L. Tupchong

Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience.

The development of second malignant tumors (SMTs), in patients who have had their first tumor treated successfully, represents a serious limitation of current therapeutic strategies for head and neck cancers. To improve our understanding of the current magnitude of the problem and the various factors that might influence its importance, we reviewed the Radiation Therapy Oncology Groups (RTOG) prospectively collected registry of all head and neck patients seen in participating member institutions between February 1977 and April 1980. A total of 928 patients were identified who had squamous cell carcinomas of the head and neck region, no prior or coincident history of another malignant tumor, and whose planned treatment consisted of radiation therapy only. A total of 110 second, independent, malignant tumors occurred in these patients. Overall, the estimated risk of developing a second tumor within 3 years of radiotherapy was 10%, within 5 years 15%, and within 8 years 23%. Minor differences in frequency were observed for different primary sites. These SMTs unquestionably influenced subsequent survival adversely. Analysis of the database also revealed that the extent of the primary tumor influenced the risk of a second; most occurred in patients who presented with the smallest primary tumors because of their better survival. Our data indicate that preventive medicine should have its greatest impact in those patients who are treated for an early stage primary tumor.

HUMAN TUMOR EXTRACELLULAR PH AS A FUNCTION OF BLOOD GLUCOSE CONCENTRATION

PURPOSEnMammalian cells are sensitized to hyperthermia when the extracellular pH (pHe) is acutely reduced to < pH 7.0-7.2. However, cells chronically adapted to low pHe may not demonstrate such sensitivity. Although much of the extracellular environment of human tumors is at lower than normal physiological pH, it may be necessary to acutely acidify tumors to cause a change in the therapeutic response to hyperthermia. The purpose of this study was to reduce extracellular pH in human tumors by elevation of blood glucose.nnnMETHODS AND MATERIALSnThe change in tumor pHe was measured as a function of the change in blood glucose concentration after oral administration of 100 g glucose in 25 fasting, nondiabetic patients. pHe was determined by needle microelectrodes, and blood glucose determined by Chemstrips and a glucometer. In some patients blood glucose concentration rose with time after ingestion to a peak change of 50-100 mg/dL between 30-70 min and then began to decrease. In another group of patients glucose concentration increased by 100-200 mg/dL over 30-90 min and remained elevated as if the patients in this group were Type II diabetics.nnnRESULTSnIn 14 transient hyperglycemic patients (56%), as blood glucose increased tumor pHe decreased by a mean of -0.17 +/- 0.04 pH units (p < or = 0.0001, range of -0.41-(+)0.07). By contrast in eight persistent hyperglycemic patients, tumor pHe remained unchanged or actually increased an average of 0.03 +/- 0.04 pH units (range of -0.15-(-)0.14). Normal tissue pHe in five patients was unchanged by hyperglycemia, pHe = 7.33 +/- 0.03. Among all patients, 52% exhibited a pHe decrease > or = 0.1 pH unit, and 24% exhibited a pHe decrease > or = 0.2 pH unit. In five transient hyperglycemic patients whose preglucose tumor pHe was between 6.90 and 7.22, the average decrease in pHe induced by hyperglycemia was 0.25 +/- 0.05 pH unit. A linear relationship was observed between the change of pHe and the maximum change in blood glucose such that the greatest decrease in tumor pHe occurred when the glucose change was minimal. The slope was 0.0017 +/- 0.0005 pH units/mg/dL glucose (p < or = 0.005). The linear relationship included both tumors in transient hyperglycemic patients and in persistent hyperglycemia patients.nnnCONCLUSIONnSince patients who exhibited the lowest change in blood glucose exhibited the greatest decrease in tumor pHe, it may be that cells in these patients were better able to transport glucose intracellularly which in tumor cells would permit a more rapid production of lactic acid from aerobic and/or anaerobic glycolysis. These data may be helpful in predicting the response of individual patients to oral hyperglycemia as a clinical thermosensitizer.

TUMOR EXTRACELLULAR PH AS A PROGNOSTIC FACTOR IN THERMORADIOTHERAPY

PURPOSEnTumor extracellular pH measurements in 26 human tumors were evaluated for the purpose of prognostic indication of response to thermoradiotherapy.nnnMETHODS AND MATERIALSnTwenty-six patients (10 male, 16 female; mean age 62 years, range 18-89) were treated with external microwave hyperthermia (915 MHz) combined with radiation therapy. Tumor histologies included: 46% adenocarcinoma, 38% squamous cell carcinoma, 12% soft tissue sarcoma, and 4% malignant melanoma. The mean tumor depth was 1.6 +/- 0.2 cm (range 0.4-3 cm) and the mean tumor volume was 73 +/- 11 cm3 (range 1-192 cm3). The mean radiation dose administered concurrently with hyperthermia was 39 +/- 1 Gy (range 24-60 Gy, median of 40 Gy), in 15 fractions (range 8-25), over 32 elapsed days (range 15-43). The mean number of hyperthermia sessions administered was 5.4 +/- 0.5 (range 2-10). A battery operated pH meter and combination 21 ga recessed glass, beveled needle microelectrodes were used for tumor pH measurements. Calibration in pH buffers was performed before and after each pH measurement. The needle microelectrodes were 2.5 cm in length.nnnRESULTSnA complete response (CR) was obtained in 20 of 26 patients (77%) and a partial response in six (23%). The mean extracellular tumor pH was 6.88 +/- 0.09 in CR patients while it was 7.24 +/- 0.09 in noncompletely responding (NCR) patients (p = 0.08). Logistic regression analysis indicated that the probability of obtaining a complete response was influenced by the tumor volume (p = 0.02), tumor depth (p = 0.05), and extracellular tumor pH (p = 0.08). Lesions in the pH range of 6.00-6.40 and lesions in the pH range of 6.41-6.80 exhibited a CR rate of 100%, while those lesions in the pH range of 6.81-7.20 exhibited a CR of 90% and those in the pH range of 7.21-7.52 exhibited a CR of 50% (p = 0.002). In lesions with depth < or = 1.5 cm, the CR rate was 100% when the tumor pH was < 7.15 and 75% when the tumor pH was > or = 7.15. In lesions with depth between 1.5 and 3 cm, the CR rate was 66% when the tumor pH was < 7.15 and 43% when the tumor pH was > or = 7.15 (p = 0.02). In small tumors, that is, < or = 20 cm3, tumor pH increased with volume, whereas in larger tumors, that is, > 20 cm3, tumor pH decreased as a function of tumor volume.nnnCONCLUSIONnTumor extracellular pH may be useful as a prognostic indicator of tumor response to thermoradiotherapy.

Randomized trial of one versus two adjuvant hyperthermia treatments per week in patients with superficial tumours

One test for thermotolerance development in a clinical situation is to evaluate the effects of altering the hyperthermia fractionation interval on tumour response to thermoradiotherapy. Between 1983 and 1990 44 evaluable advanced superficial tumours of miscellaneous origin in 41 patients were randomized to receive either once-weekly or twice-weekly external microwave hyperthermia treatments combined with radiation therapy. The mean age of patients was 62 years, and 85% had failed previous therapy. All lesions were less than 8 x 8 x 4 cm (L x W x D) and were heated by external 915 MHz microwaves. The mean radiation dose was 44 +/- 3 Gy (mean +/- SE) in the once-weekly group and 46 +/- 3 Gy in the twice-weekly group (p = 0.64). The mean volume of the lesions heated once weekly was 17 +/- 6 versus 23 +/- 5 cm3 for those heated twice weekly (p = 0.45). Hyperthermia was administered once weekly for 4.6 +/- 0.2 sessions (range 3-7) or twice weekly for 8.1 +/- 0.3 sessions (range 4-10). Thermometry was performed using 3.4 +/- 0.2 catheters and 5.1 +/- 0.6 thermal sensors per tumour in the once-weekly group, and 2.7 +/- 0.2 catheters and 5.8 +/- 0.3 thermal sensors per tumour in the twice-weekly group. Of the 44 evaluable randomized lesions a complete response (CR) at 2 months post-treatment was observed in 59% (13/22) heated once weekly and 55% (12/22) in those heated twice weekly. The prognostic factors predictive of tumour complete response were found by logistic regression analysis to be radiation dose and tumour volume, while the prognostic factors predictive of duration of response (Cox proportional hazards analysis) were median minimum tumour temperature (Tmin), minimum tumour temperature during the first heat treatment (Tmin1) and tumour volume. The duration of local control in lesions with Tmin < or = 39.5 degrees C was 11.7 +/- 1.9 months while for lesions with Tmin > 39.5 degrees C it was 23.0 +/- 4.2 months (p = 0.01). The ED50 was calculated by logistic regression to be 40 Gy (95% CI = 22-54 Gy) for once- and twice-weekly heated lesions. There was not a significant difference in tumour response or duration of response between populations randomized to receive once- versus twice-weekly hyperthermia treatments. There was also no difference in skin reaction rates between once- and twice-weekly hyperthermia treatments, nor could a correlation be found between any thermal parameter and skin reactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Hyperthermia and radiation in advanced malignant melanoma

Advanced melanoma (48 lesions in 40 patients) was treated with external microwave hyperthermia combined with radiation therapy between 1980-1988. Thirty-three lesions in 28 patients were evaluable for tumor response (mean age 64 years, 19 male, 9 female). Evaluable lesions received 13 to 66 Gy (mean 37 +/- 2 Gy) over 5 to 16 fractions (mean of 10) in 14 to 56 elapsed days (mean of 25). Tumor volume (pi/6*length*width*depth) was 62 +/- 16 cm3 (1-377 cm3). Hyperthermia was administered in 6.6 +/- 0.4 sessions (range 1-14), there were 3.2 +/- 0.4 thermal sensors per tumor (range 1-11) and 27 fields were treated twice-weekly (82%). Of the 33 evaluable lesions, 12 exhibited a complete response (36%), and 17 had a partial response (52%). Among the 12 complete responders four recurrences (33%) were observed at 8.6 +/- 1.4 months (median of 8.2 months). In superficial tumors with depth < or = 3 cm and with lateral dimensions within 2 cm of the boundaries of the microwave applicator, the complete response rate was 50% (11/22); whereas for patients with deeper tumors with depth > 3 cm, the complete response rate was 9% (1/11), p = 0.02. The minimal tumor thermal dose during the first hyperthermia treatment session correlated with response (t43min1 = 20 +/- 7 vs. 6 +/- 3 minEq43 degrees C for complete responders and noncomplete responders, respectively, p = 0.06); and 7 of 10 lesions that had t43min 1 > or = 8 minEq43 degrees C achieved a complete response whereas only 5 of 22 lesions (23%) that had t43min1 < 8 minEq43 degrees C did so (p = 0.01). However, neither the minimum tumor temperature during the first treatment, the median minimum tumor temperature over all treatment sessions nor the sum of minimum thermal dose over all treatment sessions correlated with tumor response. Twenty-three patients with 28 lesions died during follow-up (82%). The survival for complete responding patients with superficial lesions was 21.3 +/- 1.5 months compared to 4.5 +/- 0.5 months for patients with superficial lesions that did not experience a complete response (p = 0.0001). For patients with noncomplete responding lesions deeper than 3 cm survival was 4.4 +/- 0.6 months. Twenty lesions were treated without any skin reaction (42%, 20/48). Of the rest, 23 had erythema (48%, 23/48), seven had blistering (14%, 7/48) and one had ulceration of the skin.(ABSTRACT TRUNCATED AT 400 WORDS)

Thermoradiation therapy for superficial malignant tumors

Background. Between 1980–1990, 126 patients were treated with radiation therapy (RT) and hyperthermia using 915‐MHz external microwave applicators. All but 11 patients had failed to respond to previous therapy.

Thermoradiotherapy with combined interstitial and external hyperthermia in advanced tumours in the head and neck with depth ≫3 cm

Advanced tumours in the head and neck 3-6 cm depth are too deep to be completely heated by external 915 MHz microwaves. A preliminary study was performed using interstitial plus external hyperthermia combined with external beam radiation therapy to heat tumours to depths > or = 3 cm. Nine advanced metastatic lesions of squamous cell carcinoma located in the head and neck were treated between 1987 and 1990 with the combined hyperthermia technique and radiation doses of 38-60 Gy (mean of 49 +/- 3 Gy). The mean tumour volume was 58 +/- 9 (SE) cm3 (range 24-94 cm3) with a mean tumour depth of 3.9 +/- 0.3 cm (range 3-5.5 cm). The deeper aspects of the tumour were heated by interstitial 915 MHz microwave antennas and the superficial aspects heated by external 915 MHz applicators. A single plane of polyurethane closed-end catheters, 16 Ga, were inserted under local anaesthesia approximately 1.5-2 cm apart in parallel arrays at the base of a lesion behind the sternomastoid muscle, or an equivalent site in a dissected neck, extending forward and angled deeply no more than 15 degrees. Hyperthermia was administered twice weekly immediately after radiation therapy in a mean of 5.3 +/- 0.7 external heat sessions (range 3-7) and a mean of 3.5 +/- 0.6 interstitial heat sessions (range of 1-6). Interstitial hyperthermia was usually administered in alternating sessions with external hyperthermia, but in some patients all of the sessions of one modality were administered followed by all of the sessions of the other modality. In no case were both interstitial and external heatings performed on the same day. Surface thermometers were used to monitor skin temperature during external hyperthermia sessions. Results showed that by 8 weeks after completion of treatment, six lesions exhibited a complete response (67%) and three a partial response (33%). One of the partial responses continued to regress and became a complete response (78% complete response). The recurrence rate in complete responders was 14% (1/7) with time to recurrence of 7.7 months. Six lesions were recurrence-free at last follow-up of 21.3 +/- 8.8 months. Skin reactions were absent in four fields (44%), erythema was noted in five (56%) and thermal blistering in one (11%). Ulceration occurred only in association with tumour breakdown when the skin was infiltrated by tumour (three patients, 33%).(ABSTRACT TRUNCATED AT 400 WORDS)

Optimization of hyperthermia with CT scanning

In a prospective study CT scanning was used to evaluate the precision of thermometry catheter placement in tumours in the head and neck or on the chest wall in 30 consecutive patients prior to hyperthermia treatment. Patients had variable-sized tumours from several primary sites. Thermometry catheter placement was guided by palpation with or without a prior CT scan. Catheter placement was confirmed by CT. All lesions were less than 8 x 8 x 6 cm (L x W x D) in size. A mean of 4.2 +/- 0.2 (+/- 1 SEM, range 2-7) closed-end polyurethane catheters were inserted orthogonally by the same experienced radiation oncologist. Horizontal thermometry catheters were intended to traverse the centre and base of the tumour mass, and a vertical catheter was often inserted to intersect a horizontal catheter. After catheter placement, wire cables with 1 cm spacings were inserted into the catheters and positions determined using orthogonal films and CT scans. The success of catheter placement was judged on the following criteria: (1) catheter distribution factor (CDF = proportion of tumour CT slices transected by at least one catheter); (2) catheter hit ratio (CHR = average number of catheters in tumour per CT slice); (3) catheter miss factor (CMF = average number of catheters out of tumour per CT slice); (4) catheter placement index, CPI = [(CHR)(CDF)]-CMF; and (5) distance of nearest catheter from the visually estimated centre of tumour in the most central tumour CT scan. In the first seven lesions with 3-6 cm depth catheter insertion was guided by palpation only. In the next 23 lesions catheter insertion was guided by a prior CT scan. In the latter group, 15 lesions had depth 3-6 cm while eight lesions had depth < or = 3 cm. Catheter placement by palpation only, without the benefit of CT scan, was much less accurate in terms of the nearest catheter to the centre of the tumour (p = .001), the proportion of CT slices with catheter in tumour (CDF, p = 0.04) and the probability of a catheter being outside the tumour (CMF, p = 0.01). The catheter placement index (CPI) was a good measure of the accuracy and adequacy of catheter placement in large tumours (p = 0.04). Displacement of normal tissue structures by tumour precluded accurate catheter placement and led to a low CPI. It was difficult to accurately instrument lesions < or = 3 cm depth even with the benefit of a prior CT scan.(ABSTRACT TRUNCATED AT 400 WORDS)

Predictive factors for skin reactions in patients treated with thermoradiotherapy

In this study we performed univariate analyses to analyse the predictive factors for skin reactions, i.e. erythema, thermal blisters and ulceration, that occur during thermoradiotherapy. One hundred and twenty-six fields in 126 patients were treated with thermoradiotherapy using 915 MHz external microwave hyperthermia. Mean age of patients was 62 years. All but 11 lesions received previous therapy. Prior treatment included surgery (75%), chemotherapy (60%) and/or radiation therapy (51%). The mean previous radiation dose was 54 +/- 2 Gy. The concurrent tumour radiation dose was 45 +/- 1 Gy, in 16 fractions, over 35 elapsed days (dose per fraction of 1.6-4.8 Gy). The mean number of heat sessions administered was 5.5 +/- 0.2 (range 1-14). In 83% of cases hyperthermia was administered biweekly. Forty-two patients were treated without any skin reaction (33%), erythema occurred in 59 fields (47%), transient thermal blisters occurred in 25 fields (20%) and ulceration occurred in 23 fields (18%). In 25 cases, two or more skin reactions (20%) were observed concurrently. Concurrent radiation dose correlated with skin reactions (p = 0.02). The incidence of skin reactions was inversely correlated with previous radiation therapy (p = 0.04) and previous radiation therapy dose (p = 0.04) possibly due to fibrosis. None of the tumour or skin thermal parameters correlated with the reaction rate.

‘Patchwork’ fields in thermoradiotherapy for extensive chest wall recurrences of breast carcinoma

SummaryChest wall lesions of advanced breast carcinoma in 23 patients were treated with thermoradiotherapy with clinical intent between January 1987 and March 1992. Treatment consisted of external 915 MHz microwave hyperthermia with commercially available applicators and radiation therapy to doses between 32–58 Gy. Twenty-three large, diffuse lesions were treated with multiple field patchwork hyperthermia. All lesions were diffuse with or without multiple nodules ≤ 3 cm depth. All lesions had failed previous therapy. The mean number of hyperthermia fields per patient was 3.2 ± 0.4 (range of 2–7). The complete response rate was 91% in this group of extensive, diffuse lesions treated by the patchwork technique. Mean total radiation dose administered concurrently with multiple field patchwork hyperthermia was 42 ± 1 Gy. The recurrence rate was 5%. The mean survival in patients who had a complete response was 9.0 ± 1.3 months. The reduced survival among patchwork treated patients was due to the extensive tumor burden existing outside of the treated fields in these patients. The skin reactions were minor, causing minimal discomfort. There was no evidence of increased thermal damage to skin, or of tumor recurrence at junctions of hyperthermia field overlap. It is concluded that extensive, diffuse lesions of chest wall recurrence of advanced carcinoma of the breast can be treated effectively with multiple field patchwork thermotherapy.