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97 Larynx preservation: Present and future
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COMPARISON OF DOSIMETRY TECHNIQUES FOR THE ESTIMATION OF SUPERFICIAL SKIN DOSE IN EXTERNAL BEAM RADIOTHERAPY
LARYNX PRESERVATION : PRESENT AND FUTURE
Anssi V~m~nen, Santa Remes and Tapani l.ahtineu Depa~ment of Oncelogy, Kuopio University Hospital, Kuopio, Finland.
J.L. LEFEBVRE, M.D. E.O.R.T.C. Head and Neck Cancer Cooperative Group
Direct measurement of absorbed dose at different depths in epidermis and dermis is not possible with conventional dosemeters. Therefore, dosemeters and phantoms simulating the clinical situation or superficially positioned desemeters have to be used. A plane parallel ionization chamber cannot be used due to a large variation of the radiation quality in the build-up region and contamination from beam limitting and attenuating devices. In order to estimate the skin dose in breast cancer patients having postmastectomy radiotherapy, we have used three techniques; extrapolation chamber, extrapolation TLD (ETLD) method and thin-window semiconductor diode. All the measurements were done in the same geometry than the patient treatments. The extrapolation chamber was regarded as a reference method. At the depths of 0.1, 0.5, 1.0 and 2.0 ram, the diode and ETLD measurements differed 1 - 7% from the reference values with olx:n and irregular electron fields. The maximun difference for open and irregular photon fields was -20% and -34% for ETLD and diode, ~ i v e l y . Although the extrapolation chamber is the most tedious of the tested methods, it is considered the most accurate for skin desimetry. The ETLD method is suitable for in vivo measurements from 0.1 to 1 ram. The semiconductor is applicable from 0.5 mm to higher depths.
Over the past decade, many papers have been published about larynx preservation. Most of them related non randomized studies using induction chemotherapy (ICT) as a selection for either a subsequent radiation therapy (in good responders) or, on the contrary, a subsequent surgery (in poor rsesponders). One randomized study, comparing surgery with this ICT-based strategy, has been published in the United States on larynx SCC by the Veterans Affairs. Another similar randomized trial was conducted under the auspices of EORTC on hypopharynx SCC. In this trial (EORTC 24891) 94 pts. were ovaluable in the surgery arm and 100 in the chemotherapy arm. 53 % of pts. were complete resbonders to ICT. The median duration of survival was 25 months in the surgery arm and 44 months in the chemo arm but at 5 years survival curves did not differ any longer. The slippage in survival was explained by a delay in appearance of distant metastases in the chemo arm. Finally, tacking into account only deaths of local evolution, the 3 year survival with a functional larynx in place in the chemo arm was 42 %. These two randomized tdals have shown that radical surgery could be avoided in some cases. But, if larynx preservation is unquestionable, it remains investigational since we miss comparison between sequential and concomitant chamoradiation therapy or between irradiation and chemoradiation. EORTC 22954 and 24954 will try to answer these questions in terms of disease control, survival but also quality of life, quality assurance and cost evaluation.
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99
Direct InU'at~mor(IT) gene mmsfer using recombinantadenoviral (rAd) vectors : a phase I study in lung cancer (LC) patients (pts). T. Tursz~, A. Le Cesne'. P. Baldeyrou', A. Andremont' P. Opoinn~, C.S ChatS, A. Pavireni=, M. Courmeya, D. Lamyz, R. Monier'. E. Haddada', M Perricaudet', T. Le ChevalieP - 'lnstitut Gustave-Roussy - Villejuif, ~ Transgene, Strasbottrg, France. : The direct transfer of tumor suppressor genes or toxic gene products that specifically promote tumor cell death and span) non malignant cells is a potentially novel anticancer Ireat~nentapproachthat should be investigated. Purn~se : Based on compelling preclinical data, we conducted a phase I study in humans to evaluate the feasibility, tolerance and clinical, biological and immunological effects of the inwammor administration of a recombinant, replication-deficientadenoviros (Ad RSVB-gal), using the RSV promoter to drive transcription of the Escheriehia Coil lacZ marker gene that encodes for the bacterial enzyme beta-gnlactosidas¢(B-gal), in pts with inoperable lung cancer and an endobronchial lesion accessible by bronchoseopy. The t'u'st single dose level was l0T(3 pts), the second was 10' (3pin) and the third was l0) plaque-forming units Cofu)(2 pts). Biopsies of tumor and surrounding mucosa, performed at days 8, and at I, 2 and 3 months following injection, were analyzed using PCR and Xgal staining. Pts and medical slaffwere monitored for wild type and tAd infections by PCR. culture and serologic analyses. Pits remained in TL2 isolation until negative results of PCR and cultures of biologic fluid specimens were cunfmned. All pts received concomimmchemotherapy. Results : Seven pts with NSCLC and one with neuroendocrine tumor entered this ongoing study. Expression B-gal was observed in 5/8 tumor biopsies (I at 10~, 2 at 10' and 2 at l0~ dose level). Bronchoalveolaslavage collected immediately after injection were positive for recombinant adenoviros by culture and PCR. All biological fluids were negative by PCR after day 12. The three and 2 pts ~eated at 10s and l09 pill respecdvely had PCR positive blood samples on day I. Pts were in isolation for a median of 17 days. Moderate bleeding (2 pts) during bronchoseopy and fever (4 pts) were the most common toxicities. Endoscopic and clinical objective tumor responses were seen in five pts. The 3 pts treated at the second dose level, all with stage IilB disease, were daemed operable .after chemotherapy. They all had a complete surgical resection of their tumor 112 to 152 days alter viral injactinn. Hospital staff remained negative for recombinant adanovirus infaction throughout the study. Conclusions : This ongoing study demonstrates that a marker gene can be safely introduced into humans using a rAd vector and that the gene product is expressed by host lung tumor cells. We will continue our program by using this methodology to study the antitumor effects mediated by transfer of tumor suppressor or cytokine genes into endobronchial lesions in LC pts.
RADIONUCLIDE T H E R A P Y DOSIMETRY AND T R E A T M E N T PLANNING Sven-Erik STrand, Michael Ljungberg, Bob Ott (1) Radiation Physics Department, Lund University, Sweden (1) Inst. Cancer Research, Royal Marsden NI-IS Trust, Sutton, Surrey, UK. .......................................................................................... i r-=~,, r-=~,, ~ ,,~,,g spEcr~s-r [ ~ ~,ay" • 4
|~o-~:
When the area of radionuclide therapy expands with new t h e r a p e u t i c radiopharmaceuticals, more patients will be eligible for such therapy. Regardless if to be used either as a standalone therapy or in combination with other therapies, a
dose calculation for the patient available. These ~m= ,i calculations should form • the base for correlation of the therapeutic effect to [,,,=,c,,,,~~_..~f,,-,:~-. t "o " absorbed dose and more ~ M[~,~.~ P=k,~.~preferably for individual "~"•~-' dose planning prior to therapy. Such a treatment [~,~ planning scheme needs to be based on accurate . methods available for the ................................................................ calculations using both quantitative methods and precise calculation methods. Our work under development is a complete treatment planning system in radionuclide therapy, which can be broken down into discrete steps indicated in the flow sheet. It includes : I. Multimodality image registration (SPECT, PET, CT, MR); 2. Quantitative functional imaging (PET, SPECT); 3. Dose planning and calculation, and 4. Dose/volume histogram tumour control prediction. This paper will discuss the different steps in a treatment planning system. •
96
97
COMPARISON OF DOSIMETRY TECHNIQUES FOR THE ESTIMATION OF SUPERFICIAL SKIN DOSE IN EXTERNAL BEAM RADIOTHERAPY
LARYNX PRESERVATION : PRESENT AND FUTURE
Anssi V~m~nen, Santa Remes and Tapani l.ahtineu Depa~ment of Oncelogy, Kuopio University Hospital, Kuopio, Finland.
J.L. LEFEBVRE, M.D. E.O.R.T.C. Head and Neck Cancer Cooperative Group
Direct measurement of absorbed dose at different depths in epidermis and dermis is not possible with conventional dosemeters. Therefore, dosemeters and phantoms simulating the clinical situation or superficially positioned desemeters have to be used. A plane parallel ionization chamber cannot be used due to a large variation of the radiation quality in the build-up region and contamination from beam limitting and attenuating devices. In order to estimate the skin dose in breast cancer patients having postmastectomy radiotherapy, we have used three techniques; extrapolation chamber, extrapolation TLD (ETLD) method and thin-window semiconductor diode. All the measurements were done in the same geometry than the patient treatments. The extrapolation chamber was regarded as a reference method. At the depths of 0.1, 0.5, 1.0 and 2.0 ram, the diode and ETLD measurements differed 1 - 7% from the reference values with olx:n and irregular electron fields. The maximun difference for open and irregular photon fields was -20% and -34% for ETLD and diode, ~ i v e l y . Although the extrapolation chamber is the most tedious of the tested methods, it is considered the most accurate for skin desimetry. The ETLD method is suitable for in vivo measurements from 0.1 to 1 ram. The semiconductor is applicable from 0.5 mm to higher depths.
Over the past decade, many papers have been published about larynx preservation. Most of them related non randomized studies using induction chemotherapy (ICT) as a selection for either a subsequent radiation therapy (in good responders) or, on the contrary, a subsequent surgery (in poor rsesponders). One randomized study, comparing surgery with this ICT-based strategy, has been published in the United States on larynx SCC by the Veterans Affairs. Another similar randomized trial was conducted under the auspices of EORTC on hypopharynx SCC. In this trial (EORTC 24891) 94 pts. were ovaluable in the surgery arm and 100 in the chemotherapy arm. 53 % of pts. were complete resbonders to ICT. The median duration of survival was 25 months in the surgery arm and 44 months in the chemo arm but at 5 years survival curves did not differ any longer. The slippage in survival was explained by a delay in appearance of distant metastases in the chemo arm. Finally, tacking into account only deaths of local evolution, the 3 year survival with a functional larynx in place in the chemo arm was 42 %. These two randomized tdals have shown that radical surgery could be avoided in some cases. But, if larynx preservation is unquestionable, it remains investigational since we miss comparison between sequential and concomitant chamoradiation therapy or between irradiation and chemoradiation. EORTC 22954 and 24954 will try to answer these questions in terms of disease control, survival but also quality of life, quality assurance and cost evaluation.
98
99
Direct InU'at~mor(IT) gene mmsfer using recombinantadenoviral (rAd) vectors : a phase I study in lung cancer (LC) patients (pts). T. Tursz~, A. Le Cesne'. P. Baldeyrou', A. Andremont' P. Opoinn~, C.S ChatS, A. Pavireni=, M. Courmeya, D. Lamyz, R. Monier'. E. Haddada', M Perricaudet', T. Le ChevalieP - 'lnstitut Gustave-Roussy - Villejuif, ~ Transgene, Strasbottrg, France. : The direct transfer of tumor suppressor genes or toxic gene products that specifically promote tumor cell death and span) non malignant cells is a potentially novel anticancer Ireat~nentapproachthat should be investigated. Purn~se : Based on compelling preclinical data, we conducted a phase I study in humans to evaluate the feasibility, tolerance and clinical, biological and immunological effects of the inwammor administration of a recombinant, replication-deficientadenoviros (Ad RSVB-gal), using the RSV promoter to drive transcription of the Escheriehia Coil lacZ marker gene that encodes for the bacterial enzyme beta-gnlactosidas¢(B-gal), in pts with inoperable lung cancer and an endobronchial lesion accessible by bronchoseopy. The t'u'st single dose level was l0T(3 pts), the second was 10' (3pin) and the third was l0) plaque-forming units Cofu)(2 pts). Biopsies of tumor and surrounding mucosa, performed at days 8, and at I, 2 and 3 months following injection, were analyzed using PCR and Xgal staining. Pts and medical slaffwere monitored for wild type and tAd infections by PCR. culture and serologic analyses. Pits remained in TL2 isolation until negative results of PCR and cultures of biologic fluid specimens were cunfmned. All pts received concomimmchemotherapy. Results : Seven pts with NSCLC and one with neuroendocrine tumor entered this ongoing study. Expression B-gal was observed in 5/8 tumor biopsies (I at 10~, 2 at 10' and 2 at l0~ dose level). Bronchoalveolaslavage collected immediately after injection were positive for recombinant adenoviros by culture and PCR. All biological fluids were negative by PCR after day 12. The three and 2 pts ~eated at 10s and l09 pill respecdvely had PCR positive blood samples on day I. Pts were in isolation for a median of 17 days. Moderate bleeding (2 pts) during bronchoseopy and fever (4 pts) were the most common toxicities. Endoscopic and clinical objective tumor responses were seen in five pts. The 3 pts treated at the second dose level, all with stage IilB disease, were daemed operable .after chemotherapy. They all had a complete surgical resection of their tumor 112 to 152 days alter viral injactinn. Hospital staff remained negative for recombinant adanovirus infaction throughout the study. Conclusions : This ongoing study demonstrates that a marker gene can be safely introduced into humans using a rAd vector and that the gene product is expressed by host lung tumor cells. We will continue our program by using this methodology to study the antitumor effects mediated by transfer of tumor suppressor or cytokine genes into endobronchial lesions in LC pts.
RADIONUCLIDE T H E R A P Y DOSIMETRY AND T R E A T M E N T PLANNING Sven-Erik STrand, Michael Ljungberg, Bob Ott (1) Radiation Physics Department, Lund University, Sweden (1) Inst. Cancer Research, Royal Marsden NI-IS Trust, Sutton, Surrey, UK. .......................................................................................... i r-=~,, r-=~,, ~ ,,~,,g spEcr~s-r [ ~ ~,ay" • 4
|~o-~:
When the area of radionuclide therapy expands with new t h e r a p e u t i c radiopharmaceuticals, more patients will be eligible for such therapy. Regardless if to be used either as a standalone therapy or in combination with other therapies, a
dose calculation for the patient available. These ~m= ,i calculations should form • the base for correlation of the therapeutic effect to [,,,=,c,,,,~~_..~f,,-,:~-. t "o " absorbed dose and more ~ M[~,~.~ P=k,~.~preferably for individual "~"•~-' dose planning prior to therapy. Such a treatment [~,~ planning scheme needs to be based on accurate . methods available for the ................................................................ calculations using both quantitative methods and precise calculation methods. Our work under development is a complete treatment planning system in radionuclide therapy, which can be broken down into discrete steps indicated in the flow sheet. It includes : I. Multimodality image registration (SPECT, PET, CT, MR); 2. Quantitative functional imaging (PET, SPECT); 3. Dose planning and calculation, and 4. Dose/volume histogram tumour control prediction. This paper will discuss the different steps in a treatment planning system. •