), 4th group: RT on day 12 (TCP50 61.9 + 2.4 Gy). 2nd experiment: tumor in leg. END POINT: percentage of tumor regrowth. Mice were randomly assigned to three groups: 1st control group (tumor growth in all mice), 2nd surgical excision of macroscopically evident tumor on day 7-9 from injection (tumor regrowth in 85% of mice), 3rd as the previous group plus 30 Gy radiation treatment within 24 hours from excision (tumor regrowth in 33% of cases). The radiation dose was selected on the basis of TCP50 observed in the 1st experiment for mice with sub-clinical disease. These data indicate that the radiation dose able to control 50% of tumors increases with the time interval between tumor cells injection and RT. A short time interval between surgery and RT should increase the probability of local control, supporting the rationale of intraoperative radiation therapy (IORT) as adjuvant therapy after surgical resection, when subclinical residual cells are suspected.

Combined radiation and drugs: the effect of intra-arterial chemotherapy followed by radiotherapy in head and neck cancer.

This study was designed to ascertain whether a prior reduction of tumor size by drugs could affect the final outcome of tumors treated with radiation. 142 patients with head and neck cancer (oropharynx, maxillary antrum and intra-oral) were randomized for the study. In 72 cases, irradiation was preceded by a continuous intra-arterial infusion of 3-5 mg/day methotrexate to a total dose of 90-120 mg; the other 70 patients were treated with radiotherapy alone. Chemotherapy, given prior to radiotherapy, caused a shift in the tumor stage (i.e. a reduction in tumor size) in more than one third of the cases. The overall 5-year survival was 43% in the combined treatment group and 25% in the group treated with radiation alone (statistical difference: p less than .05). However, when analysed separately the difference was statistically significant only in oral cavity tumors (5-year survival of 54% in the combined modality group vs. 27% in the control group), although local control rates after both single and combined modalities were not statistically different from those of oropharynx and maxillary antrum tumors. In these last lesions, however, the dissemination of disease was more frequent; therefore, the lack of improvement of cure rate with the combined modality in these cases seems to be related to both the higher tendency of these tumors to disseminate and the low effectiveness of intra-arterial chemotherapy in controlling distant metastases. Mild and transient local and systemic toxicities were observed during chemotherapy infusion, but no radiosensitising effect on normal skin and mucosa was seen during radiotherapy in patients who had received pre-irradiation chemotherapy.

Tumor control and therapeutic gain with different schedules of combined radiotherapy and local external hyperthermia in human cancer.

Tumor control and therapeutic gain have been evaluated in a series of studies on patients with multiple lesions employing different protocols of combined radiotherapy (RT) and local external hyperthermia (HT). Tumor response has been evaluated during a follow-up ranging 6 to 18 months. Therapeutic enhancement factor (TEF) was defined as the ratio of thermal enhancement (TE) of tumors to TE of skin, where TE was clinically evaluated as the ratio of percent response (i.e., complete tumor clearance and moist desquamation, respectively) after combined modality to percent response after RT alone. Local tumor control was constantly better in lesions treated with any combined modalities in comparison with RT alone. The use of high RT dose per fraction appeared to increase tumor control only in the combined modalities groups, the immediate (so called "simultaneous") schedule (HT at 42.5 degrees C/45 min, applied immediately after each RT fraction, twice a week) being more effective than the delayed (so called "sequential") treatment (HT at 42.5 degrees C/45 min, delivered 4 h after each RT fraction, twice a week). The combination of high RT dose per fraction with high temperature HT (45 degrees C for 30 min) achieved the best tumor control. No increased radiation skin reaction was observed when a conventional fraction size of RT was used (3 daily fractions of 1.5-2 Gy, 4 h interval between fractions) in association with HT (42.5 degrees C/45 min, every other day, immediately after the second daily RT fraction). A remarkable enhancement of skin reaction was observed, however, when using high RT doses per fraction in association with 42.5 degrees C HT, especially with the immediate treatment schedule. No enhancement of skin reaction was obtained after high RT doses per fractions and 45 degrees C HT because an active skin cooling by means of circulating cold water was used in these cases. Consequently, a good TEF (1.58) was obtained when conventional RT doses per fraction were used in association with 42.5 degrees C HT. TEF values of 1.40 and 1.15 were observed when high RT doses per fraction were employed in association with the delayed and immediate 42.5 degrees C HT, respectively. HT at 45 degrees C can be safely employed only when tumors can be heated selectively or at least preferentially in comparison with normal tissue; in the lesions treated with such a schedule a TEF of 2.10 was obtained.

[Elective radiotherapy in breast carcinoma]. / Trattamento radiante elettivo del carcinoma mammario.

From March 1972 to November 1979 a total of 157 patients with stage I to III primary breast cancers have been irradiated after segmental resection (12 cases), tilectomy (89 cases) or biopsy (56 cases). Complete local control was achieved in all Stage I lesions, in 97% of Stage II lesions and in 68% of Stage III lesions. Non recurrence has been observed in patients previously operated by segmental resections, while local failures occurred in 6/89 and in 16/56 patients operated by tilectomy or biopsy, respectively. Of the 28 Stage I patients, 24 (86%) are alive, one with distant metastases. Four patients of this group are dead, 2 of intercurrent disease and 2 of breast cancer. Of the 61 (Stage II) patients, 38 (62%) are alive, 5 of these with distant metastases. Twenty-three patients are dead, 15 with active disease, and 8 suffered intercurrent death. Of the 68 Stage III patients, 21 (31%) are alive, 6 of these with distant metastases. Fourty-seven patients are dead, 43 of breast cancer and 4 of intercurrent disease. The high probability of initial subclinical deposits is evidenced by the fact that 49 of the 68 patients in this group developed distant metastases. The patients with T1 lesions appear to comprise the most favourable group with a relapse free survival at five years of 76%. The 5 years relapse free survival was 62% for T2 lesions and 25% for T3 and T4 lesions. N0 status does not confer the same favourable prognosis as T1 status. N+ status, however, resulted in a definitely negative prognostic factor. Cosmetic results after our treatment approach appear to be extremely good. A marked difference between the irradiated and controlateral breast occurred only in 10 of the 125 patients after a minimum of 2 years observation.