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Systemically induced effects associated with PDT with PHOTOFRIN consist of photosensitivity and mild constipation. All patients who receive PHOTOFRIN will be photosensitive and must observe precautions to avoid sunlight and bright indoor light. Photosensitivity reactions (mostly mild erythema on the face and hands) occurred in approximately 20% of patients treated with PHOTOFRIN.
Most toxicities associated with this therapy are local effects seen in the region of illumination and occasionally in surrounding tissues. The local adverse reactions are characteristic of an inflammatory response induced by the photodynamic effect.
The following adverse events were reported over the entire follow-up period in at least 5% of patients treated with PHOTOFRIN PDT, who had completely or partially obstructing esophageal cancer. Table 5 presents data from 88 patients who received the currently marketed formulation. The relationship of many of these adverse events to PDT with PHOTOFRIN is uncertain.
| TABLE 5. Adverse Events Reported in 5% or More of Patients (a) with Obstructing Esophageal Cancer | ||
| BODY SYSTEM/Adverse Event | Number (%) of Patients n = 88 |
|
| Patients with at least one adverse event | 84 | (95%) |
| AUTONOMIC NERVOUS SYSTEM | ||
| Hypertension | 5 | (6%) |
| Hypotension | 6 | (7%) |
| BODY AS A WHOLE | ||
| Asthenia | 5 | (6%) |
| Back pain | 10 | (11%) |
| Chest pain | 19 | (22%) |
| Chest pain (substernal) | 4 | (5%) |
| Edema generalized | 4 | (5%) |
| Edema peripheral | 6 | (7%) |
| Fever | 27 | (31%) |
| Pain | 19 | (22%) |
| Surgical Complicatin | 4 | (5%) |
| CARDIOVASCULAR | ||
| Cardiac Failure | 6 | (7%) |
| GASTROINTESTINAL | ||
| Abdominal Pain | 18 | (20%) |
| Constipation | 21 | (24%) |
| Diarrhea | 4 | (5%) |
| Dyspepsia | 5 | (6%) |
| Dysphagia | 9 | (10%) |
| Eructation | 4 | (5%) |
| Esophageal Edema | 7 | (8%) |
| Esophageal Tumor Bleeding | 7 | (8%) |
| Esophageal Stricture | 5 | (6%) |
| Esophagitis | 4 | (5%) |
| Hematemesis | 7 | (8%) |
| Melena | 4 | (5%) |
| Nausea | 21 | (24%) |
| Vomiting | 15 | (17%) |
| HEART RATE/RHYTHM | ||
| Atrial Fibrillation | 9 | (10%) |
| Tachycardia | 5 | (6%) |
| METABOLIC & NUTRITIONAL | ||
| Dehydration | 6 | (7%) |
| Weight Decrease | 8 | (9%) |
| PSYCHIATRIC | ||
| Anorexia | 7 | (8%) |
| Anxiety | 6 | (7%) |
| Confusion | 7 | (8%) |
| Insomnia | 12 | (14%) |
| RED BLOOD CELL | ||
| Anemia | 28 | (32%) |
| RESISTANCE MECHANISM | ||
| Moniliasis | 8 | (9%) |
| RESPIRATORY | ||
| Coughing | 6 | (7%) |
| Dyspnea | 18 | (20%) |
| Pharyngitis | 10 | (11%) |
| Pleural Effusion | 28 | (32%) |
| Pneumonia | 16 | (18%) |
| Respiratory Insufficiency | 9 | (10%) |
| Tracheoesophageal Fistula | 5 | (65) |
| SKIN AND APPENDAGES | ||
| Photosensitivity Reaction | 17 | (19%) |
| URINARY | ||
| Urinary Tract Infection | 6 | (7%) |
(a) Based on adverse events reported at any time during the entire period of follow-up
Location of the tumor was a prognostic factor for three adverse events: upper third of the esophagus (esophageal edema), middle-third (atrial fibrillation), and lower-third, the most vascular region (anemia). Also, patients with large tumors (>10 cm) were more likely to experience anemia. Two of 17 patients with complete esophageal obstruction from tumor experienced esophageal perforations which were considered to be possibly treatment associated; these perforations occurred during subsequent endoscopies.
Serious and other notable adverse events observed in less than 5% of PDT-treated patients with obstructing esophageal cancer in the clinical studies include the following; their relationship to therapy is uncertain. In the gastrointestinal system, esophageal perforation, gastric ulcer, ileus, jaundice, and peritonitis have occurred. Sepsis has been reported occasionally. Cardiovascular events have included agina pectoris, bradycardia, myocardial infarction, sick sinus syndrome, and supraventicular tachycardia. Respiratory events of bronchitis, bronchospasm, laryngotracheal edema, pneumonitis, pulmonary hemorrhage, pulmonary edema, respiratory failure, and stridor have occurred. The temporal relationship of some gastrointestinal, cardiovascular and respiratory events to the administration of light was suggestive of mediastinal inflammation in some patients. Vision related events of abnormal vision, diplopia, eye pain and photophobia have been reported.
The following table presents adverse events that were reported over the entire follow-up period in at least 5% of patients with obstructing endobronchial cancers treated with PHOTOFRIN PDT or Nd:YAG. These data are based on the 86 patients who received the currently marketed formulation. Since it seems likely that most adverse events caused by these acute acting therapies would occur within 30 days of treatment, the table presents those events occurring within 30 days of a treatment procedure, as well as those occurring over the entire follow-up period. It should be noted that follow-up was 33% longer for the PDT group than for the Nd:YAG group, thereby introducing a bias against PDT when adverse event rates are compared for the entire follow-up period. The extent of follow-up in the 30 day period following treatment was comparable between groups (only 9% more for PDT).
Transient inflammatory reactions in PDT-treated patients occur in about 10% of patients and manifest as fever, bronchitis, chest pain and dyspnea. The incidences of bronchitis and dyspnea were higher with PDT than with Nd:YAG. Most cases of bronchitis occurred within 1 week of treatment and all but one were mild or moderate in intensity. The events usually resolved within 10 days with antibiotic therapy. Treatment-related worsening of dyspnea is generally transient and self limiting. Debridement of the treated area is mandatory to remove exudate and necrotic tissue. Life-threatening respiratory insufficiency likely due to therapy occurred in 3% of PDT-treated patients and 2% of Nd:YAG-treated patients.
There was a trend toward a higher rate of hemoptysis (FMH) occurring on the PDT arm (10%) versus the Nd:YAG arm (5%), however, the rate of FMH occurring within 30 days of treatment was the same for PDT and Nd:YAG (4% of total events, 3% treatment-associated events). Patients who have received radiation therapy have a higher incidence of FMH after treatment with PDT and after other forms of local therapy than patients who have not received radiation therapy, but analyses suggest that this increased risk may be due to associated prognostic factors such as having a centrally located tumor. The incidence of FMH in patients previously treated with radiotherapy was 21% (6/20) in the PDT group and 10% (3/29) in the Nd:YAG group. In patients with no prior radiotherapy, the overall incidence of FMH was less than 1%.
| Adverse Events Reported in 5% or More of Patients with Obstructing Endobronchial Cancers Number (%) of Patients | ||||
| BODY SYSTEM/Adverse Event | Within 30 days of Treatment | Entire followup Period | ||
| PDT n = 86 |
Nd:YAG n = 86 |
PDT n = 86 |
Nd:YAG n = 86 |
|
| Patients with at Least One Adverse Event | 43 (50%) | 33 (38%) | 62 (72%) | 48 (56%) |
| BODY AS A WHOLE | ||||
| Back Pain | 3 (3%) | 1 (1%) | 3 (3%) | 5 (6%) |
| Chest Pain | ||||
| Edema Peripheral | 3 (3%) | 3 (3%) | 4 (5%) | 3 (3%) |
| Fever | 7 (8%) | 7 (8%) | 14 (6%) | 8 (9%) |
| Pain | 1 (1%) | 4 (5%) | 4 (5%) | 8 (9%) |
| CENTRAL NERVOUS SYSTEM | ||||
| Dysphonia | 3 (3%) | 2 (2%) | 4 (5%) | 2 (2%) |
| GASTROINTESTINAL | ||||
| Constipation | 4 (5%) | 1 (1%) | 4 (5%) | 2 (2%) |
| Dyspepsia | 1 (1%) | 4 (5%) | 2 (2%) | 5 (6%) |
| PYSCHIATRIC | ||||
| Anxiety | 3 (3%) | 0 (0%) | 5 (6%) | 0 (0%) |
| Insomnia | 4 (5%) | 2 (2%) | 4 (5%) | 3 (4%) |
| RESPIRATORY | ||||
| Bronchitis | 9 (10%) | 2 (2%) | 9 (10%) | 2 (2%) |
| Coughing | 5 (6%) | 8 (9%) | 13 (15%) | 11 (13%) |
| Dyspnea | 15 (17%) | 7 (8%) | 26 (30%) | 13 (15%) |
| Hemoptysis | 6 (7%) | 5 (6%) | 14 (16%) | 7 (8%0 |
| Pleural Effusion | 0 (0%) | 0 (0%) | 4 (5%) | 1 (1%) |
| Pneumonia | 5 (6%) | 4 (5%) | 10 (12%) | 5 (6%) |
| Pneumothorax | 0 (0%) | 0 (0%) | 0 (0%) | 4 (5%) |
| Respiratory Insufficiency | 0 (0%) | 0 (0%) | 5 (6%) | 1 (1%) |
| Sputum Increased | 4 (5%) | 5 (6%) | 7 (8%) | 6 (7%) |
| SKIN & APPENDAGES | ||||
| Photosensitivity Reaction | 4 (5%) | 0 (0%) | 18 (21%) | 0 (0%) |
(a) Follow-up was 33% longer for the PDT group than for the Nd:YAG group, introducing a bias against PDT when adverse events are compared for the entire follow-up period.
Other serious or notable adverse events were observed in less than 5% of PDT-treated patients with endobronchial cancer; their relationship to therapy is uncertain. In the respiratory system, pulmonary thrombosis, pulmonary embolism and lung abscess have occurred. Cardiac failure, sepsis and possible cerebrovascular accident have also been reported in one patient each.
The following adverse events were reported in at least 5% of patients with superficial tumors (microinvasive or carcinoma in situ) who received the currently marketed formulation.
| Adverse Events Reported in 5% or More of Patients (a) with Superficial Endobronchial Tumors | |
| Adverse Event | Number (%) of Patients n = 90 |
| Patient with at Least One Adverse Event | 44 (49%) |
| Photosensitivity Reaction | 20 (22%) |
| Coughing | 8 (9%) |
| Dyspnea | 6 (7%) |
| Edema | 16 (18%) |
| Exudate | 20 (22%) |
| Obstruction | 19 (21%) |
| Stricture | 10 (11%) |
| Ulceration | 8 (9%) |
(a) Based on adverse events reported at any time during the entire period of follow-up
In patients with superficial endobronchial tumors, 44 of 90 patients (49%) experienced an adverse event, two-thirds of which were related to the respiratory system. The most common reaction to therapy was a mucositis reaction in one-fifth of the patients which manifested as edema, exudate and obstruction. The obstruction (mucus plug) is easily removed with suction or forceps. Mucositis can be minimized by avoiding exposure of normal tissue to excessive light. Three patients experienced life-threatening dyspnea: one was given a double dose of light, one was treated concurrently in both mainstem bronchi and the other had had prior pneumonectomy and was treated in the sole remaining airway. Stent placement was required in 3% of the patients due to endobronchial stricture. Fatal hemoptysis occurred within 30 days of treatment in one patient with superficial tumors (1%).
In patients with esophageal cancer, PDT with PHOTFRIN may result in anemia due to tumor bleeding. No consistent effects were observed for other parameters or in patients with endobronchial carcinoma.
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