Treatment planning facilitates clinical decision making for hyperthermia treatments.

Background: Treatment quality is important in clinical hyperthermia. Guideline-based treatment protocols are used to determine system settings and treatment strategies to ensure effective tumor heating and prevent unwanted treatment-limiting normal tissue hot spots. Realizing both these goals can prove challenging using generic guideline-based and operator-dependent treatment strategies. Hyperthermia treatment planning (HTP) can be very useful to support treatment strategies. Although HTP is increasingly integrated into the standard clinical workflow, active clinical application is still limited to a small number of hyperthermia centers and should be further stimulated.Purpose: This paper aims to serve as a practical guide, demonstrating how HTP can be applied in clinical decision making for both superficial and locoregional hyperthermia treatments.HTP in clinical decision making: Seven problems that occur in daily clinical practice are described and we show how HTP can enhance insight to formulate an adequate treatment strategy. Examples use representative commercially available hyperthermia devices and cover all stages during the clinical workflow. Problems include selecting adequate phase settings, heating ability analysis, hot spot suppression, applicator selection, evaluation of target coverage and heating depth, and predicting possible thermal toxicity in case of an implant. Since we aim to promote a general use of HTP in daily practice, basic simulation strategies are used in these problems, avoiding a need for the application of dedicated advanced optimization routines that are not generally available.Conclusion: Even fairly basic HTP can facilitate clinical decision making, providing a meaningful and clinically relevant contribution to maintaining and improving treatment quality.

The addition of deep hyperthermia to gemcitabine-based chemoradiation may achieve enhanced survival in unresectable locally advanced adenocarcinoma of the pancreas.

INTRODUCTION: Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC. METHODS: Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy. RESULTS: One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%. CONCLUSIONS: Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC.

Magnetic nanoparticle-induced hyperthermia with appropriate payloads: Paul Ehrlich's "magic (nano)bullet" for cancer theranostics?

Effective multimodal cancer management requires the optimal integration of diagnostic and therapeutic modalities. Radiation therapy, chemotherapy and immunotherapy, alone or in combination, are integral parts of various cancer treatment protocols. Hyperthermia at 39-45°C is a potent radiosensitiser and has been shown to improve therapeutic outcomes in various tumours through its synergy with chemotherapy. Gene silencing approaches, using small interfering RNAs and microRNAs, are also being explored in clinical trials in oncology. The rapid developments in multifunctional nanoparticles provide ample opportunities to integrate both diagnostic and therapeutic modalities into a single effective cancer "theranostic" vector. Nanoparticles could extravasate passively into the tumour tissues in preference to the adjacent normal tissues by capitalizing on the enhanced permeability and retention effect. Tumour targeting might be further augmented by conjugating tumour-specific peptides and antibodies onto the surface of these nanoparticles or by activation through electromagnetic radiations, laser or ultrasound. Magnetic nanoparticles can induce hyperthermia in the presence of an alternating magnetic field, thereby multifunctionally with tumour-specific payloads empowering tumour specific radiotheranostics (for both imaging and radiotherapy), chemotherapy drug delivery, immunotherapy and gene silencing therapy. Such a (nano)bullet could realise the "magic bullet" conceived by Paul Ehrlich more than a century ago. This article discusses the various aspects of this "magic (nano)bullet" and the challenges that need to be addressed to usher in this new paradigm in modern cancer diagnostics and therapeutics.

Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future.

Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment delivery, thermal treatment planning, thermal dose monitoring through noninvasive thermometry and online adaptive temperature modulation. The review summarizes the outcomes from various clinical studies (both randomized and nonrandomized) where hyperthermia is used as a thermal sensitizer of radiotherapy and-/or chemotherapy in various solid tumors and presents an overview of the progresses in loco-regional hyperthermia. These recent developments, supported by positive clinical outcomes should merit hyperthermia to be incorporated in the therapeutic armamentarium as a safe and an effective addendum to the existing oncological treatment modalities.

Epitrochlear lymph node metastases from invasive ductal breast cancer.

Metastasis to an epitrochlear lymph node from a primary invasive breast cancer has not been reported earlier. We report a case of epitrochlear lymph node metastasis that presented 10 years after the primary breast malignancy had been treated with radiotherapy, chemotherapy, and hormonal therapy. The patient was successfully treated and continues to remain asymptomatic more than 2 years after she presented with the metastasis.

Chordoma with increased prolactin levels (pseudoprolactinoma) mimicking pituitary adenoma: a case report with review of the literature.

The article deals with a rare case of chordoma with increased prolactin levels. It could often result in a diagnostic dilemma and problems in differentiating it from a pituitary adenoma.

Implications of p53 over-expression in the outcome with radiation in head and neck cancers.

BACKGROUND: Abnormalities in the p53 tumor suppressor gene and in the expression of its protein are commonly seen in several tumors. The prognostic implication of these p53 abnormalities was studied in 55 patients with advanced head and neck cancers. PURPOSE: To identify p53 as a prognostic factor in assessment of response and survival outcome to radiotherapy in head and neck malignancies. MATERIALS AND METHODS: This prospective study was carried out from April 1998 to December 1999. Fifty five patients with proven squamous cell carcinoma of the head and neck region were treated by radiotherapy (RT) (n=34) with or without chemotherapy (CT) (n=21). A dose of 70 Gy/35#/7 weeks was given with or without concurrent administration of weekly cisplatin (35 mg/m2). Paraffin sections obtained at the time of diagnosis, were examined immunohistochemically for p53 overexpression with monoclonal antibody DO-7 (DAKO). The scoring of p53 positive cells was carried out by a trained pathologist. Selected areas of p53 positive cells were viewed under high power field for quantitative assessment of the p53 over expression. A minimum of 1000 cells were counted and the labeling index (LI) was calculated in terms of percentage of p53 positive cells over the total number of cells counted. A 10% nuclear reactivity exhibiting chromogen positivity cutoff point was established. OBSERVATIONS: The data was analyzed as of January 2006. Median follow-up of all the patients was eight months (1-95 months). The median age of this study group was 58 years and of the 55 patients, 48 were males. Positive expression of p53 gene protein was documented by immunohistochemistry in 24 (44%) patients. Over expression of p53 was not associated with T or N stage, site of disease, radiation response or survival outcomes (P=0.143). Stage was the only independent prognostic variable, both for the response to treatment (radiation) and survival (P=0.01). CONCLUSIONS: Over expression of p53 protein, when detected immunohistochemically, does not predict for radiation response in these tumors.

Does the evidence support the use of concurrent chemoradiotherapy as a standard in the management of locally advanced cancer of the cervix, especially in developing countries?

Locally advanced cancer of the cervix (FIGO stages III and IVA) is one of the most common malignancies in developing countries. Conventional treatment has been a judicious combination of external radiotherapy and intracavitary brachytherapy. However, prompted by the results of five randomised-controlled trials (RCTs) published in close succession, The National Cancer Institute (NCI) alert in 1999, and two meta-analyses, the management of cancer of the cervix has gradually changed. Concurrent chemoradiotherapy with cisplatin alone, or in combination, is gradually being favoured for the treatment of cancer of the cervix. This overview examines whether the published evidence is sufficiently adequate to justify the use of chemoradiotherapy using cisplatin as standard care in the management of cancer of the cervix, especially in developing countries, where most women present with locally advanced cancer of the cervix. A critical review of the various phase III randomised trials and meta-analyses indicates that, although chemoradiotherapy could be a standard form of treatment for early cancer of the cervix, its role in advanced stages needs further exploration before this could be incorporated into routine clinical care.

Variations in clinical estimates of tumor volume regression parameters and time factor during external radiotherapy in cancer cervix: does it mimic the linear-quadratic model of cell survival?

BACKGROUND: Tumor regression parameters and time factor during external radiotherapy (EXTRT) are of paramount importance. AIMS: To quantify the parameters of tumor regression and time factor during EXTRT in cancer cervix. SETTINGS AND DESIGN: Patients, treated solely with radiotherapy and enrolled for other prospective studies having weekly tumor regressions recorded were considered. MATERIALS AND METHODS: Seventy-seven patients received 50 Gy of EXTRT followed by intracavitary brachytherapy. Loco-regional regressions were assessed clinically and regression fraction (RF) was represented as RF=c + a 1D + a 2 D2 sub - a 3T, with c, D and T as constant, cumulative EXTRT dose and treatment time respectively. STATISTICAL ANALYSIS USED: Step wise linear regression was performed for RF. Scatter plots were fitted using linear-quadratic fit. RESULTS: Coefficients of parameters D, D2 sub and T were computed for various dose intervals, namely 0--20 Gy, 0--30 Gy, 0--40 Gy and 0--50 Gy. At 0--20 Gy and 0--30 Gy, only the coefficient of D2 was significant (P 2 sub and T turned significant (P 2 sub and T showed significance, leading to an estimate of 26 Gy for a1/a2 and 0.96 Gy/day for a3/a1. CONCLUSIONS: As with alpha/beta and gamma/alpha of post-irradiation cell survival curves, a1/a2 and a3/a1 represents the cumulative effect of various radiobiological factors influencing clinical regression of tumor during the course of EXTRT. The dynamic changes in the coefficients of D, D2 sub and T, indicate their relative importance during various phases of EXTRT.

An audit of postoperative radiotherapy after non-curative resection for cancer of the oesophagus.

AIMS: The role of postoperative radiotherapy (PORT) after non-curative resections for cancer oesophagus is not well defined. A policy of offering PORT after non-curative resections for cancer oesophagus has been followed at our institution, and we report an audit of our experience. MATERIAL AND METHODS: Between March 1990 and September 2002, 139 patients underwent resections for cancer oesophagus. Of these, 86 patients received PORT to a dose of 45-50.4 Gy/25-28 fractions. Eleven of these patients also received concurrent and adjuvant 5-fluorouracil (5-FU). Disease-free survival and overall survival were computed from the day of surgery using the Kaplan-Meier method. RESULTS: Seventy-six per cent (65/86) of patients had squamous cell carcinoma and 69% (59/86) of patients had tumours in the lower-third of the oesophagus. The median interval between surgery and PORT was 41 days, and 93% of patients received doses as planned. Strictures at the anastomotic site and ulcerations in the stomach mucosa were seen in 17% and 5% of patients, respectively. The median and 5-year disease-free survival was 12 months (95% CI 9.9-14.1) and 14%; whereas the median and 5-year overall survival was 17 months (95% CI 12.4-21.6) and 17%, respectively. Local and distant failures were seen in 29% and 45% of patients, respectively. CONCLUSIONS: PORT, after a non-curative resection of cancer oesophagus, is well tolerated with acceptable morbidity and survival.

Postoperative residual tumour imaged by contrast-enhanced computed tomography and 201Tl single photon emission tomography: can they predict progression-free survival in high-grade gliomas?

AIMS: To evaluate if postoperative residual tumour imaged by either computed tomography or 201Tl single photon emission tomography (SPECT) carried out postoperatively could predict progression-free survival (PFS) in high-grade malignant gliomas. MATERIALS AND METHODS: Thirty-three patients with high-grade malignant gliomas underwent both contrast-enhanced CT scan and 201Tl-SPECT postoperatively before receiving radiotherapy. The PFS was evaluated against the individual reports of the above two imaging studies by univariate analysis. RESULTS: CT and 201Tl-SPECT were carried out within a median interval of 17 days after surgery. Of the 33 patients, CT and 201Tl-SPECT were reported as positive for residual tumours in 23 (69.7%) and 30 (91%) patients, respectively. Sensitivity, specificity and overall accuracy were 71.4%, 40% and 66.6% for CT, and 96.4%, 40% and 87.8% for 201Tl-SPECT, respectively, and were based on their last follow-up status (P = 0.627 for CT; P = 0.053 for 201Tl-SPECT). The median PFS for patients reported to be positive or negative on CT scan was 4 and 5 months, respectively (P = 0.202). With 201Tl-SPECT, although the median PFS for patients with a positive 201Tl uptake was also 4 months, it had not even reached for those reported having a negative 201Tl uptake (cumulative survival 66.7% at last follow-up) (P = 0.198). However, Karnofsky performance status (KPS) was the only significant predictor on univariate analysis (KPS: < 80 vs. > or = 80; P < 0.001) for PFS. CONCLUSIONS: Although both the imaging modalities have a poor specificity, postoperative 201Tl-SPECT had a significantly better accuracy to predict the status at last follow-up than contrast-enhanced CT. Nevertheless, KPS remained the most significant outcome predictor for PFS in high-grade malignant gliomas.

Problems and uncertainties with multiple point A's during multiple high-dose-rate intracavitary brachytherapy in carcinoma of the cervix.

AIMS: This study evaluates the consequences of point A as a dose prescription point during multiple high-dose-rate (HDR) intracavitary brachytherapy (ICBT) in cancer cervix. MATERIALS AND METHODS: Fifty patients who had received teletherapy were randomised into two groups of 25 to receive three HDR ICBT fractions of 6 Gy each at point A with either a flexible Ralstron (Shimadzu Corporation, Japan) or rigid Rotterdam (Nucletron, Netherlands) applicator. The orthogonal radiographs of the 150 applications were evaluated for applicator geometry and point A co-ordinates. RESULTS: Irrespective of the nature and rigidity of the applicators, its various components exhibited a highly significant variation during multiple fractionated HDR ICBT. The Cartesian co-ordinates of point A (left and right) for the applicator geometry also showed significant variation during multiple HDR ICBT procedures. This resulted in an average shift of 9.5 mm (SD= +/-4.4) and 11.1 mm (SD= +/-6.4) in right point A, 10.2 mm (SD= +/-4.5) and 10.8 mm (SD= +/-6.6) in left point A for Ralstron and Rotterdam applicator, respectively, during the three HDR ICBT. Consequently, doses to both right and left point A's showed significant variation during multiple ICBT application and were independent of the applicator type. CONCLUSION: Applicator variation in the components and spatial position in the pelvis during multiple HDR ICBT results in multiple point A's irrespective of the nature of applicator, leading to uncertainty in the dose prescription. These uncertainties, which have a bearing on clinical end points, could be minimised by shifting from point-based dose prescription to image-based target localisation and treatment planning in ICBT.

Tumor regression dynamics with external radiotherapy in cancer cervix and its implications.

BACKGROUND: To study the external radiotherapy (EXTRT) regression patterns in cancer of the cervix. AIMS: Evaluate EXTRT tumor regression doses (TRD) for 50% (TRD50), 80% response (TRD80), normalized dose response gradient (g50) and slope (slope50) with clinical outcome. SETTINGS AND DESIGN: Patients, treated solely with radiotherapy and enrolled for other prospective studies having weekly tumor regressions recorded were considered. MATERIAL AND METHODS: Seventy-seven patients received 50Gy of EXTRT at 2 Gy/fraction followed by 18Gy of high-dose rate intracavitary brachytherapy at 6 Gy/fraction. Loco-regional regressions were assessed clinically at weekly intervals during EXTRT to generate EXTRT dose-response curves. STATISTICAL ANALYSIS USED: Student's t test, logistic regression, Kaplan Meier and Cox's proportional hazard model. Scatter plots were fitted using cubic fit. RESULTS: Age (P=0.052) and absence or presence of gross residual tumor (AGRT and PGRT respectively) following EXTRT (P<0.001) were the only determinants for complete response (CR) at 1 month following completion of radiotherapy. EXTRT tumor regression sigmoid curves obtained for various patient characteristics differed only for those with AGRT and PGRT with differences in TRD50, (P<0.001); TRD80 (P<0.001) and slope50 (P=0.001). Response status to EXTRT was a prognosticator for loco-regional disease free survival (LDFS) (AGRT vs. PGRT; P=0.046). On multivariate analysis, both TRD50 and TRD80 emerged as significant predictors for tumor status at end of EXTRT while TRD80 was the sole determinant of LDFS. CONCLUSION: Extent of tumor regression to EXTRT is an important predictor for treatment outcome in cancer cervix as evident from TRD50 and TRD80 values of EXTRT tumor regression curves.

Early occurrence of acute myeloid leukemia following adjuvant radiotherapy and higher cumulative dose of cyclophosphamide in carcinoma breast.

We report a case of cancer breast developing acute myeloid leukemia (AML) within a relatively short interval of two and a half years of her primary treatment. This could be attributed to post operative radiotherapy and a higher cumulative dose of cyclophosphamide (14.4 gm) which had to be given as a part of her combination chemotherapy regimen, initially as adjuvant and then later as salvage chemotherapy. The successful salvage therapy for secondary AML instituted in this case is also discussed.

Predictors of survival end points in patients with cancer of the cervix on long-term follow-up: inferences and implications from an audit of patients treated with a specific radiotherapy protocol.

AIMS: An audit of patients with cancer of the cervix treated with a specified protocol of external beam radiotherapy (EXRT) followed by intracavitary brachytherapy (ICBT) was carried out to determine the prognosticators for major survival end points. MATERIALS AND METHODS: Patients treated between 1991 and 2003 with a uniform protocol of EXRT (50 Gy/25 fractions/5 weeks) followed by high-dose-rate ICBT (18 Gy/3 fractions/3 weeks) were selected from the database. Various clinical and treatment parameters were evaluated for extent of locoregional response at completion of EXRT, namely absence or presence of gross residual tumour (AGRT and PGRT, respectively) and survival end points. These included locoregional disease-free survival (LDFS), disease-free survival (DFS) and overall survival (OS). RESULTS: Of the 157 evaluable patients, 145 (92%) belonged to FIGO stages II and III. Eighty-three (53%) at completion of EXRT had AGRT, which was influenced by age and gross tumour features. The estimated 10-year LDFS, DFS and OS were 38.6%, 33.1% and 38.5%, respectively. Factors significant on univariate analysis for these survival end points were EXRT duration, ICBT time, overall treatment time (OTT) and EXRT response. On multivariate analysis, AGRT to EXRT, an OTT of < or = 67 days, and patients older than 50 years were the significant favourable determinants for all the above survival end points. CONCLUSION: The audit highlights that younger people, especially those with bulky tumours that determine response to EXRT, are poor prognosticators for survival end points. They could perhaps benefit from treatment intensification regimens using chemoradiotherapy, provided that OTT is not unduly prolonged.

Spontaneous expulsion of a mediastinal lymph node in carcinoma of the esophagus.

A case of spontaneous expulsion of a mediastinal lymph node, which developed during the follow up of a patient with carcinoma of the esophagus is presented. To the best of our knowledge, no such instance of natural extrusion of mediastinal lymph node has been reported in the literature.