Tumori Journal

Continuing medical education (CME) has always been considered very important in modern medical practice. Physicians should not be left completly free to continuously educate themselves, but they should receive at least a minimal level of education accreditated by scientific and/or Government Institutions. The main goal of CME is to improve the quality of medical practice. In order to adequately define programs and contents of CME in radiation oncology, we must first identify the professional profile of the radiation oncologist: he is a physician engaged in the clinical practice of oncology, and in particular in the loco-regional cure of cancer by sophisticated technologies; he has the responsibility of diagnosis, treatment, follow-up and supportive care of cancer patients, collaborating within a multidisciplinary approach with the radiologist, the medical oncologist, the surgeon and the medical physicist. The european core curriculum in radiotherapy and the procedures employed in the daily practice could be models to develop postgraduate teaching and CME for the radiation oncologists in Italy. In fact, many countries, such as the USA, France, Belgium and the United Kingdom, have already developed accreditated programs of CME. Unfortunately, Italy still lacks this type of program. What is mostly needed to implement CME activities is a close cooperation between representatives of radiation oncology associations and Government Institutions to define laws, programs, an Accreditation Council, a minimum of formative credits, accreditated categories of education regulating CME, as well as the resources devoted to it.

Introducing a Quality Assurance methodology appears particularly useful in Radiation Oncology due to the complexity of the procedures involved and the heterogeneity of the standards adopted, if any, in the great majority of the Centers. There are two possible ways of evaluating quality in the Health Environment: a formal, Institutional certification, or a voluntary one obtained through a mechanism of peer review. The European Society for Therapeutic Radiology and Oncology (ESTRO) started in 1994 with the publication of a methodological Report intended to be adopted by the individual national Societies, and this paper is an invitation to do it.

The normal tissue tolerance and the related early side effects represent the main constraint on the total radiation dose which can be administered to the target volume. The most common disorders during radiotherapy or chemo-radiotherapy are summarized in this review. Since in the recent years great advances have been made towards the improvement of acute tolerance, practically every adverse symptoms can be controlled or lowered with an adequate treatment. Some suggestions are reported in order to prevent or lower the degree and the incidence of major complications, specifically mucositis-related symptoms like stomatitis, diarrhea, cystitis. Possibly, a multicenter effort is to be made in order to optimize the quality of supportive care for irradiated patients in all radiation therapy centers.

The modern practice of radiotherapy centres on the development of conformai radiotherapy, techniques to ensure the high-dose volume is tightly wrapped around the diseased tissue and excluded as far as possible from adjacent normal structures. The development of conformai radiotherapy is a chain of processes involving treatment planning, development of new methods to deliver radiation, verification of the accuracy of radiation delivery and improvement of biological outcome. This is an enormous field of activity. This invited review paper summarises some of the main elements of progress towards implementing intensity-modulated conformai radiotherapy. This is the newest and most exciting development and, when achieved clinically, will lead to a quantum leap in tumour control probability with a fixed level of normal tissue damage.

Radiation therapy treatment planning and treatment delivery are in the process of changing dramatically over the next several years. This change has been driven in large part by continued advances in computer hardware and software and in medical imaging. Three-dimensional radiation treatment planning systems are rapidly being implemented in clinics around the world. These developments in turn have prompted manufacturers to employ advanced microcircuitry and computer technology to produce treatment delivery systems capable of precise shaping of dose distributions via computer-controlled multileaf collimators which cause the beam intensity to be varied across the beam. Image-based 3D planning and beam intensity modulated delivery systems show significant potential for improving the quality of radiotherapy and improving the efficiency with which radiation therapy can be planned and delivered. However, significant research and development work on these systems and their clinical use remains to be performed. The techniques used for the treatment planning and the methods used for quality assurance procedures and testing must all be revised and/or redesigned to allow efficient clinical use of these technological advances. Although much of the current 3D radiation therapy process requires interactive tasks (and some still very laborious) the path is clear toward solving the technological obstacles so that a nearly automated planning, delivery, and verification system will become a reality over the next decade. Such systems will allow radiation oncologists to significantly increase dose to many tumor sites while concomitantly lowering doses to critical organs-at-risk. Most of the tasks will be automated, thus lowering the overall costs currently needed to provide high-quality external beam radiation therapy.

During a radiotherapy treatment, a dosimetric verification or a geometric localization can be done, in order to assess the quality of the treatment. The dosimetric verification is generally performed measuring the dose at some points inside (natural cavities) or outside the patient, and comparing it to the dose at the same points calculated and predicted by the treatment planning system. This can be done either with thermoluminescent or diodes dosimeters or with ionization chambers. The geometric localization can be done acquiring a portal image of the patient. Portal imaging can be performed either with films placed between metallic screens, or with an electronic portal imaging device such as fluoroscopic systems, solid state devices or matrix ionization chamber systems. In order to assess possible field placement errors, the portal images have to be compared with images obtained with the simulator in the same geometric conditions and/or with the digitally reconstructed radiograph (DRR) obtained with the treatment planning system. In particular, when using matrix ionization chamber systems, the portal images contain also information regarding the exit dose. This means that this kind of imaging device can be used both for geometric localization and for dosimetric verification. In this case, the exit dose measured by the portal image can be compared with the exit dose calculated and predicted by the treatment planning system. Some “in-vivo” applications of this methodology are presented.

New challenging dosimetric approaches, such as narrow beams and 3D algorithms, are being used in radiotherapy. In this paper two quality control (QC) procedures are reported. The first one concerns the QC of the dosimetry of small x-ray beams, generally carried out by using silicon detectors. The comparison of dose values obtained by a silicon diode, a diamond detector, and radiochromic films shows that for x-ray beams of high energy, the silicon diode can give an overestimation of the output factors in phantom, up to 4%. This is due to the higher than unit density silicon diode and the surrounding envelope that restore the lateral electron equilibrium. About the 3D algorithms for breast treatment planning, a quality control test has been adopted to verify the accuracy of the computed dosimetry when “loss of scatter” occurs. The results show a sensible agreement (within 1.5%) between computed and experimental data.

Differences between late-responding (slowly proliferating) normal tissues and early-responding (rapidly proliferating) normal tissues and tumor cells and the event of tumor cell repopulation occurring during treatment have essentially led to the development of altered fractionation schemes. Altered fractionation regimens mainly refer to schedules utilising two or more (small dose) fractions per day for part of or for the entire treatment course. It must be underlined that a true standard or conventional fractionation regimen does not exist: no schedule is universally recognised as the standard of reference to be compared with. However, continental European and U.S. conventional regimens are the considered control arm with which the new experimental regimens have to be compared. For this reason they are generally recognised as the standards. The basic rationale for hyperfractionated or accelerated regimens respectively lies in the possibility (a) to deliver higher total doses reducing late-responding normal tissue damage, (b) to deliver total doses in a reduced overall treatment time to defeat tumor clonogen repopulation. Multiple fractions per day should not be delivered with interfraction intervals smaller than 6 hours. Clinical results of phase I-II and limited but convincing phase III randomised trials suggest that a therapeutic benefit can be achieved with new altered regimens.

The Authors present a review of randomized trials on non conventional fractionation in head and neck cancer radiotherapy with conventional fractionation as control arm. Hyperfractionation was studied in 5 trials, accelerated hyperfractionation in 4 trials and accelerated fractionation in 3 trials. Furthermore, the reviews of eminent Authors dealing with the above mentioned trials are summarized. In spite of improved local control rate reported with hyperfractionation, non conventional radiotherapy schedules are not yet recommended as routine clinical practice, but all the radiation oncologists are invited to join trials on this subject.

In 1989 we started an accelerated hyperfractionated schedule of radiotherapy (two 1.6 Gy daily fractions) in standard risk localized Ewing's sarcoma of bone, with the aim at reducing late effects in young patients and at improving disease control through a better integration of treatment modalities. From 1991, the same schedule was used in preoperative radiotherapy of adult soft tissue sarcomas of the extremities: the main purpose was to reduce the time to surgery and to evaluate surgical complications in comparison with a previous experience of hypofractionated radiotherapy (one 3 Gy daily fraction). From 1991 to 1997, 76 patients with Ewing's sarcoma and 24 patients with soft tissue sarcoma were treated at our Institution. Results and complication rates are analyzed in comparison with historical data. In Ewing's sarcoma, a correct evaluation of improvement in local control was difficult because of changing treatment policy (bulky disease was not included in the present series). Late effects, as evaluated in patients with a minimum follow-up of 3 years, occurred with similar incidence, but at higher total dose levels in patients treated with accelerated hyperfractionation. In patients with soft tissue sarcomas, incidence of surgical complications is reduced as compared to historical experience. Major problems of wound healing were seen in association with intraoperative brachitherapy boost.

Clinical trials on altered fractionation radiotherapy (RT) regimens currently play a significant role in lung cancer, due to the importance of local control and to the disappointing therapeutic results in this disease. In non-small-cell lung cancer (NSCLC) two strategies are being actively investigated: hyperfractionation with a “curative” aim, and hypofractionation with a palliative aim; in small-cell lung cancer (SCLC) altered fractionation seems to play a minor role at this moment. In this review paper the results of reported randomised trials are summarised and discussed. Conclusions may indicate that through hyperfractionation, particularly if accelerated, clinical outcome of non-metastatic NSCLC patients can be improved; data are however not sufficiently mature to advise its use outside controlled clinical trials. In the palliative setting, hypofractionation should be considered standard treatment.

Malignant brain tumors (primary and metastatic) are apparently resistant to most therapeutic efforts. Several randomized trials have provided evidence supporting the efficacy of radiation therapy. Attempts at improving the results of external beam radiotherapy include altered fractionation, radiation sensitizers and concomitant chemotherapy. In low-grade gliomas, all clinical studies with radiotherapy have employed conventional dose fractionation regimens. In high-grade gliomas, hypofractionation schedules represent effective palliative regimens in poor prognosis subsets of patients; short-term survival in these patients has not allowed to evaluate late toxicity. In tumors arising within the central nervous system, hyperfractionated irradiation exploits the differences in repair capacity between tumour and late responding normal tissues. It may allow for higher total dose and may result in increased tumor cell kill. Accelerated radiotherapy may reduce the repopulation of tumor cells between fractions. It may potentially improve tumor control for a given dose level, provided that there is no increase in late normal tissue injury. In supratentorial malignant gliomas, superiority of accelerated hyperfractionated over conventionally fractionated schedules was observed in a randomized trial; however, the gain in survival was less than 6 months. At present no other randomized trial supports the preferential choice for altered fractionation irradiation. Also in pediatric brainstem tumors there are no data to confirm the routine use of hyperfractionated irradiation, and significant late sequelae have been reported in the few long-term survivors. Shorter treatment courses with accelerated hyperfractionated radiotherapy may represent a useful alternative to conventional irradiation for the palliation of brain metastases. Different considerations have been proposed to explain this gap between theory and clinical data. Patients included in dose/effect studies are not stratified by prognostic factors and other treatment-related parameters. This observation precludes any definite conclusion about the relative role of conventional and of altered fractionation. New approaches are currently in progress. More prolonged radiation treatments, up to higher total doses, could delay time to tumor progression and improve survival in good prognosis subsets of patients; altered fractionation may be an effective therapeutic tool to achieve this goal.

Hadrontherapy was born in 1938, when neutron beams were used in cancer therapy, but it has become an accepted therapeutical modality only in the last five years. Fast neutrons are still in use, even if their limitations are now apparent. Charged hadron beams are more favorable, since the largest specific energy deposition occurs at the end of their range in matter. The most used hadrons are at present protons and carbon ions. Both allow a dose deposition which conforms to the tumour target. Radiobiological experiments and the results of the first clinical trials indicate that carbon ions have, on top of this macroscopic property, a different way of interacting with cells at the microscopic level. There are thus solid hopes to use carbon beams of about 4500 MeV to control tumours which are radioresistant both to X-rays and protons. After discussing these macroscopic and microscopic properties of hadrontherapy, the hospital-based facilities, running or under construction, are reviewed. The conclusion is that, while in USA and Japan twelve of these centres will be running around the year 2001, in Europe very little is foreseen to use hadrontherapy to treat deep-seated tumours. The most advanced programme is the Italian one, which is described in the last Sections of the report. The main activities concern the construction, near Milano, of a centre for protons and carbon ions called CNAO (National Centre for Oncological Hadrontherapy) and the development of new type of proton accelerators. The Istituto Superiore di Sanità in Rome obtained the initial financing for constructing, in collaboration with ENEA, a 3 GHz linac, which eventually will accelerate protons to 200 MeV, so as to allow deep protontherapy. These, and other hadrontherapy centres in Italy and Europe, will be connected with oncology centres, hospitals and clinics by a multimedial network called RITA, so that before referral each patient's case can be discussed directly by doctors, even located far away, with the experts sitting in the hadrontherapy centres.

In the history of external beam radiotherapy, the trend for a better conformation as well as for a higher biological efficiency has been the driving force for the improvement of clinical results. However, these two goals had to be followed with separate types of radiation, i.e. photons and neutrons, and could not be combined. For the first time being, beams of heavy ions like carbon offer the possibility to combine both advantageous properties: better targeting and higher biological efficiency. Particle beams have an inverse depth dose profile, with a maximum dose in the deep seated tumor, a finite range, small lateral scattering, and a drastically increased biological efficiency in the tumor. These properties maximize the deletion effects on tumor cells. In addition, particle beams can be directed precisely in the limit of one or two millimeters, and can be monitored using positron emission tomography (PET) with the same precision. In the following paper the conditions are given that are necessary to translate these properties into clinical routine.

In radiotherapy, the use of proton beams is one of the most promising approaches in order to reduce the treatment volume and, consenquently, increase the total dose avoiding severe complications to the normal tissues surrounding the target. Among the new hospital-based facilities that are planned for the next future, the italian project is in an advanced stage of study. Because of the complexity and high cost of the italian centre, one of the most important information in order to establish the cost/benefit balance, is represented by the number of potential patients to be treated for the various pathologies. For this reason it is useful to define a priority scale of clinical indications and, on this basis, to estimate the yearly patient afflux to the center, taking into account the incidence and the expected new cases to be treated with protons. Indications have been divided into two categories, according to decreasing priority. Category A includes all the tumors in which the use of proton therapy has clearly demonstrated to be advantageous, being the only way to give a curative dose to the target. In Italy, the extimated number of this category of patients is 825 each year. Category B comprises a great variety of tumors characterized mainly by a local evolution, with a limited likelihood of distant spread, and therefore potentially cured if the local control can be obtained. The total number of potential patients in this category is more than 10,000.

The basis for interest in proton beams by clinical radiation oncologists lies in reduction in treatment volume. The yields from employing a smaller treatment volume are the increase of tumor control probability and the reduction of normal tissues complication probability. The clinical use of proton therapy began in 1954 at Uppsala University in Sweden and in 1961 at Harvard Cyclotron Laboratory in Boston, USA. So far, the total number of worldwide patients treated by protons is about 20,000. In this paper attention will be given to the treatment of patients at the Massachusetts General Hospital-Massachusetts Eye and Ear Infirmary-Harvard Cyclotron Laboratory, and at the Loma Linda University Medical Center. In particular, a review of the literature about the techniques and the results of treatment of skull base and cervical spine chordoma and low-grade chondrosarcoma, skull base meningioma, pituitary tumors, paranasal sinus carcinoma, glioblastoma multiforme, artero-venous malformations, uveal melanoma, macular degeneration, retinoblastoma, thoracic spine-sacrum tumors, and prostate carcinoma is presented. In order to verify and improve the clinical results, the conduct of prospective trials on an inter-institutional basis is essential. To facilitate the conduct of such studies the US National Cancer Institute and the American College of Radiology have established the Proton Therapy Oncology Group (PROG). Several phase III and some phase I-II trials are active at the Massachusetts General Hospital, Harvard Cyclotron Laboratory, and at the Loma Linda University Medical Center.

In this paper we analyse the problems related to the “state of the art” in the treatment of stage I and II breast cancer which has become, in Italy too, an increasingly prominent problem: it is the most frequently diagnosed female cancer, accounting for about 45,000 new cases/year (150/100,000 women). In the last decade the approach to this disease has greatly evolved because of new surgical techniques, advances in adjuvant medical therapies, innovations in the field of radiotherapy, and wider use of biological parameters. We emphasize the emerging problem of ductal and lobular carcinoma in situ, because their biological patterns will be better indentified and the related treatment extensively practiced in the next future. The innovations in surgery, which has now a less demolishing role, are reviewed focusing on the “sentinel axillary node” and the actual need for axillary dissection. In relation to chemotherapy (CT), we evaluate the role of adjuvant treatment also in node negative patients, and the impact of neoadjuvant schedules on survival and toxicity. Radiotherapy (RT) is complementary to conservative surgery, and its important role in preventing local relapse and in increasing OS (overall survival) has been established; recent and more sophisticated techniques have reduced its acute and late toxicity. We are however waiting for answers concerning the usefulness of a booster dose, the impact of RT on local relapse in DCIS, and the impact of RT to the breast regional lymph nodes on OS and disease-free survival (DFS). The optimal sequencing and timing of postoperative RT and CT are unknown, both concerning each other and surgery. Some possibilities include giving all planned CT before RT, all CT after RT, giving both concurrently, or giving a portion of CT before RT and then completing CT afterwards (sandwich technique): we analyse the advantages and the problems of these different therapeutic schedules in relation to the OS, the DFS and cosmesis. In conclusion, there are very few certainties to guide us in the clinical practice: the general feeling is that we need to collect more data on homogeneous groups of patients to better understand which are the prognostic factors we can rely on, in order to choose the best treatment strategy, and which are the optimal schedules of adjuvant treatments (CT and RT), with the aim of improving OS, DFS and cosmesis.

Radiotherapy is the standard treatment for locally advanced cervical cancer; nevertheless it fails to control disease progression within the irradiation fields in more than 40% of cases, particularly in patients with bulky tumor. Distant metastases are not infrequent in more advanced cases. Chemotherapy has been integrated with radiotherapy to improve local control and treat distant subclinical metastases. Schedules of combined treatment more frequently represented by neoadjuvant chemotherapy followed by radiation (NACT) and by concomitant chemotherapy and radiation (CT-RT). A review of the recent literature is presented. The role of NACT is controversial: high response rates are reported but doubtful advantages in terms of survival or local control have been shown. In randomized trials, hydroxyurea concomitant to radiation improves local control and survival, particularly in stage IIIB and IVA. Several randomized trials of concurrent chemoradiation with 5FU, cisplatin and mitomycin C are underway, but few have been published: no significative differences are reported in term of local control or survival. Acute toxicity is higher than in radiation alone, but usually manageable. For the analysis of late morbidity a longer follow-up is required. Large randomized trials of adequate radiotherapy versus concomitant chemoradiation are necessary to refine our understanding of the benefits of this integrated treatment.

Since the first reports in the late 1950's, a large amount of data have been collected. The analysis of the main evidence from the major randomized trials will be analyzed in this paper according to preoperative, postoperative and chemoradiation approaches. Fifteen randomized preoperative trials were reported; they have been grouped according to the fractionation schedule. In the hypofractionation group (5 Gy for fraction), all five studies that delivered 3-5 doses in one week had a significant improvement in local control and one of them also showed improvement in survival. Operative mortality was higher in the radiotherapy arm if inadequate techniques had been applied. In 3 out of 8 studies with conventional fractionation there was a significant improvement in local control, but no impact in survival was detected. No studies with total dose lower than 34 Gy had an improvement in local control. None of the six randomized postoperative studies showed an improvement in local control or survival. In all trials the local control rate was uniform; ranging from 76% to 84%. Toxicity was higher in the radiotherapy arm. One preoperative and five postoperative randomized studies that used chemoradiation were analyzed. One postoperative chemoradiation study showed a significant improvement in survival in comparison to the surgery arm, and another showed the same advantage compared to the postoperative arm. Protracted infusional administration of 5FU concomitant to radiotherapy showed better survival than bolus administration. No advantages were shown in using MeCCNU or Levamisole in two studies. Toxicity was high and related to the dose and the modality of administration of the drugs in order to adequately treat the different stages of rectal cancer, patients must be carefully selected in order to prescribe the most effective and the least toxic treatment for the individual stage; organ preservation should be an essential goal for its impact on quality of life, and the cost estimates should be taken into account.

Conventional treatment of anal cancer has been the demolitive Miles operation for decades. Radiotherapy has been utilized in a limited number of centers for early cancers only. Radio-chemotherapy has become the treatment of choice for all stages of anal cancer after the first experiences by the group of Detroit and after the confirmation of successful results by many other centers. Infusional chemotherapy (5-FU and Mitomycin C or CDDP) and concurrent irradiation are able to achieve local control in more than 80% of patients. Surgery currently represents a rescue treatment for partial responders or in relapsing patients. A brief review of the literature and the experience at the Istituto Tumori in Milano are presented.

Surgery alone, more or less demolitive, is the treatment of choice of vulvar cancers. Cure rates are high for early cancers only, while locally advanced tumors with or without inguinal adenopathies and recurrences have a bad prognosis. The excellent results of concurrent chemo-radiotherapy of anal cancers suggested to adopt the same approach for locally advanced vulvar cancers. The shrinkage of the tumor allowed surgery, often less demolitive than usual, and the pathological examination demonstrated an overall complete response in 40% of cases. Survival has been improved through this multidisciplinary approach. Patients not suitable for surgery obtained important remissions and an improved quality of life. Clinical experience at the Istituto Tumori of Milano is presented.

We have performed a review of recent literature about combined modality therapy in esophageal cancer. Radiobiological principles and radio-chemotherapy interactions modalities in clinical experiences have been considered. Therapeutic schedules, modalities of implementation, and the most relevant clinical results obtained by the major clinical research groups have been emphasized. We also comment on the current role of surgery and on the clinical questions arising in combined radio-chemotherapy treatment.

This paper describes the mechanisms of action of ionizing radiations combined with antineoplastic drugs. Some relevant drugs for the combined modality treatments of locally advanced lung cancer are reported. The meta-analyses including randomized trials comparing single agent (radiotherapy or chemotherapy) versus combined chemoterapy and radiotherapy in patients with unresectable non small cell lung cancer and limited small cell lung cancer are then reviewed. The clinical outcome in relation to different schedules of chemoradiotherapy (sequential, alternating and concurrent) is also focussed.

Childhood cancer is rare, representing only 1% of the total cancer problem. Of children diagnosed with cancer today, more than 70% are predicted to be long-term survivors. Essentially all pediatric cancers are treated by interdigitating radiation with surgical resection and systemic chemotherapy. The use of irradiation, important to achieve high rates of disease local control, must be always balanced against late effects specifically related to this treatment modality, principally growth retardation and second tumors induction. Using neuroblastoma, Wilms’ tumor and rhabdomyosarcoma as examples, the advances in the optimal multimodality treatment of childhood cancer and the evolution of the role of radiation therapy are discussed.

The severity of nausea and vomiting in patients undergoing radiotherapy is lower than that associated with chemotherapy regimens, but its duration may be considerably longer. Total body irradiation and irradiation of the upper part of the abdomen or whole abdomen are considered the most emetogenic regimens in radiotherapy. Instead, the emetogenic potential is considered moderate in radiotherapy of the thorax, pelvis and lower half-body irradiation, and low in radiotherapy of head and neck, extremities, brain and skin. In contrast to the very extensive literature on the prevention of chemotherapy-induced emesis, relatively few studies have been published on patients submitted to radiotherapy. Metoclopramide, prochlorperazine and cannabinoids offer only limited symptom control in patients undergoing radiotherapy of moderate to severe emetogenic potential. Double-blind randomized studies showed the superior antiemetic efficacy of the 5-HT3 antagonists with respect to placebo and to the older antiemetic drugs in patients submitted to single dose or fractionated doses of radiotherapy to the upper abdomen, to lower hemibody radiotherapy and to total body irradiation. In all these cases the 5-HT3 antagonists should be considered the antiemetic treatment of choice and should be administered as prophylactic agents. The optimal duration of antiemetic therapy with the 5-HT3 antagonists is unknown. Whether corticosteroids added to the 5-HT3 antagonists will increase their antiemetic efficacy, as in chemotherapy-treated patients, remains to be demonstrated in double-blind controlled trials. Patients submitted to radiotherapy of low emetogenic risk do not require any antiemetic prophylaxis. In this case a rescue antiemetic treatment can be administered if patients present vomiting or moderate to severe nausea.